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PubMed1994

Radiofrequency ablation for the fast pathway of atrioventricular node reentry. Evidence for partial damage to the fast and lower common pathways.

Radiofrequency ablation was attempted in a 30-year-old woman with atrioventricular (AV) node reentry of the common variety. Energy was delivered to ablate a fast pathway. After energy delivery, the atrio-His interval prolonged following transient AV node block. Retrograde conduction was no longer present. However, dual AV nodal physiology and AV node reentry with similar retrograde atrial activation sequence could be shown post-ablation. These observations suggest that both fast and lower common pathways were partially damaged by ablation.

Adult↗

PubMed2006

Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of apoptotic pathways.

Apoptosis, a Greek descriptive term for falling leaves or petals, plays an important role in the progression of many diseases. Apoptosis is essential for the development and survival of multi-cellular organisms. Malignant diseases, including haematologic malignancies, are associated with defects in the cell death mechanism. These defects are not only important for the growth advantage of malignant clones, but when understood can be used for specific therapeutic targeting of malignant cells while sparing normal cells. The cellular and molecular mechanisms of apoptosis have been extensively demonstrated and are reviewed in this article. In this part of the review we focus on basic details of the apoptosis pathways, key players of the receptor-mediated apoptosis, and molecules involved in the cross-talk between individual apoptosis pathways and apoptosis regulation.

Animals↗

PubMed1991

Investigations on the metabolic pathways of cyclosporine: II. Elucidation of the metabolic pathways in vitro by human liver microsomes.

1. Cyclosporine and its metabolites, isolated from human bile and identified by FAB mass spectrometry and 1H-n.m.r. spectroscopy, were metabolized by human liver microsomes for the identification of new cyclosporine metabolites. From these data a metabolic pathway for cyclosporine, which includes these new cyclosporine metabolites, has been proposed. The new metabolites were isolated by semi-preparative h.p.l.c. and their chemical structures were elucidated by FAB mass spectrometry. These isolated metabolites were further metabolized and the products identified by FAB mass spectrometry. 2. Fourteen metabolites, whose structure has not yet been elucidated, were isolated after metabolism of structurally identified cyclosporine metabolites, and chemical structures for five of these metabolites were proposed. 3. The structures of the new cyclosporine metabolites were: (i) a N-demethylated, carboxylated derivative (AM1A4N), (ii) a di-hydroxylated, N-demethylated derivative (AM14N9), (iii) a hydroxylated and carboxylated derivative (AM1A9), (iv) a di-hydroxylated, cyclized and N-demethylated derivative (AM1c4N9) and (v) a cyclized and carboxylated (AM1cA) derivative. 4. A proposed cyclosporine metabolic pathway comprises a total of 29 metabolites. It consists of four main branches originating from metabolites AM1, AM1c, AM9 and AM4N.

Bile↗

PubMed2000

The Agrin/MuSK signaling pathway is spatially segregated from the neuregulin/ErbB receptor signaling pathway at the neuromuscular junction.

The neuregulin/erbB receptor and agrin/MuSK pathways are critical for communication between the nerve, muscle, and Schwann cell that establishes the precise topological arrangement at the vertebrate neuromuscular junction (NMJ). ErbB2, erbB3, and erbB4 as well as neuregulin, agrin, and MuSK are known to be concentrated at the NMJ. Here we have examined NMJs from gastrocnemius muscle of adult rat using immunofluorescence confocal microscopy to characterize in detail the distribution of these proteins relative to the distribution of acetylcholine receptors (AChRs). We have determined that erbB2 and erbB4 are enriched in the depths of the secondary junctional folds on the postsynaptic muscle membrane. In contrast, erbB3 at the NMJ was concentrated at presynaptic terminal Schwann cells. This distribution strongly argues that erbB2/erbB4 heterodimers are the functional postsynaptic neuregulin receptors of the NMJ. Neuregulin was localized to the axon terminal, secondary folds, and terminal Schwann cells, where it was in a position to signal through erbB receptors. MuSK was concentrated in the postsynaptic primary gutter region where it was codistributed with AChRs. Agrin was present at the axon terminal and in the basal lamina associated with the primary gutter region, but not in the secondary junctional folds. The differential distributions of the neuregulin and agrin signaling pathways argue against neuregulin and erbB receptors being localized to the NMJ via direct interactions with either agrin or MuSK.

Agrin↗

PubMed2001

The MEK1-ERK map kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells.

Primary liver cancers, which are generally hypervascular in nature, depend highly on blood supply. So far there are few reports on apoptosis of liver cancer cells upon deprivation of serum-derived survival factors. The aim of our study is to clarify molecular mechanisms by which liver cancer cells survive with the aid of serum. In HepG2 liver cancer cells, serum deprivation induced time-dependent increase in the number of apoptotic cells, which was detected by fragmentation of genomic DNA and fluorescent nuclear staining. The activity of extracellular signal-regulated kinase (ERK) did not decrease considerably after serum deprivation, although it increased after serum stimulation. However, we found that the MEK1 inhibitor PD98059, but not the p38 kinase inhibitor SB203580, potently induced apoptosis of the liver cancer cells in the presence of serum, indicating that the MEK-ERK signaling pathway is required for serum-dependent survival of HepG2 cells. In agreement with this notion, transient expression of active MEK1 prevented apoptosis in serum-deprived condition. We also found that the protective effect of serum against apoptosis was totally abrogated by LY294002 or wortmannin, which are the inhibitors of phosphatidylinositol (PI) 3-kinase. The activity of Akt, the target of PI 3-kinase, decreased gradually after deprivation of serum, whereas it was rapidly reactivated upon serum stimulation. These data indicate that survival of HepG2 liver cancer cells depends upon serum and that both the MEK1-ERK- and the PI 3-kinase-Akt- pathways are required for survival signaling to the nucleus.

Apoptosis↗

PubMed1991

[Right accessory pathway simulating a nodo-ventricular pathway: an electrophysiologic study and intraoperative mapping].

We report a case of a patient with episodes of wide QRS tachycardia and syncope. During the electrophysiologic study, a wide QRS tachycardia (200 b/m) with left bundle branch block morphology was reproducibly induced by incremental atrial pacing with progressive shortening of the HV interval and lengthening of the AV interval, suggesting the presence of a nodoventricular accessory pathway (Mahaim fiber). The intraoperative mapping performed during tachycardia showed the earliest ventricular activation to be over the right antero-lateral AV groove, different from the usual epicardial activation previously described. According to the earliest epicardial breakthrough point, we performed an epicardial AV fat pad dissection which produced irreversible disappearance of preexcitation, confirmed at the postoperative electrophysiologic study. No recurrence of tachycardia was observed during a follow-up of 11 months. This case further confirms previous data that the "so-called" Mahaim fibers could be a right accessory pathway with decremental properties.

Adult↗

PubMed1987

Analysis of two distinct B cell activation pathways mediated by a monoclonal T helper cell. I. MHC-restricted activation of B cells by an IL 2-dependent pathway.

The present study was carried out to determine whether the MHC-restricted and MHC-unrestricted B cell activation pathways mediated by a single cloned Th cell are separable, and whether these two pathways are mediated by distinct mechanisms. It was demonstrated that the two B cell activating functions of a single cloned Th cell could be separated by their sensitivity to irradiation. It was shown that MHC-restricted B cell activation is mediated by a radiosensitive Th cell function, whereas MHC-unrestricted B cell activation is mediated by a radioresistant function of the same Th cell. In addition, it was shown that recombinant IL 2 can restore or replace the radiosensitive component of MHC-restricted cognate helper function.

Animals↗

PubMed1977

Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway.

It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).

Antigen-Antibody Complex↗

PubMed1980

Effect of the 5-hydroperoxide of eicosatetraenoic acid and inhibitors of the lipoxygenase pathway on the formation of slow reacting substance by rat basophilic leukemia cells; direct evidence that slow reacting substance is a product of the lipoxygenase pathway.

Previous studies in a line of rat basophilic leukemia (RBL 1) cells have indicated that the slow reacting substance (SRS) made during stimulation with the divalent cation ionophore, A23187, is derived from arachidonic acid (AA). In the present report, various inhibitors of AA metabolism were compared with regard to their effects on SRS formation and incorporation of radioactivity from [1-14C]-AA into known metabolites of the lipoxygenase and cyclooxygenase pathways. An apparently close parallel between lipoxygenase product formation and SRS synthesis is demonstrated. In addition, exogenous 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) has been shown to markedly enhance SRS synthesis, even when A23187 is absent. The data provide very strong evidence that SRS is produced through the lipoxygenase pathway.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1981

[Electrophysiologic demonstration of dual atrioventricular nodal pathways and final common pathway in a case of A-V nodal paroxysmal tachycardia. Considerations on the functional complexity of the A-V node (author's transl)].

The AA. studied the A-V nodal conduction using the technique of induced PAB in a patient with A-V reentrant paroxysmal tachycardia. They observed that the conduction through the A-V node failed when coupling intervals A1-A2 were between 280 and 260 msec and, after, recovered, with consistent slackening, when A1-A2 intervals were shortened, until the atrial ERP was reached. This uncommon response indicates the functional complexity of the A-V node and, particularly, suggests the presence of a final common pathway distal to the fast and slow A-V pathways, that are the anatomic-functional basis of the reentry circuit in A-V nodal paroxismal tachycardia.

Atrioventricular Node↗

PubMed1975

Energy metabolism of spermatozoa. V. The Embden-Myerhof pathway of glycolysis: activities of pathway enzymes in hypotonically treated rabbit epididymal spermatozoa.

Seven enzymes of the Embden-Myerhof pathway of glycolysis were assayed in hypotonically treated epididymal sperm from mature rabbits. These were: fructose-biphosphate aldolase, triosephosphate isomerase, glyceraldehydephosphate dehydrogenase, 3-phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase. These enzymes were firmly enough bound to the cell structure to resist removal by washing after hypotonic treatment and had maximal activities comparable to, or greater than, the rate of mitochondrial pyruvate oxidation, so that rapid oxygen uptake was observed with intermediates of the glycolytic pathway. The activity of lactate dehydrogenase in a typical preparation of hypotonically treated cells was 5.3 mumoles/minute x 10(9) cells at 25 degrees C for pyruvate reduction in the hypotonically treated cells and 4.8 mumoles/minute x 10(9) cells in the thrice-washed hypotonically treated cells. The Km for pyruvate was 1.4 mM while that for lactate was 4.4 mM. By contrast, the maximal activity of pyruvate oxidation by mitochondria was 0.10 microgram atom of oxygen/minute x 10(9) cells, corresponding to 0.020 mumole of pyruvate/minute x 10(9) cells, and the Km for pyruvate was 5 microM. These enzyme parameters favor high lactate production from glucose in aerobic glycolysis.

Animals↗

PubMed1997

Anti-human class I MHC antibodies induce apoptosis by a pathway that is distinct from the Fas antigen-mediated pathway.

5H7, an anti-human class I MHC mAb that recognizes a monomorphic determinant of the alpha3 domain, profoundly inhibits T lymphocyte activation. The present study was designed to determine the role of programmed cell death in 5H7-mediated immune suppression. Incubation of PBMC with 5H7 mAb induced a marked reduction in viable cell recovery (VCR) of T cells (<10% VCR), NK cells (<1% VCR), and B cells (<1% VCR). In addition, 5H7 inhibited proliferation and VCR of JY, DBS-521, and BevD tumor lines as well as cells transfected with HLA-B27. Morphologic changes characteristic of apoptosis were induced by 5H7, including cell membrane blebbing, cytoplasmic vacuolization, condensation of nuclear chromatin, and nuclear fragmentation. Furthermore, DNA fragmentation was demonstrated in 5H7-treated PBMC using a TdT-mediated end-labeling (TUNEL) technique. 5H7, but not anti-Fas mAb, induced apoptosis of cell lines derived from patients with Niemann-Pick disease that lack acidic sphingomyelinase activity. In addition, induction of cell death by 5H7 was not inhibited by IL-1beta-converting enzyme (ICE) inhibitors under conditions that fully suppressed Fas-mediated apoptosis. These findings suggest that signal transduction through "classical" human class I MHC molecules induces apoptosis by a Fas-independent pathway that does not require acidic sphingomyelinase, is independent of ICE protease, and may represent a unique pathway of cell death in human lymphocytes.

Adult↗

PubMed1997

Cross-Pathway and Pathway-Specific Control of Amino Acid Biosynthesis in Magnaporthe grisea

The gene encoding the small subunit of the arginine-specific carbamoyl phosphate synthetase, ARG2, of Magnaporthe grisea was characterized to examine the basic regulation of biosynthetic genes in this plant pathogen. The transcript of the ARG2 gene contains an upstream open reading frame (uORF) that is similar to uORFs found in the homologous genes of Neurospora crassa (arg-2) and Saccharomyces cerevisiae (CPA1), suggesting that the M. grisea gene is translationally regulated by a mechanism that is conserved in these fungi. Amino acid imbalance leads to elevated levels of ARG2 mRNA, indicating that in addition to translational control, ARG2 is subject to cross-pathway transcriptional control. A DNA-binding activity that has properties similar to those of the global transcriptional regulator mediating cross-pathway control in N. crassa was detected in M. grisea cell extracts. Thus, it appears that both specific regulation of ARG2 by arginine and global regulation of amino acid biosynthesis are present in M. grisea and highly conserved among M. grisea, N. crassa, and S. cerevisiae.

Journal Article↗

PubMed1997

Cross-pathway and pathway-specific control of amino acid biosynthesis in Magnaporthe grisea.

Amino Acid Sequence↗

PubMed1988

Auditory pathways in the budgerigar. II. Intratelencephalic pathways.

The projections of two telencephalic areas in receipt of projections from the auditory relay nucleus of the thalamus (nucleus ovoidalis) were studied in the budgerigar (Melopsittacus undulatus) with autoradiographic methods. These nuclei are called field 'L' and neostriatum intermedium pars dorsolateralis (NIDL). The results show that neurons in both fields project laterally to a portion of the neostriatum intermedium pars ventrolateralis (NIVL) and rostrally to the rostromedial archistriatum. Horseradish peroxidase experiments confirm these projections and indicate that field 'L', NIDL and NIVL also receive projections from neurons in the hyperstriatum ventrale (HV). The projections of field 'L' and NIDL neurons to the rostromedial archistriatum may act as pathways subserving auditory feedback. Neurons in this portion of the archistriatum project to the contralateral field 'L', NIDL and NIVL. Furthermore, the medial archistriatal projection field of neurons within field 'L', NIDL and NIVL (i.e. rostromedial archistriatum) is located adjacent to a large archistriatal neuronal field projecting to the medulla, including the lateral reticular formation of the medulla. This large archistriatal field includes the nucleus archistriatalis robustus, the telencephalic nucleus identified as the source of projections to the lower motoneurons of the syrinx. Thus, projections from auditory telencephalic areas to the rostromedial archistriatum may serve functions related to processes associated with learning and vocal motor control.

Animals↗

PubMed1995

Caudal medullary pathways to lumbosacral motoneuronal cell groups in the cat: evidence for direct projections possibly representing the final common pathway for lordosis.

The nucleus retroambiguus (NRA) projects to distinct brainstem and cervical and thoracic cord motoneuronal cell groups. The present paper describes NRA projections to distinct motoneuronal cell groups in the lumbar enlargement. Lumbosacral injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) were made to localize and quantify the retrogradely labeled neurons in the caudal medullary lateral tegmentum. These injections were combined with spinal hemisections to distinguish between neurons having ipsi-or contralaterally descending axons. The NRA-lumbosacral fibers descend almost exclusively contralaterally, but neurons in areas surrounding the NRA project mainly ipsilaterally. In an anterograde tracing study, injections of WGA-HRP or tritiated leucine were made in the region of the NRA to determine the NRA targets in the lumbosarcral cord. Hemisections in C2 made it possible to distinguish between NRA projections and projections from neurons in the adjoining lateral tegmentum. The results show delicate NRA projections to distinct lumbosacral motoneuronal cell groups innervating specific hindlimb muscles (iliopsoas, adductors, and hamstrings) as well as axial muscles (medial longissimus and proximal tail muscles). The projection is bilateral, with a contralateral predominance. Ipsilaterally terminating fibers are derived from NRA neurons whose axons cross the midline at the level of the obex, descend through the contralateral spinal white matter, and recross at the level of termination. A conceptual description is presented in which the periaqueductal gray-NRA-lumbosacral projections form the final common pathway for lordosis in the cat.

Animals↗

PubMed1989

The organization of descending tectofugal pathways underlying orienting in the frog, Rana pipiens. II. Evidence for the involvement of a tecto-tegmento-spinal pathway.

In the frog, identical orienting deficits, involving a failure to turn toward stimuli in the ipsilateral hemifield, can be produced by small white matter lesions either in the caudal mesencephalon (Kostyk and Grobstein, 1987a) or in the caudal medulla (Masino and Grobstein, 1989). These findings suggest that descending turn signals may run uninterrupted from the midbrain to the spinal cord, and that something other than tectospinal axons may carry such signals. We here report studies to determine whether there is a tecto-recipient structure whose axons pass through the known critical lesion sites in the caudal mesencephalon and medulla, and whether damage to such a structure, sparing tectospinal pathways, produces an orienting deficit. Horseradish peroxidase (HRP) was applied to behaviorally effective lesions in the caudal medulla and the resulting labelling patterns compared with those resulting from application of HRP to nearby but behaviorally ineffective lesions at the same rostrocaudal level. A column of large cells in the ventrolateral midbrain tegmentum (including nMLF as well as parts of AV and PV) was robustly labelled in all effective lesion cases, and less frequently labelled in ineffective cases. A quantitative analysis showed labelling in this region to be more highly correlated with the existence of a behavioral deficit than that in any other brain region. Reconstructions of single retrogradely labelled cells in the rostral part of the column (nMLF) showed that they have dendrites in a position to receive tectal input and axons which pass through the critical lesion sites in both the caudal mesencephalon and the caudal medulla. Tegmental lesions, sparing the tectospinal tracts, produced ipsilateral turning deficits in cases where the large cell column was completely removed but did not when the column was spared. The findings support the hypothesis that tectofugal signals involved in orienting turns descend uninterrupted to the spinal cord on something other than tectospinal axons, and suggest that the critical projections derive from the large cell column of the ventral tegmentum.

Animals↗

PubMed2003

Significance of the non-oxidative route of the pentose phosphate pathway for supplying carbon to the purine-nucleotide pathway in Corynebacterium ammoniagenes.

To evaluate the strategy of supplying ribose 5-phosphate to the purine-nucleotide pathway exclusively via the nonoxidative route, the glucose 6-phosphate dehydrogenase gene zwf was disrupted in inosine- and 5'-xanthylic acid-producers of Corynebacterium ammoniagenes. In both producers, interruption of the oxidative route caused a decrease in production yields of about 50%. Attempts to increase the capacity of the nonoxidative route through overexpression of the transketolase or transaldolase gene in the zwf mutants led to no discernable effects on production, indicating that, in C. ammoniagenes, the nonoxidative route alone cannot provide sufficient ribose 5-phosphate for high-level production, although nonoxidative synthesis of the precursor is possible.

Carbon↗