(Circulation. 1999;99:800-806.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Development of the Cardiac Conduction Tissue in Human Embryos Using HNK-1 Antigen Expression
Possible Relevance for Understanding of Abnormal Atrial Automaticity
From the Department of Pediatric Cardiology (N.A.B., J.O.) and Department of Anatomy and Embryology (A.C.G.d.G., M.C.D., R.E.P., M.M.T.M.), Leiden University Medical Center, Leiden, the Netherlands
Correspondence to Prof Dr Adriana C. Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9602, 2300 RC Leiden, Netherlands. E-mail acgitten{at}rullf2.leidenuniv.nl
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Abstract |
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Background—Abnormal atrial automaticity in young patients with structurally normal hearts is often located around the pulmonary veins and in sinus venosus–related parts of the right atrium. We hypothesize that these ectopic pacemaker sites correspond to areas of embryonic myocardium with an early phenotypic differentiation, as indicated by differences in antigen expression during normal cardiac development.
Methods and Results—In human embryos ranging in age from 42 to 54 days of gestation, the development of the cardiac conduction system was studied with the use of HNK-1 immunohistochemistry. HNK-1 stains the developing atrioventricular conduction system, ie, the bundle branches, His bundle, right atrioventricular ring, and retroaortic ring. In addition, the myocardium around the common pulmonary vein showed transient HNK-1 antigen expression. In the right atrium, 3 HNK-1–positive connections were demonstrated between the sinoatrial node and the right atrioventricular ring. An anterior tract through the septum spurium connects the sinoatrial node with the anterior right atrioventricular ring, and 2 posterior tracts connect the sinoatrial node with the posterior right atrioventricular ring through the right venous valve (future crista terminalis) and sinus septum, encircling the coronary sinus. The medioposterior part of the right atrioventricular ring connected to the His bundle and the medioanterior part form 2 node-like structures.
Conclusions—In patients with abnormal atrial automaticity, the distribution of left and right atrial pacemaker foci correspond to areas of the embryonic myocardium that temporarily express the HNK-1 antigen.
Key Words: morphogenesis • conduction • arrhythmia • atrioventricular node
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Abnormal atrial automaticity is a rare form of supraventricular tachycardia in (usually) young patients with otherwise normal hearts. Although the pathophysiology is not known, electrophysiological studies and radiofrequency catheter therapy have demonstrated that these ectopic pacemaker foci are often located around the pulmonary veins in the left atrium or in sinus venosus–related structures in the right atrium, like the crista terminalis and the orifice of the coronary sinus.1 2 3 We hypothesize that the sites of abnormal automaticity correspond to parts of the embryonic myocardium with an early phenotypic differentiation, as indicated by differences in antigen expression during normal cardiac development.
The use of immunohistochemical markers to study the developing cardiac conduction system has provided important new data, although none of these markers are unique for the cardiac conduction tissue.4 5 6 7 8 9 10 11 With the use of a neural tissue antigen (GlN2), it was demonstrated that the developing atrioventricular conduction tissue in human embryonic hearts, including the compact atrioventricular node, develops from one specialized ring between the primitive ventricles.4 Very similar to GlN2, HNK-1 (Leu-7) antigen expression has been used to study the developing cardiac conduction tissue in different species. The monoclonal antibody HNK-1, originally used to identify human natural killer cells,12 was first described as a marker of neural crest cells during embryonic development.13 Later transient HNK-1 expression has been reported both in the developing atrioventricular conduction system and in the sinus venosus myocardium of different species, including humans.5 6 7 8 9
Although it is generally believed that the sinoatrial node is derived from the sinus venosus or sinoatrial transition, the role of the sinus venosus in the developing cardiac conduction system has not been clarified in human embryos. In this study, we investigated whether the HNK-1 antigen could be used as a marker to study the developing cardiac conduction system in human embryonic hearts, with special reference to the sinus venosus myocardium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five human embryos ranging in age from 42 to 54 days of gestation were studied. The embryos were obtained after legal abortion and the studies were approved by the medical-ethical committee of the Leiden University Medical Center. The developmental stage of the embryos was determined and they did not show malformations. Whole embryos were fixed at room temperature in 4% phosphate-buffered formalin solution, embedded in paraffin, serially sectioned (6 µm) transversely and washed in PBS. This was followed by 15 minutes in PBS with hydrogen peroxide to block the endogenous peroxidase activity; the embryos were then washed again. Alternate sections were incubated with the monoclonal antibody HNK-1 (Hybridomabank, Iowa City, Iowa) and the monoclonal anti-muscle actin antibody HHF-35 (Dako M635, Carpinteria, Calif), diluted in PBS with 1% ovalbumin and 0.05% Tween-20. After overnight incubation, the sections were rinsed in PBS. Rinsing was followed by incubation for 2 hours with 1:200 diluted rabbit anti-mouse conjugated to horseradish peroxidase (Dako, P260, Carpinteria, Calif), 2-hour incubation with 1:50 goat anti-rabbit immunoglobulin (Nordic, Tilburg, Netherlands), and 2 hours with 1:500 rabbit peroxidase anti-peroxidase (Nordic, Tilburg, Netherlands). After washing, the staining reaction was performed with 0.04% diaminobenzidine tetrahydrochloride (Sigma, D5637, St. Louis, Mo) in 0.05 M tris-maleic acid (pH 7.6) and 0.006% hydrogen peroxide for 10 minutes; this was followed by washing. The slides were counterstained with Mayer's hematoxylin for 10 s. Graphic 3D reconstructions were made to obtain a better cognition of the distribution of HNK-1–positive myocardium and its relationship to other cardiac structures.
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Results |
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Stage 18 (42 to 46 Days, Crown-rump [CR] Length 14 mm)
In this youngest embryo, the separation of the aorta and pulmonary trunk at orifice level is complete. Both right and left portions of the atrioventricular canal are present and the ventricular and atrial septation have progressed. The sinus venosus has been incorporated into the atrium, and the entrance of the superior caval vein is guarded by 2 large valves, the right and left venous valves. Dorsocranially, these valves fuse to become the septum spurium, a marked structure that runs anteriorly through the roof of the right atrium.
HNK-1 staining is present in the ring of myocardium
around the right part of the atrioventricular canal,
the so-called right atrioventricular ring (RAVR). The
medioanterior and, in particular, the medioposterior part of this ring
form 2 compact HNK-1–positive areas. The distance between these 2
areas is relatively large with thick cushion tissue separating them.
The medioposterior part is connected with HNK-1–positive
myocardium in the top of the interventricular
septum, ie, the His bundle which divides into both bundle branches.
HNK-1 antigen expression is also detected in parts of the sinus venosus
myocardium, whereas the myocardium of both
atria and the septum primum remain HNK-1 negative. HNK-1 is present
in the sinoatrial node (SAN), located in front of the superior caval
vein. Three tracts of HNK-1–positive myocardium converge
in this area. One tract runs anteriorly in the roof of the right atrium
through the septum spurium to make contact with the HNK-1– positive
mass of the anterior part of the RAVR. A second tract runs posterior
and through the base of the right venous valve, around the
orifice of the coronary sinus to the base of the atrial septum.
A third tract leaves the SAN and runs posterior and through the base of
the left venous valve and the base of the atrial septum. These 2
posterior bands are still remote from the posterior part of the RAVR
and the His bundle. In addition, the myocardium around the
orifice of the common pulmonary vein is HNK-1–positive. This
region is continuous with the HNK-1–positive myocardium of
the sinus venosus in the right atrium through the base of the atrial
septum (Figure 1
). A graphic 3D reconstruction of the
distribution of the HNK-1 antigen expression is shown in Figure 2.
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) indicate
HNK-1–positive myocardium; open arrowheads (
), positive
dorsal mesocardium. a, The myocardium of both atria and
ventricles show HHF-35 staining. b, HNK-1 expression in the wall of the
coronary sinus (CS) and base of the atrial septum (BAS). Strong
immunoreactivity is present in the RAVR and top of the
ventricular septum (VS). c, At a more caudal level to a,
HNK-1 staining around the orifice of the CS and in the right venous
valve (RVV), in the RAVR and His bundle (HIS). d, The medioposterior
part of the RAVR forms a HNK-1–positive node-like structure.
Magnification x18. AVC indicates atrioventricular
cushion; LA, left atrium; LV, left ventricle; N, nerve; PAVN, posterior
atrioventricular node; RA, right atrium; and RV, right
ventricle.
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Stage 19 to 20 (47 to 51 Days, CR Lengths 17,19, and 21
mm, Respectively)
At these stages, the ventricular septation is well
advanced. The sinus venosus has become further incorporated into the
right atrium. By now, the septum spurium is less marked, but the left
venous valve is still a large structure. The 3 embryos that have been
studied have similar HNK-1 staining patterns.
The RAVR remains HNK-1–positive and is continuous anteriorly with an HNK-1 band of myocardium behind the aorta, the so-called retroaortic ring. The distance between the medioanterior and the medioposterior node–like parts of the RAVR has become much smaller. The latter remains connected with the His bundle and bundle branches, and the medioanterior part is continuous with the retroaortic ring.
The SAN forms a semicircular HNK-1–positive structure in front of the
superior caval vein. The same 3 HNK-1–positive myocardial bands
connected to this area can be easily recognized. The anterior tract
through the septum spurium is still continuous with the medioanterior
RAVR, thus connecting the SAN with the primitive
atrioventricular conduction tissue. The second HNK-1
band remains present in the base of the right venous valve (around
the coronary sinus to the base of the atrial septum) and
surrounds the orifice of the inferior caval vein. The third
band of HNK-1–positive myocardium leaving the SAN is
present in the left venous valve and continues in the base of the
atrial septum. These 2 posterior HNK-1–positive bands are adjacent but
not connected to the posterior RAVR and His bundle. HNK-1 staining
around the common pulmonary vein is still in continuity with
the HNK-1–positive myocardium of the sinus venosus in the
right atrium through the base of the atrial septum (Figures 3 and 4).
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Stage 22 (54 Days, CR Length 23 mm)
The ventricular septation is complete and the
atrioventricular insulation has progressed. The septum
spurium is difficult to recognize as a separate structure in the roof
of the right atrium. At this stage, the left venous valve is reduced in
size. HNK-1 is only faintly present in both bundle branches and His
bundle. The His bundle runs through the fibrous skeleton where it meets
the medioposterior node–like structure which consists of strongly
HNK-1–positive myocardial cells and which is still part of the
posterior RAVR. Also, the medioanterior part of the RAVR is still a
compact HNK-1–positive area. By now, the distance between these 2
node-like structures has become minute, although they have not fused.
The staining has disappeared in the left venous valve and around the
common pulmonary vein. The SAN, now located at the lateral
margin of the superior caval vein, is only faintly positive. The
anterior HNK-1 tract through the roof of the right atrium (septum
spurium) toward the medioanterior part of the RAVR is faint but still
present.
Importantly, the posterior HNK-1 band running from the SAN through the
right venous valve is connected to the medioposterior RAVR. Also, the
sinus septum and the base of the atrial septum are HNK-1–positive and
continuous within this same region (Figures 5 and 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In humans, as in other species, the development of the cardiac conduction system and the origin of its different elements remains a topic of controversy. Although the use of immunohistochemical markers for the conduction system such as neurofilament, nodal MHC, HNK-1 (Leu-7), GlN2, and others has resulted in new insights, none of these markers are specific for conduction systems only, which make the interpretation of these results difficult.4 5 6 7 8 9 10 11
With the so-called ring theory, Wenink14 and Anderson15 proposed that the cardiac conduction system was derived from 4 separate rings of specialized myocardium found between the primitive segments of the heart and partially disappearing during development. According to this theory, the sinoatrial node is derived from the sinoatrial ring, the AV node from the atrioventricular ring, and the His bundle and bundle branches from the interventricular ring. Later, Wessels et al4 demonstrated in human embryos, with the use of a neural tissue antigen (GlN2), that the so-called retroaortic ring, the right atrioventricular ring, the compact AV node, the His bundle, and bundle branches all originate from one ring between the primitive ventricles, the interventricular ring. The composition of the AV node and the role of the sinus venosus in the development of the cardiac conduction system remains undescribed.
In human embryonic hearts, and presumably in those of other species, the GlN2 antigen expression seems identical to the HNK-1 expression with regard to the developing atrioventricular conduction system.4 5 6 7 8 Transient HNK-1 expression is also present in sinus venosus myocardium of birds and mammals (including humans).5 7 8 9 16 Many studies have been published that use HNK-1 (Leu-7) as a marker of the developing cardiac conduction system in rat embryos. They mention 3 tracts of HNK-1–positive myocardial cells that connect the HNK-1–positive sinoatrial node with 2 atrioventricular node primordia that fuse later on.5 7 8 In our department, DeRuiter et al16 demonstrated that the entire sinus venosus, as well as the orifice of the common pulmonary vein, expressed the HNK-1 antigen in chicken embryos at early stages.
In the present study on human embryos, we demonstrate that the HNK-1 antigen is transiently expressed in parts of the myocardium of the sinus venosus and around the common pulmonary vein, whereas the myocardium of both atria and septum primum remain HNK-1 negative. Surprisingly, we identified, in the youngest embryo, an anterior HNK-1 tract that runs anteriorly through the roof of the right atrium in the septum spurium; this tract was found between the sinoatrial node and the medioanterior part of the right atrioventricular ring. At a later stage, the sinoatrial node and medioposterior part of the right atrioventricular ring show connections of HNK-1–positive myocardial bands, in the base of the right venous valve and sinus septum, running laterally and medially to the coronary sinus. These posterior connections seem to be the result of the incorporation of the sinus venosus into the atrium and the invagination of the sulcus tissue.
In addition, transient HNK-1 staining appeared present in the myocardium around the orifice of the common pulmonary vein. The HNK-1–positive right atrioventricular ring forms medioanteriorly and medioposteriorly 2 node-like structures that approach each other but remain separated at the stages examined. The medioposterior part, forming a large node, is in continuity with the His bundle and bundle branches at all stages examined, and the medioanterior part is continuous with the retroaortic ring. We have not been able to confirm fusion of these areas as reported by Aoyama,8 and there are studies that demonstrate that the anterior "primordium" always remains separated from the posterior node and His bundle by fibrous tissue.4 17
The function of the HNK-1 antigen has not been clear up to now. What the known glycoproteins carrying this epitope have in common is that they all play a role in cell-cell or cell-substrate interaction.9 13 Although HNK-1 is present in all parts of the developing conduction system, including the sinoatrial node, it is difficult to appoint a functional role to the HNK-1–positive sinus venosus myocardium. Experiments in chicken embryos have demonstrated that the sinus venosus segment is electrophysiologically distinct from the embryonic atrial myocardium at early stages of development.18 This seems to correspond to the transient HNK-1 staining of the entire sinus venosus myocardium in chicken embryos at these stages.16
In the present study on human embryos, we show that HNK-1 staining is present in parts of the sinus venosus myocardium. In the postnatal heart, the crista terminalis, the myocardium medial and lateral to the coronary sinus, and the junction of the medial wall of the right atrial appendage (septum spurium) correspond to the HNK-1–positive parts in the right embryonic atrium. Electrophysiological studies and radiofrequency ablations have shown that abnormal right atrial automaticity in children and adults with structurally normal hearts cluster along the crista terminalis, around the coronary sinus, or near the right atrial appendage,1 2 3 corresponding to the areas of transient HNK-1 expression. Although the right atrial appendage develops from the embryonic atrial segment (HNK-1 negative), we speculate that the automatic foci often reported at the junction of the right atrial appendage could relate to the HNK-1–positive septum spurium.
In the normally developed heart, the relevance of the embryonic presence of HNK-1–positive connections between the developing sinoatrial node and the atrioventricular conduction tissue is unknown. The tracts are very similar to the HNK-1–positive internodal connections as reported in rat embryos;5 7 8 they also resemble the tracts of pale myocytes in human fetal hearts as described by Gittenberger-de Groot and Wenink,19 suggesting the fetal presence of cells from the sinoatrial ring. The distal parts of these HNK-1 bands also seem to correspond with the localization of 3 atrionodal bundles that converge and become continuous with the atrioventricular node as described in dogs.20 However, these bundles end in the atrial myocardium and do not connect the 2 nodes. From the present study, we cannot decide the debate on the presence or absence of specialized "internodal tracts." In the human heart, 3 internodal tracts have been proposed by Sherf and James21 : one posterior pathway running along the crista terminalis and the middle and anterior pathway, along the posterior and anterior aspect of the atrial septum. One of the described pathways, the posterior, corresponds exactly to our HNK-1 tract through the right venous valve. The other two HNK-1–positive tracts have a slightly different position as compared to those described by Sherf and James.21 Other authors have not been able to demonstrate discrete tracts of specialized myocytes between the nodes.22 23 Furthermore, it is generally agreed that the lack of insulation of these internodal pathways from the surrounding myocardium is an important histological criterion against the existence of true specialized internodal conduction tracts.24 25
Another important finding is the HNK-1 staining around the orifice of the common pulmonary vein, which is continuous with the positive myocardium of the sinus venosus through the base of the atrial septum. Although the staining pattern suggests that this HNK-1–positive myocardium originates from the same segment of the heart, younger embryos are required to demonstrate this. Different theories exist on the development of the pulmonary vein in different species. Questions remain as to whether the common pulmonary vein originates from the sinus venosus segment of the heart16 26 or if it is always discrete from the sinus venosus.27 28 The present study cannot bring a resolution to this controversy. The myocardium that encloses the pulmonary vein is of special interest in abnormal atrial automaticity. In adult rats, node-like cells have been described in this region29 ; and in experiments with guinea pigs, Cheung30 demonstrated pacemaker activity of the myocardium of the pulmonary vein propagating action potentials to the right atrium. Furthermore, Gorza et al,10 11 described this same area around the pulmonary vein with the use of nodal myosin heavy chain expression in bovine embryos and anti-neurofilament antibodies in rabbit embryos as markers of conduction tissue.
Electrophysiological studies and radiofrequency ablations in young patients with ectopic atrial tachycardia have shown that the foci are located mostly around the orifices of the pulmonary veins,1 and recently it has been reported that arrhythmogenic foci around or even inside the pulmonary veins sometimes play a role in atrial fibrillation.31 As in the right atrium, abnormal atrial automaticity in the left atrium corresponds to the transient HNK-1 antigen expression of the embryonic myocardium around the common pulmonary vein, as shown in our study.
We have demonstrated that during normal cardiac development, specific areas of embryonic myocardium with an early phenotypic differentiation might provide the foci of abnormal atrial automaticity, as seen in patients without structural heart disease.
Received May 4, 1998; revision received October 14, 1998; accepted October 26, 1998.
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A. T. Soufan, M. J.B. van den Hoff, J. M. Ruijter, P. A.J. de Boer, J. Hagoort, S. Webb, R. H. Anderson, and A. F.M. Moorman Reconstruction of the Patterns of Gene Expression in the Developing Mouse Heart Reveals an Architectural Arrangement That Facilitates the Understanding of Atrial Malformations and Arrhythmias Circ. Res., December 10, 2004; 95(12): 1207 - 1215. [Abstract] [Full Text] [PDF]
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M. D. Gonzalez, L. J. Contreras, M. R.M. Jongbloed, J. Rivera, T. P. Donahue, A. B. Curtis, M. S. Bailey, J. B. Conti, G. I. Fishman, M. J. Schalij, et al. Left Atrial Tachycardia Originating From the Mitral Annulus-Aorta Junction Circulation, November 16, 2004; 110(20): 3187 - 3192. [Abstract] [Full Text] [PDF]
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 M. Haissaguerre, P. Sanders, M. Hocini, P. Jais, and J. Clementy Pulmonary veins in the substrate for atrial fibrillation: The "venous wave" hypothesis J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2290 - 2292. [Full Text] [PDF]
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 C.-C. Chou, S. Zhou, Y. Miyauchi, H.-N. Pak, Y. Okuyama, M. C. Fishbein, H. S. Karagueuzian, and P.-S. Chen Effects of procainamide on electrical activity in thoracic veins and atria in canine model of sustained atrial fibrillation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1936 - H1945. [Abstract] [Full Text] [PDF]
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J. A. Airey, G. Almeida-Porada, E. J. Colletti, C. D. Porada, J. Chamberlain, M. Movsesian, J. L. Sutko, and E. D. Zanjani Human Mesenchymal Stem Cells Form Purkinje Fibers in Fetal Sheep Heart Circulation, March 23, 2004; 109(11): 1401 - 1407. [Abstract] [Full Text] [PDF]
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 B. Ghaye, D. Szapiro, J.-N. Dacher, L.-M. Rodriguez, C. Timmermans, D. Devillers, and R. F. Dondelinger Percutaneous Ablation for Atrial Fibrillation: The Role of Cross-sectional Imaging RadioGraphics, October 1, 2003; 23(90001): S19 - 33. [Abstract] [Full Text] [PDF]
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H. Honjo, M. R. Boyett, R. Niwa, S. Inada, M. Yamamoto, K. Mitsui, T. Horiuchi, N. Shibata, K. Kamiya, and I. Kodama Pacing-Induced Spontaneous Activity in Myocardial Sleeves of Pulmonary Veins After Treatment With Ryanodine Circulation, April 15, 2003; 107(14): 1937 - 1943. [Abstract] [Full Text] [PDF]
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 H. Kubota, S. Takamoto, T. Morota, T. Ohtsuka, N. Motomura, Y. Kotsuka, and K. Sudo Epicardial pulmonary vein isolation by cryoablation as concomitant cardiac operation to treat nonvalvular atrial fibrillation Ann. Thorac. Surg., February 1, 2003; 75(2): 590 - 593. [Abstract] [Full Text] [PDF]
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T. Arentz, P. Ott, J. von Rosenthal, T. Blum, and D. Kalusche Effect of atrial overdrive pacing on pulmonary vein focal discharge in patients with atrial fibrillation Europace, January 1, 2003; 5(1): 25 - 31. [Abstract] [PDF]
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S. Verheule, E. E Wilson, R. Arora, S. K Engle, L. R Scott, and J. E Olgin Tissue structure and connexin expression of canine pulmonary veins Cardiovasc Res, September 1, 2002; 55(4): 727 - 738. [Abstract] [Full Text] [PDF]
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J. M.T. de Bakker, S. Y. Ho, and M. Hocini Basic and clinical electrophysiology of pulmonary vein ectopy Cardiovasc Res, May 1, 2002; 54(2): 287 - 294. [Abstract] [Full Text] [PDF]
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Y.-J. Chen, S.-A. Chen, Y.-C. Chen, H.-I Yeh, P. Chan, M.-S. Chang, and C.-I Lin Effects of Rapid Atrial Pacing on the Arrhythmogenic Activity of Single Cardiomyocytes From Pulmonary Veins: Implication in Initiation of Atrial Fibrillation Circulation, December 4, 2001; 104(23): 2849 - 2854. [Abstract] [Full Text] [PDF]
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U. Bartram, D. G. M. Molin, L. J. Wisse, A. Mohamad, L. P. Sanford, T. Doetschman, C. P. Speer, R. E. Poelmann, and A. C. Gittenberger-de Groot Double-Outlet Right Ventricle and Overriding Tricuspid Valve Reflect Disturbances of Looping, Myocardialization, Endocardial Cushion Differentiation, and Apoptosis in TGF-{beta}2-Knockout Mice Circulation, June 5, 2001; 103(22): 2745 - 2752. [Abstract] [Full Text] [PDF]
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M. M. Scheinman and F. Morady Nonpharmacological Approaches to Atrial Fibrillation Circulation, April 24, 2001; 103(16): 2120 - 2125. [Abstract] [Full Text] [PDF]
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H. J. J. Wellens Pulmonary Vein Ablation in Atrial Fibrillation : Hype or Hope? Circulation, November 21, 2000; 102(21): 2562 - 2564. [Full Text] [PDF]
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Y.-J. Chen, S.-A. Chen, M.-S. Chang, and C.-I Lin Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation Cardiovasc Res, November 1, 2000; 48(2): 265 - 273. [Abstract] [Full Text] [PDF]
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S.A. Chen, C.T. Tai, M.H. Hsieh, C.F. Tsai, Y.A. Ding, and M.S. Chang Radiofrequency catheter ablation of atrial fibrillation initiated by spontaneous ectopic beats Europace, January 1, 2000; 2(2): 99 - 105. [Abstract] [PDF]
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