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PubMed2002

Two functionally distinct organic osmolyte pathways in Plasmodium gallinaceum-infected chicken red blood cells.

Red cells infected with the human malaria parasite Plasmodium falciparum have an increased permeability to a range of small, structurally unrelated solutes via a malaria-induced pathway. We report here a similar pathway present in parasitised red cells from chickens infected with the avian malaria parasite, Plasmodium gallinaceum. Parasitised cells showed a marked increase in the rate of influx of sorbitol (76-fold) and, to a lesser degree, taurine (3-fold) when compared with red cells from uninfected chickens. Pharmacological data suggest that both sorbitol and taurine are transported via a single malaria-induced pathway, which is sensitive to inhibition by 5-nitro-2-(3-phenylpropylamino)benzoic acid (IC(50) approximately 7 microM). The malaria-induced pathway differed in its inhibition by a range of anion channel inhibitors when compared to the endogenous, volume-activated osmolyte pathway of chicken red cells. There were also differences in the selectivity of sorbitol and taurine by the two permeation routes. The data presented here are consistent with the presence of two distinct organic solute pathways in infected chicken red cells. The first is an endogenous volume-activated pathway, which is not activated by the parasite and the second is a malaria-induced pathway, similar to those that are induced by other types of malaria in other host species.

Animals↗
PubMed2000

Roles of mitogen-activated protein kinase pathways for mediator release from human cultured mast cells.

Human cultured mast cells (HCMC) secrete histamine, sulfidoleukotrienes (LTs), and prostaglandin D(2) (PGD(2)), and produce a variety of cytokines after aggregation of high-affinity receptors for IgE (FcepsilonRI). With respect to the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinases (JNKs), and p38 mitogen-activated protein kinase (p38 MAPK) are known. To investigate the roles of these kinase pathways for mediator release from human mast cells, we examined the participation of the activation of these kinases in mediator release, using 1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), an ERK pathway inhibitor, and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imid azo le (SB203580), a p38 MAPK pathway inhibitor. U0126 inhibited ERK activation, LT and PGD(2) release, and granulocyte macrophage-colony stimulating factor (GM-CSF) production after stimulation of HCMC. SB203580, on the other hand, potentiated JNK activation and GM-CSF production. The findings of the present study demonstrated that: (i) the release of arachidonic acid metabolites is mediated by the ERK pathway; (ii) GM-CSF production may be driven by both the ERK and JNK pathways; and (iii) the p38 MAPK pathway negatively regulates the JNK pathway. This suggests that MAPK pathways play important roles in mediator release from human mast cells.

Butadienes↗
PubMed2000

Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways.

Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.

Cardiomegaly↗
PubMed2003

The kinase domain of MEKK1 induces apoptosis by dysregulation of MAP kinase pathways.

MAP kinase pathways comprise a group of parallel protein phosphorylation cascades, which are involved in signaling triggered by a variety of stimuli. Previous findings suggested that the ERK and the JNK pathways have opposing roles in regulating proliferation and survival or apoptosis and that apoptosis can be promoted by inhibiting the ERK pathway or by activation of the JNK pathway. In order to test this hypothesis and explore whether it can be exploited as a strategy for killing human cancer cells, we used gene transfer experiments with a range of cancer cell lines. We expressed the catalytic fragment of human MEKK1 to activate JNK and the Ras-binding domain (RBD) of Raf-1 to inhibit the Ras-ERK pathway. In addition, we designed several RBD-MEKK1 fusion proteins aiming to simultaneously activate the JNK and block the ERK pathway. We found that the MEKK1 proteins as well as the RBD alone could reduce colony formation in all cell lines. The survival time of MEKK1-expressing cells depended on the cell line. In HeLa cells, survival could be prolonged by inhibition of caspases but not by coexpression of the anti-apoptotic protein Bcl-2. Due to a lower kinase activity the RBD-MEKK1 fusion proteins were less effective in apoptosis induction than the MEKK1 kinase domain alone. Using mutant forms of Ras and Raf-1 we could show that the reduced kinase activity of RBD-MEKK1 fusion proteins was caused by binding to the Ras protein. The expression of lethal doses of MEKK1 resulted in a strong activation of all three major MAP kinase families JNK, ERK, and p38. Blocking these pathways either by coexpressing a dominant negative form of MKK4 or with inhibitors of MEK or p38 failed to inhibit apoptosis. This suggests that MEKK1 induces apoptosis by causing a general deregulation of MAP kinase signaling rather than by the activation of a single pathway.

Apoptosis↗
PubMed2003

Shc-dependent pathway is redundant but dominant in MAPK cascade activation by EGF receptors: a modeling inference.

In cell signaling cascades, one stimulus often leads to various physiological functions by multiple pathways. Perturbation of one pathway by blocking or overexpressing one of its components will result in changes in multiple pathways and multiple cell functions. Thus, it is important to reveal the relative contribution of each pathway to each function in order to assess the consequence of perturbations (e.g. drug delivery). By exploring an established mathematical model, the Shc-dependent pathway is found to be both redundant and dominant during activation of the mitogen-activated protein kinase cascade by epidermal growth factor receptor (EGFR). Its dominance results from the majority consumption of the common precursor ((EGF-EGFR*)2-GAP) by this pathway. The key steps for the dominance are the binding and phosphorylation of Shc. In conclusion, cells may prefer the long Shc-dependent pathway to the short Shc-independent pathway.

Adaptor Proteins, Vesicular Transport↗
PubMed1999

Intracellular pathways mediating Na+/H+ exchange activation by platelet-derived growth factor in rat hepatic stellate cells.

BACKGROUND & AIMS: The Na+/H+ exchanger is the main intracellular pH regulator in hepatic stellate cells (HSCs), and its activity is increased by platelet-derived growth factor (PDGF). Amiloride, an Na+/H+ exchange inhibitor, reduces PDGF-induced HSC proliferation, suggesting that the Na+/H+ exchanger plays a role in regulating HSC proliferative response. The aim of this study was to characterize the intracellular pathways mediating activation of the Na+/H+ exchanger by PDGF in HSCs. METHODS: The activity of the Na+/H+ exchanger and HSC proliferation rate were evaluated under control condition and after incubation with PDGF in the absence or presence of specific inhibitors of the main intracellular pathways of signal transduction. Na+/H+ exchange protein expression was evaluated by means of Western blot. RESULTS: PDGF induced a significant increase in the activity of the Na+/H+ exchanger without modifying protein expression. Inhibition of the calcium/calmodulin- and protein kinase C-dependent pathways resulted in a significant inhibition of both Na+/H+ exchange activity and of PDGF-induced HSC proliferation. The involvement of the two pathways was confirmed by showing that incubation of HSCs with both phorbol-12-myristate-13-acetate, a potent protein kinase C activator, and thapsigargin, which increases intracellular calcium levels, significantly increased both the Na+/H+ exchanger activity and HSC proliferation rate. Inhibition of the protein kinase A pathway did not modify either PDGF-induced Na+/H+ exchange activation or PDGF-induced HSC proliferation. On the contrary, inhibition of the mitogen-activated protein kinase- and of phosphatidylinositol 3-kinase-dependent pathways significantly reduced PDGF-induced HSC proliferation without affecting the activity of the Na+/H+ exchanger. CONCLUSIONS: Activation of the Na+/H+ exchanger by PDGF in HSCs is mediated by calcium/calmodulin- and protein kinase C-dependent pathways. PDGF-induced HSC proliferation is mediated by Na+/H+ exchange-dependent and -independent pathways.

Animals↗
PubMed1992

Evolution of metabolic pathways by chance assembly of enzyme proteins generated from sense and antisense strands of pre-existing genes.

In order to get an insight into the evolutionary aspect of metabolic pathways, especially of the ubiquitous glycolytic pathway, we have carried out an extensive search of sense-sense and sense-antisense similarities for enzyme proteins in the glycolytic pathway, the pentose phosphate cycle, alcohol and lactate fermentation pathways and the TCA cycle. This investigation of amino acid sequences reveals a curious pattern of similarity relations; no similarity can be found between the enzyme proteins in a section of the glycolytic pathway where the glyceraldehyde-3-phosphate or even glycerol-3-phosphate is converted into the pyruvate while many examples of sense-sense and sense-antisense similarities are found even between enzyme proteins in distant blocks, e.g. between the proteins in the TCA cycle and those in the pentose phosphate cycle, as well as between the functionally associated proteins in each of these blocks. Complementary to this characteristic pattern of amino acid sequence similarity, the search for similarities of nucleotide sequences also finds that the similarities of glycolytic enzyme genes, some sense-sense and others sense-antisense similarities, are concentrated on the nucleotide sequences of prokaryotic 16S or eukaryotic 18S ribosomal RNA gene with its flanks, although some of the copy sequences are also found in transfer RNA genes as well as in 23S or 26S ribosomal RNA gene. These results strongly suggest that the metabolic pathways have been developed by the chance assembly of enzyme proteins generated from the sense and antisense strands of pre-existing genes, e.g. the fermentation pathways and pentose phosphate cycle by the proteins from the genes of enzymes in the glycolytic pathway and the TCA cycle from all these successively increased genes, ascribing the origin of metabolic enzyme genes to the close relation between the glycolytic enzyme protein genes and the RNA gene cluster.

Animals↗
PubMed2000

Tissue factor pathway inhibitor levels in patients with homocystinuria.

Thrombotic events are a well-recognized complication of homocystinuria. However, the mechanisms involved in the atherogenic and thrombotic effects of homocyst(e)ine remain incompletely understood. The objective of this study was to determine the role of endothelial cell activation/damage as indicated by levels of thrombomodulin, tissue factor and tissue factor pathway inhibitor, and factor VII activity in patients with homocystinuria. Six patients with homocystinuria, nonresponsive to pyridoxine, treated only with trimethylglycine (betaine) were injected with a bolus of 20 IU/kg body weight of unfractionated commercial heparin to induce the release of tissue factor pathway inhibitor from the vascular endothelium. Tissue factor, thrombomodulin, and factor VII activity were measured by enzyme-linked immunosorbent assay and clotting assay before heparin administration. Tissue factor pathway inhibitor antigen and activity were measured before and 5 minutes after the bolus of heparin. Levels of homocyst(e)ine were elevated (patients: 144.2+/-19.2 micromol/L; controls: 10.2+/-0.9 micromol/L); however, levels of thrombomodulin, tissue factor, and tissue factor pathway inhibitor antigen were not statistically different from the control group. In contrast, tissue factor pathway inhibitor activity showed a significantly increased level (patients: 2.09+/-0.34 U/L; controls: 1.14+/-0.20 U/L; p<0.05) that was correlated with homocyst(e)ine. Factor VII activity was significantly decreased (patients: 64.7+/-5.1%; controls: 91.4+/-4.7%; p<0.05) and inversely correlated with homocyst(e)ine. After heparin the patients released higher amounts of tissue factor pathway inhibitor antigen and activity compared with the control group; however, the difference was not statistically significant. Although not treated with antithrombotic drugs, none of the patients had any thromboembolic complications after starting betaine. In addition to betaine treatment, the enhanced factor pathway inhibitor antigen activity observed in this small series of patients suggests that factor pathway inhibitor antigen may play an additional, as yet unexplained, role in this genetic disorder.

Adult↗
PubMed2000

Alternative protein sorting pathways.

The term "nonclassical protein targeting" has been used to describe those pathways that have been recently discovered and differ mechanistically from the more studied "classical pathways." Because this nomenclature is rather arbitrary in terms of cellular relevance, we have chosen to group these protein sorting mechanisms under the heading "alternative protein sorting pathways" for the purpose of this review. Many of the alternative targeting pathways described are of primary importance. For example, without retrograde transport, both membrane material and targeting machinery accumulate at distal sites in the endomembrane system, preventing anterograde transport. Further, lysosome/vacuole delivery of degradative substrates by autophagic pathways is central to the role of this organelle as a primary site for intracellular degradation. Finally, targeting through the classical CPY pathway requires the ALP pathway for delivery of the vacuolar t-SNARE Vam3p. Analysis of these alternative targeting pathways provides a more complete understanding of eukaryotic cellular physiology.

Animals↗
PubMed2002

Polyol pathway and diabetic peripheral neuropathy.

This chapter critically examines the concept of the polyol pathway and how it relates to the pathogenesis of diabetic peripheral neuropathy. The two enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, are reviewed. The structure, biochemistry, physiological role, tissue distribution, and localization in peripheral nerve of each enzyme are summarized, along with current informaiton about the location and structure of their genes, their alleles, and the possible links of each enzyme and its alleles to diabetic neuropathy. Inhibitors of pathway enzyme and results obtained to date with pathway inhibitors in experimental models and human neuropathy trials are updated and discussed. Experimental and clinical data are analyzed in the context of a newly developed metabolic odel of the in vivo relationship between nerve sorbitol concentration and metabolic flux through aldose reuctase. Overall, the data will be interpreted as supporting the hypothesis that metabolic flux through the polyol pathway, rather than nerve concentration of sorbitol, is the predominant polyol pathway-linked pathogeneic factor in diabetic preipheral nerve. Finally, key questions and future directions for bsic and clinical research in this area are considered. It is concluded that robust inhibition of metabolic flux through the polyol pathway in peripheral nerve will likely result in substantial clinical benefit in treating and preventing the currently intractable condition of diabetic peripheral neuropathy. To accomplish this, it is imperative to develop and test a new generation of "super-potent" polyol pathway inhibitors.

Aldehyde Reductase↗
PubMed2001

Aeration and drainage pathways of Prussak's space.

OBJECTIVE: the purpose of this study was to document the aeration and drainage pathways of Prussak's space. METHODS: 55 temporal bones with an age range from neonate to 11 years of age were serially sectioned to 20 microns, every 10th section was saved and stained by Hematoxylin eosin. Each consecutive section was studied as to the connections of Prussak's space to adjacent compartments and measurements of the dimensions were made for both Prussak's space and its aeration pathways. RESULTS: the classic aeration pathway via the posterior pouch, as described by Prussak in 1867, was found in 34 ears (62%). In 19 (36%), aeration occurred superior to the posterior pouch in the region of the lower lateral attic and the upper mesotympanum. In these ears the posterior pouch had formed, but its superior limit ended blindly in the tympanic membrane. In two temporal bones the aeration pathway was from the anterior pouch and in these cases also a blind posterior pouch had developed. In one temporal bone an auxiliary pathway in addition to the route via the posterior pouch was through the roof (the lateral malleal ligamental fold) of Prussak's space to the overlying lateral malleal space. The height of the posterior pouch varied with a range from 0.5 to 2.4 mm, and the greatest width, which was towards the posterior tympanic spine, varied from 1.6 to 3.2 mm. The superiorly blind posterior pouch was shorter, ranging from 0.4 to 1.2 mm in height. The most frequent route of the chorda tympani nerve was running from 0.5 to 1 mm medial to the posterior malleal ligament in the anterior half of the pouch, joining it posteriorly, or it was connected to it by a short fold, 37 ears (67%). In 18 cases (33%) the chorda was surrounded by its own fold, thus entirely separate from the posterior malleal ligamental fold during its entire course across the tympanum. CONCLUSIONS: we have made a detailed documentation of the aeration and drainage pathways of Prussak's space and the findings concur, with important modifications, with Prussak's original description. There is no evidence for contemporary claims that Prussak's space would be aerated superiorly between the lateral incudal and malleal folds. Prussak's space and its aeration pathway is an unit of its own, entirely separate of the major epitympanic compartments which are aerated via the tympanic isthmus. Due to frequent disease processes in the lower lateral attic and posterior mesotympanum, Prussak's space and its aeration pathway are likely to become blocked. This may lead to obliteration of Prussak's space and to the development of retraction pocket or papillary ingrowth cholesteatoma.

Child↗
PubMed2000

Least-effort pathways?: a GIS analysis of livestock trails in rugged terrain.

Livestock trails frequently evolve in pastures when plant growth or establishment cannot keep pace with vegetation disturbance. In some instances, man-made trails are established in rangeland settings to encourage uniform use of forages or facilitate livestock passage through dense vegetation or across rugged terrain. A long-term assumption has been that livestock establish pathways of least resistance between frequented areas of their pastures, but this hypothesis has never been tested. We mapped cattle trails in three 800+ ha pastures with global positioning units. A geographic information system (GIS) helped quantify characteristics of trails and the landscape and was used to plot least-effort pathways between water sources and distant points on selected trails in the pastures. Characteristics of the cattle trails and least-effort pathways were compared to test the hypothesis that cattle develop least-effort routes of travel in rugged terrain. The mean slope of the three pastures was 13.5%, and the average slope of the topography traversed by the cattle trails was 8%. The slope of the trails was reduced to 5.2% by selection of cross-slope routes. When we compared the characteristics of 10 selected cattle trails and least-effort pathways generated by our GIS, the cattle trails were 11% shorter (P=0.046) than the least-effort pathways, and the topography traversed by cattle had a gradient about 1% less than the least-effort pathways (P=0.02). The slope of the selected trails (5.5%) and pathways (5.6%) were similar (P=0.74), however. Analyses of values extracted from cost surfaces indicated that, on the average, 183 units of effort were needed to traverse the trails and 170 units of effort expended to traverse the least-effort pathways (P=0.07). These data support the hypothesis that cattle establish least-effort routes between distant points in rugged terrain and suggest that GIS software may be useful in designing systems of livestock trails in extensive settings.

Journal Article↗
PubMed1998

Effects of feedback inhibition on transit time in a linear pathway of Michaelis-Menten-type reactions.

An analysis of the effects of external and internal metabolites on the steady-state behavior of linear pathways comprising a sequence of three Michaelis-Menten-type reactions with and without a simple feedback inhibition (i.e. an interaction of an internal metabolite with the pathway) is performed with respect to the transit time tau by its formulation as rectangular-hyperbolic functions of the flux J, instead of direct expressions in terms of the external metabolite concentrations. For a given concentration of the external metabolite M1 (substrate of the pathway) or M4 (product of the pathway), the flux J has a lower value in the pathway with feedback inhibition than in the pathway without feedback inhibition. With variation in the M1 concentration the transit time tau shows a concave relationship with the flux J which is virtually identical for both pathways, yielding a minimum at a certain value of J. With variation in the M4 concentration the transit time tau monotonously decreases with higher value of J, and for a given value of J the feedback inhibition allows a lower transit time. This effect is enhanced with stronger feedback inhibition, and is in turn greatly reduced with higher values of total concentration and rate constants for the first enzyme in the pathway.

Enzymes↗
PubMed1986

Characterization of retrograde conduction by direct endocardial recording from an accessory atrioventricular pathway.

Accessory pathway electrograms are rarely recorded in patients with Wolff-Parkinson-White syndrome. In one patient, during electrophysiologic study, simultaneous local ventricular (V) accessory pathway (AP) and atrial (A) deflections were recorded during bipolar catheter endocardial mapping over the pathway. Analysis of changes in electrographic intervals during performance of the ventricular extrastimulus technique allowed characterization of the retrograde conduction properties of the pathway. As coupling intervals were decreased, an initial increase was seen in the AP2A2 interval with subsequent ventriculoatrial block between the accessory pathway and atrium. When coupling intervals were further decreased, the V2AP2 interval lengthened with ultimate block between the ventricle and accessory pathway. These findings support the concept of impedance mismatch as the cause of conduction block in accessory pathways with the distal junction of the accessory pathway being the most vulnerable.

Adult↗
PubMed1996

Slow pathway ablation in patients with documented but noninducible paroxysmal supraventricular tachycardia.

OBJECTIVES: The purpose of this study was to assess the clinical efficacy of radiofrequency ablation of the slow pathway in patients with documented but noninducible paroxysmal supraventricular tachycardia (PSVT) who have evidence of dual atrioventricular (AV) node pathways. BACKGROUND: Patients with a documented history of PSVT at times do not have inducible PSVT in the electrophysiology laboratory. Because dual AV node pathways serve as the substrate for AV node reentrant tachycardia (AVNRT), ablation of the slow pathway potentially may be useful in these patients. METHODS: The subjects in this prospective study were seven consecutive patients who underwent an electrophysiologic procedure because of documented PSVT and were found to have dual AV node physiology or inducible single AV node echo beats, but no inducible PSVT despite the administration of isoproterenol and atropine. Their mean (+/- SD) age was 33 +/- 13 years, and they had been symptomatic for 12 +/- 12 years. The frequency of the episodes of PSVT ranged from > or = 1/day to 1/month. The rate of the documented episodes ranged from 170 to 260 beats/min, and discrete P waves were not apparent. Slow pathway ablation was performed with 9 +/- 4 applications of radiofrequency energy using a combined anatomic and electrogram mapping approach. RESULTS: All evidence of dual AV node pathways was eliminated in six patients, and dual AV node physiology remained present in one patient. During a mean follow-up period of 15 +/- 10 months (range 8 to 27), no patient had a recurrence of symptomatic tachycardia (success rate 95% confidence interval 65% to 100%). CONCLUSIONS: Slow pathway ablation may be clinically useful in patients with documented but noinducible PSVT who have evidence of dual AV node pathways.

Adult↗
PubMed1998

Demonstration of a posterior atrial input to the atrioventricular node during sustained anterograde slow pathway conduction.

OBJECTIVES: This study sought to demonstrate electrophysiologic evidence for the existence of different anatomic atrial input sites of fast and slow conduction pathways in patients with dual atrioventricular (AV) node physiology. BACKGROUND: Although a separate posterior exit site exists for a retrograde slow AV node pathway, it remains unresolved whether a separate atrial input site into the AV node actually exists in patients with dual anterograde AV node pathway physiology. METHODS: In 10 patients with dual AV node pathway physiology, atrial pacing at three chosen drive cycle lengths (DCL1, DCL2 and DCL3) was performed at an anterior site (A) just above the His bundle recording site and at a posterior atrial site (P) just below the coronary sinus ostium. DCL3 was chosen as the one cycle length that resulted in a long AH interval consistent with slow pathway conduction. The stimulus to His bundle conduction times (SH) at both sites (SH(P) and SH(A), respectively) and their differences (deltaSH = SH(P) - SH(A)) at each of the three drive cycle lengths were analyzed. RESULTS: The mean +/- SD deltaSH values for DCL1 and DCL2 measured 9 +/- 16 and 8 +/- 18 ms, respectively, and the mean deltaSH value at DCL3 measured -34 +/- 24 ms, which was significantly different from the mean deltaSH values at DCL1 and DCL2 (both p < 0.05). CONCLUSIONS: The significant change in the deltaSH (SH(P) - SH(A)) value during slow pathway conduction could be accounted for by a corresponding shift of anterograde input from an anterior to a posterior entry site to the AV node. These findings support the notion that a separate anterograde entry site of the slow pathway does exist in patients with dual AV node pathway physiology.

Atrioventricular Node↗
PubMed1999

Gated blood-pool SPECT evaluation of changes after radiofrequency catheter ablation of accessory pathways: evidence for persistent ventricular preexcitation despite successful therapy.

OBJECTIVES: This study was designed to prospectively evaluate the effects of radiofrequency ablation in Wolff-Parkinson-White (WPW) syndrome by scintigraphic analysis. BACKGROUND: The functional changes triggered by radiofrequency current ablation of atrioventricular accessory pathways are not fully known. METHODS: Forty-four patients with WPW syndrome were consecutively investigated before and 48 h after radiofrequency therapy. Fourteen patients had right sided atrioventricular pathways and 30 patients had left sided bypass-tracts. Planar gated imaging and gated blood pool tomography were performed in all of these patients. RESULTS: A significant increase in the left ventricular ejection fraction (LVEF) was demonstrated in patients with left preexcitation (62.2+/-7.9% before ablation against 64.4+/-6.3% after ablation, p = 0.02) but not for those with right sided anomalous pathway. Phase analysis only gave significant differences following ablation of right sided pathways (left-to-right phase difference = 14.4+/-13.8 degrees before ablation versus 7.5+/-7.2 degrees after ablation, p<0.05). Early abnormal ventricular contraction persisted in 12 patients with right accessory pathways and in 8 patients with left accessory pathways despite the complete disappearance of any abnormal conduction as proven electrophysiologically. CONCLUSIONS: Following catheter ablation of atrioventricular accessory pathways: 1) an improvement of left ventricular function may be seen, particularly in patients with left sided accessory pathways, and 2) unexpected persistence of local ventricular preexcitation at the site of successful ablation may be detected.

Adult↗
PubMed2002

A ubiquitin-proteasome pathway represses the Drosophila immune deficiency signaling cascade.

BACKGROUND: The inducible production of antimicrobial peptides is a major immune response in Drosophila. The genes encoding these peptides are activated by NF-kappaB transcription factors that are controlled by two independent signaling cascades: the Toll pathway that regulates the NF-kappaB homologs, Dorsal and DIF; and the IMD pathway that regulates the compound NF-kappaB-like protein, Relish. Although numerous components of each pathway that are required to induce antimicrobial gene expression have been identified, less is known about the mechanisms that either repress antimicrobial genes in the absence of infection or that downregulate these genes after infection. RESULTS: In a screen for factors that negatively regulate the IMD pathway, we isolated two partial loss-of-function mutations in the SkpA gene that constitutively induce the antibacterial peptide gene, Diptericin, a target of the IMD pathway. These mutations do not affect the systemic expression of the antifungal peptide gene, Drosomycin, a target of the Toll pathway. SkpA encodes a homolog of the yeast and human Skp1 proteins. Skp1 proteins function as subunits of SCF-E3 ubiquitin ligases that target substrates to the 26S proteasome, and mutations affecting either the Drosophila SCF components, Slimb and dCullin1, or the proteasome also induce Diptericin expression. In cultured cells, inhibition of SkpA and Slimb via RNAi increases levels of both the full-length Relish protein and the processed Rel-homology domain. CONCLUSIONS: In contrast to other NF-kappaB activation pathways, the Drosophila IMD pathway is repressed by the ubiquitin-proteasome system. A possible target of this proteolytic activity is the Relish transcription factor, suggesting a mechanism for NF-kappaB downregulation in Drosophila.

Amino Acid Sequence↗