© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs
aDepartment of Medicine and Physiology, University of Wisconsin, Madison, WI, USA
bDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester MN, USA
cDepartment of Pediatrics/Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester MN, USA
dDepartment of Medicine/Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester MN, USA
* Corresponding author. Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Guggenheim 501, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1-507-284-0101; fax: +1-507-284-3757. Email address: ackerman.michael{at}mayo.edu
Received 18 December 2003; revised 13 January 2004; accepted 20 January 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: The human cardiac SCN5A gene encodes for the
subunit of the human cardiac voltage-dependent sodium channel hNav1.5 [Neuron 28 (2) (2000) 365] and carries inward Na current (INa). Mutations in SCN5A cause arrhythmia syndromes including Brugada syndrome (BrS) and congenital long QT syndrome subtype 3 (LQT3). Here, we report a trafficking defective BrS-causing SCN5A mutation that was drug-rescued.
Methods and Results: A 14-year-old Caucasian male was diagnosed with BrS with typical ECG pattern for BrS and ventricular fibrillation was easily induced. He also had significant HV interval delay (
65 ms) and high (31 J) defibrillation thresholds (DFTs). Genomic analysis revealed the SCN5A mutation (G1743R). We engineered G1743R into the cardiac Na channel and transfected HEK-293 cells for functional studies. The mutant channel yielded nearly undetectable sodium channel currents. Coexpression with the β1 subunit, or incubation at low temperature did not increase current density. However, mexiletine, a sodium channel blocker, increased current density 93-fold in G1743R, but only twofold in WT.
Conclusions: This study identifies an expression-defective BrS mutation in SCN5A with pharmacological rescue. The profoundly decreased sodium current associated with the G1743R suggests a molecular basis for the delayed His-Purkinje conduction and elevated DFTs observed in the proband. Whether the mutant channel may be rescued in vivo by mexiletine and normalize the patient's electrophysiologic parameters remains to be tested.
KEYWORDS Arrhythmia (mechanisms); Na-channel; Ion channels; Brugada syndrome; SCN5A; NaV1.5; Genetic testing
Abbreviations: SCN5A, official gene designation for the cardiac sodium channel gene residing on chromosome 3p21 • NaV1.5, nomenclature for the channel protein product of SCN5A • hH1c, cDNA clone used to construct the mutant channel for heterologous expression • WT, "wild-type" Na channel • G1743R, mutated SCN5A channel containing an arginine (R) at position 1743 instead of the normal glycine (G) residue
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The human cardiac sodium channel
-subunit, hNav1.5, encoded by SCN5A is responsible for excitability in cardiac atrial and ventricular cells [1]. The voltage-gated sodium channel activates to produce depolarizing inward sodium current (INa), and then inactivates nearly completely within a few milliseconds. Mutations in SCN5A cause several arrhythmogenic syndromes including Brugada syndrome subtype 1 (BrS1), progressive cardiac conduction disease, and long QT syndrome subtype 3 (LQT3). Except for LQT3, these syndromes originate from sodium conductance "loss-of-function" in which INa is decreased [2]. The mechanism for the majority of functionally characterized BrS-causing SCN5A mutations involves perturbations in kinetics of inactivation, namely accelerated channel inactivation (see review by Antzelevitch et al. [2]). There is a single manuscript detailing a BrS-causing SCN5A mutation that fails to traffic to the cell membrane properly resulting in markedly reduced sodium channel current density [3]. Previously, we identified a novel mutation, M1766L, in a toddler who died secondary to LQT3 [4]. In heterologous expression systems, the mutant channel was trafficking defective, being retained in the endoplasmic reticulum (ER) [5]. However, in the context of the common polymorphism H558R, expression of the mutant channel was rescued albeit with persistent late sodium current consistent with the decedent's clinical phenotype, suggesting that a "double hit" was necessary to express the LQT3 phenotype.
Here, we report the case of a patient with BrS and a SCN5A missense mutation, G1743R (glycine replaced with arginine at position 1743). This mutation has also been found but not otherwise characterized in a single Japanese kindred [6]. Voltage clamp studies of this mutated channel in HEK cells yielded negligible INa and immunostaining studies confirmed the retention of G1743R in the ER. The trafficking defect was not corrected by the polymorphism H558R. However, INa density was increased dramatically in vitro by incubation with antiarrhythmic drugs, mexiletine or quinidine. The rescue of the defective Na+ channel expression in Brugada syndrome with mexiletine and quinidine suggests a potentially novel antiarrhythmic drug mechanism and offers a possible mutation-specific treatment strategy.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1 Mutational analysis of SCN5A
Comprehensive mutational analysis of all protein-encoding exons of the cardiac sodium channel gene, SCN5A, was performed using polymerase chain reaction, denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing as previously described [4,7–10]. The investigation conforms with the principles outlined in the Declaration of Helsinki.
2.2. G1743R site-directed mutagenesis and transfection of cell lines
The G1743R–SCN5A mutation was engineered using the hH1c cDNA clone (Accession #AY148488) by site-directed mutagenesis (ExSite, Stratagene) using the pcDNA3 vector (Invitrogen). Wild type (WT) and G1743R-SCN5A mutants were transiently transfected into HEK-293 cells as described previously [4,11].
2.3. Electrophysiological characterization
The voltage clamp protocols are described briefly with the data and have been published previously in detail [4,12]. Technical issues including a discussion of the adequacy of voltage control, endogenous currents, and the rate of negative shift in kinetic parameters for this preparation and voltage clamp method have been discussed previously [11].
2.4. Immunocytochemistry
The FLAG epitope was introduced between S1 and S2 in domain I of SCN5A for the immunocytochemistry experiments using confocal microscopy. Details of the procedure have been previously published [5].
2.5. Data analysis
Data are shown as symbols with standard error of the mean (S.E.M.) bars. Determinations of statistical significance were performed using a Student t-test for comparisons of two means or using analysis of variance (ANOVA) for comparisons of multiple means. A p value of <0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Clinical case and molecular characterization of G1743R-BrS-causing defect
The proband was diagnosed clinically with BrS at 14 years of age after experiencing five episodes of exertional syncope with onset at age 8 years. Initial evaluation in 1996 included an electrocardiogram demonstrating apparent right bundle branch block and a normal echocardiogram. Two months later, his second episode of syncope occurred while swimming. Two years later (1998), after his third episode of syncope following a vigorous hockey practice, the beta-blocker atenolol was started empirically. He was event free for 2 years until beta-blocker therapy was discontinued. Shortly thereafter, he experienced another syncopal episode while playing basketball. This prompted further investigation that included an electrophysiology study. In addition to intraventricular conduction delay on baseline ECG, there was marked prolongation of the His-Purkinje conduction (HV interval 65–70 ms) and easily inducible atrial tachycardia with burst atrial pacing. These findings prompted referral to Mayo Clinic for further diagnostic evaluation and consideration for possible radiofrequency ablation.
The family history was unremarkable with the exception of an unexplained sudden death of his great great grandfather in his early 30s. Both parents were asymptomatic with normal electrocardiograms. After review of previous electrocardiograms and the one shown in Fig. 1, Brugada syndrome (BrS) was suspected. Procainamide provocation studies resulted in accentuation of the resting right precordial ST segment elevation in the proband and elicited ST segment elevation in the proband's mother as well (data not shown).
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A repeat study at the Mayo Clinic again demonstrated marked HV interval prolongation and easily inducible ventricular fibrillation. With the history of exertional syncope, suspected diagnosis of BrS, and presence of inducible VF, the patient received an internal cardioverter defibrillator (ICD) device. Testing during implantation revealed exceedingly high defibrillation thresholds (DFTs>31 J) necessitating device revision with addition of a Sub-Q Array system. This yielded successful defibrillation with 21-J DFTs.
Since implantation of the ICD device in May 2001, there have been six additional episodes of exertional syncope and approximately 20 appropriate ICD therapies rendered for either ventricular tachycardia or ventricular fibrillation. Consequently, beta-blocker therapy has been resumed. In addition, after recurrence of ICD discharges, quinidine was added to target the transient outward potassium current Ito [13]. The patient has been free of ICD events for the past 18 months.
Mutational analysis of SCN5A using DHPLC elucidated an abnormal amplicon in exon 28 (Fig. 2A). DNA sequencing revealed a nonsynonymous single nucleotide substitution (g>a) involving codon 1743 (ggg-to-agg) yielding a G1743R missense mutation whereby a neutral residue (glycine, G) is replaced by a positively charged basic residue (arginine, R) at position 1743 (Fig. 2B). This mutation was found previously in a Japanese patient [6] but not otherwise characterized. The G1743 residue localizes to the pore region between S5 and S6 of the fourth domain and this region is highly conserved between various species including Drosophila, yeast, mice, and man. The mutation was confirmed in the proband's mother and maternal grandmother as well (Fig. 3). The mutation was absent in over 1600 reference alleles including 590 ethnic-matched alleles (data not shown).
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=males, 
=females, slashed=deceased). Arrow denotes the proband. Positive (+) sign indicates presence of G1743R mutation.3.2. G1743R: a "loss-of-function" defect rescued by mexiletine and quinidine
Transfected HEK-293 cells transiently expressing either WT or mutated G1743R channels were investigated for functional properties using the whole cell configuration of the patch-clamp technique. Fig. 4 shows examples of current traces for WT and for the G1743R mutant channels. The sodium current amplitude for G1743R was extremely low, at less than 1% of normal current. Reduction in current density could be due to a dysfunctional channel or abnormal trafficking of an otherwise functional channel. Abnormal cardiac ion channel trafficking has previously been rescued pharmacologically or by modulation of temperature [4,14].
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Therefore, HEK-293 cells expressing WT or G1743R channels were incubated for 24 or 48 h with either 500 µM mexiletine or 100 µM quinidine at physiological temperature in the absence of the β1 subunit. Drug treatment increased current density (measured after drug removal) in both WT and mutant channels, but more markedly for G1743R (Fig. 4A and B). After 48 h incubation in mexiletine, WT current was increased by twofold compared to nonincubation, and for G1743R the increase in current was 93-fold compared with control nonincubated cells. Quinidine also rescued the defective G1743R mutant channels but to a lesser extent than mexiletine (27-fold vs. 93-fold). Other attempts to restore current density in G1743R such as incubation at low temperature and coexpression with the β1 subunit, known to increase sodium channel density, failed to restore the current density for G1743R (data not shown). Moreover, the double mutation H558R/G1743R did not yield rescued INa expression (data not shown). Lower concentrations of both drugs (10 µM) that would approximate therapeutic serum levels also rescued but to a lesser extent (data not shown).
3.3. G1743R trafficking defect corrected by drugs
Na channels labeled using the FLAG epitope were expressed in HEK cells and their location determined by confocal microscopy and immunocytochemistry (Fig. 5). A regular transmittance picture is shown at the left of each picture so that the location and the size of the surface membrane can be noted. Defective trafficking is noted when the channel is localized within the cell and does not make it to the cell surface membrane. A nontransfected cell as control shows no immunostaining (Fig. 5A). An example of a cell transfected with WT channel shows localization to the cell surface (Fig. 5B), but a cell transfected with G1743R shows that the channel is retained within the cell and does not make it to the cell surface (Fig. 5C). When cells expressing the G1743R mutant channel were incubated with mexiletine, the more normal pattern of trafficking to the cell surface is seen (Fig. 5D). These results, confirmed by at least four additional experiments in each case, show that the decreased current density for G1743R is caused by a defect in trafficking to the cell surface membrane, and that incubation with mexiletine restores trafficking. Similar restoration of trafficking was seen with quinidine as well (data not shown).
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3.4. Electrophysiological properties of rescued G1743R
Analysis of drug-rescued G1743R channels revealed perturbations in channel kinetics (Fig. 6). Except for the significant difference in overall current amplitude, the electrophysiological properties of quinidine-rescued G1743R channels were virtually identical to that of mexiletine-rescued G1743R (data not shown). Fig. 6A demonstrates the family of macroscopic INa recorded from HEK-293 cells expressing WT and the G1743R mutant channels rescued by prior exposure to the antiarrhythmic drug, mexiletine. Currents were obtained after 24 ms depolarization from a holding potential of –140 mV. After drug was washed out, the drug-rescued G1743R INa showed similar activation characteristics compared to WT (Fig. 6B). The midpoint of activation (V1/2) and the slope (k) for rescued G1743R were –40±6 and 4.6±0.1 mV (n=10) vs. WT –42±2 and 5.1±0.3 mV (n=15). Steady state fast inactivation for the drug-rescued G1743R mutant channel also was not different from WT, using two-step protocols with 1-s conditioning depolarization to different voltages from a holding potential of –140 mV (Fig. 6C inset). For G1743R, the midpoint of inactivation was –84.6±1.2 mV (n=10) and for WT –84.3±1.0 mV (n=20, Fig. 6C).
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are the midpoint and the slope factor, respectively, and GNa=INa(norm)/(V-Vrev) where Vrev is the reversal potential, k are the midpoint and the slope factor, respectively, and V is the membrane potential. (C) Steady state availability from inactivation for WT (Recovery from inactivation was assessed by a two-pulse recovery protocol (Fig. 7A) where a conditioning potential to 0 mV of 1 s duration was used to inactivate channels, followed by a variable recovery interval at –140 mV. The recovery course for both channels was best fit with two exponential components where the fast time constant
f, the slow time constant s, and the amplitude of the slow component As were obtained. The early time course of recovery is displayed on a log scale (inset Fig. 7A) for better resolution. The slow recovery time constant (s) for rescued G1743R channels was significantly slower than WT. For drug-rescued G1743R, the time constants were 5.4±1.2 ms (f) and 80±28 ms (s) compared to 2.4±0.2 ms (f) and 29±4 ms (s) for WT. The relative amplitude of the slow component (As) was similar for both channels: 24±3% for G1743R and 21±1.8% for WT.
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Drug-rescued G1743R mutant channels exhibited significantly increased slow (also called intermediate) inactivation (Fig. 7B). A two-pulse protocol with a variable prepulse was used to develop slow inactivation and a 20 ms recovery period was used to recover from fast inactivation (see inset Fig. 7B). The drug-rescued G1743R channels developed slower inactivation than WT for prepulse duration longer than 0.5 s (Fig. 7B).
Because the increased slow inactivation and slower recovery from inactivation would both tend to decrease peak INa, we looked at the INa in response to trains of depolarization with a rate sufficiently rapid (3 Hz) to decrease INa. Reduction of the INa at rapid stimulation rates was indeed observed in both WT and drug-rescued G1743R channels (Fig. 8). This rate- or use-dependent reduction in peak INa current was significantly more pronounced in the drug-rescued G1743R mutant channel (Fig. 8B).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Brugada syndrome (BrS) is recognized currently as a sodium channelopathy. However, only 10–20% of families with suspected BrS have SCN5A defects [15]. To date, approximately 55 distinct BrS-causing mutations in SCN5A have been described and these mutations are scattered throughout the coding region of SCN5A. All are characterized by a "loss of function" or decreased current amplitude, but the mechanisms for this loss vary in those mutations that have been functionally characterized. Some show decreased current due to an alteration in kinetics such as enhanced inactivation [16] while others have been shown to be due to a defect in expression [3]. This mutation, G1743R, previously described and now functionally characterized here appears to be primarily a trafficking-defective mutant. However, when expression was pharmacologically rescued, G1743R channels also showed some kinetic features (enhanced slow inactivation) that would also result in some loss of function.
The first description of an SCN5A expression defect rescued by drug was the LQT3-causing mutation M1766L [4]. The presentation of the patient as LQT3 harboring this M1766L mutation was initially confusing. Although the drug-rescued channels showed an increased late INa as in other LQT3 syndromes, an expression defect would have been expected to present as Brugada syndrome or as a conduction defect. Clarity was provided with the discovery that M1766L, when expressed in the context of the common H558R polymorphism for which the patient was heterozygous, yielded a restored channel with enhanced late INa [5]. For expression of the clinical LQT3 phenotype, a "double hit" of M1766 and H558R were required. M1766L alone might be expected to yield the clinical phenotype of BrS, but this has not yet been described.
G1743R, therefore, represents the first Brugada syndrome-causing mutation where drug-rescue has been demonstrated, and in this case, such rescue attempts to enhance channel expression might be potentially therapeutic. Whether or not other Brugada syndrome mutations with expression defects might be drug rescuable is not yet known. Based upon the near absence of current for the G1743R mutation in vitro, we can surmise that a patient heterozygous for this mutation may possess a 50% reduction in peak INa density. The proband's significantly prolonged HV interval (65–70 ms) and marked DFTs are consistent with such a substantial reduction in peak INa density. Prolongation of the HV interval has been observed in a subset of patients with BrS and may be a risk factor for sudden death [17]. To our knowledge, the increased DFTs we report for G1743R have not been reported previously in BrS and may be secondary to the marked reduction in INa density. Sodium channel blockade via low to medium doses of lidocaine has been implicated in raising DFTs [18].
Whether or not this pharmacological rescue of an expression defect in BrS translates into the possibility of mutation-specific pharmacotherapy for this proband awaits further investigation. The extent of rescue if any in vivo is unknown and may be less. Rescue was less at lower concentrations. Also, in a patient, the drug would be more or less continuously present and might be expected to block INa. However, the use-dependent nature of mexiletine block and the rapid kinetics of this Class IB drug mean that little or no block occurs under normal conditions (moderate heart rate and no ischemia) as evidenced by minimal effects of these drugs on the QRS duration [19] suggesting that rescue could occur with minimal block. Nonetheless, the theoretical possibility that mexiletine therapy could instead further aggravate the DFT by interfering with the already reduced population of sodium channels stemming solely from expression of the patient's normal allele has thus far prevented a trial with this mutation-specific therapy.
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Acknowledgements |
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The authors wish to acknowledge the family affected by this mutation and trust that the knowledge derived herein will not only advance the science but also ultimately translate into refined care for this young man. Further, the authors are grateful to Drs. Andrew Merliss and Rodrigo Rios for referral of this family to the Mayo Clinic for evaluation, management, and genetic testing and for the excellent ongoing care provided to this family. We thank Mr. Matthew Pagel for technical assistance. This work was supported by NIH NHLBI HL-66378 (JCM), NIH HD42569 (MJA), and the Doris Duke Charitable Foundation (MJA).
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Notes |
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1 Contributed equally to this work.
Time for primary review 10 days
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