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Results for “pathways”

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PubMed2002

Atrioventricular nodal reentrant tachycardia in children: effect of slow pathway ablation on fast pathway function.

INTRODUCTION: Prior studies in adults have shown significant shortening of the fast pathway effective refractory period after successful slow pathway ablation. As differences between adults and children exist in other characteristics of AV nodal reentrant tachycardia (AVNRT), we sought to characterize the effect of slow pathway ablation or modification in a multicenter study of pediatric patients. METHODS AND RESULTS: Data from procedures in pediatric patients were gathered retrospectively from five institutions. Entry criteria were age <21 years, typical AVNRT inducible with/without isoproterenol infusion, and attempted slow pathway ablation or modification. Dual AV nodal pathways were defined as those with > or =50 msec jump in A2-H2 with a 10-msec decrease in A1-A2. Successful ablation was defined as elimination of AVNRT inducibility. A total of 159 patients (age 4.4 to 21 years, mean 13.1) were studied and had attempted slow pathway ablation. AVNRT was inducible in the baseline state in 74 (47%) of 159 patients and with isoproterenol in the remainder. Dual AV nodal pathways were noted in 98 (62%) of 159 patients in the baseline state. Ablation was successful in 154 (97%) of 159 patients. In patients with dual AV nodal pathways and successful slow pathway ablation, the mean fast pathway effective refractory period was 343+/-68 msec before ablation and 263+/-64 msec after ablation. Mean decrease in the fast pathway effective refractory period was 81+/-82 msec (P < 0.0001) and was not explained by changes in autonomic tone, as measured by changes in sinus cycle length during the ablation procedure. Electrophysiologic measurements were correlated with age. Fast pathway effective refractory period was related to age both before (P = 0.0044) and after ablation (P < 0.0001). AV block cycle length was related to age both before (P = 0.0005) and after ablation (P < 0.0001). However, in dual AV nodal pathway patients, the magnitude of change in the fast pathway effective refractory period after ablation was not related to age. CONCLUSION: Lack of clear dual AV node physiology is common in pediatric patients with inducible AVNRT (38%). Fast pathway effective refractory period shortens substantially in response to slow pathway ablation. The magnitude of change is large compared with adult reports and is not completely explained by changes in autonomic tone. Prospective studies in children using autonomic blockade are needed.

Adolescent↗

PubMed1990

IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway.

IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.

Adenylyl Cyclase Inhibitors↗

PubMed2005

Electrocardiogram in patients with fasciculoventricular pathways: a comparative study with anteroseptal and midseptal accessory pathways.

OBJECTIVES: The purpose of this study was to describe the ECG profile of a cohort of patients with fasciculoventricular pathways and compare the profile with the ECG of patients with anteroseptal and midseptal accessory pathways. BACKGROUND: Electrophysiologic findings suggest fasciculoventricular pathways insert into the septal region. Findings also suggest the 12-lead surface ECG during sinus rhythm is similar to the ECG of patients with anteroseptal and midseptal bypass tracts. METHODS: Four different observers analyzed the 12-lead ECG of seven patients with fasciculoventricular pathways (group I) and the ECG of 20 patients with midseptal AV accessory pathways (group II) and 20 patients with anteroseptal AV accessory pathways (group III). The following variables were analyzed: ECG frontal plane QRS and delta wave axis; angle between the QRS and the delta wave axis; QRS width; R/S ratio in lead III; presence of a negative delta wave in inferior leads; and precordial lead transition to R/S >1. RESULTS: The ECG of fasciculoventricular pathways shows a variable pattern. It shares some features with an anteroseptal accessory pathway and others with a midseptal accessory pathway. A narrower QRS width was the most important variable in distinguishing a fasciculoventricular pathway from a septally located AV bypass tract (P <.0001). The angle between the QRS and the delta wave frontal plane axis could differentiate a fasciculoventricular pathway from an anteroseptal bypass tract (P <.0001) but not from a midseptal accessory pathway. CONCLUSIONS: The sinus rhythm ECG of patients with fasciculoventricular pathways shows similarities with ECGs of patients with anteroseptal and midseptal accessory pathways, but the QRS complex usually is narrower. The ECG recorded during sinus rhythm cannot reliably differentiate fasciculoventricular pathways with a broad QRS complex from anteroseptal or midseptal bypass tracts.

Adult↗

PubMed2006

The outcomes of pathway database computations depend on pathway ontology.

Different biological notions of pathways are used in different pathway databases. Those pathway ontologies significantly impact pathway computations. Computational users of pathway databases will obtain different results depending on the pathway ontology used by the databases they employ, and different pathway ontologies are preferable for different end uses. We explore differences in pathway ontologies by comparing the BioCyc and KEGG ontologies. The BioCyc ontology defines a pathway as a conserved, atomic module of the metabolic network of a single organism, i.e. often regulated as a unit, whose boundaries are defined at high-connectivity stable metabolites. KEGG pathways are on average 4.2 times larger than BioCyc pathways, and combine multiple biological processes from different organisms to produce a substrate-centered reaction mosaic. We compared KEGG and BioCyc pathways using genome context methods, which determine the functional relatedness of pairs of genes. For each method we employed, a pair of genes randomly selected from a BioCyc pathway is more likely to be related by that method than is a pair of genes randomly selected from a KEGG pathway, supporting the conclusion that the BioCyc pathway conceptualization is closer to a single conserved biological process than is that of KEGG.

Computational Biology↗

PubMed1997

Effects of slow pathway ablation on fast pathway function in patients with atrioventricular nodal reentrant tachycardia.

INTRODUCTION: This study investigated whether fast pathway conduction properties are altered by slow pathway ablation in patients with AV nodal reentrant tachycardia. METHODS AND RESULTS: Forty consecutive patients who underwent successful ablation of the slow pathway were prospective subjects for the study. Isoproterenol was used to enhance conduction and to differentiate interactive mechanisms. Potential electrotonic interactions were assessed by comparing patients with and those without residual dual AV node physiology after slow pathway ablation. Paired and unpaired t-tests were used when appropriate P < 0.05 was considered statistically significant. In the entire study population, heart rates were not significantly different before and after slow pathway ablation (RR = 770 +/- 114 msec before and 745 +/- 99 msec after, P = 0.07). Anterograde fast pathway conduction properties were unchanged after slow pathway ablation (effective refractory period, 348 +/- 84 msec before and 336 +/- 86 msec after, P = 0.13; shortest 1:1 conduction, 410 +/- 93 msec before and 400 +/- 82 msec after, P = 0.39). Retrograde fast pathway characteristics also were similar before and after ablation. Neither anterograde nor retrograde fast pathway conduction properties during isoproterenol infusion were changed by slow pathway ablation. When the study population was further divided into patients with (n = 13) or without (n = 27) residual dual AV node physiology, no significant change was detected in fast pathway function in either group after slow pathway ablation. CONCLUSIONS: Fast pathway conduction characteristics were not affected by slow pathway ablation. In patients with AV nodal reentrant tachycardia, observations suggest that fast and slow pathways are functionally distinct.

Adolescent↗

PubMed1997

The effect of variable retrograde penetration on dual AV nodal pathways: observations before and after slow pathway ablation LDD.

Retrograde VA conduction is usually over the fast pathway and rarely over the slow pathway in patients with dual AV nodal pathways. It is unknown whether this apparent unidirectional conduction of the slow pathway is due to the lack of its retrograde conducting ability or the result of concealment. The effect of variable retrograde AV nodal penetration on antegrade AV nodal conduction was determined in patients with typical AV nodal reentrant tachycardia before and after the slow pathway ablation. Variable retrograde penetration was produced by delivering a ventricular extrastimulus simultaneously with (VE-0), 50 ms after (VE-50), or 100 ms after (VE-100) the last basic atrial stimulus, while atrial extrastimuli were used to determine changes of anterograde AV nodal effective refractory period (ERP) and A-H interval. The AV nodal functions measured without the ventricular extrastimuli served as the baseline. Although the mean slow pathway ERP was not significantly different among the different stimulation protocols, a significant shortening of the slow pathway conduction time (A-H from 348 +/- 60 to 324 +/- 119 ms, P < 0.05) was observed with upper level retrograde penetration of the AV node (VE-0). This facilitating effect became a prolonging effect when the retrograde penetration level moved to the lower level (VE-100, A-H from 324 +/- 119 to 366 +/- 122 ms, P < 0.05). The fast pathway ERP shortened with an upper level penetration (VE-0) but tended to prolong with a lower level retrograde-penetration (VE-100) both before and after the slow pathway ablation (preablation, from 348 +/- 143 of the baseline to 302 +/- 114 to 360 +/- 143 ms, P < 0.05; postablation, from 314 +/- 101 of the baseline to 274 +/- 118 to 361 +/- 143 ms, P < 0.05). The mean A2-H2 interval of the slow pathway was significantly shorter than the baseline (350 +/- 44 ms) with VE-0 (249 +/- 48 ms, P < 0.05) and VE-50 stimulation (285 +/- 82 ms, P < 0.05) but not with VE-100 stimulation (330 +/- 83 ms, P = NS). Before slow pathway ablation, the A2-H2 interval of the fast pathway at equal coupling intervals was shorter than the baseline (165 +/- 53 ms) with VE-0 (144 +/- 47 ms, P < 0.01) and VE-50 stimulation (152 +/- 43 ms, P < 0.05) but tended to be longer with VE-100 stimulation (175 +/- 47 ms, P = NS). After slow pathway ablation, the mean A2-H2 interval at the same coupling interval was shorter than the baseline (173 +/- 39 ms) with VE-0 (139 +/- 35 ms, P < 0.05), VE-50 (153 +/- 32 ms, P = 0.05) but tended to be longer with VE-100 stimulation (178 +/- 49 ms, P = NS). We conclude that: (1) concealed retrograde conduction can be demonstrated in both the slow and the fast AV nodal pathways; and (2) concealed retrograde conduction may either shorten or prolong anterograde refractoriness and conduction time, depending on the level of retrograde penetration.

Adult↗

PubMed1998

New evidence that AV node slow pathway conduction directly influences fast pathway function.

INTRODUCTION: Shortening of the AV node fast pathway effective refractory period (ERP) following successful slow pathway ablation may be a nonspecific effect of energy application at the AV junction or may be due to elimination of a direct effect of slow pathway conduction on the fast pathway. METHODS AND RESULTS: Twenty-six consecutive patients (20 women and 6 men; mean age 45 +/- 3 years) with typical AV nodal reentrant tachycardia who underwent successful slow pathway ablation (defined as complete elimination of dual AV node physiology) were studied. The fast pathway ERP (at a drive train cycle length of 600 msec) was determined prior to ablation (baseline) and following unsuccessful and successful ablation attempts. Successful slow pathway ablation shortened the fast pathway ERP significantly (317 +/- 9 msec; P < 0.001) compared to baseline (386 +/- 12 msec), whereas unsuccessful ablations had no effect (376 +/- 11 msec). Sinus cycle length, the AH interval, and blood pressure were unchanged following successful ablation. Shortening of the fast pathway ERP did not correlate with the number of energy applications or with two measures of the proximity between the slow and the fast pathway. CONCLUSION: These results support the hypothesis that shortening of the fast pathway ERP following slow pathway ablation is due to elimination of a direct effect of slow pathway conduction on fast pathway function rather than a nonspecific effect of repeated energy delivery at the AV junction.

Adolescent↗

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↗

PubMed2006

Targeting changes in cancer: assessing pathway stability by comparing pathway gene expression coherence levels in tumor and normal tissues.

The purpose of this study is to examine gene expression changes occurring in cancer from a pathway perspective by analyzing the level of pathway coherence in tumor tissues in comparison with their normal counterparts. Instability in pathway regulation patterns can be considered either as a result of or as a contributing factor to genetic instability and possibly cancer. Our analysis has identified pathways that show a significant change in their coherence level in tumor tissues, some of which are tumor type specific, indicating novel targets for cancer type-specific therapies. Pathways are found to have a general tendency to lose their gene expression coherence in tumor tissues when compared with normal tissues, especially for signaling pathways. The selective growth advantage of cancer cells over normal cells seems to originate from their preserved control over vital pathways to ensure survival and altered signaling, allowing excessive proliferation. We have additionally investigated the tissue-related instability of pathways, providing valuable clues to the cellular processes underlying the tumorigenesis and/or growth of specific cancer types. Pathways that contain known cancer genes (i.e., "cancer pathways") show significantly greater instability and are more likely to become incoherent in tumor tissues. Finally, we have proposed strategies to target instability (i.e., pathways that are prone to changes) by identifying compound groups that show selective activity against pathways with a detectable coherence change in cancer. These results can serve as guidelines for selecting novel agents that have the potential to specifically target a particular pathway that has relevance in cancer.

Gene Expression↗

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↗