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Biomedical subjects

R A Gray

Publications and source records attributed to R A Gray.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of atrial defibrillation shocks on the ventricles in isolated sheep hearts.

BACKGROUND: The effects of cardioversion of atrial fibrillation on the activation sequence of the ventricles have not been previously studied. In this study we examined the events in the ventricle that follow the application of atrial defibrillatory shocks. METHODS AND RESULTS: We used video imaging technology to study the sequence of activation on the surface of the ventricles in the Langendorff-perfused sheep heart. We recorded transmembrane potentials simultaneously from over 20000 sites on the epicardium before and after biphasic shocks applied by a programmable atrial defibrillator. The first epicardial activation after the shock depended on both the voltage and timing of the shock. During ventricular diastole shocks as low as 10 V produced ventricular excitation, although the time between the shock and the first epicardial activation (latency) was approximately 30 ms. As the shock voltage was increased to 120 V, latency decreased to zero and the entire epicardium was depolarized within 30 ms. For 120-V shocks delivered late in systole, the depolarization sequence produced by the shock was similar to the previous repolarization sequence. Shocks of 120 V applied 150 to 300 ms after the previous ventricular excitation induced ventricular fibrillation. Ventricular fibrillation was induced by multiple focal beats after the shock, which produced waves that propagated but broke down into reentry within regions of high repolarization gradients. CONCLUSIONS: These results demonstrate that atrial defibrillation shocks excite the ventricles even at low shock voltages. In addition, ventricular fibrillation can be induced by shocks given in the vulnerable period by producing focal patterns that break down into reentrant waves.

Animals↗
PubMed1998

Spatial and temporal organization during cardiac fibrillation.

Cardiac fibrillation (spontaneous, asynchronous contractions of cardiac muscle fibres) is the leading cause of death in the industrialized world, yet it is not clear how it occurs. It has been debated whether or not fibrillation is a random phenomenon. There is some determinism during fibrillation, perhaps resulting from rotating waves of electrical activity. Here we present a new algorithm that markedly reduces the amount of data required to depict the complex spatiotemporal patterns of fibrillation. We use a potentiometric dye and video imaging to record the dynamics of transmembrane potentials at many sites during fibrillation. Transmembrane signals at each site exhibit a strong periodic component centred near 8 Hz. This periodicity is seen as an attractor in two-dimensional-phase space and each site can be represented by its phase around the attractor. Spatial phase maps at each instant reveal the 'sources' of fibrillation in the form of topological defects, or phase singularities, at a few sites. Using our method of identifying phase singularities, we can elucidate the mechanisms for the formation and termination of these singularities, and represent an episode of fibrillation by locating singularities. Our results indicate an unprecedented amount of temporal and spatial organization during cardiac fibrillation.

Algorithms↗
PubMed1998

Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse.

Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.

Animals↗
PubMed1997

Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart.

OBJECTIVES: This study sought to 1) test the hypothesis that in the setting of bradycardia and drug-induced action potential prolongation, multiple foci of early afterdepolarizations (EADs) result in beat to beat changes in the origin and direction of the excitation wave front and are responsible for polymorphic arrhythmias; and 2) determine whether EADs may initiate nonstationary reentry, giving rise to the typical torsade de pointes (TDP) pattern. BACKGROUND: In the past, it has been difficult to associate EADs or reentry with the undulating electrocardiographic (ECG) patterns of TDP. METHODS: A voltage-sensitive dye was used for high resolution video imaging of electrical waves on the epicardial and endocardial surface of the Langendorff-perfused rabbit heart. ECG and monophasic action potentials from the right septal region were also recorded. Bradycardia was induced by ablation of the atrioventricular node. RESULTS: Perfusion of low potassium chloride Tyrode solution plus quinidine led to prolongation of the action potential and the QT interval. Eventually, EADs and triggered activity ensued, giving rise to intermittent episodes of polymorphic arrhythmia. In one experiment, triggered activity was followed by a long episode of vortex-like reentry with an ECG pattern characteristic of TDP. However, in most experiments, focal activity of varying origins and propagation patterns was observed. Triggered responses also showed varying degrees of local block. Similar results were obtained with E-4031. Burst pacing both at control conditions and in the presence of quinidine consistently led to vortex-like reentry whose ECG pattern resembled TDP. However, the cycle length of the arrhythmia with quinidine was longer than that for control ([mean +/- SEM] 194 +/- 12 vs. 132 +/- 8 ms, p < 0.03). CONCLUSIONS: Drug-induced polymorphic ventricular arrhythmias may result from beat to beat changes in wave propagation patterns initiated by EADs or EAD-induced nonstationary reentrant activity. In contrast, burst pacing-induced polymorphic tachycardia in the presence or absence of drugs is the result of nonstationary reentrant activity.

Action Potentials↗
PubMed1997

Video imaging of atrial defibrillation in the sheep heart.

BACKGROUND: The effects of defibrillatory shocks on the organization of atrial fibrillation (AF) have not been studied previously. In this study, we examined the events that precede, accompany, and follow the application of atrial defibrillatory shocks. METHODS AND RESULTS: We used video imaging to study the sequence of activation on the surface of the atria in the Langendorff-perfused sheep heart. We recorded transmembrane potentials simultaneously from > 20000 sites on the epicardium during AF as well as during and after biphasic shocks applied by a programmable atrial defibrillator. Defibrillatory shocks (1.2 +/- 0.6 J; n = 6) depolarized all epicardial regions of the atria, and asynchronous repolarization occurred. The shocks resulted in four types of responses: (1) immediate cessation of epicardial activity. (2) single postshock activation. (3) organized activation for 0.8 to 1.5 seconds followed by termination, and (4) organized activity followed by degeneration back into AF. Types 2 through 4 involved a quiescent period lasting 110 +/- 28 ms immediately after the shock, then an activation sequence similar to those observed during sinus rhythm. The first cycle length after the shock for types 3 and 4 (170 +/- 36 ms) was longer than during AF (144 +/- 33 ms). Repolarization time after a shock was significantly longer for successful compared with unsuccessful shocks. CONCLUSIONS: These results indicate that the shock depolarized the entire atrial epicardial surface, followed by a quiescent period, after which organized activation emanated from the sinoatrial pacemaker region.

Analysis of Variance↗
PubMed1997

Two case reports of breast carcinoma associated with prolactinoma.

Two cases of breast carcinoma associated with prolactinoma are presented. Literature review reveals only five previous case reports of this association. Both of our cases occurred in women, aged 55 and 34. Both were typical of the reported cases in that they had long histories of amenorrhea before diagnosis of prolactinomas and breast carcinomas. One patient had a three and a half year history of atypical ductal hyperplasia and a prominent intraduct component in the invasive tumor. Both had axillary lymph node metastases. The significance of the association of breast carcinoma with prolactinoma is discussed. Whereas studies in animals have shown prolactin to be an initiator and promoter of breast carcinoma, studies in humans have been inconclusive. Some studies have shown raised levels of prolactin in patients with breast carcinoma and their daughters, while others have not. The paucity of case reports linking breast carcinoma and prolactinoma may indicate that the association is mere coincidence, but studies evaluating the relationship between breast carcinoma and all forms of hyperprolactinemia need to be conducted before a causal link is dismissed. Prolactin may act as a cofactor with, for example, estrogen or stress, to induce breast carcinoma.

Breast Neoplasms↗
PubMed1997

Spatio-temporal patterns of atrial fibrillation: role of the subendocardial structure.

Despite many years of research and speculation, the precise mechanisms underlying atrial fibrillation remain elusive. Prevalent understanding relies on assumptions, which are based on two-dimensional numerical simulations and on the idea that atrial fibrillation is the result of total disorganization of electrical activity, with multiple wavelets wandering randomly throughout the atria. However, recent studies both clinical and basic, have suggested that focal mechanisms, either re-entrant or automatic, may explain fibrillatory activity in some cases. Here we review the major hypotheses that have prevailed at one time or another to explain this complex arrhythmia and discuss some recent experimental results that strongly suggest that, whatever the electrophysiological basis of atrial fibrillation may be, it must involve complex patterns of propagation through the intricate multidimensional anatomical structure of the atria.

Animals↗
PubMed1996

Incomplete reentry and epicardial breakthrough patterns during atrial fibrillation in the sheep heart.

BACKGROUND: The mechanisms underlying atrial fibrillation and its initiation are not fully understood. Our hypothesis is that atrial fibrillation results from complex activation involving the subendocardial muscle network. METHODS AND RESULTS: We have used video imaging to study the sequence of activation on the surface of the right atrium of the Langendorff-perfused sheep heart during pacing, atrial fibrillation, and its initiation. We recorded transmembrane potentials simultaneously from over 20,000 sites. We observed two types of patterns of wave propagation during the initiation of atrial fibrillation. The first type resulted from heterogeneties of refractoriness and transmural propagation near the stimulating electrode. The second type involved heterogeneity in conduction away from the pacing site. During atrial fibrillation, the average period of activation was 138 +/- 25 ms (n = 6), and complete reentrant pathways were never observed. Propagation patterns were characterized by a combination of incomplete reentry, breakthrough patterns, and wave collisions. Incomplete reentry occurred when waves propagated around thin lines of block and then terminated. Breakthrough patterns were frequent and occurred every 215 ms on average. The location of these breakthrough sites and the lines of block during incomplete reentry were not randomly distributed but appeared to be related to preferential propagation in the underlying subendocardial muscle structures. A computer model of atrial free wall connected to a pectinate muscle suggested that subendocardial muscles lead to epicardial breakthrough patterns that act to destabilize reentry. CONCLUSIONS: These results suggest that the complex three-dimensional structure of the atria plays a major role in the activation sequences during atrial fibrillation and its initiation.

Action Potentials↗
PubMed1996

Vortex shedding as a precursor of turbulent electrical activity in cardiac muscle.

In cardiac tissue, during partial blockade of the membrane sodium channels, or at high frequencies of excitation, inexcitable obstacles with sharp edges may destabilize the propagation of electrical excitation waves, causing the formation of self-sustained vortices and turbulent cardiac electrical activity. The formation of such vortices, which visually resembles vortex shedding in hydrodynamic turbulent flows, was observed in sheep epicardial tissue using voltage-sensitive dyes in combination with video-imaging techniques. Vortex shedding is a potential mechanism leading to the spontaneous initiation of uncontrolled high-frequency excitation of the heart.

Animals↗
PubMed1995

Nonstationary vortexlike reentrant activity as a mechanism of polymorphic ventricular tachycardia in the isolated rabbit heart.

BACKGROUND: Ventricular tachycardia may result from vortexlike reentrant excitation of the myocardium. Our general hypothesis is that in the structurally normal heart, these arrhythmias are the result of one or two nonstationary three-dimensional electrical scroll waves activating the heart muscle at very high frequencies. METHODS AND RESULTS: We used a combination of high-resolution video imaging, electrocardiography, and image processing in the isolated rabbit heart, together with mathematical modeling. We characterized the dynamics of changes in transmembrane potential patterns on the epicardial surface of the ventricles using optical mapping. Image processing techniques were used to identify the surface manifestation of the reentrant organizing centers, and the location of these centers was used to determine the movement of the reentrant pathway. We also used numerical simulations incorporating Fitzhugh-Nagumo kinetics and realistic heart geometry to study how stationary and nonstationary scroll waves are manifest on the epicardial surface and in the simulated ECG. We present epicardial surface manifestations (reentrant spiral waves) and ECG patterns of nonstationary reentrant activity that are consistent with those generated by scroll waves established at the right and left ventricles. We identified the organizing centers of the reentrant circuits on the epicardial surface during polymorphic tachycardia, and these centers moved during the episodes. In addition, the arrhythmias that showed the greatest movement of the reentrant centers displayed the largest changes in QRS morphology. The numerical simulations showed that stationary scroll waves give rise to monomorphic ECG signals, but nonstationary meandering scroll waves give rise to undulating ECGs characteristic of torsade de pointes. CONCLUSIONS: Polymorphic ventricular tachycardia in the healthy, isolated rabbit heart is the result of either a single or paired ("figure-of-eight") nonstationary scroll waves. The extent of the scroll wave movement corresponds to the degree of polymorphism in the ECG. These results are consistent with our numerical simulations that showed monomorphic ECG patterns of activity for stationary scroll waves but polymorphic patterns for scroll waves that were nonstationary.

Animals↗
PubMed1994

Delta-sleep-inducing peptide: solution conformational studies of a membrane-permeable peptide.

Peptides and peptide-like molecules as a class have very poor permeability through biological membranes, which severely compromises their potential effectiveness as therapeutic agents. In order to gain insight into the problem of delivering peptide and protein drugs and to establish a model in which the effects of systematic structural variations on transport can be explored, an investigation of the solution conformation of a membrane-permeable peptide was undertaken. Delta-sleep-inducing peptide (DSIP, MW 849) was used in this investigation. DSIP is a charged, hydrophilic peptide that possesses the unusual ability to diffuse passively across the blood-brain barrier (BBB) in vivo [Kastin, A. J., Banks, W. A., Castellanos, P. F., Nissen, C., & Coy, D. H. (1982) Pharmacol. Biochem. Behav. 17, 1187-1191] and across monolayers of brain microvessel endothelial cells in vitro, a model of the BBB [Raeissi, S., & Audus, K. L. (1989) J. Pharm. Pharmacol. 41, 848-852]. This nonapeptide was studied in solution using one- and two-dimensional nuclear magnetic resonance (NMR), circular dichroism (CD), Fourier transform infrared (FT-IR), and fluorescence spectroscopies in conjunction with molecular modeling. Our spectroscopic findings suggest that DSIP exists in a dynamic equilibrium between unordered and folded structures. Residues 2-5 and 6-9 tend to form type I beta-turns in aqueous solution and a similar, but more ordered, helix-like structure inducible in 40% trifluoroethanol (TFE). NMR, FT-IR, and CD studies in aqueous solution support the dynamic equilibrium hypothesis with the IR data, suggesting that the beta-turn population is approximately 40%.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle.

We have investigated the role of wave-front curvature on propagation by following the wave front that was diffracted through a narrow isthmus created in a two-dimensional ionic model (Luo-Rudy) of ventricular muscle and in a thin (0.5-mm) sheet of sheep ventricular epicardial muscle. The electrical activity in the experimental preparations was imaged by using a high-resolution video camera that monitored the changes in fluorescence of the potentiometric dye di-4-ANEPPS on the surface of the tissue. Isthmuses were created both parallel and perpendicular to the fiber orientation. In both numerical and biological experiments, when a planar wave front reached the isthmus, it was diffracted to an elliptical wave front whose pronounced curvature was very similar to that of a wave front initiated by point stimulation. In addition, the velocity of propagation was reduced in relation to that of the original planar wave. Furthermore, as shown by the numerical results, wave-front curvature changed as a function of the distance from the isthmus. Such changes in local curvature were accompanied by corresponding changes in velocity of propagation. In the model, the critical isthmus width was 200 microns for longitudinal propagation and 600 microns for transverse propagation of a single planar wave initiated proximal to the isthmus. In the experiments, propagation depended on the width of the isthmus for a fixed stimulation frequency. Propagation through an isthmus of fixed width was rate dependent both along and across fibers. Thus, the critical isthmus width for propagation was estimated in both directions for different frequencies of stimulation. In the longitudinal direction, for cycle lengths between 200 and 500 milliseconds, the critical width was < 1 mm; for 150 milliseconds, it was estimated to be between 1.3 and 2 mm; and for the maximum frequency of stimulation (117 +/- 15 milliseconds), it was > 2.5 mm. In the transverse direction, critical width was between 1.78 and 2.32 mm for a basic cycle length of 200 milliseconds. It increased to values between 2.46 and 3.53 mm for a basic cycle length of 150 milliseconds. The overall results demonstrate that the curvature of the wave front plays an important role in propagation in two-dimensional cardiac muscle and that changes in curvature may cause slow conduction or block.

Animals↗
PubMed1989

Bioavailable copper complexes offer a physiologic approach to treatment of chronic diseases.

Copper (II)2(3,5-Diisopropylsalicylate)4(H2O)2 has been found to have antiinflammatory, antiulcer, anticonvulsant, anticancer, anticarcinogenic, antimutagenic, and radiation recovery activities and it prevents reperfusion injury. To study pharmacokinetic parameters accounting for these pharmacological effects the double labeled 67Cu(II)2(carboxy-14C-3,5-diisopropylsalicylate)4 complex was synthesized and used to obtain these parameters. Treatment of mice with 1 mumol of this complex revealed that 67Cu was distributed to blood, liver, kidney, intestine, lung, thymus, femur, muscle, spleen, brain, urine, and feces within 0.5 hr and patterned changes in 67Cu content of these tissues and excreta were found throughout the 96 hr term of this study.

Animals↗
PubMed1987

Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of injected cell dose.

Lethally irradiated mice were repopulated with low (10(5)), medium (10(6)) or high (10(7)) doses of congenic bone marrow cells. Marrow donors were heterozygous for the X-chromosome-encoded allozyme marker phosphoglycerate kinase (PGK-1). A second allozyme marker, phosphoglucose isomerase (GPI-1), distinguished between donor and radioresistant host cells. Use of these markers allowed the numbers and dispersion of repopulating hematopoietic clones to be estimated by binomial statistics. The number of major repopulating clones was related to the injected cell dose in a linear fashion, the inferred frequency of clonogenic cells in donor bone marrow being about 1:40,000. In high-dose recipients, the clones grew locally, with little or no dispersion between bones. Low-dose recipients, in contrast, carried widely dispersed clones; these tended to become reduced in number with increasing time after repopulation. Most of the (few) bone marrow clones present in low-dose recipients were also present in the thymus. In contrast, only about 10% of bone marrow clones in high-dose recipients were substantially represented in the thymus at any one time--about 16 clones in each lobe.

Animals↗
PubMed1983

Right angle light scatter: a necessary parameter in flow cytofluorimetric analysis of human peripheral blood mononuclear cells.

The techniques of flow cytometry are being increasingly used to classify lymphocytes according to their surface antigens. Accurate analyses depend on the exclusion of non-lymphocytic contaminant cells. Using a fluorescence-activated cell sorter (FACS IV), virtually complete separation of human lymphocytes from monocytes and granulocytes can be achieved by means of wide-angle (90 degrees) light scatter. The technique described is simple and suitable for routine use. Used in conjunction with fluorescein-labelled monoclonal antibodies and logarithmic amplification of the fluorescence signals, it improves the accuracy of lymphocyte subset analysis. Its use is particularly necessary in the study of subjects such as renal allograft recipients, who have a high or variable contaminant cell:lymphocyte ratio.

Antibodies, Monoclonal↗