Elevated Electron Temperature Coincident with Observed Fusion Reactions in a Sheared-Flow-Stabilized Z Pinch.

The sheared-flow-stabilized Z pinch concept has been studied extensively and is able to produce fusion-relevant plasma parameters along with neutron production over several microseconds. We present here elevated electron temperature results spatially and temporally coincident with the plasma neutron source. An optical Thomson scattering apparatus designed for the FuZE device measures temperatures in the range of 1-3 keV on the axis of the device, 20 cm downstream of the nose cone. The 17-fiber system measures the radial profiles of the electron temperature. Scanning the laser time with respect to the neutron pulse time over a series of discharges allows the reconstruction of the T_{e} temporal response, confirming that the electron temperature peaks simultaneously with the neutron output, as well as the pinch current and inductive voltage generated within the plasma. Comparison to spectroscopic ion temperature measurements suggests a plasma in thermal equilibrium. The elevated T_{e} confirms the presence of a plasma assembled on axis, and indicates limited radiative losses, demonstrating a basis for scaling this device toward net gain fusion conditions.

The roles of intensity, exposure duration, and modulation on the biological effects of radiofrequency radiation and exposure guidelines.

In this paper, we review the literature on three important exposure metrics that are inadequately represented in most major radiofrequency radiation (RFR) exposure guidelines today: intensity, exposure duration, and signal modulation. Exposure intensity produces unpredictable effects as demonstrated by nonlinear effects. This is most likely caused by the biological system's ability to adjust and compensate but could lead to eventual biomic breakdown after prolonged exposure. A review of 112 low-intensity studies reveals that biological effects of RFR could occur at a median specific absorption rate of 0.0165 W/kg. Intensity and exposure duration interact since the dose of energy absorbed is the product of intensity and time. The result is that RFR behaves like a biological "stressor" capable of affecting numerous living systems. In addition to intensity and duration, man-made RFR is generally modulated to allow information to be encrypted. The effects of modulation on biological functions are not well understood. Four types of modulation outcomes are discussed. In addition, it is invalid to make direct comparisons between thermal energy and radiofrequency electromagnetic energy. Research data indicate that electromagnetic energy is more biologically potent in causing effects than thermal changes. The two likely functionthrough different mechanisms. As such, any current RFR exposure guidelines based on acute continuous-wave exposure are inadequate for health protection.

Community-based real-world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.

Health and environmental effects to wildlife from radio telemetry and tracking devices-state of the science and best management practices.

This paper discusses the potential health risks and benefits to tagged wildlife from the use of radio tracking, radio telemetry, and related microchip and data-logger technologies used to study, monitor and track mostly wildlife in their native habitats. Domestic pets, especially canids, are briefly discussed as radio-tagging devices are also used on/in them. Radio tracking uses very high frequency (VHF), ultra-high frequency (UHF), and global positioning system (GPS) technologies, including via satellites where platform terminal transmitters (PTTs) are used, as well as geo-locating capabilities using satellites, radio-frequency identification (RFID) chips, and passive integrated responder (PIT) tags, among others. Such tracking technologies have resulted in cutting-edge findings worldwide that have served to protect and better understand the behaviors of myriad wildlife species. As a result, scientists, field researchers, technicians, fish and wildlife biologists and managers, plus wildlife and other veterinarian specialists, frequently opt for its use without fully understanding the ramifications to target species and their behaviors. These include negative physiological effects from electromagnetic fields (EMF) to which many nonhuman species are exquisitely sensitive, as well as direct placement/use-attachment impacts from radio collars, transmitters, and implants themselves. This paper provides pertinent studies, suggests best management practices, and compares technologies currently available to those considering and/or using such technologies. The primary focus is on the health and environmental risk/benefit decisions that should come into play, including ethical considerations, along with recommendations for more caution in the wildlife and veterinarian communities before such technologies are used in the first place.

Cellular and molecular effects of non-ionizing electromagnetic fields.

The way that living cells respond to non-ionizing electromagnetic fields (EMF), including static/extremely-low frequency and radiofrequency electromagnetic fields, fits the pattern of 'cellular stress response' - a mechanism manifest at the cellular level intended to preserve the entire organism. It is a set pattern of cellular and molecular responses to environmental stressors, such as heat, ionizing radiation, oxidation, etc. It is triggered by cellular macromolecular damage (in proteins, lipids, and DNA) with the goal of repairing and returning cell functions to homeostasis. The pattern is independent of the type of stressor encountered. It involves cell cycle arrest, induction of specific molecular mechanisms for repair, damage removal, cell proliferation, and cell death if damage is too great. This response could be triggered by EMF-induced alternation in oxidative processes in cells. The concept that biological response to EMF is a 'cellular stress response' explains many observed effects of EMF, such as nonlinear dose- and time-dependency, increased and decreased risks of cancer and neurodegenerative diseases, enhanced nerve regeneration, and bone healing. These responses could be either detrimental or beneficial to health, depending on the duration and intensity of the exposure, as well as specific aspects of the living organism being exposed. A corollary to electromagnetic hypersensitivity syndrome (EHS) could be an inappropriate response of the hippocampus/limbic system to EMF, involving glucocorticoids on the hypothalamic-pituitary-adrenal axis.

Probing local electron temperature and density inside a sheared flow stabilized Z-pinch using portable optical Thomson scattering.

We report the first optical Thomson scattering measurements inside a high electron temperature (≳1 keV) and moderate electron density (mid 1016 cm-3) plasma. This diagnostic has been built to provide critical plasma parameters, such as electron temperature and density, for Advanced Research Projects Agency-Energy-supported fusion-energy concepts. It uses an 8 J laser at 532 nm in 1.5 ns to measure the high frequency feature of the Thomson scattering profile at 17 locations along the probe axis. It is able to measure electron density from 5 × 1017 cm-3 to several 1019 cm-3 and electron temperatures from tens of eV to several keV. Here, we describe the design, deployment, and analysis on the sheared flow stabilized Z-pinch machine at Zap Energy named FuZE. The probe beam is aimed at an axial distance of 20 cm from the central electrode and is timed within the temporal envelope of neutron emission. The high temperature and moderate density plasmas generated on FuZE lie in an unconventional regime for Thomson scattering as they are between tokamaks and laser-produced plasmas. We described the analysis considerations in this regime, show that the electron density was below 5 × 1016 cm-3 at all times during these measurements, and present a sample shot where the inferred electron temperature varied from 167 ± 16 eV to 700 ± 85 eV over 1.6 cm.

Implementation of extreme ultraviolet spectroscopy on a sheared-flow-stabilized Z pinch.

A diagnostic for extreme ultraviolet spectroscopy was fielded on the sheared-flow-stabilized (SFS) fusion Z-pinch experiment (FuZE-Q) for the first time. The spectrometer collected time-gated plasma emission spectra in the 5-40 nm wavelength (30-250 eV) range for impurity identification, radiative power studies, and for plasma temperature and density measurements. The unique implementation of the diagnostic included fast (10 ns risetime) pulsed high voltage electronics and a multi-stage differential pumping system that allowed the vacuum-coupled spectrometer to collect three independently timed spectra per FuZE-Q shot while also protecting sensitive internal components. Analysis of line emission identifies oxygen (N-, C-, B-, Be-, Li-, and He-like O), peaking in intensity shortly after maximum current (>500 kA). This work provides a foundation for future high energy spectroscopy experiments on SFS Z-pinch devices.

Effects of non-ionizing electromagnetic fields on flora and fauna, Part 3. Exposure standards, public policy, laws, and future directions.

Due to the continuous rising ambient levels of nonionizing electromagnetic fields (EMFs) used in modern societies-primarily from wireless technologies-that have now become a ubiquitous biologically active environmental pollutant, a new vision on how to regulate such exposures for non-human species at the ecosystem level is needed. Government standards adopted for human exposures are examined for applicability to wildlife. Existing environmental laws, such as the National Environmental Policy Act and the Migratory Bird Treaty Act in the U.S. and others used in Canada and throughout Europe, should be strengthened and enforced. New laws should be written to accommodate the ever-increasing EMF exposures. Radiofrequency radiation exposure standards that have been adopted by worldwide agencies and governments warrant more stringent controls given the new and unusual signaling characteristics used in 5G technology. No such standards take wildlife into consideration. Many species of flora and fauna, because of distinctive physiologies, have been found sensitive to exogenous EMF in ways that surpass human reactivity. Such exposures may now be capable of affecting endogenous bioelectric states in some species. Numerous studies across all frequencies and taxa indicate that low-level EMF exposures have numerous adverse effects, including on orientation, migration, food finding, reproduction, mating, nest and den building, territorial maintenance, defense, vitality, longevity, and survivorship. Cyto- and geno-toxic effects have long been observed. It is time to recognize ambient EMF as a novel form of pollution and develop rules at regulatory agencies that designate air as 'habitat' so EMF can be regulated like other pollutants. Wildlife loss is often unseen and undocumented until tipping points are reached. A robust dialog regarding technology's high-impact role in the nascent field of electroecology needs to commence. Long-term chronic low-level EMF exposure standards should be set accordingly for wildlife, including, but not limited to, the redesign of wireless devices, as well as infrastructure, in order to reduce the rising ambient levels (explored in Part 1). Possible environmental approaches are discussed. This is Part 3 of a three-part series.

Low-level EMF effects on wildlife and plants: What research tells us about an ecosystem approach.

There is enough evidence to indicate we may be damaging non-human species at ecosystem and biosphere levels across all taxa from rising background levels of anthropogenic non-ionizing electromagnetic fields (EMF) from 0 Hz to 300 GHz. The focus of this Perspective paper is on the unique physiology of non-human species, their extraordinary sensitivity to both natural and anthropogenic EMF, and the likelihood that artificial EMF in the static, extremely low frequency (ELF) and radiofrequency (RF) ranges of the non-ionizing electromagnetic spectrum are capable at very low intensities of adversely affecting both fauna and flora in all species studied. Any existing exposure standards are for humans only; wildlife is unprotected, including within the safety margins of existing guidelines, which are inappropriate for trans-species sensitivities and different non-human physiology. Mechanistic, genotoxic, and potential ecosystem effects are discussed.

Effects of non-ionizing electromagnetic fields on flora and fauna, part 1. Rising ambient EMF levels in the environment.

Ambient levels of electromagnetic fields (EMF) have risen sharply in the last 80 years, creating a novel energetic exposure that previously did not exist. Most recent decades have seen exponential increases in nearly all environments, including rural/remote areas and lower atmospheric regions. Because of unique physiologies, some species of flora and fauna are sensitive to exogenous EMF in ways that may surpass human reactivity. There is limited, but comprehensive, baseline data in the U.S. from the 1980s against which to compare significant new surveys from different countries. This now provides broader and more precise data on potential transient and chronic exposures to wildlife and habitats. Biological effects have been seen broadly across all taxa and frequencies at vanishingly low intensities comparable to today's ambient exposures. Broad wildlife effects have been seen on orientation and migration, food finding, reproduction, mating, nest and den building, territorial maintenance and defense, and longevity and survivorship. Cyto- and geno-toxic effects have been observed. The above issues are explored in three consecutive parts: Part 1 questions today's ambient EMF capabilities to adversely affect wildlife, with more urgency regarding 5G technologies. Part 2 explores natural and man-made fields, animal magnetoreception mechanisms, and pertinent studies to all wildlife kingdoms. Part 3 examines current exposure standards, applicable laws, and future directions. It is time to recognize ambient EMF as a novel form of pollution and develop rules at regulatory agencies that designate air as 'habitat' so EMF can be regulated like other pollutants. Wildlife loss is often unseen and undocumented until tipping points are reached. Long-term chronic low-level EMF exposure standards, which do not now exist, should be set accordingly for wildlife, and environmental laws should be strictly enforced.

Effects of non-ionizing electromagnetic fields on flora and fauna, Part 2 impacts: how species interact with natural and man-made EMF.

Ambient levels of nonionizing electromagnetic fields (EMF) have risen sharply in the last five decades to become a ubiquitous, continuous, biologically active environmental pollutant, even in rural and remote areas. Many species of flora and fauna, because of unique physiologies and habitats, are sensitive to exogenous EMF in ways that surpass human reactivity. This can lead to complex endogenous reactions that are highly variable, largely unseen, and a possible contributing factor in species extinctions, sometimes localized. Non-human magnetoreception mechanisms are explored. Numerous studies across all frequencies and taxa indicate that current low-level anthropogenic EMF can have myriad adverse and synergistic effects, including on orientation and migration, food finding, reproduction, mating, nest and den building, territorial maintenance and defense, and on vitality, longevity and survivorship itself. Effects have been observed in mammals such as bats, cervids, cetaceans, and pinnipeds among others, and on birds, insects, amphibians, reptiles, microbes and many species of flora. Cyto- and geno-toxic effects have long been observed in laboratory research on animal models that can be extrapolated to wildlife. Unusual multi-system mechanisms can come into play with non-human species - including in aquatic environments - that rely on the Earth's natural geomagnetic fields for critical life-sustaining information. Part 2 of this 3-part series includes four online supplement tables of effects seen in animals from both ELF and RFR at vanishingly low intensities. Taken as a whole, this indicates enough information to raise concerns about ambient exposures to nonionizing radiation at ecosystem levels. Wildlife loss is often unseen and undocumented until tipping points are reached. It is time to recognize ambient EMF as a novel form of pollution and develop rules at regulatory agencies that designate air as 'habitat' so EMF can be regulated like other pollutants. Long-term chronic low-level EMF exposure standards, which do not now exist, should be set accordingly for wildlife, and environmental laws should be strictly enforced - a subject explored in Part 3.

Complement activation pathways in murine immune complex-induced arthritis and in C3a and C5a generation in vitro.

The alternative pathway (AP) of complement alone is capable of mediating immune complex-induced arthritis in the collagen antibody-induced arthritis (CAIA) model in mice. Whether the classical pathway (CP) or lectin pathway (LP) alone can mediate CAIA is not known. Using mice genetically deficient in different complement components, our results reported herein establish that the CP and LP alone are each incapable of mediating CAIA. A lower level or absence of C3 and/or C5 activation by the CP may be possible explanations for the importance of the AP in CAIA and in many murine models of disease. In addition, other investigators have reported that CP C5 convertase activity is absent in mouse sera. To address these questions, we employed an in vitro system of adherent immunoglobulin (Ig)G-induced complement activation using plates coated with murine anti-collagen monoclonal antibody (mAb). These experiments used complement-deficient mouse sera and wild-type mouse or normal human sera under conditions inactivating either the CP (Ca(++) deficiency) or the AP (mAb inhibitory to factor B). Robust generation of both C3a and C5a by either the AP or CP alone were observed with both mouse and human sera, although there were some small differences between the species of sera. We conclude that neither the CP nor LP alone is capable of mediating CAIA in vivo and that mouse sera exhibits a high level of IgG-induced C5a generation in vitro through either the CP or AP.

Response to pegylated interferon and ribavirin in Asian American patients with chronic hepatitis C genotypes 1 vs 2/3 vs 6.

Chronic hepatitis C is generally underappreciated in Asian Americans, and most pivotal studies were conducted in western countries and only included a small numbers of Asian patients. Our goal was to examine and compare treatment outcomes in these patients with genotypes 1 vs 2/3 vs 6. We performed a retrospective cohort study of 167 consecutive treatment-naïve Asian American patients treated with pegylated interferon (PEG IFN) plus ribavirin (RBV) at two community clinics in Northern California from 12/00 to 1/08. Primary outcome was sustained virological response rate by intention-to-treat analysis. The overall completion rate was 76%, and treatment adherence (completion of ≥ 75-80% PEG IFN + RBV dose for ≥ 75-80% of intended duration) was 74%. Significant depression was noted in only 4% of patients. Sustained virologic response in patients with genotype 6 treated for 48 weeks was similar to that seen in those with genotype 2/3 (74%vs 75%, P = 0.89) and significantly higher than those with genotype 1 (74%vs 49%, P = 0.016). On multivariate analysis inclusive of sex, age, body mass index (≤ 25 vs > 25) and viral load, only treatment adherence and genotype (2/3 and 6 treated for 48 weeks) were found to be significant predictors of sustained virologic response. We conclude that significant depression is rare in Asian American patients (4%). Patients with genotype 6 treated for 48 weeks appear to have a similar treatment response rate as patients with genotype 2/3 and a significantly higher response rate than those with genotype 1.

Effects of actodigin on the heart.

Actodigin is a new semisynthetic cardiac glycoside reported to have a rapid onset and brief duration of action in dogs. Five patients with congestive heart failure in normal sinus rhythm were given incremental doses of actodigin. Overall, there was no significant change in heart rate, aortic or pulmonary artery pressure, systemic vascular resistance, cardiac index, and stroke volume. This lack of response to actodigin is consistent with previous reports of acute administration of other cardiac glycosides. Four patients with atrial fibrillation and a rapid ventricular rate were given similar doses of actodigin. The ventricular rate was readily controlled. After drug administration was stopped, the ventricular rate quickly returned toward predrug levels. Thus, the rapid onset and brief duration of action of actodigin may be useful in the initial management of atrial fibrillation.

A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine.

BACKGROUND AND OBJECTIVES: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. METHODS: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. RESULTS: A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. CONCLUSION: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

Effects of phosphodiesterase inhibition on skeletal muscle vasculature.

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.

The effect of diphenidol on ouabain cardiotoxicity in the cat.

The capacity of diphenidol to influence ouabain-induced cardiotoxicity was studied in anaesthetized cats with and without spinal cord transection. 2 Diphenidol pretreatment increased the lethal dose of ouabain in both intact cats and cats in which the spinal cords had been transected. Diphenidol pretreatment increased the myocardial content of ouabain associated with death in the intact animals, but failed to influence the lethal ventricular concentration in cats with transected spinal cords. 3 The failure of diphenidol to influence tissue thresholds for toxicity in the spinal cat and the equivalence of tissue ouabain requirements for death in spinal cats and diphenidol-treated intact animals, suggest a neural mechanism for the protective effect in intact animals. 4 Ouabain administration prolonged atrio-ventricular conduction time in all animals and diphenidol attenuated this effect. Thus, the influence of both drugs on antrioventricular conduction may not be entirely mediated by central neurones.

Echocardiographic findings in a patient with Candida endocarditis of the aortic valve.

The echocardiographic appearance of fungal endocarditis of the aortic valve is described in a patient who subsequently died from this disease. In addition, the progressive growth of the vegetation on serial echocardiograms was recorded, and premature closure of the mitral valve was absent, notwithstanding perforation of two aortic cusps.

The assessment of antidysrhythmic drugs.

Assessments of efficacy of antidysrhythmic drugs at different clinical arrhythmia centers frequently produce discordant data, probably because of differences in patient population, technology to assess efficacy, study design, and concomitant drugs such as digitalis, diuretics, beta-adrenergic blocking agents, and calcium channel blockers. Furthermore, different doses employed may greatly influence the toxicity and efficacy of both conventional and experimental antiarrhythmic drugs. These variables make the design of studies in the field of antiarrhythmic therapy both difficult and of critical importance. The serious and complex nature of the disease entity against which these drugs are directed constitutes a considerable public health problem which requires that the problems be addressed in a definite and timely way.