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PubMed2005

Nox 2 stimulates muscle differentiation via NF-kappaB/iNOS pathway.

The NF-kappaB/iNOS pathway stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway and diverse antioxidants block muscle differentiation. Therefore, we here investigated whether Nox 2 links those two myogenic pathways in H9c2 and C2C12 myoblasts. Compared with the proliferation stage, ROS generation was enhanced from the early stage of differentiation and gradually increased as differentiation progressed. Antioxidants suppressed the activated NF-kappaB/iNOS pathway during muscle differentiation. Nox 2 activity was also increased during muscle differentiation. Treatment with DPI and apocynin, two inhibitors of NADPH oxidase, and suppression of Nox 2 expression using siRNA, but not Nox 1, inhibited NADPH oxidase activity, muscle differentiation, and the NF-kappaB/iNOS pathway. Inhibition of PI 3-kinase and p38 MAPK suppressed the Nox 2/NF-kappaB/iNOS pathway. Nitric oxide restored muscle differentiation blocked by treatment with antioxidants or suppression of the Nox 2/NF-kappaB/iNOS pathway. In conclusion, Nox 2 stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway by activating the NF-kappaB/iNOS pathway via ROS generation.

Animals↗

PubMed2006

The combined use of esophageal electrocardiogram and multiple right parasternal chest leads in the diagnosis of PSVT and determination of accessory pathways involved: a new simple noninvasive approach.

INTRODUCTION: Paroxysmal Supraventricular Tachycardia (PSVT) resulting from any cause can at times lead to diagnostic difficulty mainly when due to AVNRT and AVRT. In this study we used a non-invasive approach using esophageal ECG (ECGe) and ECG derived from the various right parasternal chest leads (RPCL) to correctly diagnose the type of PSVT as well the accessory pathways involved in AVRT. METHODS AND RESULTS: We studied a total of 161 patients (89 male) all having a history of palpitation. All the patients underwent routine 12 lead ECG, ECGe, RPCL and electrophysiologic study. With use of ECGe and RPCL, 71 (44.1%) were diagnosed as having AVNRT and 90 (55.9%) having AVRT with various accessory pathways compared to only 49 (30.4%) and 22 (13.7%) respectively with routine 12 lead ECG. With combined ECGe and RPCL, 80 (49.7%) showed accessory pathway in the left free wall, 4 (2.5%) showed in the right free wall, 6 (3.7%) septal accessory pathway, 60 (37.3%) in the anterior wall and 30 (18.6%) in the posterior wall. In comparison, EPS could show accessory pathways in the left free wall in 81 (50.3%), in the right free wall in 5 (3.1%), in the septum in 4 (2.5%), in the anterior wall in 53 (32.9%) and in the posterior wall in 37 (23.0%) out of the 161 patients. CONCLUSIONS: ECGe+RPCL can be used as a reliable noninvasive diagnostic tool to identify the nature of tachycardia and the pathways involved in the reentrant ring of PSVT especially in those with multiple atrioventricular accessory pathways or a combination of atrioventricular accessory pathways and dual atrioventricular nodal pathway.

Adolescent↗

PubMed2004

Rapid signalling pathway activation by androgens in epithelial and stromal cells.

Estradiol rapidly activates Src as well as the Src-dependent pathway in human mammary cancer-derived MCF-7 cells, in human prostate cancer-derived LNCaP cells and in Cos cells transiently expressing hERs [EMBO J. 15 (1996) 1292; EMBO J. 17 (1998) 2008]. In addition, estradiol immediately stimulates, yes, an ubiquitous member of the Src kinase family, in human colon carcinoma-derived Caco-2 cells [Cancer Res. 56 (1996) 4516]. Progestins and androgens activate the same pathway in human mammary and prostate cancer-derived cells [EMBO J. 17 (1998) 2008; EMBO J. 19 (2000) 5406]. We observed that estradiol also stimulates the phosphatidylinositol-3-kinase (PI3K)/AKT pathway in MCF-7 cells [EMBO J. 20 (2001) 6050]. In these cells, activation of the Src- and the PI3 K-dependent pathways is simultaneous and mediated by direct interactions of the two kinases with ERalpha. The signalling pathway activation by sex-steroid hormones leads to DNA synthesis and cell growth in human mammary and prostate cancer-derived cells [EMBO J. 19 (2000) 5406; EMBO J. 20 (2001) 6050; EMBO J. 18 (1999) 2500]. Furthermore, androgen stimulation of NIH3T3 fibroblasts activates the same pathways triggered by this hormone in LNCaP cells and promotes the S-phase entry or cytoskeleton changes in these cells [J. Cell Biol. 161 (2003) 547]. All the described effects are rapid and require classic steroid receptors, but, surprisingly, not their transcriptional activity. Indeed, a transcriptionally inactive mutant of hER mediates the estrogen-stimulated DNA synthesis of NIH3T3 fibroblasts [EMBO J. 18 (1999) 2500]. Furthermore, AR in NIH3T3 cells does not enter nuclei and is unable to respond to the hormone with transcription stimulation, whereas it activates signaling pathways and triggers important biological responses. Signaling pathway activation by steroids has also been described by other groups under different experimental conditions and/or in different cell types. In these cells, steroid stimulation triggers various effects, such as neuroprotection, vasorelaxation or bone protection [J. Neurosci. Res. 60 (2000) 321; Nature 407 (2000) 538; J. Cell Biochem. 76 (1999) 206]. Analysis of the mechanisms responsible for the hormone-dependent and steroid receptor-mediated pathway activation in epithelial as well as stromal cells reveals immediate association of steroid receptors with extranuclear signaling effectors [EMBO J. 17 (1998) 2008; Cancer Res. 56 (1996) 4516; EMBO J. 19 (2000) 5406; EMBO J. 20 (2001) 6050; J. Cell Biol. 161 (2003) 547]. These results further highlight the central role of the hormone-regulated protein-protein interactions in the steroid action. They also offer the possibility of interfering with important activities of hormones, such as proliferation or survival, cytoskeleton changes as well as invasiveness and vasorelaxation, without affecting the steroid effects that depend on receptor transcriptional activity.

Androgens↗

PubMed1997

Atrioventricular node reentrant tachycardia in patients with a long fast pathway effective refractory period: clinical features, electrophysiologic characteristics, and results of radiofrequency ablation.

Twenty-two patients (group 1) with AV node reentrant tachycardia and a baseline fast pathway effective refractory period (ERP) > or = 500 msec were compared with 30 consecutive patients (group 2) with AV node reentrant tachycardia and a fast pathway ERP < 500 msec. Both groups underwent slow pathway ablation. In the patients with complete elimination of slow pathway, the fast pathway ERP and shortest 1:1 conduction cycle length shortened significantly after ablation but was greater in group 1 (n = 14) than in group 2 (n = 21) (125 +/- 78 msec vs 48 +/- 29 msec, p < 0.001 and 103 +/- 72 msec vs 52 +/- 30 msec, p < 0.001, respectively). In group 1, the shortening of fast pathway ERP was correlated to baseline difference between anterograde fast and anterograde slow ERP (r = 0.806, p < 0.001, slope = 1.08), and the shortening of fast pathway shortest 1:1 conduction cycle length was correlated to baseline difference between anterograde fast and anterograde slow shortest 1:1 conduction cycle length (r = 0.885, p < 0.001, slope = 1.47). During follow-up bradycardia did not develop in any patient and no one required pacing. This shortening of the fast pathway ERP and shortest 1:1 conduction cycle length after complete elimination of slow pathway reduced the concern of subsequent impairment of AV node conduction.

Adrenergic beta-Agonists↗

PubMed2001

Activation pathways of 5-fluorouracil in rat organs and in PC12 cells.

Activation of the pyrimidine analogue 5-fluorouracil (5-FU) to the ribonucleotide level may occur through one of the following three pathways: 1) the 5-phosphoribosyl 1-pyrophosphate (PRPP)-mediated direct transfer of ribose 5-phosphate to 5-FU as catalysed by orotate phosphoribosyltransferase; 2) the ribose 1-phosphate (Rib1-P)-mediated addition of ribose by uridine phosphorylase, followed by the action of uridine kinase; and 3) the 2'-deoxyribose 1-phosphate (deoxyRib1-P)-mediated addition of deoxyribose, thought to be catalysed by thymidine phosphorylase, followed by the action of thymidine kinase. Many of the conclusions as to the precise pathways by which normal tissues and different cell lines activate uracil are indirectly derived from drug interactions affecting the availability of the substrates of the three pathways, or from measurement of activities of the enzymes metabolising 5-FU in normal tissues and tumours. In previous papers (Cappiello et al. Biochim Biophys Acta 1998;1425:273--81; Mascia et al. Biochim Biophys Acta 1999;1472:93--8), we assessed the molecular mechanisms by which the natural base uracil is salvaged in vitro to uracil ribonucleotides and deoxyribonucleotides in rat liver and brain. In this paper, we investigated the pathways of 5-FU activation to cytotoxic ribonucleotide and deoxyribonucleotide levels in normal rat tissues and PC12 cell extracts. The results clearly showed that normal rat tissues activated 5-FU mainly via the Rib1-P pathway, and to a lesser extent via the PRPP pathway. The deoxyRib1-P pathway was absent. PC12 cells activated 5-FU mainly via the PRPP pathway and to a lesser extent by the other two pathways.

Animals↗

PubMed1980

Enhanced atrioventricular nodal conduction in a patient with dual extranodal pathways.

A patient was admitted to the hospital with wide complex tachycardia and a history of recurrent palpitations. Electrophysiologic studies showed evidence of dual atrioventricular (AV) accessory pathways. One proved to be an anteroseptal (possible right anterior) pathway probably capable of only unidirectional conduction. The other pathway was in the posterior septum and conducted only in the retrograde direction. The tachycardia circuit involved anterograde conduction via either the AV node-His axis or the anteroseptal pathway and retroconduction over the posteroseptal accessory pathway. In addition, enhanced AV nodal conduction coupled with two accessory AV nodal pathways has rarely been described in English medical literature. Previous reports have carefully described anatomic, electrocardiographic, and electrophysiologic evidence of more than one accessory pathway in patients with the Wolff-Parkinson-White syndrome. The introduction of surgical techniques for ablation of an accessory pathway demands precision in the electrophysiologic evaluation of patients with ventricular preexcitation. Reported herein is a patient with the unique finding of two extranodal accessory pathways and enhanced atrioventricular (AV) nodal conduction (or AV nodal bypass).

Atrioventricular Node↗

PubMed1996

A new ECG algorithm for the localization of accessory pathways using only the polarity of the QRS complex.

A new algorithm is proposed for localization of accessory atrioventricular pathways by use of a 12-lead electrocardiogram (ECG). The polarity of the QRS complex in leads III, V1, and V2 from 102 patients with Wolff-Parkinson-White syndrome with manifested preexcitation who underwent successful radiofrequency catheter ablation was analyzed. Accessory pathways on the right side of the heart were localized to three regions around the tricuspid annulus, and left-sided pathways were localized to two regions around the mitral valve annulus. In 42 of 46 patients (91%) with left posterolateral accessory pathways, a common characteristic of the ECG was a positive QRS complex in leads III and V1 (sensitivity 91%, specificity 95%). Of 19 patients with left inferior paraseptal or inferior accessory pathways, 16 (84%) had a negative QRS complex in lead III and a positive QRS complex in lead V1 (sensitivity 84%, specificity 98%). All six patients with right anterosuperior paraseptal accessory pathways had a positive QRS complex in lead III but a negative QRS complex in lead V1 (sensitivity 100%, specificity 97%). The 25 patients with right inferior paraseptal or inferior accessory pathways had a negative or isodiphasic QRS complex in leads III and V1, but the QRS complex was positive in lead V2 in 21 (84%) of these patients (sensitivity 84%, specificity 100%). Finally, five of the six patients (83%) with right anterior accessory pathways had a negative QRS complex in leads III, V1, and V2 (sensitivity 83%, specificity 96%). With the algorithm, the localization of accessory pathways was thus identified in 90 of the 102 patients (88%).

Adolescent↗

PubMed2001

Signal transduction pathways and the modification of chromatin structure.

Mechanical and chemical signaling pathways are involved in transmitting information from the exterior of a cell to its chromatin. The mechanical signaling pathway consists of a tissue matrix system that links together the three-dimensional skeletal networks, the extracellular matrix, cytoskeleton, and karyoskeleton. The tissue matrix system governs cell and nuclear shape and forms a structural and functional connection between the cell periphery and chromatin. Further, this mechanical signaling pathway has a role in controlling cell cycle progression and gene expression. Chemical signaling pathways such as the Ras/mitogen-activated protein kinase (MAPK) pathway can stimulate the activity of kinases that modify transcription factors, nonhistone chromosomal proteins, and histones. Activation of the Ras/MAPK pathway results in the alteration of chromatin structure and gene expression. The tissue matrix and chemical signaling pathways are not independent and one signaling pathway can affect the other. In this chapter, we will review chromatin organization, histone variants and modifications, and the impact that signaling pathways have on chromatin structure and function.

Acetyltransferases↗

PubMed1995

Developing and evaluating an emergency nursing orientation pathway.

OBJECTIVE: Orientee evaluation forms frequently focus on tasks and technical skills rather than decision-making skills. An orientation pathway was developed to evaluate orientee clinical decision-making skills. The pathway can assist in identifying orientees who require additional educational resources or interventions. Early interventions may decrease the length of orientation, increase an employee's length of stay in the institution, and contribute to cost savings. METHODS: The pathway was developed with employee exit interview data, preceptor interviews, identification of critical indicators, and the orientation literature. The pathway consists of six categories. Indicators within each category were identified and ranked according to four levels of proficiency (level 1 for the least proficient and level 4 for the most proficient). A convenience sample of seven ED orientee and preceptor pairs agreed to participate in the pilot use of the pathway. An expected timeline of progress had been developed by a group of 20 preceptors during a preceptor workshop. An average proficiency level (score) was obtained for each category for 12 weeks with the weekly scores plotted on the pathway. This level was compared with the expected proficiency level in each category for each week. Demographic information was obtained from the orientee and preceptor pairs to determine whether certain characteristics facilitate pathway progression. Data were analyzed with frequency distributions, and measures of central tendency and variance. Spearman's rank correlations were used to examine the proficiency level in each category for each week in relation to demographic characteristics of the preceptor and orientee. RESULTS: Orientees progressed faster than expected in all categories. It took 8 weeks for an orientee to attain the highest proficiency level in all categories. The fastest progress was made in the category " Accurately Evaluates Patient Responses." Slowest progress was made in the category "Safety in Blood and Drug Administration." Preceptors and orientees rated in the pathway as very useful. DISCUSSION: Further studies with the orientation pathway may help to determine the ideal time frame for orientation, characteristics of orientees who progress as expected or faster, and educational strategies to facilitate orientee progression and clinical decision making.

Clinical Competence↗

PubMedDate not supplied

C-type lectins and galectins mediate innate and adaptive immune functions: their roles in the complement activation pathway.

In recent years, a 'new' pathway for complement activation mediated by the mannose-binding lectin (MBL) has been described as a key mechanism for the mammalian acute phase response to infection. This complement activation pathway is initiated by a non-self recognition step: the binding of a humoral C-type lectin [mannose-binding lectin (MBL)] to microbial surfaces bearing 'foreign' carbohydrate determinants. The recognition factor, MBL, is associated with a serine protease [MBL-associated serine protease (MASP)] which, upon MBL binding to the microbial ligand, activates the complement component C3, leading to either (a) phagocytosis of the opsonized target via the complement receptor, or (b) humoral cell killing via assembly of the membrane attack complex. Galectins (formerly known as S-type lectins) modulate activity of the complement receptor 3 (CR3), the macrophage membrane receptor for complement components C3b and iC3b, downstream products of the MBL pathway which are covalently bound to 'target cells. Galectins also mediate macrophage- and dendrocyte-adhesion to lymphocytes activated by signaling through another C-type lectin, the L-selectin, leading to immunoglobulin-mediated responses. Thus, the functional interplay of MBL, galectins and L-selectin in the acute phase response neutralizes the microbial challenge, and lead to further adaptive immunity. Although the observation of various components of the lectin pathway in different invertebrate species demonstrates the high conservation and ancient roots of the components of innate immunity, there has previously been no evidence supporting the possibility that the integral lectin-mediated complement activation pathway is present in invertebrates. We now have evidence for the coexistence of homologs of all the pathway's key components (MBL, MASP, C3, and galectin) in the protochordate Clavelina picta, suggesting the lectin-mediated pathway of complement activation preceded the immunoglobulin pathway in evolution. Therefore, despite being 'new' to the textbooks, experimental evidence indicates that this pathway is ancient, and has been conserved intact throughout its evolution.

Amino Acid Sequence↗

PubMed2003

FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures.

Neuronal death is a prominent neuropathological component of fetal alcohol syndrome (FAS). Identification of molecular agents and pathways that can ameliorate alcohol-induced cell loss offers possible therapeutic strategies for FAS and potential insight into its pathogenesis. This study investigated the effects of growth factors on cellular survival in alcohol-exposed cerebellar granule cell (CGC) cultures and examined the role of the nitric oxide (NO)-cGMP-PKG (cGMP-dependent protein kinase) pathway in the cell survival-promoting effects of these growth factors. Primary CGC cultures were exposed to 0 or 400 mg/dl ethanol, accompanied by either no growth factor or 30 ng/ml fibroblast growth factor-2 (FGF-2), nerve growth factor (NGF), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF) or epidermal growth factor (EGF). Viable neurons were quantified after 1 day of exposure. Two distinct types of cell survival-promoting effects of growth factors were detectable: (1) a neurotrophic effect, in which the growth factors diminished the background death of neurons that occurred in alcohol-free cultures; and (2) a neuroprotective effect, in which the growth factors diminished alcohol-induced cell death. The various growth factors differed markedly in their patterns of cell survival promotion. While BDNF and FGF-2 exerted both a neurotrophic and a neuroprotective effect, IGF-1 had only a neurotrophic effect and did not protect against alcohol toxicity, and NGF had only a neuroprotective effect and did not diminish background cell death. EGF had neither a neurotrophic nor a neuroprotective effect. In order to determine the role of the NO-cGMP-PKG pathway in the cell survival-promoting effects mediated by growth factors, cultures were exposed to one of several pharmacological inhibitors of the pathway, including NAME, LY83583 and PKG inhibitor. The cell survival-promoting effects of FGF-2, NGF and IGF-1 were all substantially reduced by each of the pathway inhibitors. In contrast, neither the neurotrophic nor the neuroprotective effects of BDNF were altered by any of the pathway inhibitors. Thus, growth factors differ in their patterns of neurotrophic and neuroprotective effects, and they differ in their reliance on the NO-cGMP-PKG pathway. While FGF-2, NGF and IGF-1 all signal their survival-promoting effects through the NO-cGMP-PKG pathway, BDNF does not rely upon this pathway for signal transduction in CGC cultures.

Aminoquinolines↗

PubMed2001

Novel pathway for phosphatidylcholine biosynthesis in bacteria associated with eukaryotes.

Phosphatidylcholine (PC) is the major membrane-forming phospholipid in eukaryotes and can be synthesised by either of two pathways, the CDP-choline pathway or the methylation pathway. Many prokaryotes lack PC, but it can be found in significant amounts in membranes of distantly related bacteria such as Rhizobacteria and Spirochetes. Enzymatic methylation of phosphatidylethanolamine via the methylation pathway was thought to be the only biosynthetic pathway to yield PC in bacteria. However, a novel choline-dependent pathway for PC biosynthesis has been discovered in Sinorhizobium meliloti. In this pathway, a novel enzymatic activity, PC synthase, condenses choline directly with CDP-diacylglyceride to form PC in one step. Surprisingly, genomes of some pathogens (Pseudomonas aeruginosa, Borrelia burgdorferi and Legionella pneumophila) contain genes similar to the sinorhizobial gene for phosphatidylcholine synthase. We, therefore, suggest that the new PC synthase pathway is present in a number of bacteria displaying symbiotic or pathogenic associations with eukaryotes and that the eukaryotic host functions as the provider of choline for this pathway.

Amino Acid Sequence↗

PubMed1992

Catheter ablation from right atrium of anteroseptal accessory pathways using radiofrequency current.

Catheter ablation with radiofrequency current has recently been introduced as a therapeutic regimen for symptomatic patients with the Wolff-Parkinson-White syndrome or atrioventricular (AV) tachycardia mediated by a retrogradely conducting (concealed) accessory AV pathway. These pathways may be located, although infrequently, in the anteroseptal region of the heart in close proximity to the AV node-His bundle conduction system. Any attempt to interrupt an anteroseptal accessory pathway therefore is subject to the potential complication of inadvertent impairment of normal AV conduction. This study was conducted to establish whether abolition of anteroseptal accessory pathways by radiofrequency current aimed at the atrial as opposed to the ventricular insertion of the pathway can be achieved with preservation of AV node-His bundle conduction. Twelve patients (mean age 37 +/- 13 years; 10 with Wolff-Parkinson-White syndrome, 2 with a concealed accessory pathway) were studied. In the majority of patients, radiofrequency current (500 kHz; mean energy 577 +/- 207 J) was applied through a steerable catheter with a long tip electrode placed in the anterior septal space at the atrial aspect of the tricuspid anulus, with the intention to destroy the atrial insertion of the accessory pathway. All pathways were successfully ablated. The AV node or His bundle conduction was not impaired in any patient. Right bundle branch block was induced in two patients (17%). There were no complications related to the procedure. It is concluded that catheter ablation from the right atrium using radiofrequency current provides effective and safe interruption of anteroseptal accessory pathways with good preservation of the normal conduction system.

Adult↗

PubMed1984

Attempted nonsurgical electrical ablation of accessory pathways via the coronary sinus in the Wolff-Parkinson-White syndrome.

Previous canine experiments suggested that transvenous catheters placed in the coronary sinus could be used to deliver limited energy shocks, resulting in fibrosis in the atrial wall and coronary sulcus with sparing of the coronary artery. From the distribution of the fibrosis, it appeared that this approach could be used for attempted ablation of accessory pathways in patients with the Wolff-Parkinson-White syndrome. Eight patients with symptomatic Wolff-Parkinson-White syndrome underwent electrophysiologic testing with attempted ablation of 10 accessory pathways. Shocks were limited to 40 to 80 J, except in one patient who received shocks of 100 and 150 J. From 2 to 26 shocks were given to each accessory pathway. All the accessory pathways were blocked completely immediately after the shocks. Subsequently, evidence of accessory pathway conduction recurred in each patient. Three had early promise of long-term improvement after the procedure, with prolongation of the refractory periods of the accessory pathways during the remainder of the initial hospitalization. Several weeks later, however, there was evidence of return toward original values in two of these. Another patient who appeared not to benefit during her initial hospitalization returned 7 weeks later with very depressed accessory pathway conduction, possibly due to developing fibrosis. The only significant complication occurred in the patient receiving shocks of 100 and 150 J; he had apparent rupture of the coronary sinus requiring pericardial drainage. In two patients in whom nonsurgical ablation was not successful, intraoperative mapping showed that the accessory pathway was located in an area of fibrosis at the site of the attempted ablation. In summary, nonsurgical electrical ablation of accessory pathways via the coronary sinus may be successful using limited energy levels in a few patients. The procedure remains experimental, and widespread application must await more effective means of delivering the shocks.

Adolescent↗

PubMed1997

Induction of atrioventricular node reentrant tachycardia with adenosine: differential effect of adenosine on fast and slow atrioventricular node pathways.

OBJECTIVES: This study sought to evaluate the sensitivity of fast and slow atrioventricular (AV) node pathways to incremental doses of adenosine in patients with typical AV node reentrant tachycardia. BACKGROUND: Although adenosine is known to depress conduction through the AV node, the relative sensitivity to adenosine of the anterograde fast and slow pathways in patients with dual AV node pathways and typical AV node reentrant tachycardia has not previously been studied. METHODS: Sixteen patients with dual AV node physiology and typical AV node reentrant tachycardia and 10 control patients were given incremental doses of adenosine during atrial pacing. RESULTS: In 14 of 16 patients with dual-AV node physiology, administration of small doses of adenosine during atrial pacing led consistently to transient block of impulse conduction in the fast pathway before block in the slow pathway, resulting in abrupt prolongation of the AH interval with continued 1:1 AV conduction. The mean (+/- SD) doses of adenosine required to cause conduction block in the fast and slow pathways were 2.7 +/- 3.0 and 7.2 +/- 4.7 mg, respectively (p = 0.004). In 9 of 16 patients, administration of low dose adenosine led to initiation of AV node reentrant tachycardia. The control patients showed no abrupt increases in AH interval with administration of adenosine during atrial pacing. CONCLUSIONS: In most patients with dual AV node pathways and typical AV node reentrant tachycardia, the fast pathway is more sensitive than the slow pathway to the effects of adenosine.

Adenosine↗

PubMed2000

Screening for risk factors for thrombosis using a new generation of assays developed to evaluate the functionality of the protein C anticoagulant pathway.

These results, obtained in a small series of patients, suggest that both the ProC Global assay and the PCP Test would be suitable, using well-defined cut-off levels, to identify all the carriers of the Factor V Leiden mutation and all the patients with a protein C deficiency or with combined defects of the protein C pathway. For both assays, however, the sensitivity for protein S deficiency was below 60%. These results in selected patients are congruent with those previously reported in the literature about the ProC Global assay, the PCP Test, and other assays evaluating the functionality of the protein C anticoagulant pathway. All demonstrated a weak sensitivity to protein S deficiency, suggesting that protein S plays only a minor role as an APC cofactor in such global assays. A major discrepancy between the two evaluated assays was obtained in the group of patients without abnormality of the protein C pathway. Actually, using the ProC Global assay, more than 40% of the patients had a decreased PCAT-NR while presenting with none of the three tested abnormalities, whereas none of the studied patients had a ratio below 1.80, and only 5 of 143 (3.5%) had a ratio below 2.00 when using the PCP Test. The observation that around 40% of the control patients had a decreased PCAT-NR could suggest the influence of currently unknown defects of the protein C/protein S pathway on the ProC Global assay. It could also be hypothesized that the higher factor VIII levels already reported in patients with a history of thrombosis than in controls had a significant role in the low responsiveness, but this parameter was not tested in the authors' series. In that connection, it is also well established that elevated factor VIII levels both shorten the APTT and reduce the anticoagulant effect of heparin when evaluated using APTT. Actually, some of the samples investigated in this study were obtained during the acute phase of thrombosis. It is not possible to draw out the hypothesis of an association of biologically undetectable minor changes in various factors involved in the protein C anticoagulant pathway; all the individual factors would remain within their normal ranges. Finally, because 40% of the patients without abnormalities of the protein C pathway had a decreased PCAT-NR, the question arises whether the ProC Global assay might in itself be a biologic marker of thrombophilia, independent of its sensitivity for abnormalities of the protein C anticoagulant pathway. In that connection, the correlation between the result of the ProC Global assay and the risk for thromboembolism was recently evaluated by two different groups. In both cases, the preliminary results suggested that a decreased response to the ProC Global assay might be an independent risk factor for venous thrombosis. The two global assays could therefore have distinctly different applications. If the global assays are used in the hemostasis laboratory to screen for abnormalities of the protein C pathway, and thus to rationalize the use of specific assays, the PCP Test should be chosen, because of its high specificity. Because only 3.5% of the control patients had a ratio below 2.00 (and none had a ratio below 1.80), the PCP Test could be accurately used as a first-step assay in the laboratory screening for these abnormalities of the protein C anticoagulant pathway. Using such a flow chart, the specific assays for APC resistance or the identification of the factor V Leiden mutation and protein C would be performed only in case of a ratio below a cut-off defined using receiver operating characteristic (ROC)-analysis in unselected patients. Because of the weak sensitivity of this assay to both constitutional and acquired protein S deficiencies (below 15% using 1.80 as the cut-off level, or 60% using 2.00), the measurement of this parameter had to be performed in all cases. If, on the other hand, the assay is used to screen for risk factors for thrombosis, the ProC Global assay could b

Adolescent↗

PubMed2001

Radiofrequency catheter ablation of left-sided accessory pathways in pediatric patients.

In many cases, radiofrequency catheter ablation has replaced the long-term use of antiarrhythmic medication for symptomatic tachycardia, and has all but eliminated arrhythmia surgery. The most common substrate for radiofrequency catheter ablation in pediatric patients is atrioventricular (AV) reentry tachycardia due to a concealed or manifest accessory pathway. Accessory pathways are distributed unevenly along the right and left atrioventricular valve annuli, and left-sided accessory pathways are most common. Although some centers advocate an abbreviated diagnostic and mapping approach to both concealed and manifest left-sided accessory pathways, most still use a complete electrophysiological evaluation and complex catheter manipulation for mapping, followed by the application of radiofrequency energy. Left-sided accessory pathways may be approached from the transatrial approach, the retrograde aortic approach, or less commonly from within the coronary sinus. Each approach has proven to be associated with success, but also with a distinct set of risks. Possibly because left-sided accessory pathways are most common, catheter ablation of this substrate has proven highly successful and has the lowest risk of recurrence. However, recent data also suggest that this substrate is associated with greater risk of complications than of right-sided accessory pathways or pathways located in the posteroseptal region. The following report reviews some of the recently described diagnostic and mapping techniques, success rates, risks and follow-up data in pediatric patients undergoing radiofrequency catheter ablation of left-sided accessory pathways.

Journal Article↗

PubMed2003

Evidence that the appressorial development in barley powdery mildew is controlled by MAP kinase activity in conjunction with the cAMP pathway.

Development of the barley powdery mildew fungus involves the sequential formation of a primary germ tube, an appressorial germ tube, and an appressorium. Previously, we have shown that the cAMP pathway controls the emergence of the two germ tubes. Following identification of two MAP kinase genes in an EST database from developing conidia we studied the role of the MAP kinase pathway and its interaction with the cAMP pathway. Fungal MAP kinase activity increased rapidly during mildew development, reaching a maximum between 2 and 8h after inoculation. Sphingosine or PAF-16, activators of the MAP kinase pathway, increased activity and appressorial development whilst an inhibitor, PD 98059, decreased both. Studies on the interaction between the cAMP and MAPK pathways revealed that several effectors of the MAPK pathway had no effect on cAMP levels. However upstream effectors of the cAMP pathway, such as cholera toxin and pertussis toxin (activators of G(alpha) proteins) increased MAPK activities whereas downstream effectors such as forskolin (adenylyl cyclase activator) or H89 (PKA inhibitor) had no effect. Combined application of forskolin and sphingosine produced a rise in appressorial germ tube and appressorial formation higher than when either pathway was stimulated individually. These results suggest that the two pathways cooperate in appressorial development.

Ascomycota↗