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The fossil dinosaur bone material, 80 million years old was studied. Samples for analysis were prepared with specially elaborated methods. Images obtained in the light, transmission electron, and scanning electron microscopes revealed the spatial distribution of the osteocytes lying near and far from the vascular canal. Osteocytes of particular kind were found to be present in the immediate vicinity of the canal. The characteristic morphological structure and the localization of this osteocytes between the vascular canal and the osteocytes lying farther from the canal, as well as the mediation of this cell in the system of connections between those elements, served as a basis for the separation of this cells as the intermediary osteocyte. Among the osteocytes situated farther from the vascular canal, three kinds were distinguished: mono-, bi-, and multipolar, according to the kinds of processes and their distribution in relation to the mother cell body. By analogy with modern bone, in dinosaur bone specific functions may be ascribed to the distinguished types of osteocytes and to their differentiated processes in the conduction of nutrient and building elements and metabolites from the vascular canal to the intermediary osteocytes and, with their participation, to other osteocytes lying farther from the canal. This should naturally be analysed as the two-way tract.
Under normal conditions, TFPI expression is restricted to megakaryocytes and the endothelium of the microvasculature. It is not synthesized by normal hepatocytes or by the endothelium of larger vessels. In contrast, endothelium and peripheral blood cells do not express tissue factor under normal conditions. Expression of tissue factor under normal physiologic conditions is widespread and is localized in areas which are physically separated from the circulating blood. During an inflammatory response, circulating monocytes have been shown to express tissue factor, whereas in general, expression of tissue factor has not been observed in the endothelium. Adherent monocytes/macrophages express both tissue factor and TFPI under pathologic conditions. Whether or not circulating peripheral blood monocytes under inflammatory conditions express TFPI is not known.
Dithiothreitol (DTT) activation of the adhesive function of several different integrins suggests the existence of a common DTT-sensitive integrin regulatory element. Ui11/E3, a natural killer (NK) cell-resistant murine target cell line genetically engineered to constitutively express human intercellular adhesion molecule-1 (ICAM-1; CD54) was used in a flow cytometric experimental model to evaluate DTT effects on the NK cell integrin adhesion molecule, leukocyte function antigen-1 (LFA-1; alpha L beta 2, CD11a/CD18). DTT and several structurally related dithiol compounds elicited a dramatic elevation in conjugate formation that was dependent on target cell ICAM-1 expression, was blocked by LFA-1 alpha L or beta 2 chain-specific antibodies, and occurred in the absence of Ui11/E3 target cell exposure to DTT or quantitative changes in NK cell membrane LFA-1 expression. This avidity modulation of LFA-1 by DTT required actin polymerization, was abrogated by the protein kinase C inhibitor calphostin C, involved activities of calyculin A- and okadaic acid-sensitive serine/threonine protein phosphatases PP-1 and/or PP-2A but not geldanamycin-sensitive tyrosine kinases, and differed with respect to kinetics and enzyme inhibitor sensitivity from LFA-1 activation promoted by cross-linking of NK cell CD16 or phorbol ester treatment. A key structural feature of DTT was the presence of two thiol groups, both reduced but not physically adjacent as in the nonstimulatory dithiol, 2,3-dimercaptopropanol. LFA-1 activation was not because of DTT chelation of Ca2+ or Zn2+. Immunoblotting studies identified multiple NK cell plasma membrane-associated proteins to be reduced by DTT under LFA-1-activating conditions, but similar effects were also promoted by reducing agent treatments that failed to alter adhesive function. Direct chemical modification of LFA-1 seemed an unlikely basis of activation because (1) DTT activated LFA-1 in HSB2 T cells without detectable disulfide reduction in LFA-1 alpha L or beta 2 chains immunoprecipitated from these cells and (2) DTT treatment of NK cells did not hinder binding of KIM127 and KIM185, monoclonal antibodies that recognize epitopes in the potentially DTT-susceptible cysteine-rich domain of the beta 2 chain. Thus, these results extended the range of DTT-activatible integrins to include NK cell LFA-1 and characterized for the first time signaling-associated enzymatic activities involved in DTT activation of NK cell LFA-1. Moreover, they suggested that structural features of DTT, particularly SH group spatial positioning, are important in LFA-activation for reasons other than cation chelation or disulfide reduction.(ABSTRACT TRUNCATED AT 400 WORDS)
Interleukin-2 (IL-2) induces DNA binding of STAT5, a member of the family of cytokine-regulated transcription factors termed 'signal transducers and activators of transcription'. IL-2-stimulated STAT5-DNA complexes include two tyrosine phosphoproteins which exhibit distinct mobilities in SDS-PAGE gels. Our studies have shown that IL-2 rapidly induces both tyrosine phosphorylation and serine phosphorylation of STAT5 and that the two STAT5 tyrosine phosphoproteins detected in IL-2-activated cells differ in their levels of phosphorylation on serine residues. The two different phosphoforms of STAT5 have identical in vitro DNA binding specificity and reactivity with tyrosine phosphopeptides, but differ in their cellular localization. As well, the present data indicate that the transcriptional activity of STAT5 is regulated by serine kinases in T lymphocytes. Two previously characterized serine kinases activated by IL-2, MAP kinase/ERK2 and p70 S6 kinase, do not appear to be involved in STAT5 regulation by this cytokine. Accordingly, STAT5 activation in T cells requires the convergent action of tyrosine kinases and a distinct serine/threonine kinase which has not previously been implicated in IL-2 signalling.
The tyrosine phosphatase specific inhibitor pervanadate is a potent activator of T lymphocytes through induction of tyrosine phosphorylation and downstream events of the activation cascade. Using CD45- or CD3-negative variants of the Jurkat leukemic T-cell line we show that the different biochemical events induced by pervanadate appeared to be dependent on the presence at the cell surface of either CD45 or CD3. CD45-dependent events such as tyrosine phosphorylation of Shc, activation of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), transcription factors, and stimulation of interleukin-2 (IL-2) promoter and of CD69 and CD25 surface expression paralleled activation of the tyrosine kinases lck and fyn. By contrast, stimulation of calcium influx, a CD3-dependent event, paralleled zap-70 activation. The data demonstrate that the T-cell antigen receptor-CD3 (TcR-CD3) complex is functionally linked to two different protein tyrosine kinase (PTK) modules with separate specific functions and that CD45 may be an important regulator of this coupling.
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MOTIVATION: We seek to determine the accuracy of computational methods for predicting metabolic pathways in sequenced genomes, and to understand the contributions of both the prediction algorithms, and the reference pathway databases used by those algorithms, to the prediction accuracy. RESULTS: The comparisons we performed were as follows. (1) We compared two predictions of the pathway complements of Helicobacter pylori that were computed by an early version of our pathway-prediction algorithm: prediction A used the EcoCyc E. coli pathway DB as the reference database (DB) for prediction, and prediction B used the MetaCyc pathway DB (a superset of EcoCyc) as the reference pathway DB. The MetaCyc-based prediction contained 75% more pathway predictions, but we believe a significant number of those predictions were false positives. (2) We compared two predictions of the pathway complement of H. pylori that used MetaCyc as the reference pathway DB, but that used different algorithms: the original PathoLogic algorithm, and an enhanced version of the algorithm designed to eliminate false-positive pathway predictions. The improved algorithm predicted 30\% fewer metabolic pathways than the original algorithm; all of the eliminated pathways are believed to be false-positive predictions. (3) We compared the 98 pathways predicted by the enhanced algorithm with the results of a manual analysis of the pathways of H. pylori. Results: 40 of the computationally predicted pathways were consistent with the manual analysis, 13 pathways are considered false-positive predictions, and four pathways had partially overlapping topologies. Twenty-six predicted pathways were not mentioned in the manual analysis; we believe these are correct predictions by PathoLogic that were not found by the manual analysis. Five pathways from the manual analysis were not found computationally. Agreement between the computational and manual predictions was good overall, with the computational analysis inferring many pathways that the manual analysis did not identify. Ultimately the manual analysis is also partially speculative, and therefore is not an absolute measure of correctness. The algorithm is designed to err on the side of more false positives to bring more potential pathways to the user's attention. The resulting H. pylori pathway DB is freely available at http://ecocyc.org:1555/HPY/organism-summary?object=HPY. AVAILABILITY: The Pathway Tools software is freely available to academic users, and is available to commercial users for a fee. Contact pkarp@ai.sri.com for information on obtaining the software.
OBJECTIVES: This study sought to investigate electrophysiologic characteristics and possible anatomic sites of multiple anterograde slow atrioventricular (AV) node pathways and to compare these findings with those in dual anterograde AV node pathways. BACKGROUND: Although multiple anterograde AV node pathways have been demonstrated by the presence of multiple discontinuities in the AV node conduction curve, the role of these pathways in the initiation and maintenance of AV node reentrant tachycardia (AVNRT) is still unclear, and possible anatomic sites of these pathways have not been reported. METHODS: This study included 500 consecutive patients with AVNRT who underwent electrophysiologic study and radiofrequency ablation. Twenty-six patients (5.2%) with triple or more anterograde AV node pathways were designated as Group I (16 female, 10 male, mean age 48 +/- 14 years), and the other 474 patients (including 451 with and 23 without dual anterograde AV node pathways) were designated as Group II (257 female, 217 male; mean age 52 +/- 16 years). RESULTS: Of the 21 patients with triple anterograde AV node pathways, AVNRT was initiated through the first slow pathway only in 3, through the second slow pathway only in 8 and through the two slow pathways in 9. Of the five patients with quadruple anterograde AV node pathways, AVNRT was initiated through all three anterograde slow pathways in three and through the two slower pathways (the second and third slow pathways) in two. After radiofrequency catheter ablation, no patient had inducible AVNRT. Eleven patients (42.3%) in Group I had multiple anterograde slow pathways eliminated simultaneously at a single ablation site. Eight patients (30.7%) had these slow pathways eliminated at different ablation sites; the slow pathways with a longer conduction time were ablated more posteriorly in the Koch's triangle than those with a shorter conduction time. The remaining seven patients (27%) had a residual slow pathway after delivery of radiofrequency energy at a single or different ablation sites. The patients in Group I had a longer tachycardia cycle length, poorer retrograde conduction properties and a higher incidence of multiple types of AVNRT than those in Group II. CONCLUSIONS: Multiple anterograde AV node pathways are not rare in patients with AVNRT. However, not all of the anterograde slow pathways were involved in the initiation and maintenance of tachycardia. Radiofrequency catheter ablation was safe and effective in eliminating critical slow pathways to cure AVNRT.
BACKGROUND/OBJECTIVES: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. METHODS: We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. RESULTS: Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. CONCLUSIONS: This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.
INTRODUCTION: Recent studies have demonstrated that the most common site of accessory pathway conduction block following the introduction of a premature atrial stimulus during atrial pacing is between the accessory pathway potential and the ventricular electrogram, consistent with block at the ventricular insertion of the accessory pathway. However, no prior study has evaluated the site of conduction block during radiofrequency catheter ablation procedures. Therefore, the objective of this study was to determine the site of conduction block after catheter ablation of accessory pathways by analyzing and comparing the local electrograms recorded before and after radiofrequency energy delivery at successful ablation sites. METHODS AND RESULTS: The electrograms evaluated in this study were obtained from 85 consecutive patients who underwent successful radiofrequency catheter ablation of a manifest accessory pathway. The 50 left free-wall accessory pathways were ablated using a ventricular approach and the 35 right free-wall or posteroseptal accessory pathways were ablated using an atrial approach. The characteristics of local electrograms recorded immediately before and immediately after successful ablation of the accessory pathway were determined in each patient. The site of accessory pathway block was determined by comparing the amplitude, timing, and morphology of the local electrograms at successful sites of radiofrequency catheter ablation before and after delivery of radiofrequency energy. A putative accessory pathway potential was present at the successful target site in 74 of the 85 patients (87%). Conduction block occurred between the atrial electrogram and the accessory pathway potential in 66 patients (78%) and between the accessory pathway potential and the ventricular electrogram in eight patients (9%). The site of block could not be determined in 11 patients (13%) in whom an accessory pathway potential was absent. Conduction block occurred most frequently between the atrial electrogram and the accessory pathway potential regardless of accessory pathway location. No electrogram parameter or accessory pathway characteristic was predictive of the site of conduction block. CONCLUSION: The results of this study demonstrate that conduction block occurs most frequently between the local atrial electrogram and the accessory pathway potential during radiofrequency catheter ablation of accessory pathways. This is true regardless of whether the accessory pathway is ablated from the atrial or ventricular aspect of the mitral or tricuspid annulus.
So-called "Mahaim-pathways" represent a distinct subset of accessory pathways and the preexcitation syndromes with unique electrophysiologic properties. During sinus rhythm, preexcitation is minimal or absent whereas incremental atrial stimulation reveals preexcitation with a left bundle branch block like morphology. "Mahaim-fibers" exhibit long conduction times, decremental conduction properties by atrial extrastimuli or incremental atrial pacing, and conduction only in the anterograde direction. The typical atrioventricular reentrant tachycardia incorporating a "Mahaim-pathway" is a preexcited antidromic tachycardia with anterograde conduction over the accessory pathway and retrograde conduction over the AV node. "Mahaim-fibers" may be associated with dual AV node physiology or common atrioventricular accessory pathways. The original concept of "Mahaim-fibers" consisted of accessory pathways originating in the AV node and inserting into the distal right bundle branch ("nodofascicular" pathways) or the right ventricle ("nodoventricular" pathways). This understanding has been challenged by surgical interventions identifying the atrial insertion of "Mahaim-pathways" at the parietal tricuspid annulus. Later, electrophysiologic and surgical studies have confirmed the antero-to posterolateral atrial origin of these accessory pathways remote from the atrioventricular node. Therefore, the concept of nodoventricular pathways has been replaced by the concept of atriofascicular pathways. Recently, endocardial catheter mapping and radiofrequency catheter ablation have substantially contributed to the characterization of this unusual form of the preexcitation syndrome. Distinct, high-frequency activation potentials of atriofascicular accessory pathways can be recorded at the atrial insertion at the antero- to posterolateral tricuspid annulus and along the entire ventricular course up to the ventricular insertion in the right ventricular apical region near or at the distal right bundle branch. The long conduction times and the decremental conduction properties result from a delay in the interval from the local atrial activation at the atrial insertion to the activation potential of the accessory pathway whereas the conduction time between the activation potential of the accessory pathway and the local activation at the ventricular insertion is relatively constant. Overall, the current knowledge about atriofascicular pathways is indicative of a proximal AV-node-like component and a distal bundle-branch-like component and, therefore, suggestive of an accessory AV conduction system. Radiofrequency current application for ablation of atriofascicular pathways can be accomplished at their atrial insertion and along their entire ventricular course. Highfrequency activation potentials of the atriofascicular pathways identify target sites for ablation. Transient mechanical conduction block by catheter manipulation at the subannular level of the atrial insertion has also been introduced as a marker for successful ablation of these unusual accessory pathways.
OBJECTIVES: To evaluate the effectiveness of procedure-specific surgical critical pathways on reducing resource utilization in a university surgical intensive care unit (ICU). DESIGN AND SETTING: Prospective cohort study in a university surgical ICU. PATIENTS: 194 patients, accounting for 255 patient days, sampled on randomly selected days over a 12-month period of time. MEASUREMENTS AND RESULTS: The primary outcomes of this study were pathway eligibility and laboratory utilization. Patients were eligible for a procedure-specific pathway in 34% of patient days identified, and the patient's clinical course was "on" pathway in 22% of patient days. Of those "on" the pathway, 54% had a pathway present in the chart and 32% of these included documentation of the patient's clinical course. Thus in 78% of the patient days the patient was either not eligible for a critical pathway or the patient's clinical course was "off" pathway. In those patients "on" the pathway 46 % did not have a pathway present in the chart. Being on a critical pathway did not reduce laboratory utilization. Laboratory utilization did not vary between patients "on" and "off" the pathway (19.1 +/- 11.3 laboratory tests/patient day versus 20.4 +/- 5.7 laboratory tests/patient day). Predicted laboratory utilization by the pathway was 5.6 laboratory tests/patient day. By reducing actual laboratory utilization to that predicted by the critical pathway we would reduce laboratory utilization at our institution by $1.2 million per year. CONCLUSIONS: Procedure-specific surgical critical pathways are not an effective tool for reducing resource utilization in our ICU. Most of our patients were not eligible for an available pathway, and those who were eligible and were "on" the pathway did not appear to have laboratory utilization guided by the pathway. Future initiatives need to explore other means such as ICU-specific care processes to reduce resource utilization in the ICU.
INTRODUCTION: AV nodal reentrant tachycardia (AVNRT) usually involves anterograde conduction over a slowly conducting ("slow") pathway and retrograde conduction over a rapidly conducting ("fast") pathway. A variety of drugs, such as beta blockers, digitalis, and calcium channel blockers, have been reported to prolong AV nodal refractoriness in both the anterograde and retrograde limbs of the circuit. However, few data are available that address whether the fast and slow pathways respond in a quantitatively different manner to drugs such as beta-adrenergic antagonists. In addition, it is not known whether the effects of these agents on refractoriness parallel the effects on conduction in the fast and slow pathways. The present study was performed to measure the effect of the intravenous beta-adrenergic agent, esmolol, on refractoriness and conduction in both the fast and slow AV nodal pathways in patients with AVNRT. METHODS AND RESULTS: Thirteen patients with discontinuous AV nodal conduction properties and typical AVNRT were studied. Anterograde and retrograde AV nodal functional assessment was performed at baseline and following steady-state drug infusion of intravenous esmolol at a dose of 500 micrograms/kg for 1 minute, 150 micrograms/kg per minute for the next 4 minutes, followed by a continuous maintenance infusion of 50 to 100 micrograms/kg per minute. The anterograde effective refractory period of the fast pathway increased from 381 +/- 75 msec at baseline to 453 +/- 92 msec during the infusion of esmolol (P = 0.003). The anterograde effective refractory period of the slow pathway was also prolonged by esmolol, from 289 +/- 26 msec to 310 +/- 17 msec (P = 0.005). However, the absolute magnitude of the change in the anterograde effective refractory period of the fast pathway (+72 +/- 59 msec) was significantly greater than the change in anterograde effective refractory period of the slow pathway (+21 +/- 16 msec, P = 0.01). The mean retrograde effective refractory period of the fast pathway increased from 276 +/- 46 msec to 376 +/- 61 msec during esmolol infusion (P = 0.03). Retrograde slow pathway conduction that could not be demonstrated at baseline became manifest in three patients during esmolol infusion. In contrast to the effects of esmolol on refractoriness, the AH interval during anterograde slow pathway conduction prolonged to a far greater extent (+84 msec) than the HA interval associated with retrograde fast pathway conduction (+5 msec, P = 0.04). CONCLUSION: The beta-adrenergic antagonist, esmolol, has a quantitatively greater effect on anterograde refractoriness of the fast than the slow AV nodal pathway. However, the effects on conduction intervals during AVNRT are greater in the anterograde slow pathway than in the retrograde fast pathway. These observations suggest that the fast and slow pathways may have differential sensitivities to autonomic influences. This difference in the response to beta-adrenergic antagonists may be exploited as a clinically useful method for demonstrating slow pathway conduction in some individuals with AVNRT.
Published data on the relationship between dual AV node pathway physiology, locations and numbers of accessory pathways are limited. The purpose of this study is to appraise the dual AV node pathway physiology in a large group of patients with accessory AV pathways. A consecutive series of 759 patients was included for analysis. The incidence of antegrade or retrograde dual AV node pathway physiology and AV node reentrant tachycardia was similar for patients with accessory pathway at different locations. However, the incidence of bidirectional dual AV node pathway physiology (11.1%) and fast-slow type AV node reentrant echo (8.3%) was significantly higher in anteromidseptal accessory pathways. The incidence of antegrade (24.2% vs. 30.8%, P > 0.05), retrograde (4.9% vs. 2.9%, P > 0.05) and bidirectional dual AV node pathway physiology (3.0% vs. 2.9%, P > 0.05) was similar between the patients with a single pathway and multiple accessory pathways. Furthermore, the patients with multiple accessory pathways had a higher incidence of slow-fast form AV node reentrant tachycardia (8.8% vs. 3.0%, P = 0.034) and fast-slow form AV node reentrant echo (8.8% vs. 2.7%, P = 0.02). Thirty-four patients (4.5%) received slow pathway ablation for AV node reentrant tachycardia and none had recurrent tachycardia during the follow up period (26 +/- 7, range 1-56 months). We conclude that it is possible to find dual AV node pathway physiology in patients with accessory pathways because this phenomenon was not rare, especially in patients with a single pathway located in the anteromidseptal area or in patients with multiple accessory pathways.