Feasibility study of an internally cooled bipolar applicator for RF coagulation of hepatic tissue: Experimental and computational study

Purpose: To study the capacity of an internally cooled radiofrequency (RF) bipolar applicator to create sufficiently deep thermal lesions in hepatic tissue. Materials and methods: Three complementary methodologies were employed to check the electrical and thermal behaviour of the applicator under test. The experimental studies were based on excised bovine (ex vivo study) and porcine liver (in vivo study) and the theoretical models were solved by means of the finite element method (FEM). Results: Experimental and computational results showed good agreement in terms of impedance progress and lesion depth (4 and 4.5 mm respectively for ex vivo conditions, and approximately 7 and 9 mm respectively for in vivo conditions), although the lesion widths were overestimated by the computer simulations. This could have been due to the method used to assess the thermal lesions; the experimental lesions were assessed by the white coagulation zone, whereas the tissue damage function was used to assess the computational lesions. Conclusions: The experimental results suggest that this applicator could create in vivo lesions to a depth of around 7mm. It was also observed that the thermal lesion is mainly confined to the area between both electrodes, which would allow lesion width to be controlled by selecting a specific applicator design. The comparison between the experimental and computational results suggests that the theoretical model could be usefully applied in further studies of the performance of this device. © 2012 Informa UK Ltd All rights reserved.This work received financial support from the Spanish Plan Nacional de I+D+I del Ministerio de Ciencia e Innovacion TEC2011-27133-C02-(01 and 02), from Universitat Politecnica de Valencia (INNOVA11-01-5502; and PAID-06-11 Ref. 1988). A. Gonzalez-Suarez is the recipient of grant VaLi+D (ACIF/2011/194) from the Generalitat Valenciana. The proof-reading of this paper was funded by the Universitat Politecnica de Valencia, Spain. The authors alone are responsible for the content and writing of the paper.González Suárez, A.; Trujillo Guillen, M.; Burdío Pinilla, F.; Andaluz Martínez, AM.; Berjano Zanón, E. (2012). Feasibility study of an internally cooled bipolar applicator for RF coagulation of hepatic tissue: Experimental and computational study. International Journal of Hyperthermia. 28(7):663-673. https://doi.org/10.3109/02656736.2012.716900S663673287Topp, S. A., McClurken, M., Lipson, D., Upadhya, G. A., Ritter, J. H., Linehan, D., & Strasberg, S. M. (2004). Saline-Linked Surface Radiofrequency Ablation. Annals of Surgery, 239(4), 518-527. doi:10.1097/01.sla.0000118927.83650.a4Gnerlich, J. L., Ritter, J. H., Linehan, D. C., Hawkins, W. G., & Strasberg, S. M. (2009). Saline-Linked Surface Radiofrequency Ablation. 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Impaired right ventricular calcium cycling is an early risk factor in r14del-phospholamban arrhythmias

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset

The kinetics of competitive antagonism by cisatracurium of embryonic and adult nicotinic acetylcholine receptors. Molecular Pharmacology 60

ABSTRACT Competitive antagonists to nicotinic acetylcholine receptors are clinically used as muscle relaxants. Previously, we reported the kinetics of inhibition (in the absence of acetylcholine) by (ϩ)-tubocurarine and pancuronium on embryonic receptors. Here, we examine cisatracurium, a commonly used muscle relaxant. Outside-out patches were equilibrated with cisatracurium before application of 300 M acetylcholine. cisatracurium inhibited the initial peak current, but the decay of these currents displayed a pronounced biphasic behavior. The IC 50 value was 54 Ϯ 2 nM and 115 Ϯ 4 nM for adult and embryonic receptors, respectively. We designed a rapid perfusion system to apply or remove cisatracurium for various times before application of acetylcholine. We determined the association (embryonic, 3.4 Ϯ 0.4 ϫ 10 8 M Ϫ1 s Ϫ1 ; adult, 1.8 Ϯ 0.3 ϫ 10 8 M Ϫ1 s Ϫ1 ) and dissociation (embryonic, 34 Ϯ 6/s; adult: 13 Ϯ 5/s) rates for cisatracurium. Association was 2.9-and 1.3-fold greater than that of (ϩ)-tubocurarine and pancuronium, respectively. Dissociation was 6-and 16-fold higher than (ϩ)-tubocurarine and pancuronium, respectively. These measurements correspond to dissociation of cisatracurium from receptors in the absence of acetylcholine. Physiologically, acetylcholine interacts with receptors equilibrated with antagonist. We developed a mathematical technique that removes the effect of desensitization and determined dissociation (embryonic, 52 Ϯ 9/s; adult, 33 Ϯ 5/s) in the presence of acetylcholine. These data suggest that presence of acetylcholine on one binding site of the receptor increases the dissociation rate of antagonist from the other binding site. We incorporated all of these rates into a computer simulation of a comprehensive 11-state Markov model. There was excellent agreement (without curve fitting) between simulated and experimental currents. The nicotinic acetylcholine receptor (nAChR), found on neurons in the central and peripheral nervous system and muscle cells at the neuromuscular junction, is the prototypical ionotropic ligand-gated ion channel (Dilger, 1997). There are two isoforms of muscle-type nAChR. The embryonic isoform differs from the adult by one subunit (␥ instead of ⑀) of five and has a conductance of 40 pS (in the adult, 60 pS) and a mean open-time three times longer than in the adult isoform. Muscles that are not innervated (i.e., during development) express only embryonic nAChR that are uniformly distributed at moderate density in the synapse. During innervation, the embryonic isoform is replaced by the adult isoform at the synapse; the embryonic isoform is still present but aggregates around the periphery of the synapse. Functionally, rapid synaptic transmission is achieved partly because nAChR is a single protein containing both the ligand-receptor and ion-channel. Action potentials propagate in the presynaptic nerve terminal, and ACh is exocytosed into the synapse. ACh diffuses across the synaptic cleft (ϳ0.2 ms) and binds to sites on muscle-type nAChR at the ␣-␦ (high-affinity) and ␣-␥ (low-affinity) subunit interfaces. The channels open for an average of 1 ms and allow the entry of sodium ions that depolarize the postsynaptic terminal. Under normal circumstances, the depolarization reaches threshold and the muscle fiber fires an action potential that results in muscle contraction. After the channel closes, ACh dissociates and is hydrolyzed within ϳ0.2 ms by acetylcholinesterase; the entire synaptic event is complete within a few milliseconds. The continued presence of ACh induces nAChR to enter a nonconducting conformation, or desensitization, with a higher affinity for ACh. Competitive antagonists to nAChR are clinically used to immobilize patients during surgery. Several studies have shown they have a higher affinity (as much as 100-fold) for ␣-␥/⑀ site compared with the ␣-␦ sit

Abstract 453: Phenotyping by ECG Dynamics During Sleep Predicts Cardiovascular Disease Risk Factors in a Multicenter Study of Asymptomatic Middle-aged Community Adults

Introduction: ECG-based predictive analytics have typically focused on static assessment of beat-to-beat heart rate variability (HRV) during wakefulness. However, there is increasing evidence that quantification of time-related changes as well as non-beat-to-beat complexity indices, such as entropy, can provide important untapped insight. Methods: Analysis of HRV, QT variability (QTV), QT entropy (QTen), QT entropy rate (QTa) and RR entropy (RRen) in 5-min bins were performed on home polysomnographs of 6,300 asymptomatic community adults (Sleep Heart Health Study). Rate of change of ECG variables was quantified by linear regression in one- to four-hour epochs. Stepwise regression was used to identify age-, sex-, race-, comorbidity-, and sleep state-associated influences on ECG values. Results: Predictive multivariate models were generated for congestive heart failure, diabetes, obstructive sleep apnea, and history of myocardial infarction, each with sleep state-specific and ECG variable rate of change being of the highest predictive value in ECG-based models (Table 1). Conclusion: Although aggregate beat-to-beat HRV is associated with cardiovascular risk factors, unique time-varying and sleep stage-specific findings provide additional predictive power. By way of demonstrating that distinct classes of dynamic ECG features were predictive of each risk factor studied, our study suggests a potential role for patient-specific ECG phenotyping using a comprehensive analytical platform. Dynamic ECG assessment during sleep with attention to entropy-derived measures, in particular, may enhance precise risk stratification in otherwise low-risk individuals