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Long-term efficacy of slow-pathway catheter ablation in patients with documented but noninducible supraventricular tachycardia.

BACKGROUND: The long-term efficacy of radiofrequency catheter ablation of slow pathway in patients with dual atrioventricular node pathway and a documented but noninducible paroxysmal supraventricular tachycardia (PSVT) is not entirely clear. METHODS: Forty nine patients (Group A) with documented but noninducible PSVT and dual atrioventricular node pathway were prospectively studied. Programmed electrical stimulation induced a single atrioventricular node echo beat in 13 patients, and double echo beats in 9 at baseline or during isoproterenol infusion. Clinical and electrophysiological characteristics of Group A patients were compared with that of age- and gender-matched patients with dual atrioventricular node pathway but inducible PSVT (Group B). RESULTS: There was no significant difference in the electrophysiological properties of the fast and slow pathways between the two groups. Catheter ablation eliminated the slow pathway in all patients. There was no recurrence of PSVT in either Group A or Group B during the follow-up of 38 +/- 5 months. CONCLUSIONS: In patients with dual atrioventricular node pathway and a documented but noninducible PSVT, catheter ablation of slow pathway is highly effective in preventing tachycardia in long term.

Adult↗
PubMed2004

Contribution of different pathways to the supply of phosphatidylethanolamine and phosphatidylcholine to mitochondrial membranes of the yeast Saccharomyces cerevisiae.

In the yeast, three biosynthetic pathways lead to the formation of phosphatidylethanolamine (PtdEtn): (i) decarboxylation of phosphatidylserine (PtdSer) by phosphatidylserine decarboxylase 1 (Psd1p) in mitochondria; (ii) decarboxylation of PtdSer by Psd2p in a Golgi/vacuolar compartment; and (iii) the CDP-ethanolamine (CDP-Etn) branch of the Kennedy pathway. The major phospholipid of the yeast, phosphatidylcholine (PtdCho), is formed either by methylation of PtdEtn or via the CDP-choline branch of the Kennedy pathway. To study the contribution of these pathways to the supply of PtdEtn and PtdCho to mitochondrial membranes, labeling experiments in vivo with [(3)H]serine and [(14)C]ethanolamine, or with [(3)H]serine and [(14)C]choline, respectively, and subsequent cell fractionation were performed with psd1Delta and psd2Delta mutants. As shown by comparison of the labeling patterns of the different strains, the major source of cellular and mitochondrial PtdEtn is Psd1p. PtdEtn formed by Psd2p or the CDP-Etn pathway, however, can be imported into mitochondria, although with moderate efficiency. In contrast to mitochondria, microsomal PtdEtn is mainly derived from the CDP-Etn pathway. PtdEtn formed by Psd2p is the preferred substrate for PtdCho synthesis. PtdCho derived from the different pathways appears to be supplied to subcellular membranes from a single PtdCho pool. Thus, the different pathways of PtdEtn biosynthesis play different roles in the assembly of PtdEtn into cellular membranes.

Aldehyde-Lyases↗
PubMed2006

Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.

Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.

Animals↗
PubMed2004

Rice octadecanoid pathway.

Plant jasmonic acid (JA) and structurally similar animal prostaglandins play pivotal roles in regulating cellular responses against environmental cues, including the innate immune response(s). In plants, JA and its immediate precursor 12-oxo-phytodienoic acid (OPDA) are synthesized by the octadecanoid pathway, which employs at least five enzymes (lipase, lipoxygenase, allene oxide synthase and cyclase, and OPDA reductase), in addition to the enzymes involved in the beta-oxidation steps. Genetic, molecular, and biochemical analyses have led to the identification of almost all the genes of the octadecanoid pathway in Arabidopsis--a model dicotyledonous plant. In this regard, rice (Oryza sativa L.)--an important socio-economic monocotyledonous model research plant--remains poorly characterized. Until now, no gene has been specifically associated with this pathway. It is therefore of utmost importance to identify, characterize, and assign the pathway specific genes in rice. In this review, we have surveyed the rice genome, extracted a large number of putative genes of the octadecanoid pathway, and discussed their relationship with the known pathway genes from other plant species. Moreover, the achievements made so far on the rice octadecanoid pathway have also been summarized to reflect the contribution of rice towards extending our knowledge on this critical pathway in plants.

Animals↗
PubMed2005

Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner.

Constitutive activation of the PI3 kinase/Akt pathway is associated with the neoplastic phenotype of a large number of human tumor cells. As the anti-apoptotic role of the PI3 kinase/Akt pathway has been established, we have examined whether specific blockade of this pathway sensitizes tumor cells to DNA-damaging agent-induced cytotoxicity by enhancing apoptotic cell death. Although a PI3 kinase inhibitor, LY294002, by itself does not induce apoptotic cell death, LY294002 selectively and markedly enhances the apoptosis-inducing efficacy of doxorubicin: such an enhanced cell death is only detected in tumor cells in which the PI3 kinase/Akt pathway is constitutively activated, and it is totally dependent on the functional p53 pathway. These results suggest that the combination of a PI3 kinase/Akt pathway inhibitor and doxorubicin provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the PI3 kinase/Akt pathway is constitutively activated and the p53 pathway is functional.

Antibiotics, Antineoplastic↗
PubMed2006

TRAIL-induced apoptosis proceeding from caspase-3-dependent and -independent pathways in distinct HeLa cells.

The apoptotic pathway in higher eukaryotes remains controversial with respect to the necessity of activation of caspase-3 in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-treated cells. In this study, a fluorescence resonance energy transfer (FRET) probe was developed to image the activation of caspase-3 and the related apoptotic pathway in TRAIL-treated cells in real time. Both kinds of apoptotic pathways were observed simultaneously in the same experiment proceeding from activation and non-activation of caspase-3. The total apoptotic rate was 56.08%, the apoptotic rates for activation and non-activation of caspase-3 pathways were 21.5% and 34.58%, respectively, which were examined later for Hoechst 33258 staining and morphological characteristics. The apoptotic rate due to the activation of caspase-3 pathways in TRAIL-treated cells has been independently measured to be around 25.11% by capillary electrophoresis (CE) analysis, which confirmed the apoptotic rate due to activation of caspase-3 pathways as found by FRET analysis. This result also suggests that rest apoptosis is preceded by caspase-3-independent pathways, as CE has the ability to quantitatively detect caspase-dependent apoptosis. The observation of the coexistence of caspase-3-dependent and caspase-3-independent apoptotic pathways in the TRAIL-treated cells was unusual in comparison with the previous reports.

Apoptosis↗
PubMed2006

Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea.

Toll-like receptors (TLRs) play an important role in recognition of microbial components and induction of innate immunity. The microbial components trigger the activation of two downstream signaling pathways of TLRs; MyD88- and/or TRIF-dependent pathways leading to activation of NF-kappaB. (-)-Epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, is known to inhibit NF-kappaB activation induced by many pro-inflammatory stimuli. EGCG was shown to inhibit the activity of IKKbeta which is the key kinase in the canonical pathway for NF-kappaB activation in MyD88-dependent pathway of TLRs. However, it is not known whether EGCG inhibits TRIF-dependent pathway through which more than 70% of lipopolysaccharide (LPS)-induced genes are regulated. Therefore, we attempted to identify the molecular target of EGCG in TRIF-dependent pathways of TLR3 and TLR4. EGCG inhibited the activation of IFN regulatory factor 3 (IRF3) induced by LPS, poly[I:C], or the overexpression of TRIF. The inhibition of IRF3 activation by EGCG was mediated through the suppression of the kinase activity of TBK1. However, EGCG did not inhibit activation of IRF3 induced by overexpression of constitutively active IRF3. These results suggest that the molecular target of EGCG is TBK1 in TRIF-dependent signaling pathways of TLR3 and TLR4. Therefore, our results suggest that green tea flavonoids can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inflammatory target gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Cooperation of H2O2-mediated ERK activation with Smad pathway in TGF-beta1 induction of p21WAF1/Cip1.

Although it has been demonstrated that p21WAF1/Cip1 could be induced by transforming growth factor-beta1 (TGF-beta1) in a Smad-dependent manner, the cross-talk of Smad signaling pathway with other signaling pathways still remains poorly understood. In this study, we investigated a possible role of hydrogen peroxide (H2O2)-ERK pathway in TGF-beta1 induction of p21WAF1/Cip1 in human keratinocytes HaCaT cells. Using pharmacological inhibitors specific for MAP kinase family members, we found that ERK, but not JNK or p38, is required for TGF-beta1 induction of p21WAF1/Cip1. ERK activation by TGF-beta1 was significantly attenuated by treatment with N-acetyl-l-cysteine or catalase, indicating that reactive oxygen species (ROS) generated by TGF-beta1, mainly H2O2, stimulates ERK signaling pathway to induce the p21WAF1/Cip1 expression. In support of this, TGF-beta1 stimulation caused an increase in intracellular ROS level, which was completely abolished by pretreatment with catalase. ERK activation does not appear to be associated with nuclear translocation of Smad-3, because ERK inhibition did not affect nuclear translocation of Smads by TGF-beta1, and H2O2 treatment alone did not cause nuclear translocation of Smad-3. On the other hand, ERK inhibition ablated the phosphorylation of Sp1 by TGF-beta1, which was accompanied with the disruption of interaction between Smad-3 and Sp1 as well as of the recruitment of Sp1 to the p21WAF1/Cip1 promoter induced by TGF-beta1, indicating that ERK signaling pathway might be necessary for their interaction. Taken together, these results suggest that activation of H2O2-mediated ERK signaling pathway is required for p21WAF1/Cip1 expression by TGF-beta1 and led us to propose a cooperative model whereby TGF-beta1-induced receptor activation stimulates not only a Smad pathway but also a parallel H2O2-mediated ERK pathway that acts as a key determinant for association between Smads and Sp1 transcription factor.

Active Transport, Cell Nucleus↗
PubMed2005

Interaction between Rtg2p and Mks1p in the regulation of the RTG pathway of Saccharomyces cerevisiae.

Retrograde signaling mediates nuclear gene expression in response to changes in the functional state of mitochondria. In budding yeast, retrograde signaling, also termed the RTG pathway, relies on the heterodimeric, basic helix-loop-helix zipper transcription factors, Rtg1p and Rtg3p, for the activation of target gene expression. Activation of the RTG pathway leads to partial dephosphorylation of Rtg3p and its translocation, together with Rtg1p, from the cytoplasm to the nucleus. These processes depend on a positive regulatory factor, Rtg2p, a novel protein with a ATP binding domain similar to that of the Hsp70/actin/sugar kinase superfamily. Four negative regulatory factors, Lst8p, Mks1p, and two redundant 14-3-3 proteins, Bmh1/2p, function between Rtg2p and Rtg1/3p. Alternative interaction between Mks1p and Rtg2p or Bmh1/2p provides a means for regulation of the RTG pathway. When the RTG pathway is on, Mks1p is inactivated by its association with Rtg2p; and when the RTG pathway is off, Mks1p dissociates from Rtg2p and forms a complex with Bmh1/2p, which is the negative regulatory form of Mks1p. Here we show that Rtg2p and Mks1p can interact in the absence of other factors, and is thereby the minimal binary switch for regulation of the RTG pathway. Gel filtration experiments indicate that both Rtg2p and Mks1p exist in high molecular weight complexes. In response to changes in the activity of the RTG pathway, both Rtg2p and Mks1p shift to different sized high molecular weight complexes. Together, our data suggest that dynamic association between Mks1p and Rtg2p in high molecular weight complexes provides a means to regulate the RTG pathway.

Blotting, Western↗
PubMed2005

A preliminary multi-stable-isotopic evaluation of three synthetic pathways of Topiramate.

As a preliminary study of the utility of the natural stable-isotopic differentiation of batch samples produced by different synthetic pathways, multi-stable-isotopic analyses (delta(13)C, delta(15)N, delta(18)O, deltaD) of 53 samples of the antiepileptic drug, Topiramate, produced by three different synthetic pathways (designated "A," "B," "C") were performed. From the outset, we note that there are two fundamental variables that determine the stable-isotopic composition of materials-the stable-isotopic composition of the reagents and starting intermediates, and the isotope fractionation that occurs during manufacture of the product. In this study, the stable-isotopic composition of the raw materials was not controlled and we report here data obtained for a suite of samples that was produced by three synthetic pathways. Graphical examination of these data reveals marked data clustering by synthetic pathway, though in some cases with some overlapping values within standard errors. In general, the isotopic composition of Topiramate from the A and B pathways is distinct from the C pathway. The isotopic data from the A and B pathways typically abut each other, sometimes partially overlapping. The deuterium/hydrogen- (deltaD) and oxygen (delta(18)O) isotopic compositions are each significantly linearly related with the paired carbon (delta(13)C) isotopic composition indicating possible isotopic end-members for the raw materials of the present sample suite. Given that H and O typically derive from meteoric water, the linear correlations with delta(13)C indicate that a mixture of carbon sources (viz., perhaps terrestrial C3 photosynthetic organic carbon and marine C3 organic carbon) were used in the production of the batches tested. If the H and O analyzed were derived from meteoric water, then an elementary comparison of the span of the deltaD (DeltadeltaD = 54.6 +/- 2.1 per thousand) and of the delta(18)O (Deltadelta(18)O = 4.71 +/- 0.26 per thousand) values in the Topiramate samples to that of the global isotopic gradients indicates that the water retained in the samples spanned from as much as 11 degrees of latitude (or, approximately 760 statute miles North-to-South). The present isotope results (delta(13)C, delta(15)N, delta(18)O, deltaD) form an initial database against which future samples can be compared to infer specific synthetic pathways. It is clear that to perform a rigorous test of the variables controlling the stable-isotopic composition of pharmaceutical materials that both the stable-isotopic composition of the starting materials and synthetic isotope fractionation must be controlled in future studies.

Fructose↗
PubMed2005

Shikimate and folate pathways in the protozoan parasite, Perkinsus olseni.

We have exploited the experimental accessibility of the protozoan parasite Perkinsus olseni and its similarities to apicomplexan parasites to investigate the influence of specific drugs on its proliferation. For this purpose, shikimate and folate pathways present an attractive target for parasitic therapy given their major differences with mammalian pathways. Glyphosate, a potent inhibitor of the shikimate pathway enzyme EPSP synthase inhibited the in vitro proliferation of P. olseni in a dose-dependent manner and this effect was reversed by addition of chorismate, indicating the presence of a shikimate pathway. However, this effect was not antagonised by p-aminobenzoate or folic acid. Furthermore, antagonism was observed, via pyrimethamine to glyphosate inhibitory effect, suggesting that the shikimate pathway is not essential for the biosynthesis of folate precursors and is therefore crucial for another pathway downstream from chorismate. In addition, sulfadiazine, a well known inhibitor of dihydropteorate synthase, an enzyme of the folate biosynthetic pathway,had no inhibitory effect on P. olseni proliferation. In view of these results, the parasite does not appear to require the folate biosynthesis pathway for its survival and is most likely able to use exogenous folate. Even though pyrimethamine was found to inhibit P. atlanticus growth, this inhibitory effect could not be reversed by co-addition of folic acid. Therefore, we propose that the effect of pyrimethamine observed in this study results from the inhibition of a target other than dihydrofolate reductase. Similarly, proguanil target is likely to be separate from DHFR since only its metabolite cycloguanil has been shown to have inhibitory properties on DHFR.

Animals↗
PubMed2003

Role of the error-free damage bypass postreplication repair pathway in the maintenance of genomic stability.

The postreplication repair pathway (PRR) is composed of error-free and error-prone sub-pathways that allow bypass of DNA damage-induced replication-blocking lesions. The error-free sub-pathway is also used for bypass of spontaneous DNA damage and functions in cooperation with recombination pathways. In diploid yeast cells, error-free PRR is needed to prevent genomic instability, which is manifest as loss of heterozygosity (LOH) events of increased chromosome loss and recombination. Homologous recombination acts synergistically with the error-free damage avoidance branch of PRR to prevent chromosome loss. The DNA damage checkpoint gene MEC1 acts synergistically with the PRR pathway in maintaining genomic stability. Integration of the PRR pathway with other cellular pathways for preventing genomic instability is discussed. In diploid strains, the most dramatic increase is in the abnormality of chromosome loss when a repair or damage detection pathway is defective.

Crossing Over, Genetic↗
PubMed2004

Nitric oxide-modulated marker gene expression of signal transduction pathways in lung endothelial cells.

Nitric oxide (NO) is a signal molecule involved in regulation of physiological and pathophysiological functions of the vascular endothelium such as apoptosis. We examined whether NO-modulates marker gene expression of signal transduction pathways in cultured pulmonary artery endothelial cell (PAEC). Cells were exposed to a NO donor, 1 mM NOC-18, for 0.5, 5, and 24 h, thereafter, expression levels of 96 marker genes associated with 18 signal transduction pathways were assessed using a signal transduction pathway-finder microarray analysis system. NO modulation of apoptotic pathways and nuclear factor (NF) microarray were further analyzed. Gene array analyses revealed that 17 genes in 13 signal pathways were up- or down-regulated in cells exposed to NO, four of which were significantly altered by NO and are associated with apoptotic pathways. Apoptotic pathways resulted in identification of 11 genes in this group. Nuclear factor microarray studies demonstrated that NO-modulated expression of these signal transduction genes was associated with regulation of NF-binding activities. Gel shift analysis verified the effects of NO on DNA-binding activity of NF. These results demonstrated that NO signaling modulates at least 13 signal transduction pathways including apoptosis-related families in PAEC.

Animals↗
PubMed2006

Dynamic pathway allocation in early terpenoid biosynthesis of stress-induced lima bean leaves.

Two independent pathways contribute in higher plants to the formation of isopenteny1 diphosphate (IDP), the central building block of isoprenoids. In general, the cytosolic mevalonate pathway (MVA) provides the precursors for sesquiterpenes and sterols, whereas the plastidial methylerythritol pathway (MEP) furnishes the monoterpene-, diterpene- and carotenoids. Administration of deuterium labeled 1-deoxy-d-xylulose and mevalolactone to lima beans (Phaseolus lunatus), followed by gas chromatographic separation and mass spectrometric analysis of de novo produced volatiles revealed that the strict separation of both pathways does not exist. This could be confirmed by blocking the pathways individually with cerivastatin((R)) (MVA) and fosmidomycin (MEP), respectively. Isotopic ratio mass spectrometry (IRMS) at natural abundance levels demonstrated independently and without the need for labeled precursors a dynamic allocation of the MVA- or the MEP-pathway in the biosynthesis of the nerolidol-derived homoterpene 4,8-dimethy1-nona-1,3,7-triene (DMNT). Insect-feeding upregulated predominantly the MVA-pathway, while the fungal elicitor alamethicin stimulated the biosynthesis of DMNT via the MEP-pathway.

Gas Chromatography-Mass Spectrometry↗
PubMed2006

Comprehensive analysis of pathway or functionally related gene expression in the National Cancer Institute's anticancer screen.

We have analyzed the level of gene coregulation, using gene expression patterns measured across the National Cancer Institute's 60 tumor cell panels (NCI(60)), in the context of predefined pathways or functional categories annotated by KEGG (Kyoto Encyclopedia of Genes and Genomes), BioCarta, and GO (Gene Ontology). Statistical methods were used to evaluate the level of gene expression coherence (coordinated expression) by comparing intra- and interpathway gene-gene correlations. Our results show that gene expression in pathways, or groups of functionally related genes, has a significantly higher level of coherence than that of a randomly selected set of genes. Transcriptional-level gene regulation appears to be on a "need to be" basis, such that pathways comprising genes encoding closely interacting proteins and pathways responsible for vital cellular processes or processes that are related to growth or proliferation, specifically in cancer cells, such as those engaged in genetic information processing, cell cycle, energy metabolism, and nucleotide metabolism, tend to be more modular (lower degree of gene sharing) and to have genes significantly more coherently expressed than most signaling and regular metabolic pathways. Hierarchical clustering of pathways based on their differential gene expression in the NCI(60) further revealed interesting interpathway communications or interactions indicative of a higher level of pathway regulation. The knowledge of the nature of gene expression regulation and biological pathways can be applied to understanding the mechanism by which small drug molecules interfere with biological systems.

Algorithms↗
PubMed2004

Signal-transduction pathways involved in the hypertrophic effect of hsp56 in neonatal cardiomyocytes.

Heat shock protein (hsp) 56 (hsp56) is an immunophilin that acts as a cofactor with hsp90 and exhibits both peptidyl-prolyl isomerase activity and chaperone activity. Previous studies have shown that the hypertrophic effect of cardiotrophin-1 (CT-1) in cardiac cells is dependent on hsp56 induction. CT-1 activates a number of signal-transduction pathways. Therefore, we sought to determine whether these pathways were also important for hsp56-induced hypertrophy using overexpression with transiently transfected plasmid vectors in rat neonatal cardiomyocytes. Here we show that multiple signalling pathways are involved in hsp56-induced hypertrophy, namely the Janus kinase-signal-transducer and activator of transcription, extracellular signal-regulated protein kinase and PI3-kinase/Akt signalling pathways. Dominant-negative mutants and inhibitors of these pathways were able to block the hypertrophy observed as a result of hsp56 overexpression. However, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway was not able to block the hypertrophic effect of hsp56 overexpression. Furthermore, we show that domains I, II and IV of the hsp56 protein may be involved in its hypertrophic effect. These studies show for the first time that multiple signalling pathways are involved in the hypertrophic effect of hsp56 and that overexpression of hsp56 itself is able to activate the necessary signalling pathways, which induce hypertrophy.

Animals↗
PubMed2006

Coenzyme Q10 production in recombinant Escherichia coli strains engineered with a heterologous decaprenyl diphosphate synthase gene and foreign mevalonate pathway.

In the present work, Escherichia coli DH5alpha was metabolically engineered for CoQ(10) production by the introduction of decaprenyl diphosphate synthase gene (ddsA) from Agrobacterium tumefaciens. Grown in 2YTG medium (1.6% tryptone, 1% yeast extract, 0.5% NaCl, and 0.5% glycerol) with an initial pH of 7, the recombinant E. coli was capable of CoQ(10) production up to 470 microg/gDCW (dry cell weight). This value could be further elevated to 900 microg/gDCW simply by increasing the initial culture pH from 7 to 9. Supplementation of 4-hydroxy benzoate did not improve the productivity any further. However, engineering of a lower mevalonate semi-pathway so as to increase the isopentenyl diphosphate (IPP) supply of the recombinant strain using exogenous mevalonate efficiently increased the CoQ(10) production. Lower mevalonate semi-pathways of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, and Saccharomyces cerevisiae were tested. Among these, the pathway of Streptococcus pneumoniae proved to be superior, yielding CoQ(10) production of 2,700+/-115 microg/gDCW when supplemented with exogenous mevalonate of 3 mM. In order to construct a complete mevalonate pathway, the upper semi-pathway of the same bacterium, Streptococcus pneumoniae, was recruited. In a recombinant E. coli DH5alpha harboring three plasmids encoding for upper and lower mevalonate semi-pathways as well as DdsA enzyme, the heterologous mevalonate pathway could convert endogenous acetyl-CoA to IPP, resulting in CoQ(10) production of up to 2,428+/-75 microg/gDCW, without mevalonate supplementation. In contrast, a whole mevalonate pathway constructed in a single operon was found to be less efficient. However, it provided CoQ(10) production of up to 1,706+/-86 microg/gDCW, which was roughly 1.9 times higher than that obtained by ddsA alone.

Alkyl and Aryl Transferases↗
PubMed2003

Radiofrequency catheter ablation of septal accessory pathways in the pediatric age group.

Radiofrequency catheter ablation (RCA) of septal accessory pathways may be technically challenging in children due to the risk of inadvertent atrioventricular (AV) block in the setting of small cardiac dimensions. Outcomes were reviewed for all patients aged < or =19 years with manifest and concealed septal accessory pathways undergoing RCA since 1990 at a single institution. One hundred forty-five procedures were performed in 127 patients (mean age 11.6 years). The number of studies according to accessory pathway location were: anteroseptal (n = 36), midseptal (n = 20), mouth of coronary sinus (n = 40), middle cardiac vein (n = 6), right posteroseptal (n = 21), and left posteroseptal (n = 22). Ablation was deferred for 9 patients (6 anteroseptal and 3 midseptal) in favor of additional pharmacologic trials. Acute success rates for targeted accessory pathways were: anteroseptal (96%), midseptal (94%), mouth of coronary sinus (88%), middle cardiac vein (100%), right posteroseptal (100%), and left posteroseptal (96%). Recurrence rates during follow-up were: anteroseptal (14%), midseptal (12%), mouth of coronary sinus (3%), right posteroseptal (4%), and left posteroseptal (4%). Permanent second or third degree AV block occurred in 4 of 136 RCA attempts (3%), involving 2 anteroseptal and 2 midseptal pathways. In 3 of these 4 cases, a high probability of block was anticipated from prior ablation efforts, prompting pacemaker insertion before or in conjunction with RCA. Thus, in the pediatric age group, acute RCA success rates for septal accessory pathways can exceed 90%. The risks of AV block and accessory pathway recurrence are most relevant to anteroseptal and midseptal pathways. These data may be factored into patient selection and the decision whether to ablate.

Adolescent↗