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PubMed1986

Steady-state modelling of metabolic pathways: a guide for the prospective simulator.

Steady-state modelling and control analysis by means of computer simulation provides valuable insight into the behavior of metabolic pathways. This review, which is aimed at the newcomer to this field, discusses the objectives of steady-state modelling and the steady-state properties of the four basic metabolic structures, namely linear and branched chains, loops and cycles. It is shown how the model definition in terms of stoichiometric reactions and rate equations leads to a set of balance equations from which the conservation constraints and flux relationships can be deduced, either informally or through a rigorous analysis of the stoichiometric matrix. The initial analysis of a steady-state metabolic model is summarized in an algorithm. Key references to the literature on metabolic modelling are given.

Computer Simulation↗

PubMed1997

Pulse radiolysis studies of intramolecular electron transfer in model peptides and proteins. 7. Trp-->TyrO radical transformation in hen egg-white lysozyme. Effects of pH, temperature, Trp62 oxidation and inhibitor binding.

Intramolecular long-range electron transfer (LRET) in hen egg-white lysozyme (HEWL) accompanying Trp-->TyrO radical transformation was investigated in aqueous solution by pulse radiolysis as a function of pH (5.2-7.4) and temperature (283-328 K). The reaction was induced by highly selective oxidation of Trp with N3 radicals under low concentration of the reactants but at a high HEWL/N3 molar ratio, so that more than 99% of the oxidized protein molecules contained only a single tryptophyl radical. Synchronous decay of Trp and build-up of TyrO conformed satisfactorily to first-order kinetics, indicating that LRET involved either one or more Trp./Tyr redox pairs characterized by similar rate constants. The rate constant of LRET, k5, increased monotonously with decreasing pH showing the following characteristics: (i) in the pH range 7.4-5.2 the plot of k5 against pH was sigmoidal in shape, reflecting protonation of Glu35 (pKa approximately 6) and pointing to involvement of conformational control of the kinetics of LRET, (ii) below pH 5.2 a sharp increase in k5 was observed due to the protonation of Trp to form TrpH.+, which is known to oxidize tyrosine faster than does Trp.. Arrhenius plots of the temperature-dependence of k5 showed that the activation energy of LRET varies both with temperature and the protonation state of the enzyme. The activation energies are in the range 7.6-56.0 kJ mol-1, and are similar to those for activation of amide hydrogen exchange in native HEWL below its denaturation temperature. Selective oxidation by ozone of the Trp62 indole side-chain in HEWL to N'-formylkynurenine (NFKyn62-HEWL) caused a large drop in the initial yield of Trp. radicals, G(Trp.)i. This was accompanied by a relatively small decrease in k5 but selective oxidation by ozone had a pronounced effect on its temperature-dependence. Taken together these observations indicate that of the six tryptophans present in HEWL Trp62 contributes about 50% to the yield of the observed LRET. In the enzyme-inhibitor complex, HEWL(GlcNAc)3, where Trp62 and Trp63 are completely shielded from the solvent by the bound triacetylchitotriose, G(Trp.)i was lower than in NFKyn62-HEWL, and both the kinetic and energetic characteristics of LRET, observed at pH 5.2, were again somewhat different than in HEWL alone. Considering known solvent accessibilities of tryptophans in the complex, the observed LRET process in HEWL(GlcNAc)3 was assigned to Trp123. Theoretical evaluation of the electronic coupling for the dominant LRET pathways between all the potential Trp/Tyr redox couples in HEWL, with help of the PATHWAYS model, enabled Trp623/Tyr53, Trp63/Tyr53 and Trp123/Tyr23 to be identified as the pairs involved in the experimentally observed electron transfer.

Animals↗

PubMed2000

Molecular quantification of cell cycle-related gene expression at the protein level.

BACKGROUND: Immunofluorescence cytometry of antigen and DNA content provides relative measurements of the cell cycle phase distribution of a specific epitope. Measurement of correlated expression of epitopes on signaling and regulatory proteins will be useful in the study of the complex pathways involved in cell cycle regulation and carcinogenesis. However, to formulate regulatory pathway models, measurements of molecules per cell would be more useful than relative measurements of intensity. Here, we report on a system in which the relationship between molecules and fluorescence is determined for a reference set of cell lines that are then used to directly calculate the number of molecules for unknowns. To demonstrate the process, we calculated the cell cycle phase distribution of SV40 large T antigen (Tag) in the reference cells. METHODS: A set of cell line clones expressing different levels of Tag were isolated. Quantitative Western blots of these cells and purified, recombinant Tag were performed. Cells from the same sample were stained and analyzed by flow cytometry for Tag and DNA. The relationship between molecules and fluorescence was established and calculations were performed for the phase distributions of Tag. RESULTS: The five cell lines had 0.11, 0.27, 1.06, 2.44, and 2.63 x 10(6) molecules of Tag per cell, determined by Western blot. The average coefficient of variation was 10.6%. The relationship of molecules to fluorescence fit a linear equation (r(2) = 0.96) over the range, 0.11 - 2.63 x 10(6) molecules, however, the same equation did not fit the relationship between 0 molecules, defined by isotype staining controls, and the lowest expressing cell line. To calculate the phase distributions of molecules in the lowest cell line, a second linear equation from 0 to 110,000 molecules was used. CONCLUSIONS: This work describes a system where fixed cells expressing various levels of a target antigen quantified by Western blots can be used to standardize flow cytometric measurements of gene expression in absolute terms.

Animals↗

PubMed1990

Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy.

In the present study the antepartum relationship between maternal diabetic glucose control and fetal hypoxaemia was examined in 44 Type 1 (insulin-dependent) diabetic and 23 non-diabetic control pregnancies. Maternal HbA1C was used to assess maternal integrated blood glucose control while fetal metabolic control was evaluated by antepartum glucose, insulin, and C-peptide determinations in amniotic fluid at elective caesarean delivery. Fetal hypoxaemia was assessed indirectly by fetal umbilical vein plasma erythropoietin level at delivery. A prospectively developed statistical pathway model was used to examine the relationship of these variables. In applying forced stepwise multiple regression with this model, we observed in the diabetic subjects that mean maternal HbA1C during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery (r = 0.57, p less than 0.001). Additional significant contributions to umbilical venous erythropoietin were found for amniotic fluid glucose and amniotic fluid insulin when these two independent variables were added in stepwise fashion (p less than 0.01). We conclude that in diabetic pregnancy, antepartum control of maternal hyperglycaemia is a significant factor associated with fetal hypoxaemia. We speculate that this effect is mediated through perturbations which accelerate fetal metabolism and which is expressed by amniotic fluid levels of glucose and insulin.

Amniotic Fluid↗

PubMed2000

Voluntary modification of automatic arm movements evoked by motion of a visual target.

We have investigated whether the processes underlying the visually evoked, automatic adjustments to a reach are: (1) modifiable by the subject's intention, and (2) available to initiate movement of a stationary arm. Unpredictable movement of a target (80 m/s through 10 cm, left or right in a third of trials) either evoked a mid-flight adjustment of a reaching movement or else acted as a trigger to start an arm movement. Subjects were instructed to respond as rapidly as possible by moving their finger either in the same or in the opposite direction to the target. The target shift evoked an early (125-160 ms) and/or a later (> 160 ms) class of response in the reaching arm. The early response was highly automatic in that it could not be reversed (move opposite) by the subjects' intention. However, the subjects' intention did influence the frequency of occurrence and the size of this early response. The later response was totally modifiable in that it changed direction according to the subjects' intention. Similar classes of response were observed in stationary limbs, but the early, more automatic response was substantially weaker than that elicited during a reach. Two possible mechanisms are proposed to explain these results. The first is a dual-pathway model, which assumes that the two response classes are each generated by separate visuo-motor processes with different properties. The second model assumes both responses are generated by a single visuo-motor mechanism that is under the control of a higher, attentional process.

Adult↗

PubMed1999

Effects of protein-protein interactions on electron transfer: docking and electron transfer calculations for complexes between flavodoxin and c-type cytochromes.

Theoretical studies of protein-protein association and electron transfer were performed on the binary systems formed by Desulfovibrio vulgaris Hildenborough (D. v. H.) flavodoxin and D. v. H. cytochrome c553 and by flavodoxin and horse heart cytochrome c. Initial structures for the complexes were obtained by rigid-body docking and were refined by MD to allow for molecular flexibility. The structures thus obtained were analysed in terms of their relative stability through the calculation of excess energies. Electrostatic, van der Waals and solvation energy terms showed all to have significant contributions to the stability of complexes. In the best association solutions found for both cytochromes, these bind to different zones of flavodoxin. The binding site of flavodoxin observed for cytochrome c is in accordance with earlier works [27]. The various association modes found were characterised in terms of electron transfer using the Pathways model. For complexes between flavodoxin and horse heart cytochrome c, some correlation was observed between electron tunnelling coupling factors and conformation energy; the best conformation found for electron transfer corresponded also to the best one in terms of energy. For complexes between flavodoxin and cytochrome c553 this was not the case and a lower correlation was observed between electron tunnelling coupling factors and excess energies. These results are in accordance with the differences in the experimental dependence of electron transfer rates with ionic strength observed between these two cases.

Cytochrome c Group↗

PubMed2002

[Opportunities and chances for tissue chip microarrays in head and neck surgery. A novel technique for the rapid evaluation of potentially novel biomarkers].

Oral squamous cell carcinomas (OSCC) are malignant tumors with a poor prognosis and low long-term survival rates, even when using modern adjuvant and neoadjuvant therapy forms in addition to surgery. For the clinical estimation of each tumor, it is necessary to define stage-dependent molecular and/or cellular parameters as it is known that OSCC develop along a multistep pathway including the loss of tumor suppressor genes and the amplification of oncogenes which result in changes in protein expression. In order to establish a reliable pattern of molecular and cellular biomarkers, a large number of tumor specimens from different stages of the disease need to be analysed. In this study, biopsies of a collective of 293 OSCC in different stages were screened with the novel technique of tissue chip microarrays by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). FISH-analysis was performed on the oncogene cyclin D1 and IHC-analysis on the proteins cyclin D1, p53, p16, cdk4, bcl2, mdm2 and rb. Tissue chip technology was shown to facilitate rapid screening for molecular and cellular alterations in different stages of OSCC and revealed reliable and reproducible results that may allow the definition of a multistep pathway model for tumor progression in OSCC.

Aged↗

PubMed2005

Continuity and change in preschool ADHD symptoms: longitudinal genetic analysis with contrast effects.

The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78-0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.

Attention Deficit Disorder with Hyperactivity↗

PubMed1987

Electrophysiology of L-lysine entry across the brush-border membrane of Necturus intestine.

Microelectrode measurements of apical membrane potentials (Va) in absorptive cells of isolated Necturus intestine showed that, in the presence or absence of external Na+, 10 mM lysine added to the mucosal medium caused rapid depolarization followed by slower repolarization of Va. In Na+-free media the effects of 10 mM lysine on Va were abolished by 10 mM leucine which alone had no effect on Va under these conditions. This indicates that uncoupled electrodiffusion of lysine plays little or no role in lysine entry across the brush-border membrane. When external Na+ was greater than 10 mM the maximum depolarization of Va (delta Va') induced by [Lys] ranging from 5 to 30 mM was a simple saturable function of [Lys]. In Na+-free media, the relationship between delta Va' and [Lys] was biphasic. At first, delta Va' increased with increasing [Lys] reaching a maximum at 10 mM lysine. When [Lys] was further increased, delta Va' declined progressively to reach zero or near zero values. A single transport pathway model is proposed to account for rheogenic lysine entry across the brush-border membrane in the presence and absence of Na+. This postulates an amino acid transporter in the membrane with two binding sites. One is an amino acid site specific for the alpha-amino-alpha-carboxyl group. The other is a Na+ site. Neutral amino acids (e.g. leucine) compete with lysine for the amino acid site. The Na+ site has some affinity for the epsilon-amino group of lysine. When external Na+ is high the Na+ site is essentially 'saturated' with Na+ and formation of a mobile complex between an amino acid and the transporter depends in a saturable fashion on amino acid concentration. In Na+-free media or in media containing low [Na+]; at low external [Lys] the epsilon-amino group of a lysine molecule (simultaneously attached to the amino acid site) interacts with the Na+ site to form a mobile complex, as external [Lys] is increased, attachment of different lysine molecules to each site of an increasing number of transporters to form nontransported or poorly transported complexes results in substrate inhibition of the rheogenic lysine transport process.

Amino Acids↗

PubMed1987

Temporal integration in human vision and the opponent-color systems.

The present study demonstrated that the temporal integration time (t.i.t.) could be prolonged even if the background energy was increased, provided that the background consisted of the colors opponent to each other. This was found, more or less, irrespective of the test stimulus size. These results suggest that the t.i.t. is not determined solely at receptor sites in the visual system, but that the chromatically-opponent systems are heavily involved. Mechanisms based upon a two-sites adaptation with one detection pathway model were briefly discussed.

Adaptation, Ocular↗

PubMed1994

Reserpine increases Fos activity in the rat basal ganglia via a quinpirole-sensitive mechanism.

Expression of the immediate early gene c-fos increases acutely following neuronal depolarization. c-fos and Fos protein have been widely used to investigate basal ganglia responses to changes in dopaminergic neurotransmission. Increased dopaminergic input to D1 receptors increases Fos synthesis in striatal neurons. The role of D2 receptors in regulating Fos activity has been more difficult to establish. Because dopamine is believed to excite striatal neurons via D1 receptors and inhibit them via D2 receptors, we hypothesized that acute dopamine depletion would increase Fos activity in basal ganglia circuits normally inhibited by dopaminergic input to D2 receptors. Rats were perfused after a single dose of the dopamine-depleting drug reserpine. The brains of rats perfused 3 h after reserpine displayed numerous Fos-like immunoreactive nuclei in the striatum, entopeduncular nucleus, nucleus accumbens shell, and ventral pallidum, and sparse Fos-like immunoreactive nuclei in the globus pallidus and nucleus accumbens core. Few or no Fos-like immunoreactive nuclei were seen following perfusion 30 min, 60 min, and 24 h after reserpine. In the 3-h paradigm, pretreatment with the selective D1 antagonist SCH 23390 did not change the pattern of Fos-like immunoreactivity; pretreatment with the selective D2 agonist quinpirole completely blocked increased Fos synthesis. Acute dopamine depletion, therefore, increases Fos activity in the basal ganglia by disinhibiting D2 circuits. These results support the parallel pathway model of basal ganglia function, and show that Fos can be used to investigate the role of D2 receptors in striatal function. The findings suggest anatomic correlates for the clinical effects of acute dopamine depletion in drug therapy and advanced Parkinson's disease in humans.

Animals↗

PubMed1995

Enzymes and binding proteins affecting retinoic acid concentrations.

Free retinoids suffer promiscuous metabolism in vitro. Diverse enzymes are expressed in several subcellular fractions that are capable of converting free retinol (retinol not sequestered with specific binding proteins) into retinal or retinoic acid. If this were to occur in vivo, regulating the temporal-spatial concentrations of functionally-active retinoids, such as RA (retinoic acid), would be enigmatic. In vivo, however, retinoids occur bound to high-affinity, high-specificity binding proteins, including cellular retinol-binding protein, type I (CRBP) and cellular retinoic acid-binding protein, type I (CRABP). These binding proteins, members of the superfamily of lipid binding proteins, are expressed in concentrations that exceed those of their ligands. Considerable data favor a model pathway of RA biosynthesis and metabolism consisting of enzymes that recognize CRBP (apo and holo) and holo-CRABP as substrates and/or affecters of activity. This would restrict retinoid access to enzymes that recognize the appropriate binding protein, imparting specificity to RA homeostasis; preventing, e.g. opportunistic RA synthesis by alcohol dehydrogenases with broad substrate tolerances. An NADP-dependent microsomal retinol dehydrogenase (RDH) catalyzes the first reaction in this pathway. RDH recognizes CRBP as substrate by the dual criteria of enzyme kinetics and chemical crosslinking. A cDNA of RDH has been cloned, expressed and characterized as a short-chain alcohol dehydrogenase. Retinal generated in microsomes from holo-CRBP by RDH supports cytosolic RA synthesis by an NAD-dependent retinal dehydrogenase (RalDH). RalDH has been purified, characterized with respect to substrate specificity, and its cDNA has been cloned. CRABP is also important to modulating the steady-state concentrations of RA, through sequestering RA and facilitating its metabolism, because the complex CRABP/RA acts as a low Km substrate.

Animals↗

PubMed1995

Transuranics in bone of deceased former residents of Rongelap Atoll, Marshall Islands.

Rongelap Atoll received intensive fallout from the 1 March 1954 Bravo thermonuclear test 105 miles upwind at Bikini. Fearful of their continued exposure to radiation, the residents of Rongelap Atoll went into voluntary exile in 1985. Transuranic soil concentrations on Rongelap Island are about 2-3 orders of magnitude greater than the average for the Northern hemisphere; the three dominating transuranics are 239,240Pu and 241Am. Only conflicting information has been available about the extent of transuranic uptake by the Rongelap community. As part of the Rongelap Resettlement Project, the community endorsed the exhumation of bones of deceased former atoll residents to provide an independent estimate of plutonium intake. This approach has the advantage of reducing the uncertainties associated with pathway modeling and the interpretation of urine data. Six graves (4 adults, 2 children) were selected for exhumation. Femora and tibiae were selected as well as humeri from the children's graves. The rest of the remains was left undisturbed. The results of the analysis of 239,240Pu and 241Am are presented. Assuming that the data can be considered as representative for the Rongelap population as a whole, the contamination with transuranics on Rongelap Atoll appears to result in radiation exposures in the order of 1% of the compliance limit of 100 mrem (1 mSv) effective dose equivalent per year.

Adult↗

PubMed2005

Roles of double-strand breaks, nicks, and gaps in stimulating deletions of CTG.CAG repeats by intramolecular DNA repair.

A series of plasmids harboring CTG.CAG repeats with double-strand breaks (DSB), single-strand nicks, or single-strand gaps (15 or 30 nucleotides) within the repeat regions were used to determine their capacity to induce genetic instabilities. These plasmids were introduced into Escherichia coli in the presence of a second plasmid containing a sequence that could support homologous recombination repair between the two plasmids. The transfer of a point mutation from the second to the first plasmid was used to monitor homologous recombination (gene conversion). Only DSBs increased the overall genetic instability. This instability took place by intramolecular repair, which was not dependent on RuvA. Double-strand break-induced instabilities were partially stabilized by a mutation in recF. Gaps of 30 nt formed a distinct 30 nt deletion product, whereas single strand nicks and gaps of 15 nt did not induce expansions or deletions. Formation of this deletion product required the CTG.CAG repeats to be present in the single-stranded region and was stimulated by E.coli DNA ligase, but was not dependent upon the RecFOR pathway. Models are presented to explain the intramolecular repair-induced instabilities and the formation of the 30 nt deletion product.

Base Sequence↗

PubMed2006

The processing of prosody: Evidence of interhemispheric specialization at the age of four.

Beyond its multiple functions in language comprehension and emotional shaping, prosodic cues play a pivotal role for the infant's amazingly rapid acquisition of language. However, cortical correlates of prosodic processing are largely controversial, even in adults, and functional imaging data in children are sparse. We here use an approach which allows to experimentally determine brain activations correlating to the perception and processing of sentence prosody during childhood. In 4-year-olds, we measured focal brain activation using near-infrared spectroscopy and demonstrate that processing prosody in isolation elicits a larger right fronto-temporal activation whereas a larger left hemispheric activation is elicited by the perception of normal language with full linguistic content. Hypothesized by the dual-pathway-model, the present data provide experimental evidence that in children specific language processes rely on interhemispheric specialization with a left hemispheric dominance for processing segmental (i.e. phonological) and a right hemispheric dominance for processing suprasegmental (i.e. prosodic) information. Generally in accordance with the imaging data reported in adults, our finding underlines the notion that interhemispheric specialization is a continuous process during the development of language.

Brain↗

PubMed2005

In vivo drug-response in patients with leukemic non-Hodgkin's lymphomas is associated with in vitro chemosensitivity and gene expression profiling.

Only a few approaches are available to address the mechanisms of cell death in vivo which are induced by anticancer treatment in patients with malignancies. In this study in vitro chemosensitivity testing of primary peripheral blood leukemic cells of five patients suffering from different leukemic non-Hodgkin's lymphomas was combined with the analysis of the in vivo rate of apoptosis by flow-cytometry (Annexin V and depolarisation of mitochondrial membrane potential (MMP) by JC-1). Furthermore, changes in expression patterns of apoptosis related proteins during chemotherapeutic treatment were detected by Western Blot. Gene expression profiling (HG-U133A, Affymetrix, Santa Clara, CA) was employed to identify common marker genes of in vivo drug response. In vitro chemosensitivity was tested using the cytotoxic agents which the patients were scheduled to receive and was strongly correlated with effective reduction of leukemic lymphoma cells in patients resulting in complete remissions in all five cases. Due to the rapid clearance of apoptotic tumor cells in vivo neither the analysis of the in vivo rate of apoptosis and depolarisation of MMP nor the assessment of expression of regulators of apoptosis showed concordant results concerning the drug response. However, assessment of gene expression during therapy could identify a set of 30 genes to significantly discriminate between samples from patients before treatment compared to samples from the same patients after receiving cytotoxic therapy. Among these 30 genes we found a high proportion of genes associated with apoptotic cell death, cell proliferation and cell cycle signalling including complement lysis inhibitor (clusterin/CLU), beta-catenin interacting protein (ICAT), peroxisome proliferator activated receptor alpha (PPARalpha), TNF alpha converting enzyme (ADAM17/TACE), homeo box A3 (HOX1), inositol polyphosphatase 5-phosphatase type IV (PPI5PIV) and inhibitor of p53 induced apoptosis alpha (IPIA-Alpha/NM23-H6). These results indicate that in vitro chemosensitivity testing and gene expression profiling can successfully be utilised to analyse in vivo drug response in patients with leukemic NHL's and can be used to explore new pathway models of drug-induced cell death in vivo which are independent of different lymphoma subtypes and different treatment regimens.

Adenosine↗

PubMed2004

Life-course experiences and mortality by adult social class among young men.

Circumstances over the life-course may contribute to adult social class differences in mortality. However, it is only rarely that the life-course approach has been applied to mortality studies among young adults. The aim of this study is to determine to what extent social class differences in mortality among young Finnish men are explained by living conditions in the parental home and life paths related to transitions in youth. The data for males born in 1956-60 based on the 1990 census records are linked with death records (3184 deaths) by cause of death for 1991-98, and with information on life-course circumstances from the 1970, 1975, 1980, and 1985 censuses. Controlling for living conditions in the parental home-social class, family type, number of siblings, language and region of residence-reduced the high excess mortality of the lower non-manual (RR 1.51, 95% CI: 1.28-1.79), skilled manual (RR 2.94, 2.54-3.40), and unskilled manual class (RR 4.08, 3.51-4.73) by 10% in all-cause mortality. The equivalent reduction for cardiovascular disease was 28% and for alcohol-related causes 16%. The effect of parental home on mortality differences was mainly mediated through its effect on youth paths (pathway model). Educational, marital, and employment paths had a substantial effect-independent of parental home-on social class differences from various causes of death. When all these variables were controlled for adult social class differences in cause specific mortality were reduced by 75-86%. Most of this reduction in mortality differences can be attributed to educational path. However, marital and employment paths had their independent effects, particularly on the excess mortality of unskilled manual workers with disproportionately common exposure to long-term unemployment and living without a partner. In summary, social class differences in total mortality among men in their middle adulthood were only partly determined by parental home but they were mainly attributable to educational, marital, and employment paths in youth.

Adult↗

PubMed1997

Origin of junctional rhythm during radiofrequency ablation of atrioventricular nodal reentrant tachycardia in patients without structural heart disease.

Junctional rhythm is commonly observed during radiofrequency catheter ablation of the fast or slow pathways of atrioventricular nodal reentrant tachycardia (AVNRT). However, the origin of these beats remains unclear. We analyzed the retrograde atrial activation sequence of 16 patients (mean +/- SD: 41.2 +/- 18.9 years old) undergoing catheter ablation for typical AVNRT with detailed catheter mapping of the triangle of Koch. The earliest atrial activations were concordant during tachycardia and junctional rhythm in only 5 of 16 patients. The findings suggest that junctional rhythm is unlikely to represent direct stimulation of the atrioventricular (AV) node via a discrete slow pathway but rather results from enhanced automaticity from > or =1 sites in the AV nodal transitional zone. The ensuing atrial activation pattern results from anisotropic spread from these sites. In addition, these data imply that the original concept of the AV node comprising 2 anatomically defined pathways may not be valid, and that a functionally defined pathway model may be a more accurate representation.

Adolescent↗