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PubMed1975

Determinants of fast- and slow-pathway conduction in patients with dual atrioventricular nodal pathways.

Electrophysiological studies were performed in two patients with documented paroxysmal supraventricular tachycardia and dual atrioventricular (AV) nodal pathways as defined by the atrial extra-stimulus technique. Both patients manifested two ranges of A-H intervals (AV nodal conduction times) at critical cycle lengths, reflecting fast- and slow-pathway conduction. The occurrence of fast- and slow-pathway conduction at the same cycle length depended on a long fast-pathway effective refractory period relative to the spontaneous or driven cycle length. At critical cycle lengths with fast-pathway conduction, a shift to slow-pathway conduction could be induced by a premature atrial impulse falling within the effective refractory period of the fast pathway. Repetitive retrograde concealed conduction to the fast pathway then maintained antegrade slow-pathway conduction. Resumption of fast-pathway conduction was induced with premature atrial impulses falling within the effective refractory periods of both the fast and the slow pathways, allowing recovery of the fast pathway for antegrade conduction. Atrial echoes and AV nodal reentrant paroxysmal supraventricular tachycardia occurred when sufficient slow-pathway delay was achieved to allow recovery of the fast pathway for retrograde conduction.

Atrioventricular Node↗

PubMed1999

Lysis via the lectin pathway of complement activation: minireview and lectin pathway enhancement of endotoxin-initiated hemolysis.

Lysis via the newly discovered lectin pathway of complement activation is reviewed. Mannan-coated erythrocytes sensitized with MBL are lysed in human serum containing Mg-EGTA via the lectin pathway by a process which requires alternative pathway amplification. The inhibitory activities of C4bp and factor H, which are augmented in the presence of MBL, regulate this hemolysis. Lectin pathway activity is enhanced by IgG, which inhibits H activity, and is inhibited by C-reactive protein, which enhances the activity of H. Lectin pathway hemolysis in Mg-EGTA also is seen in other species, and is particularly intense and does not require alternative pathway amplification in the guinea pig. New investigations using E-RaLPS as the MBL-binding agent allowed comparison with classical pathway activation by rabbit anti-RaLPS using the same indicator cell. E-RaLPS-MBL are lysed in human serum-Mg-EGTA, and alternative pathway amplification is required. The addition of rabbit anti-E to E-RaLPS-MBL leads to significant enhancement of lysis in Mg-EGTA, much greater than Ig enhancement of hemolysis via the alternative pathway. Lectin pathway activation also enhances the antibody-independent C activation of the classical C pathway via C1q by ReLPS, as well as the direct activation of the alternative C pathway by wild type LPS. Thus, potentiation of reactions initiated at sites of IgG deposition and Ig-independent complement activation represents another characteristic of the lectin pathway.

Animals↗

PubMed1997

Safety of slow pathway ablation in patients with atrioventricular node reentrant tachycardia and a long fast pathway effective refractory period.

Radiofrequency catheter ablation is an accepted primary therapy for atrioventricular (AV) node reentrant tachycardia (AVNRT). There is concern that slow pathway ablation in patients with a long anterograde fast pathway effective refractory period (ERP) may potentially impair subsequent node conduction. Eighteen patients (14 women; age 53 +/- 20 years) with symptomatic AVNRT, whose fast pathway ERP at baseline was > or = 500 ms, underwent slow pathway ablation. Their outcome was compared with 24 consecutive control patients (17 women; age 42 +/- 17 years) who underwent ablation for AVNRT whose fast pathway ERP at baseline was <500 ms (controls). Slow pathway ablation was successful in 16 patients (90%). One patient had inadvertent fast pathway ablation. In a second patient the slow pathway could not be ablated because of recurrent transient AV block. Ablation was successful in all patients in the control group. Transient AV block related to current application occurred in 4 patients (22%) versus 1 control (4%) (p = 0.07). After ablation, the AV node refractory period increased in patients (368 +/- 68 to 428 +/- 92 ms, p = 0.02) and in controls (282 +/- 35 to 336 +/- 55 ms, p <0.0001), but the fast pathway ERP shortened in both groups (patients: 558 +/- 63 to 428 +/- 92 ms, p = 0.003; controls: 356 +/- 53 to 336 +/- 55 ms, p = 0.05). Furthermore, the slope of the regression line relating to shortening of the fast pathway ERP to the baseline ERP was markedly steeper in patients compared with controls (1.9 vs 0.4, p <0.0001). The shortening of the fast pathway ERP was greater in patients compared with controls (122 +/- 130 vs 21 +/- 50 ms, p = 0.001). During a mean follow-up of 18 +/- 11 months, 1 patient with severe coronary artery disease died suddenly 2 years after ablation. There was no recurrence of clinical tachycardia, and none of the patients developed symptoms of bradycardia or required permanent pacing. Thus, slow pathway ablation in patients with AVNRT and a long fast pathway ERP is safe and effective.

Adult↗

PubMed1985

Pseudosimultaneous fast and slow pathway conduction: a common electrophysiologic finding in patients with dual atrioventricular nodal pathways.

Two ventricular responses following termination of rapid atrial pacing were noted in 24 of 87 patients with dual atrioventricular (AV) nodal pathways and supraventricular tachycardia. In all 24 patients, the AH intervals of the first and second ventricular responses were comparable with those of the fast and slow pathways, respectively. Careful analysis of the whole pacing sequence revealed that, in 21 patients, this phenomenon resulted from sustained slow pathway conduction with long AH intervals. In these patients, as the AH interval of each paced beat was progressively lengthened during pacing, the corresponding His bundle and ventricular responses were pushed one cycle behind the current atrial paced beat, so that the last paced beat was followed by two His bundle and ventricular responses. In only three patients did double ventricular responses result from simultaneous fast and slow pathway conduction. One of these three patients also showed two ventricular responses resulting from sustained slow pathway conduction. Several factors predispose to the occurrence of this phenomenon in patients with dual AV nodal pathways. These include an ability to sustain slow pathway conduction, a longer slow pathway AH interval, a shorter sinus AH interval (fast pathway) and a shorter atrial paced cycle length that sustains slow pathway conduction. In conclusion, sustained slow pathway conduction with resultant long AH intervals is the mechanism of two ventricular responses following termination of atrial pacing in most patients with dual AV nodal pathways. This phenomenon should be distinguished from the rare occurrence of double ventricular responses to an atrial impulse due to simultaneous fast and slow pathway conduction.

Adolescent↗

PubMed1999

Production of 1alpha,25-dihydroxy-3-epi-vitamin D3 in two rat osteosarcoma cell lines (UMR 106 and ROS 17/2.8): existence of the C-3 epimerization pathway in ROS 17/2.8 cells in which the C-24 oxidation pathway is not expressed.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is metabolized into calcitroic acid through the carbon 24 (C-24) oxidation pathway. It is now well established that the C-24 oxidation pathway plays an important role in the target tissue inactivation of 1alpha,25(OH)2D3. Recently, we reported that 1alpha,25(OH)2D3 is also metabolized into 1alpha,25-dihydroxy-3-epi-vitamin D3 [1alpha,25(OH)2-3-epi-D3] through the carbon 3 (C-3) epimerization pathway in human keratinocytes, human colon carcinoma cells (Caco-2), and bovine parathyroid cells. In a previous study, it was demonstrated that 1alpha,25(OH)2-3-epi-D3 when compared to 1alpha,25(OH)2D3 was less active in stimulating intestinal calcium absorption, calcium mobilization from bone, and induction of calbindin D28k. These findings suggest that the C-3 epimerization pathway, like the C-24 oxidation pathway, may play a role in the target tissue inactivation of 1alpha,25(OH)2D3. In this study, we determined the relationship between the C-24 oxidation and the C-3 epimerization pathways by investigating the metabolism of 1alpha,25(OH)2D3 in two rat osteosarcoma cell lines (UMR 106 and ROS 17/2.8). These two cell lines differ from each other in their ability to metabolize 1alpha,25(OH)2D3 through the C-24 oxidation pathway. It has been previously reported that the C-24 oxidation pathway is expressed only in UMR 106 cells but not in ROS 17/2.8 cells. The results of our present study provide new evidence that both cell lines possess the ability to metabolize 1alpha,25(OH)2D3 into 1alpha,25(OH)2-3-epi-D3 through the C-3 epimerization pathway. Our results also reconfirm the findings of previous studies indicating that UMR 106 cells are the only ones which express the C-24 oxidation pathway out of the two cell lines studied. Furthermore, this study reveals for the first time that the C-3 epimerization pathway may become an alternate metabolic pathway for the target tissue inactivation of 1alpha,25(OH)2D3 in some cells, such as ROS 17/2.8, in which the C-24 oxidation pathway is not expressed.

Animals↗

PubMed2001

Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins.

BACKGROUND: Signal transduction pathways with shared components must be insulated from each other to avoid the inappropriate activation of multiple pathways by a single stimulus. Scaffold proteins are thought to contribute to this specificity by binding select substrates. RESULTS: We have studied the ability of scaffold proteins to influence signaling by the yeast kinase Ste11, a MAPKKK molecule that participates in three distinct MAP kinase pathways: mating, filamentation, and HOG. We used protein fusions to force Ste11 to associate preferentially with a subset of its possible binding partners in vivo, including Ste5, Ste7, and Pbs2. Signaling became confined to a particular pathway when Ste11 was covalently attached to these scaffolds or substrates. This pathway bias was conferred upon both stimulus-activated and constitutively active forms of Ste11. We also used membrane-targeted derivatives of the mating pathway scaffold, Ste5, to show that stimulus-independent signaling initiated by this scaffold remained pathway specific. Finally, we demonstrate that loss of pathway insulation has a negative physiological consequence, as nonspecific activation of both the HOG and mating pathways interfered with proper execution of the mating pathway. CONCLUSIONS: The signaling properties of these kinase fusions support a model in which scaffold proteins dictate substrate choice and promote pathway specificity by presenting preferred substrates in high local concentration. Furthermore, insulation is inherent to scaffold-mediated signaling and does not require that signaling be initiated by pathway-specific stimuli or activator proteins. Our results give insight into the mechanisms and physiological importance of pathway insulation and provide a foundation for the design of customized signaling proteins.

MAP Kinase Kinase Kinases↗

PubMed1980

Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convetase enzyme.

A factor, functionally characterized by its capacity to stabilize the normally labile classical pathway C3-converting complex of the classical pathway of complement, has been isolated from the serum of one patient with a case of acute glomerulonephritis, subsequent to a cutaneous infection. The factor confers long-lived stabilization of classical pathway C3 convertase complexes formed both in the solid (sensitized sheep erythrocytes bearing activated C1 and the classical pathway C3 convertase) and fluid phase. The half-life of such stabilized C3-cleaving enzymes extended beyond several hours at 37 degrees C. The stabilizing activity was associated with a protein fraction immunochemically identified as immunoglobulin (Ig)G, a sizeable population of which exhibited a gamma chain of 60,000 daltons. The IgG-associated stabilizing activity was found to bind to the classical pathway C3 convertase enzyme via a fragment bearing the antigen-binding site of the molecule [F(ab)(2) and F(ab)]. Such binding was demonstrable for classical pathway and not for alternative pathway C3 convertase. Thus, the stabilizing factor behaves like an autoantibody to the C3-converting complex of the classical pathway of complement. The binding of the antibody to the enzyme affords protection of the latter against decay-degradation. By analogy with the nephritic factor of the alternative pathway situation where IgG autoantibodies specifically bind to alternative pathway C3 convertase enzymes and protect them from degradation, the functionally unusual IgG in our patient was designated as the nephritic factor of the classical pathway. Indirect evidence suggests that nephritic factor of the classical pathway-IgG might be of the IgG3 subclass.

Adult↗

PubMed1993

Patterns of radiofrequency catheter ablation of left free-wall accessory pathways: implications for accessory pathway anatomy.

Despite the abundance of literature on the electrophysiology of accessory pathways, clinical data on their anatomic properties remain infrequent. The small and discrete nature of lesions generated by radiofrequency (RF) energy may allow better characterization of accessory pathway anatomy in the intact heart. RF catheter ablation was performed on 40 left free-wall accessory pathways in 39 consecutive patients with a unipolar endocardial approach. The patterns of accessory pathway ablation were identified. Spatial-electrophysiologic information provided by the ablation catheter at individual sites of RF application and corresponding data from the coronary sinus catheter were correlated with the effects of RF energy on accessory pathway conduction. Of 39 accessory pathways permanently (n = 37) or transiently (n = 2) ablated, 24 had "simple" ablation, with abolition of conduction by one individual RF application. In 15 of 24 pathways that could be crossed by the coronary sinus catheter, the concordance in anatomic and electrophysiologic information between the site of earliest retrograde atrial activation and the effective ablation position (ventricular approach) suggested a perpendicular fiber course. Fifteen pathways had "complex" ablations; of these, eight had spatial-electrophysiologic discordance between the atrial and ventricular insertions, suggesting an oblique fiber orientation. Seven pathways had modification or transient suppression of conduction, with or without subsequent abolition of conduction at identical or physically disparate (> 1 cm apart) sites; four pathways had sequential ablation of antegrade and retrograde conduction. These raised possibilities of broad fiber span and functional longitudinal dissociation of accessory pathway conduction. Accessory pathways with simple and complex ablations did not differ in clinical and electrophysiologic parameters. Complex ablations demanded more lengthy and difficult procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1999

Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway.

In addition to the CDP-choline pathway for phosphatidylcholine (PC) synthesis, the liver has a unique phosphatidylethanolamine (PE) methyltransferase activity for PC synthesis via three methylations of the ethanolamine moiety of PE. Previous studies indicate that the two pathways are functionally different and not interchangeable even though PC is the common product of both pathways. This study was designed to test the hypothesis that these two pathways produce different profiles of PC species. The PC species from these two pathways were labeled with specific stable isotope precursors, D9-choline and D4-ethanolamine, and analyzed by electrospray tandem mass spectrometry. Our studies revealed a profound distinction in PC profiles between the CDP-choline pathway and the PE methylation pathway. PC molecules produced from the CDP-choline pathway were mainly comprised of medium chain, saturated (e.g. 16:0/18:0) species. On the other hand, PC molecules from the PE methylation pathway were much more diverse and were comprised of significantly more long chain, polyunsaturated (e.g. 18:0/20:4) species. PC species from the methylation pathway contained a higher percentage of arachidonate and were more diverse than those from the CDP-choline pathway. This profound distinction of PC profiles may contribute to the different functions of these two pathways in the liver.

Animals↗

PubMed1994

Radiofrequency ablation of slow pathway in patients with atrioventricular nodal reentrant tachycardia. Do arrhythmia recurrences correlate with persistent slow pathway conduction or site of successful ablation?

BACKGROUND: Residual slow pathway conduction in the form of persistent jump in the atrioventricular (AV) conduction time or atrial echo beats is a common finding after successful radiofrequency (RF) ablation of the slow pathway in patients with AV nodal reentrant tachycardia (AVNRT). Sites of successful RF ablation of the slow pathway may be located anteriorly in the tricuspid annulus (cephalad to the coronary sinus os) or posteriorly (at, within, or caudal to the coronary sinus os). The aim of this study was to investigate whether arrhythmia recurrences correlate with persistent slow pathway conduction or site of successful ablation. METHODS AND RESULTS: Among 55 patients with symptomatic AVNRT having RF ablation, 23 patients (42%) (group 1) had evidence of persistent dual AV nodal pathway physiology and/or echo beats, whereas in 32 patients (group 2), slow pathway conduction had been completely eliminated. With regard to ablation sites, 14 patients (25%) (group A) had their slow pathway successfully ablated at an inferoposterior site, whereas in 41 patients (group B), the ablation site was located anteriorly to the coronary sinus os. The study patients included 17 men and 38 women, aged 37 +/- 18 years. The electrophysiological study and RF ablation were performed in a single session in 50 patients (91%). After the first session, the technique was successful in all patients (100%), with elimination of AVNRT and without affecting AV conduction. A mean of 9 +/- 6 lesions were applied. The total procedure time averaged 4 +/- 1 hours. Fluoroscopy time was 41 +/- 25 minutes. Except for transient AV block in 1 patient, no other complications occurred. Over 12 +/- 8 months, a total of 7 patients (13%) had recurrence of AVNRT, and 6 of them underwent successful repeat slow pathway RF ablation. Recurrence rate was 9% (2 patients) for group 1, with persistent jump or echo beats, and 16% (5 patients) for group 2, without residual slow pathway conduction (P = NS). Five of the recurrences (71%) were noted in group A and 2 in group B. Thus, the recurrence rate was 36% for group A (5 of 14 patients), with posterior ablations, and 5% for group B (2 of 41 patients), with anterior sites of successful RF ablation (P < .05). CONCLUSIONS: After successful RF ablation of the slow pathway in patients with AVNRT, residual slow pathway conduction does not correlate with clinical tachycardia recurrences. However, the site of successful RF ablation of the slow pathway does correlate with arrhythmia recurrences. More recurrences are observed when the site is located inferoposteriorly, at or below the os of the coronary sinus, as compared with medial and anterior locations of the ablation site.

Adolescent↗

PubMed1994

Radiofrequency catheter ablation of atrioventricular accessory pathways in Wolff-Parkinson-White syndrome with drug-refractory and symptomatic supraventricular tachycardia--its high effectiveness irrespective of accessory pathway location and properties.

Radiofrequency catheter ablation of atrioventricular accessory pathways was performed in 125 cases of the Wolff-Parkinson-White syndrome (type-A:54, type-B: 29, concealed: 42) complicated with drug-refractory and symptomatic atrioventricular reentrant tachycardia and/or paroxysmal atrial fibrillation. A total of 135 accessory pathways were identified: 50 left free-wall manifest, 34 left free-wall concealed, 21 right free-wall manifest, 2 right free-wall concealed, 15 posteroseptal manifest, 10 posteroseptal concealed, 2 right anteroseptal manifest and 1 right anteroseptal concealed. Accessory pathway conduction was successfully eliminated in 133 of these 135 accessory pathways (99%). Two right posteroseptal pathways were eventually ablated with direct current. Successful ablation required a mean 5.2 applications of radiofrequency current, a mean total energy of 2615 J and a mean fluoroscopic time of 52 min. The mean number of applications, applied energy and fluoroscopic time were greater in the right free-wall pathways than in the left free-wall pathways, and in the concealed pathways than in the manifest pathways. None of the procedures produced complications. During a mean follow-up period of 11.5 months, 1 right free-wall accessory pathway recurred and was ablated successfully in a repeat session. These results suggest that radiofrequency catheter ablation of accessory pathways is highly effective and safe irrespective of the accessory pathway location and properties, although these factors can affect the difficulty of this procedure. This technique may be an alternative to surgical therapy for Wolff-Parkinson-White syndrome with drug-refractory and symptomatic supraventricular tachyarrhythmias.

Adolescent↗

PubMed2002

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice.

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

Animals↗

PubMed2003

Anterograde slow pathway is not the same as retrograde slow pathway conducted in the reverse direction in patients with uncommon atrioventricular nodal reentrant tachycardia.

INTRODUCTION: The aim of this study was to examine the location of anterograde and retrograde slow pathways in 16 patients with uncommon atrioventricular nodal reentrant tachycardia (AVNRT), including the fast-slow form in 10, slow-slow form in 5, and both fast-slow and slow-slow forms in 1. METHODS AND RESULTS: Patients were divided into two groups according to the approach used for slow pathway ablation in the initial radiofrequency catheter ablation (RFCA): one approach used earliest atrial activation during tachycardia (ES group, n = 9), and the other used a slow potential during sinus rhythm (SP group, n = 7). When the initial RFCA failed to eliminate slow pathway conduction in the ES group, an additional RFCA guided by a slow potential was performed. The ratio of lengths from the His-bundle region to the RFCA site and coronary sinus ostium (Abl/His-CS ratio) and the ratio of amplitudes of atrial and ventricular potentials at the RFCA site (A/V ratio) were compared between the two groups. In the initial RFCA, retrograde slow pathway conduction was eliminated without impairment of anterograde slow pathway conduction in 8 (89%) patients from the ES group, and bidirectional slow pathway conduction was eliminated in 6 (86%) patients from the SP group. Residual anterograde slow pathway conduction that was preserved after the initial RFCA in 8 of 9 patients was eliminated by an additional slow potential-guided RFCA. Both the Abl/His-CS ratio (0.86 +/- 0.07 vs 0.73 +/- 0.11, P = 0.01) and A/V ratio (0.80 +/- 0.31 vs. 0.14 +/- 0.01, P < 0.001) were higher in the ES group than the SP group. The ratios for the residual anterograde slow pathway ablation in the ES group were similar to those in the SP group. CONCLUSION: The results of this study suggest that the retrograde slow pathway runs more on the atrial side of the tricuspid valve annulus at the level of the coronary sinus ostium compared with the anterograde slow pathway, although both pathways run parallel or are fused in portions more proximal to the His bundle.

Adult↗

PubMed2000

1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3: analogs of 1alpha,25-dihydroxyvitamin D3 that resist metabolism through the C-24 oxidation pathway are metabolized through the C-3 epimerization pathway.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the previously well established main side chain modification pathway, is initiated by hydroxylation at C-24 of the side chain. The C-3 epimerization pathway, the newly discovered A-ring modification pathway, is initiated by epimerization of the hydroxyl group at C-3 of the A-ring. The end products of the metabolism of 1alpha,25(OH)2D3 through the C-24 oxidation and the C-3 epimerization pathways are calcitroic acid and 1alpha,25-dihydroxy-3-epi-vitamin-D3 respectively. During the past two decades, numerous noncalcemic analogs of 1alpha,25(OH)2D3 were synthesized. Several of the analogs have altered side chain structures and as a result some of these analogs have been shown to resist their metabolism through side chain modifications. For example, two of the analogs, namely, 1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-D3] and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-D3], have been shown to resist their metabolism through the C-24 oxidation pathway. However, the possibility of the metabolism of these two analogs through the C-3 epimerization pathway has not been studied. Therefore, in our present study, we investigated the metabolism of these two analogs in rat osteosarcoma cells (UMR 106) which are known to express the C-3 epimerization pathway. The results of our study indicate that both analogs [1alpha,25(OH)2-16-ene-23-yne-D3 and 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3] are metabolized through the C-3 epimerization pathway in UMR 106 cells. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-D3 [1alpha,25(OH)2-16-ene-23-yne-3-epi-D3] was confirmed by GC/MS analysis and its comigration with synthetic 1alpha,25(OH)2-16-ene-23-yne-3-epi-D3 on both straight and reverse-phase HPLC systems. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-3-epi-D3] was confirmed by GC/MS and 1H NMR analysis. Thus, we indicate that vitamin D analogs which resist their metabolism through the C-24 oxidation pathway, have the potential to be metabolized through the C-3 epimerization pathway. In our present study, we also noted that the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 is about 10 times greater than the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-D3. Thus, we indicate for the first time that certain structural modifications of the side chain such as 20-epi modification can alter significantly the rate of C-3 epimerization of vitamin D compounds.

Animals↗

PubMed2000

Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from a pathway-oriented perspective.

Cellular metabolism is most often described and interpreted in terms of the biochemical reactions that make up the metabolic network. Genomics is providing near complete information regarding the genes/gene products participating in cellular metabolism for a growing number of organisms. As the true functional units of metabolic systems are its pathways, the time has arrived to define metabolic pathways in the context of whole-cell metabolism for the analysis of the structural design and capabilities of the metabolic network. In this study, we present the theoretical foundations for the identification of the unique set of systemically independent biochemical pathways, termed extreme pathways, based on system stochiometry and limited thermodynamics. These pathways represent the edges of the steady-state flux cone derived from convex analysis, and they can be used to represent any flux distribution achievable by the metabolic network. An algorithm is presented to determine the set of extreme pathways for a system of any complexity and a classification scheme is introduced for the characterization of these pathways. The property of systemic independence is discussed along with its implications for issues related to metabolic regulation and the evolution of cellular metabolic networks. The underlying pathway structure that is determined from the set of extreme pathways now provides us with the ability to analyse, interpret, and perhaps predict metabolic function from a pathway-based perspective in addition to the traditional reaction-based perspective. The algorithm and classification scheme developed can be used to describe the pathway structure in annotated genomes to explore the capabilities of an organism.

Algorithms↗

PubMed1990

Retrograde dual atrioventricular nodal pathway in patients with atrioventricular reciprocating tachycardia using concealed accessory pathways.

We present electrophysiological studies in two patients with atrioventricular reciprocating tachycardias. The first patient had anterograde dual atrioventricular nodal pathways with a right-sided concealed accessory pathway. The retrograde atrioventricular nodal pathway showed evidence suggestive of slow pathway properties. After block was induced with ajmaline in the accessory pathway, a typical pattern of discontinuous retrograde atrioventricular nodal conduction curves was recognized. We then observed three types of induced atrioventricular reentry. The other patient had continuous anterograde atrioventricular nodal conduction, a fast-conducting retrograde atrioventricular nodal pathway and a left-sided concealed accessory pathway. After refractoriness had been induced in the accessory pathway with ajmaline, a typical pattern of retrograde dual atrioventricular nodal pathways was recognized, and it proved impossible to induce atrioventricular nodal echoes. Induction of block or impairment of conduction with ajmaline in the concealed accessory pathway proved helpful in the disclosure of retrograde dual atrioventricular nodal pathways by means of the ventricular extrastimulus method.

Adolescent↗

PubMed1992

Clinical characteristics and electrophysiologic properties of atrioventricular accessory pathways: importance of the accessory pathway location.

OBJECTIVES: This study was designed to assess the influence of accessory atrioventricular (AV) pathway location on the clinical and electrophysiologic characteristics of 384 consecutive symptomatic patients having a single accessory pathway. METHODS: Four locations were studied: left free wall (n = 270), posteroseptal (n = 52), anteroseptal (n = 29) and right free wall (n = 33). Ten clinical variables and 12 electrophysiologic variables were analyzed, including the effective refractory period of the accessory pathway and the different clinically occurring and inducible arrhythmias. RESULTS: Only two clinical findings were associated with accessory pathway location: 1) later age at onset of symptoms in the left free wall versus other accessory pathway locations (24 +/- 12 vs. 20 +/- 11 years, p = 0.02), and 2) later age at the time of electrophysiologic study in the left free wall accessory pathway location (36 +/- 13 vs. 32 +/- 11 years, p = 0.01). Six electrophysiologic variables showed a correlation with the accessory pathway location: 1) retrograde conduction only was found less frequently in right free wall (9%) and anteroseptal (10%) than in left free wall (26%) and posteroseptal (29%) accessory pathway locations (p = 0.05); 2) the retrograde effective refractory period of the accessory pathway was shorter in anteroseptal (253 +/- 52 ms) and left free wall (270 +/- 72 ms) as compared with right free wall (296 +/- 101 ms) and posteroseptal (301 +/- 76 ms) locations (p = 0.05); 3) retrograde decremental conduction over the accessory pathway was present in the posteroseptal (17%) and left free wall (3%) but absent in the other locations (p less than 0.001); 4) anterograde decremental conduction was only seen in the right free wall location (12%) (p less than 0.001); 5) orthodromic reentrant tachycardia was induced less frequently in the right free wall than in other locations (70% vs. 93%, p less than 0.001); and 6) inducibility of atrial fibrillation was greater in anteroseptal (62%) than in right free wall (21%), left free wall (44%) and posteroseptal (36%) locations (p = 0.01). CONCLUSIONS: The location of the accessory AV pathway is associated with specific electrophysiologic characteristics.

Adolescent↗

PubMed2001

Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway.

The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, making it a point of potential convergence for multiple intracellular signaling cascades. Previous work in neurons has indicated that physiologic synaptic stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathway that dominates early signaling to CREB. Here we show in hippocampal neurons that the fast, CaMK-dependent pathway can be followed by a slower pathway that depends on Ras/mitogen-activated protein kinase (MAPK), along with CaMK. This pathway was blocked by dominant-negative Ras and was specifically recruited by depolarizations that produced strong intracellular Ca(2+) transients. When both pathways were recruited, phosphorylated CREB (pCREB) formation was overwhelmingly dominated by the CaMK pathway between 0 and 10 min, and by the MAPK pathway at 60 min, whereas the two pathways acted in concert at 30 min. The Ca(2+) signals that produced only rapid CaMK signaling to pCREB or both rapid CaMK and slow MAPK signaling deviated significantly for only approximately 1 min, yet their differential impact on pCREB extended over a much longer period, between 20 and 60 min and beyond, which is of likely significance for gene expression. The CaMK-dependent MAPK pathway may inform the nucleus about stimulus amplitude. In contrast, the CaMKIV pathway may be well suited to conveying information on the precise timing of localized synaptic stimuli, befitting its greater speed and sensitivity, whereas the previously described calcineurin pathway may carry information about stimulus duration.

Calcium-Calmodulin-Dependent Protein Kinases↗