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PubMed1996

Bilateral organization of parallel and serial pathways in the dentate gyrus demonstrated by current-source density analysis in the rat.

1. Membrane currents evoked in the dentate gyrus (DG) by stimulation of afferent pathways from the entorhinal cortex (EC) and contralateral DG were examined by current-source density (CSD) analysis in urethan-anesthetized rats. Stimulation of each afferent pathway evoked membrane currents with distinct spatial and temporal organization in the DG. CSD and anatomic analysis revealed that afferent input from the EC activated the DG bilaterally through parallel and serial pathways. The analysis provided a detailed description of the location, timing, and relative amplitude of evoked monosynaptic and multisynaptic currents in the DG. 2. Orthodromic stimulation of the perforant path (PP) evoked a large ipsilateral excitatory postsynaptic current (iEPSC) at a latency of 2.5-4 ms in the middle and outer stratum moleculare (STM) of the DG, and a population spike that was generated by an excitatory inward current at a latency of 5-9 ms in the stratum granulosum. 3. A variable, low-amplitude ipsilateral inward current followed the population spike at a latency of 13-16 ms in the inner STM, which is the site of synaptic terminals of the associational and commissural pathways arising from neurons in the hilus of the DG. Orthodromic stimulation of the commissural pathway from the hilus of the contralateral DG also evoked an inward current in the inner STM at a latency of 2-6 ms, which was 40-60% of the amplitude of the monosynaptic iEPSC. 4. Orthodromic stimulation of the EC evoked a low-amplitude contralateral excitatory postsynaptic current (cEPSC) at a latency of 3-6 ms in the outer and middle STM of the contralateral DG, which was generated by monosynaptic transmission in the sparse crossed pathway from the EC. In contrast to the variable, low-amplitude inward current in the inner STM that followed the iEPSC, the cEPSC was consistently followed by a large inward current at a latency of 8-14 ms in the inner STM of the contralateral DG. 5. The large inward current in the inner STM of the contralateral DG was abolished by transection of the PP ipsilateral and rostral to the stimulating electrode, but was unaffected by transection of the PP at a similar location in the hemisphere contralateral to the stimulating electrode. These observations suggested that this current was most likely generated by a multisynaptic pathway involving the ipsilateral PP and the commissural pathway arising from the hilus of the DG. 6. In conclusion, efferents from the EC activated the DG bilaterally by parallel and serial pathways. Parallel monosynaptic pathways from the EC activated homologous distal segments of granule cell dendrites bilaterally, by a massive input to the ipsilateral DG and a sparse input to the contralateral DG. Sequential propagation from the EC through a multisynaptic pathway that included the commissural pathway from the hilus of the DG bilaterally activated the proximal segments of granule cell dendrites at longer latencies. The amplitude of the multisynaptic currents generated by serial pathways in the proximal dendrites varied inversely with the amplitudes of the monosynaptic currents evoked by parallel pathways in the distal dendrites. These observations may have implications for synaptic integration, associative properties, and information processing in the DG.

Afferent Pathways↗
PubMed1997

Comparative analysis of Embden-Meyerhof and Entner-Doudoroff glycolytic pathways in hyperthermophilic archaea and the bacterium Thermotoga.

The Embden-Meyerhof (EM) or Entner-Doudoroff (ED) pathways of sugar degradation were analyzed in representative species of the hyperthermophilic archaeal genera Thermococcus, Desulfurococcus, Thermoproteus, and Sulfolobus, and in the hyperthermophilic (eu)bacterial genus Thermotoga. The analyses included (1) determination of 13C-labeling patterns by 1H- and 13C-NMR spectroscopy of fermentation products derived from pyruvate after fermentation of specifically 13C-labeled glucose by cell suspensions, (2) identification of intermediates of sugar degradation after conversion of 14C-labeled glucose by cell extracts, and (3) measurements of enzyme activities in cell extracts. Thermococcus celer and Thermococcus litoralis fermented 13C-glucose to acetate and alanine via a modified EM pathway (100%). This modification involves ADP-dependent hexokinase, 6-phosphofructokinase, and glyceraldehyde-3-phosphate:ferredoxin oxidoreductase (GAP:FdOR). Desulfurococcus amylolyticus fermented 13C-glucose to acetate via a modified EM pathway in which GAP:FdOR replaces GAP-DH/phosphoglycerate kinase. Thermoproteus tenax fermented 13C-glucose to low amounts of acetate and alanine via simultaneous operation of the EM pathway (85%) and the ED pathway (15%). Aerobic Sulfolobus acidocaldarius fermented 13C-labeled glucose to low amounts of acetate and alanine exclusively via the ED pathway. The anaerobic (eu)bacterium Thermotoga maritima fermented 13C-glucose to acetate and lactate via the EM pathway (85%) and the ED pathway (15%). Cell extracts contained glucose-6-phosphate dehydrogenase and 2-keto-3-deoxy-6-phosphogluconate aldolase, key enzymes of the conventional phosphorylated ED pathway, and, as reported previously, all enzymes of the conventional EM pathway. In conclusion, glucose was degraded by hyperthermophilic archaea to pyruvate either via modified EM pathways with different types of hexose kinases and GAP-oxidizing enzymes, by the nonphosphorylated ED pathway, or by a combination of both pathways. In contrast, glucose catabolism in the hyperthermophilic (eu)bacterium Thermotoga involves the conventional forms of the EM and ED pathways. The data are in accordance with various previous reports.

Archaea↗
PubMed1994

Limitations of adenosine in assessing the efficacy of radiofrequency catheter ablation of accessory pathways.

Adenosine has been shown to reliably confirm the success of accessory pathway catheter ablation by producing transient atrioventricular (AV) block during atrial and ventricular pacing. This is due to the insensitivity of accessory pathway conduction to adenosine (with the rare exception of accessory pathways with decremental conduction properties). However, 4 of 204 consecutive patients who underwent successful accessory pathway ablation (as shown by adenosine-induced transient AV block) had recurrent AV reciprocating tachycardia involving a second, previously nonmanifest accessory pathway. In each case, the second accessory pathway was localized to a site disparate from the original pathway. No pathway showed decremental anterograde or retrograde conduction properties. In 2 patients, adenosine initially did not show the presence of the second concealed accessory pathway, because the refractory period of the accessory pathway was longer than the pacing cycle length used to assess ventriculoatrial conduction. Only when the refractory period of this second accessory pathway was shortened by infusion of isoproterenol did adenosine reveal the presence of the pathway during follow-up electrophysiologic study. In another patient, a non-decremental accessory pathway was shown to be sensitive to adenosine. In the remaining patient, the second accessory pathway may have been transiently injured during the initial study, thereby simulating adenosine sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1996

Reasons for prolonged or failed attempts at radiofrequency catheter ablation of accessory pathways.

OBJECTIVES: The purpose of this study was to categorize the reasons for a prolonged or failed procedure in a series of patients undergoing catheter ablation of an accessory pathway. BACKGROUND: Radiofrequency ablation of accessory pathways at times requires a lengthy procedure or a second ablation session, or both, and not prior studies have systematically investigated the reasons for this. METHODS: In a consecutive series of 619 patients undergoing catheter ablation of an accessory pathway, the mean ablation time +/- SD was 68 +/- 64 min. The subjects of this study were 14 patients who had an ablation time >2 SD greater than the mean (>196 min) and 51 patients who required a second ablation session for a successful outcome. The accessory pathway in the 65 patients in this study was located in the right free wall in 19 patients (29%), septum in 14 (22%) and left free wall in 32 (49%). RESULTS: The primary reasons for a lengthy or failed ablation attempt were 1) inability to position the ablation catheter at the effective target site (16 patients, 25%); 2) instability of the ablation catheter or inadequate tissue contact at the target site, or both (15 patients, 23%); 3) mapping error due to an oblique course of the accessory pathway (7 patients, 11%); 4) failure to recognize a posteroseptal accessory pathway as being left-sided instead of right-sided (4 patients, 6%); 5) other errors in accessory pathway localization (6 patients, 9%); 6) epicardial location of the accessory pathway (5 patients, 8%); 7) recurrent atrial fibrillation (2 patients, 3%); 8) occurrence of a complication (2 patients, 3%); 9) unusual right-sided accessory pathway that inserted in the anterior right ventricle, 2 cm away from the lateral tricuspid annulus (1 patient, 1.5%); and 10) unexplained factors (7 patients, 11%). The most common effective strategies employed to achieve a successful outcome in these patients were 1) substitution of a more experienced operator; 2) use of ablation catheters of varying configurations; 3) switching from a retrograde aortic to a trans-septal approach; 4) switching from an inferior to a superior vena caval approach; 5) use of a 60-cm guiding sheath; 6) detailed mapping of the atrial or ventricular insertion of the accessory pathway; and 7) searching within the coronary sinus for a presumed accessory pathway potential. CONCLUSIONS: A lengthy or failed attempt at catheter ablation of an accessory pathway may be due to a variety of reasons, the most common of which are problems related to some aspect of catheter manipulation and errors in accessory pathway localization. Knowledge of the most common reasons for a lengthy or ineffective procedure may facilitate successful outcome of accessory pathway ablation.

Adult↗
PubMed1996

Electrophysiologic characteristics, electropharmacologic responses and radiofrequency ablation in patients with decremental accessory pathway.

OBJECTIVES: This study sought to characterize the functional properties of decremental accessory atrioventricular (AV) pathways and to investigate their pharmacologic responses. BACKGROUND: Although decremental AV pathways associated with incessant reciprocating tachycardia have been studied extensively, information about the electrophysiologic characteristics and pharmacologic responses of anterograde and retrograde decremental AV pathways is limited. METHODS: Of 759 consecutive patients with accessory pathway-mediated tachyarrhythmia, 74 with decremental AV pathways were investigated (mean age 43 +/- 18 years). After baseline electrophysiologic study, the serial drugs adenosine, verapamil and procainamide were tested during atrial and ventricular pacing. Finally, radiofrequency catheter ablation was performed. RESULTS: Five patients had anterograde decremental conduction over the accessory pathway but had no retrograde conduction. Of the 64 patients with retrograde decremental conduction over the accessory pathway, anterograde conduction over the pathway was absent in 41 (64%), intermittent in 5 (8%) and nondecremental in 18 (28%). In the remaining five patients, anterograde and retrograde decremental conduction over the same pathway was found. The anterograde and retrograde conduction properties and extent of decrement did not differ between anterograde and retrograde decremental pathways. Posteroseptal pathways had the highest incidences of anterograde and retrograde decremental conduction. Intravenous adenosine, procainamide and verapamil caused conduction delay or block, or both, in 10 of 10, 10 of 10 and 4 of 10 of the anterograde and 20 of 20, 20 of 20 and 8 of 20 of the retrograde decremental pathways, respectively. All patients had successful ablation of the decremental pathways without complications. During the follow-up period of 31 +/- 19 months, only one patient experienced recurrence. CONCLUSIONS: Decremental accessory pathways usually had functionally distinct conduction characteristics in the anterograde and retrograde directions. Their pharmacologic responses suggested the heterogeneous mechanisms of decremental conduction.

Adenosine↗
PubMed2002

Activation of complement pathways in xenotransplantation: an in vitro study.

Pig-to-human xenotransplantation faces the problem of hyperacute graft rejection due to the presence of human naturally occurring antibodies against the disaccharide Galalpha1-3Gal (anti-Gal antibodies) expressed on pig endothelium. Antibody-mediated complement activation is usually referred to as classical pathway activation. In this study we examined if the alternative complement pathway is also directly activated through anti-Gal antibodies or if the classical pathway is indispensable. We therefore developed a hemolysis test with rabbit erythrocytes (E), which have an activating surface for the alternative complement pathway and express abundant amounts of Galalpha1-3Gal, and used this assay in addition to the standard complement tests CH50 and AP50. In this rabbit E CH50 (RECH50) assay we were able to study activation of both major complement pathways simultaneously. FACS analysis was used to trace complement and antibody deposition on rabbit E. Anti-Gal depletion of human serum by immunoabsorption revealed a 65% reduction of rabbit E hemolysis in the RECH50 test (value before absorption: 28 +/- 5.8, after absorption: 9.9 +/- 2.8, P<0.001), but only a 35% reduction of lysis in the AP50 test (AP50 before 11.3 +/- 2.1, after 7.4 +/- 2.0, P<0.002). Repletion with purified anti-Gal fully restored hemolysis in both assays. Serum depleted of Clq showed a reduced lysis of rabbit E as compared to normal human serum; this effect increased with higher serum dilutions. The reciprocal picture, i.e. less effect on hemolysis with increasing dilution, was seen with factor D depleted serum. Comparison of the RECH50 values with the AP50 values revealed an 8.4-fold increase of lysis in the RECH50 test, in which both complement pathways are running. By FACS analysis, complement deposition on rabbit E was determined and components of the classical pathway were found, especially in sera where the alternative pathway was disrupted. We conclude that in our model anti-Gal induce lysis via both classical and alternative complement pathways, but that the alternative pathway activation is of minor importance. In addition, we saw that with higher serum dilutions, the classical pathway (i.e. anti-Gal-mediated lysis) takes a predominant role in lysing the rabbit E. As anti-Gal-mediated activation of the alternative complement cascade seems of minor importance based on our results, and as there are only few surfaces in transplanted organs that would favor the alternative pathway to be executed, the specific inhibition of early steps of the classical pathway appears as a realistic strategy in pig-to-primate xenotransplantation that-to the benefit of the patient-leaves the mainly anti-bacterial defense by the alternative pathway intact.

Animals↗
PubMed2002

Critical pathways for patients with acute chest pain at low risk.

Critical pathways are predefined protocols that define the crucial steps in evaluating and treating a clinical problem to improve quality of patient care, reduce variability and enhance efficiency. Critical pathways have proliferated for a variety of diagnoses, including evaluation of patients with chest pain, a common and costly complaint. This review will outline the development, implementation, and assessment of critical pathways using as a paradigm our experience with a pathway for patients presenting to the Emergency Department with acute chest pain who are at low risk of myocardial ischemia. The goals of the pathway were to expedite evaluation of low-risk patients and reduce admission rates among these patients and in the cohort overall without compromising outcomes. The pathway was developed by a multidisciplinary team in an iterative process that considered published literature, as well as the experience and consensus of local opinion leaders. Patients at least 30 years old presenting to the Emergency Department of an urban teaching hospital who were pain-free without heart failure or ischemic changes on EKG, but who were not considered appropriate for discharge by the treating physician, were eligible for the critical pathway. The pathway involved one set of creatine kinase-MB enzymes drawn at least 4 hours after pain, a 6 hour observation period after the last episode of pain and exercise testing. Outcomes during evaluation and admission rates were assessed. Clinical outcomes at 7 days and 6 months after evaluation and patient satisfaction at 7 days were also measured. Of 1363 patient visits, 145 (10.6%) were triaged by the pathway: 131 (90.3%) were discharged, 14 (9.7%) were admitted. The overall admission rate decreased from 63% (2898/4595) to 60% (819/1363) [p < 0.05] in comparison to a cohort studied prior to pathway implementation. Pathway patients reported low rates of subsequent cardiac procedures. No deaths or myocardial infarctions were recorded. At 7 days, only 2 respondents (2%) reported going to an Emergency Department since their evaluation. Most respondents (83%) rated their care as very good or excellent. Critical pathways designed to enhance efficiency, reduce variability, and improve the quality of care are becoming increasingly common. Our pathway for evaluation of patients with chest pain at low risk of myocardial ischemia was feasible and safe and was associated with a decline in absolute admission rates. Because of the possibility of concomitant secular trends and the effects of a changing medical environment, further rigorous research on the efficacy of individual pathways is needed.

Acute Disease↗
PubMed2005

Alignment of metabolic pathways.

MOTIVATION: Several genome-scale efforts are underway to reconstruct metabolic networks for a variety of organisms. As the resulting data accumulates, the need for analysis tools increases. A notable requirement is a pathway alignment finder that enables both the detection of conserved metabolic pathways among different species as well as divergent metabolic pathways within a species. When comparing two pathways, the tool should be powerful enough to take into account both the pathway topology as well as the nodes' labels (e.g. the enzymes they denote), and allow flexibility by matching similar--rather than identical--pathways. RESULTS: MetaPathwayHunter is a pathway alignment tool that, given a query pathway and a collection of pathways, finds and reports all approximate occurrences of the query in the collection, ranked by similarity and statistical significance. It is based on a novel, efficient graph matching algorithm that extends the functionality of known techniques. The program also supports a visualization interface with which the alignment of two homologous pathways can be graphically displayed. We employed this tool to study the similarities and differences in the metabolic networks of the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae, as represented in highly curated databases. We reaffirmed that most known metabolic pathways common to both the species are conserved. Furthermore, we discovered a few intriguing relationships between pathways that provide insight into the evolution of metabolic pathways. We conclude with a description of biologically meaningful meta-queries, demonstrating the power and flexibility of our new tool in the analysis of metabolic pathways.

Animals↗
PubMed2006

The Path-A metabolic pathway prediction web server.

Pathway Analyst (Path-A) is a publicly available web server (http://path-a.cs.ualberta.ca) that predicts metabolic pathways. It takes a FASTA format file containing a set of query protein sequences from a single organism (a partial or complete proteome) and identifies those sequences that are likely to participate in any of its supported metabolic pathways (currently 10). Path-A uses a number of machine-learning and sequence analysis techniques (e.g. SVM, BLAST and HMM) to predict pathways. Each machine-learned classifier exploits similarity between sequences in the pathways of its model organisms and sequences in the query set. It predicts the pathways that are present in the query organism and annotates each predicted reaction and catalyst, using the appropriate sequences from the query set. Path-A also provides a browsable and searchable database of the pathways for the model organisms that are used to make its predictions. Path-A's predictor sets (using different classifier technologies) have been evaluated using standard cross-validation techniques on a dataset of 10 metabolic pathways across 13 model organisms--a total of 125 organism-specific pathways. The most accurate classifier technology obtained a mean precision of 78.3% and a mean recall of 92.6% in predicting all catalyst proteins, of all reactions, in all pathways present in the dataset. Although Path-A currently only supports metabolic pathways, the underlying prediction techniques are general enough for other types of pathways. Consequently, it is our intent to extend Path-A to predict other types of pathways, including signalling pathways.

Algorithms↗
PubMed2005

MetaCyc and AraCyc. Metabolic pathway databases for plant research.

MetaCyc (http://metacyc.org) contains experimentally determined biochemical pathways to be used as a reference database for metabolism. In conjunction with the Pathway Tools software, MetaCyc can be used to computationally predict the metabolic pathway complement of an annotated genome. To increase the breadth of pathways and enzymes, more than 60 plant-specific pathways have been added or updated in MetaCyc recently. In contrast to MetaCyc, which contains metabolic data for a wide range of organisms, AraCyc is a species-specific database containing only enzymes and pathways found in the model plant Arabidopsis (Arabidopsis thaliana). AraCyc (http://arabidopsis.org/tools/aracyc/) was the first computationally predicted plant metabolism database derived from MetaCyc. Since its initial computational build, AraCyc has been under continued curation to enhance data quality and to increase breadth of pathway coverage. Twenty-eight pathways have been manually curated from the literature recently. Pathway predictions in AraCyc have also been recently updated with the latest functional annotations of Arabidopsis genes that use controlled vocabulary and literature evidence. AraCyc currently features 1,418 unique genes mapped onto 204 pathways with 1,156 literature citations. The Omics Viewer, a user data visualization and analysis tool, allows a list of genes, enzymes, or metabolites with experimental values to be painted on a diagram of the full pathway map of AraCyc. Other recent enhancements to both MetaCyc and AraCyc include implementation of an evidence ontology, which has been used to provide information on data quality, expansion of the secondary metabolism node of the pathway ontology to accommodate curation of secondary metabolic pathways, and enhancement of the cellular component ontology for storing and displaying enzyme and pathway locations within subcellular compartments.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1995

Use of adenosine to identify patients at risk for recurrence of accessory pathway conduction after initially successful radiofrequency catheter ablation.

OBJECTIVE: The use of adenosine after radiofrequency catheter ablation of accessory pathways was prospectively studied to determine its utility for identifying patients at risk for recurrence of accessory pathway conduction and to guide therapy that might reduce late recurrence in this group. BACKGROUND: Accessory pathway conduction recurs in 5%-12% of patients following initially "successful" radiofrequency catheter ablation. Adenosine may facilitate conduction over accessory pathways that have been modified by radiofrequency delivery, thus identifying patients at risk for recurrence. METHODS: Radiofrequency catheter ablation was performed in 109 patients. Prior to ablation, 12-18 mg of adenosine was administered. After ablation, when all evidence of accessory pathway conduction remained absent for at least 30 minutes, adenosine 12-18 mg was again administered. RESULTS: Adenosine given prior to radiofrequency catheter ablation did not block accessory pathway conduction in any patient. Adenosine given after elimination of accessory pathway conduction induced complete atrioventricular and ventriculoatrial block in 95 patients; 11 (11.6%) subsequently had recurrence of accessory pathway function. Accessory pathway conduction was unmasked by adenosine in 12 patients (11.2%). After further deliveries of radiofrequency energy, 7 of these 12 patients subsequently demonstrated adenosine induced atrioventricular and ventriculoatrial block; 1 of these 7 patients experienced recurrence of accessory pathway conduction. The remaining 5 patients demonstrated persistent accessory pathway conduction only with adenosine; all experienced clinical recurrence of accessory pathway function. CONCLUSION: The use of adenosine after presumed successful radiofrequency catheter ablation may reveal persistent accessory pathway conduction. Elimination of this latent accessory pathway conduction reduces the risk for recurrence.

Adenosine↗
PubMed1994

Recurrence and late block of accessory pathway conduction following radiofrequency catheter ablation.

INTRODUCTION: Many issues regarding the recurrence of accessory pathway conduction and the long-term outcome of late block of accessory pathway conduction are still unknown or controversial. METHODS AND RESULTS: Data from 217 patients who underwent an initially successful radiofrequency ablation of accessory pathways and 7 patients with late block of accessory pathway conduction following an initially unsuccessful ablation were analyzed. During a mean follow-up of 19 +/- 11 months, accessory pathway conduction resumed in 21 (10%) of 217 patients following an initially successful ablation and in 6 (86%) of 7 patients with late block of accessory pathway conduction (P < 0.01). After initially successful ablations, the recurrence rates of accessory pathway conduction at 1, 3, and 6 months were 5.9%, 7.4%, and 11.3%, respectively. A late electrophysiologic study at 6 months uncovered recurrence in only 1 of 124 asymptomatic patients, but failed to detect the late recurrence in 2 patients in whom the accessory pathway conduction resumed after more than 6 months. Multivariate analysis revealed that independent predictors for recurrence of accessory pathway conduction were concealed accessory pathway, presence of transient effect of radiofrequency pulse, and more than 5 pulses required for initial cure. Accessory pathway location, length of the tip electrode of the ablation catheter, and repeat radiofrequency pulses ("safety pulses") after effective pulses did not predict resumption of accessory pathway conduction. CONCLUSIONS: After initially successful ablation, the recurrence rates of accessory pathway conduction at 1, 3, and 6 months were 5.9%, 7.4%, and 11.3%, respectively. Late electrophysiologic testing had little prognostic value in asymptomatic patients following successful ablation. Application of "safety pulses" did not prevent recurrence. Late block of accessory pathway conduction did not predict long-term efficacy.

Adolescent↗
PubMed1984

Concealed conduction in accessory atrioventricular pathways: an important determinant of the expression of arrhythmias in patients with Wolff-Parkinson-White syndrome.

Concealed conduction into accessory atrioventricular pathways has been postulated to explain variability of R-R intervals during atrial fibrillation in patients with Wolff-Parkinson-White syndrome. We examined the occurrence of concealed conduction into atrioventricular pathways using extrastimulus techniques in 26 consecutive patients undergoing electrophysiologic studies for the Wolff-Parkinson-White syndrome. Anterograde pathway concealment was demonstrated (10 patients) by introducing a second atrial extrastimulus (A3) after block in the accessory pathway occurred following the first extrastimulus (A2). The apparent effective refractory period (ERP) of the atrioventricular pathway with A3 (after A2 blocked in the pathway), or ERPB, was always greater than the ERP of the atrioventricular pathway (505 +/- 100 vs 323 +/- 105 msec, mean +/- SD; p less than .001), a finding explained by concealment into the pathway by the blocked A2. A measure of the apparent prolongation of refractoriness due to anterograde concealment (delta ERPB), defined as the difference between ERP and ERPB at a given cycle length, was derived. The average R-R interval in atrial fibrillation correlated better with delta ERPB (r = .8, p less than .01) than with the ERP (r = .6, p = NS), supporting the influence of anterograde atrioventricular pathway concealment in modulating the ventricular response during atrial fibrillation. By similar techniques, concealed retrograde conduction in the atrioventricular pathway could be demonstrated in 16 of 26 patients. In two of these patients "bystander" atrioventricular pathway conduction during orthodromic reciprocating tachycardia that did not involve the atrioventricular pathway did not occur, even though the ERP of the pathway should have permitted it, a finding readily explained by repetitive retrograde concealment into the atrioventricular pathway during tachycardia. Concealed conduction can be demonstrated in most patients with Wolff-Parkinson-White syndrome and is an important factor in the clinical expression of their arrhythmias.

Adolescent↗
PubMed1988

Catheter ablation of accessory pathways with a direct approach. Results in 35 patients.

Thirty-five consecutive patients with an overt accessory pathway, all but two suffering from arrhythmia (atrial fibrillation, reciprocating tachycardia, or both), underwent attempted transcatheter ablation (fulguration) of their accessory pathway. Thirty-three patients had been treated with a mean of 2.3 +/- 1.4 antiarrhythmic drugs. A standard bipolar catheter was positioned on the internal surface of the right or left atrioventricular anulus with 1) a subclavian approach of the right cardiac cavities in 29 patients with right-sided accessory pathway (n = 27) or left posteroseptal accessory pathway (n = 2), 2) a patent foramen ovale in five patients (two with a left posterolateral accessory pathway and three with a left parietal accessory pathway), and a transseptal catheterism (one patient with a left parietal accessory pathway). Cathodic shocks (mean, 4.3 shocks/patient) with a mean cumulative energy of 690 J enabled the ablation (disappearance of both anterograde and retrograde conduction) of the accessory pathway in 32 patients with a follow-up ranging from 1 to 32 months (mean, 10 +/- 8 months). Two of the remaining three accessory pathways were impaired: one pathway became intermittent, the anterograde effective refractory period of the second pathway increased from 260 to 410 msec, and the third pathway was slightly impaired. This latter patient is the only one who still requires therapy, with a single antiarrhythmic drug. All others are free of arrhythmias and require no therapy. Not using coronary sinus catheterism inclusive of its os has led to only a few, benign side effects. Only one third-degree atrioventricular block occurred in a posteroseptal accessory pathway ablation. Three cases of patients with incessant reciprocating tachycardia involving a further successful ablation occurred at the beginning of our experience. The best area for ablation is, in our opinion, the recording site for the Kent-bundle activity (18 of 35 patients), but a meticulous mapping of the atrioventricular anulus during orthodromic reciprocating tachycardia makes ablation possible when the shortest ventriculoatrial time (V-A') can be recorded with reliability (mean, 85 +/- 18 msec). Such a procedure is an alternative to surgical ablation regardless of the location of the accessory pathway--not only posteroseptally.

Adult↗
PubMed2000

New steps in the Wnt/beta-catenin signal transduction pathway.

Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. Wnt family genes encode secreted glycoproteins that act as ligands for membrane receptors belonging to the Frizzled family of proteins. Wnt-1 originally was found as a proto-oncogene that was upregulated in tumors caused by the mouse mammary tumor virus. The Drosophila homologue of Wnt-1, wingless, is a segment polarity gene that regulates body patterning of the fly embryo. In Xenopus, the Wnt pathway regulates formation of the ventral-dorsal axis. Although Wnt proteins are expressed widely in mammals, the function of the Wnt signaling pathway in normal adult mammalian tissues is not understood. Downstream components of the Wnt pathway, APC (adenomatous polyposis coli) and beta-catenin, clearly are involved in human cancer. There are also several reports that Wnt ligands are highly expressed in tumors. Wnt stabilizes cytoplasmic beta-catenin and activates beta-catenin/Lef-1 (lymphoid enhancer factor), Tcf (T-cell factor)-dependent gene transcription. This regulation of cytosolic beta-catenin is mediated by glycogen synthase kinase-3 (GSK-3) activity but in neither case is the mechanism known. The mechanism by which Wnt inhibits GSK-3 is unknown. Recent studies have shown that some of the intracellular signaling molecules that mediate the Wnt pathway are in complexes, including Dishevelled (Dsh or Dvl), GSK-3beta, and APC protein. However, little is known about how Wnt or other upstream stimuli regulate these complexes to stabilize beta-catenin. We took a variety of approaches to identify new components of the Wnt pathway. Using an expression-cloning technique, we isolated casein kinase I (CKI)epsilon as a positive regulator of beta-catenin in the Wnt pathway. Overexpression of CKIepsilon mimics Wnt by stabilizing beta-catenin, thereby increasing expression of beta-catenin-dependent genes. Inhibition of endogenous CKIepsilon attenuated gene transcription stimulated by Wnt or by Dsh. CKIepsilon forms a complex with Axin and the other downstream components of the Wnt pathway. CKIepsilon is a positive regulator of the Wnt pathway and a possible functional link between upstream signals and the intracellular Axin signaling complex that regulates beta-catenin. In separate experiments, we have identified a Dishevelled-associated kinase (DAK) that binds to Dsh and regulates its functions. Dsh is required for two different pathways, the Wnt pathway and planar polarity pathway in Drosophila. DAK dramatically enhances the function of Dsh in the Wnt pathway and inhibits its function in the planar polarity pathway. This chapter will discuss these newly identified components of the Wnt pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1982

Evidence for an underestimation of the shunt pathway of mevalonate metabolism in slices of livers and kidneys from fasted rats and rats in diabetic ketosis.

Yields of (14)CO(2) from [2-(14)C]mevalonate and [5-(14)C]mevalonate have been used by others to estimate the activity of the non-sterol-forming pathway, also called the mevalonate shunt pathway, and yields of (14)C in sterols have been used to estimate the activity of the sterol-forming pathway. Both these pathways operate following the conversion of carbon 1 of mevalonate to CO(2). The estimations of the shunt pathway contribution are dependent upon the fractions of carbons 2 and 5 of mevalonate that are oxidized to CO(2) in the Krebs cycle after leaving the pathway. Unless all of carbons 2 and 5 are oxidized to CO(2), the estimates are minimal. The metabolism of mevalonate has now been examined in slices of livers and kidneys from fasted rats and rats in diabetic ketosis. Yields of (14)CO(2) from [1-(14)C]mevalonate are used as the measure of the contributions of all the pathways by which carbon 1 of mevalonate is converted to CO(2). Yields of (3)H-labeled nonsaponifiable lipids from [5-(3)H]mevalonate are used as the measure of the sterol-forming pathway. The differences in these yields are then taken as the measure of the non-sterol-forming pathway or pathways. Yields of (14)CO(2) from [1-(14)C]mevalonate markedly exceeded the sum of the yields of (14)C in CO(2) and nonsaponifiable lipids from either [2-(14)C]mevalonate or [5-(14)C]mevalonate. Therefore, in liver and kidney, under the conditions of this study, either one or more pathways other than the shunt pathway, by which mevalonate can be metabolized to other than sterols, is operative to a marked degree, or estimates of the shunt pathway's contributions as judged by yields of (14)CO(2) from [2-(14)C]mevalonate and [5-(14)C]mevalonate are significantly underestimated.-Brady, P. S., W. C. Schumann, S. Ohgaku, R. F. Scofield, and B. R. Landau. Evidence for an underestimation of the shunt pathway of mevalonate metabolism in slices of livers and kidneys from fasted rats and rats in diabetic ketosis.

Animals↗
PubMed1994

A report on selective radiofrequency ablation of dual atrioventricular node pathways in 34 cases.

Selective ablation of slow pathway by radiofrequency (RF) current in 34 patients with atrioventricular (AV) node pathways and tachycardia was performed with two methods in our section; posterior approach was used in the first 12 patients, the slow pathways were ablated successfully. Inferior approach was performed in the other 22 patients. Slow pathways were interrupted in 14 patients. Retrograde fast pathways and/or slow pathways were ablated in 6 patients. Retrograde fast pathways and slow pathways were abolished and antegrade fast pathways were injured transitorily in 2 cases. The total procedure time was shorter, RF applications were fewer by inferior approach than by posterior approach (P < 0.05). Both antegrade and retrograde conduction of fast pathways had not been affected after slow pathways were ablated (P > 0.05). After a mean of 8 months follow-up, two patients recurred and were ablated successfully again. We come to the conclusion that inferior approach might be a preferable method compared with posterior approach; the slow pathways is the compact node and its posterior input of transitional cells; the retrograde fast pathway may be the anterior superficial group of transitional cells and is not always in the same location of antegrade fast pathway.

Adult↗
PubMed2002

Assessing clinical pathways use in a community hospital: it depends on what "use" means.

BACKGROUND: Many benefits have been associated with the use of clinical pathways, yet developing them can be costly, and implementing them is not always successful. A 300-bed Midwestern community hospital began a clinical pathways program in 1995, and by fall 1998, 15 pathways were in various stages of implementation, with 3 under development. Many challenges had been encountered, but hospital leaders were eager to find ways to increase pathway use. METHODS: A qualitative case study design was used to investigate four clinical pathways, two perceived as being "used" and two that were perceived as "not used". Each pathway was analyzed as a separate case, followed by cross-case analysis. Qualitative data were collected in 65 semistructured interviews with administrators, physicians, physicians' office staff, nurses, and allied health professionals at the hospital. Data were also collected through observation and document analysis. RESULTS: The two used pathways had been introduced as part of a larger change in care, whereas the two pathways not used had been introduced as stand-alone innovations. Confusing and inadequately developed aspects of the hospital's clinical pathways program included its purposes, the definition of pathway use, pathway procedures, accountability, education, and incentives. A new case management department, ongoing administrative support, and a sophisticated medical information system were viewed as supports for continued growth in the program. CONCLUSIONS: Implementation of clinical pathways was delayed and complicated by the varied perceptions of the program among stakeholders. Lack of clarity and consistency in how information about the program was communicated made it difficult for clinicians to develop a shared understanding of clinical pathways.

Attitude of Health Personnel↗