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PubMedDate not supplied

Pathway analysis and metabolic engineering in Corynebacterium glutamicum.

The gram-positive bacterium Corynebacterium glutamicum is used for the industrial production of amino acids, e.g. of L-glutamate and L-lysine. During the last 15 years, genetic engineering and amplification of genes have become fascinating methods for studying metabolic pathways in greater detail and for the construction of strains with the desired genotypes. In order to obtain a better understanding of the central metabolism and to quantify the in vivo fluxes in C. glutamicum, the [13C]-labelling technique was combined with metabolite balancing to achieve a unifying comprehensive pathway analysis. These methods can determine the flux distribution at the branch point between glycolysis and the pentose phosphate pathway. The in vivo fluxes in the oxidative part of the pentose phosphate pathway calculated on the basis of intracellular metabolite concentrations and the kinetic constants of the purified glucose-6-phosphate and 6-phosphogluconate dehydrogenases determined in vitro were in full accordance with the fluxes measured by the [13C]-labelling technique. These data indicate that the oxidative pentose phosphate pathway in C. glutamicum is mainly regulated by the ratio of NADPH/NADP concentrations and the specific activity of glucose-6-phosphate dehydrogenase. The carbon flux via the oxidative pentose phosphate pathway correlated with the NADPH demand for L-lysine synthesis. Although it has generally been accepted that phosphoenolpyruvate carboxylase fulfills a main anaplerotic function in C. glutamicum, we recently detected that a biotin-dependent pyruvate carboxylase exists as a further anaplerotic enzyme in this bacterium. In addition to the activities of these two carboxylases three enzymes catalysing the decarboxylation of the C4 metabolites oxaloacetate or malate are also present in this bacterium. The individual flux rates at this complex anaplerotic node were investigated by using [13C]-labelled substrates. The results indicate that both carboxylation and decarboxylation occur simultaneously in C. glutamicum so that a high cyclic flux of oxaloacetate via phosphoenolpyruvate to pyruvate was found. Furthermore, we detected that in C. glutamicum two biosynthetic pathways exist for the synthesis of DL-diaminopimelate and L-lysine. As shown by NMR spectroscopy the relative use of both pathways in vivo is dependent on the ammonium concentration in the culture medium. Mutants defective in one pathway are still able to synthesise enough L-lysine for growth, but the L-lysine yields with overproducers were reduced. The luxury of having these two pathways gives C. glutamicum an increased flexibility in response to changing environmental conditions and is also related to the essential need for DL-diaminopimelate as a building block for the synthesis of the murein sacculus.

Corynebacterium↗

PubMed2002

[Impact of a clinical pathway in cases of transurethral resection of the prostate].

OBJECTIVE: Because of recent increases in health care costs, cost containment has become a important issue in medical practice. We evaluated the effect on cost and clinical outcome with the implementation of clinical care pathway for transurethral resection of the prostate (TURP) patients. MATERIALS & METHODS: Our series consists of 69 consecutive patients treated with TURP between June 1, 1999 and March 31, 2000. The patients were divided into two groups at random. Thirty-two patients were treated on the clinical pathway (pathway group) and 37 patients were not placed on the clinical pathway program (non-pathway group). Total hospital charges, average length of stay and clinical outcomes were compared in two groups. RESULTS: The average of total hospital charges (insurance points) and average length of stay were 48,424.2 point, and 12.7 days for the pathway group, and 55.365.5 point, and 14.7 days for non-pathway group respectively. Postoperative complications and rehospitalization did not differ between two groups. DISCUSSION: With the implementation of the clinical care pathway, average hospital charges and length of stay were reduced. The clinical pathway program is considered to be a good tool for health care cost management. This methodology can be applied to all patients. However, when we make the clinical pathway program, we take into account the individuality of each patients.

Aged↗

PubMed2002

Cortical synaptic arrangements of the third visual pathway in three primate species: Macaca mulatta, Saimiri sciureus, and Aotus trivirgatus.

The koniocellular (K) pathway is one of three pathways from the lateral geniculate nucleus (LGN) to primate visual cortex (V1). K pathway projections to the cytochrome oxidase (CO) blobs of V1 suggest involvement in chromatic processing given reports that the CO blobs in diurnal primates contain cells selective for color. K LGN layers and CO blobs, however, are also well developed in nocturnal primates such as owl monkeys, which are likely to be color blind. Thus, the K pathway plays either different roles in different species or some as yet unidentified common role(s). Because synaptic arrangements underlie functional mechanisms, the purpose of this investigation was to compare the synaptic circuitry related to the K pathway within the CO blobs of two diurnal primates (macaque monkeys and squirrel monkeys) and one nocturnal primate (owl monkey). Presynaptic K axons were labeled with wheat germ agglutinin-HRP, and presynaptic and postsynaptic profiles in CO blobs were identified with post-embedding immunocytochemistry for GABA and glutamate. In all three species, K axon terminals are glutamatergic and larger than local axon terminals, suggesting that they have a greater impact on postsynaptic CO blob targets than signals arriving via layer IV from the P or M pathways. A greater proportion of K axons, however, synapse with larger glutamatergic shafts in the diurnal monkeys than in the nocturnal owl monkey, perhaps reflecting the importance of color within the K pathway of these diurnal species. Alternatively, the loss of color vision in the owl monkey could impact K pathway circuitry earlier in the pathway. The basic similarities between K axon circuitry within the CO blobs of the three primate species examined also could indicate that this pathway plays some common role or roles across species.

Animals↗

PubMedDate not supplied

A clinical pathway for pelvic inflammatory disease for use on an inpatient service.

OBJECTIVE: (1) To create a guideline to improve care of adolescent patients diagnosed with pelvic inflammatory disease (PID); (2) to promote cost-effective, consistent care while minimizing delays and ensuring timely and appropriate use of laboratory tests and other interventions; and (3) to describe the process of the development and the implementation of a clinical pathway for PID. METHODS: The study involved the creation and piloting of a multidisciplinary, collaborative clinical pathway for uncomplicated PID on an inpatient service, and the development of a standardized form for analysis of demographics and variances from the pathway. The setting was an inpatient adolescent service at a children's hospital in an urban setting. All patients admitted with a clinical diagnosis of PID from April 1, 1993, to November 30, 1993, were followed up by means of the clinical pathway. All patients discharged with a diagnosis of uncomplicated PID in fiscal year 1992 (FY92: October 1, 1991, to September 30, 1992) were used as a comparison population. The main outcome measures included length of stay, charges per patient, timing of antibiotic administration, use of laboratory tests at admission and at 48 to 72 hours, and documentation of pathway variances. RESULTS: A clinical pathway was created by consensus during a period of several months. During implementation, 28 of 34 (82%) patients admitted by use of the pathway had a final diagnosis of PID; 23 of the 28 (82%) had uncomplicated PID. Variances from the pathway included missed rapid plasma reagins (RPRs) and laboratory tests that were not indicated. For uncomplicated PID, length of stay was reduced (p=.08) from a median of 4 days in FY92 (mean, 5.0 1 3.1 days; range, 2-15 days) to a median of 3 days in the study group (mean, 3.5 + 1.0 days; range, 2-4 days), with differences not reaching the level of significance. There were significantly more patients staying 5 days or longer in FY92 than in the study group (p<.03). Average charges per patient also decreased by 10% (median, $5,275 in FY92 to $4,919), although these results were not statistically significant. CONCLUSION: A clinical pathway for uncomplicated PID can be developed and implemented through a multidisciplinary, collaborative process, with ongoing use as a means of quality improvement and continuing education. Variances from the pathway highlight the need for ongoing education for health care providers. Downward trends in charges per patient and length of stay, although not significant, are encouraging; but they require longitudinal follow up with larger numbers of patients and analysis of outcomes.

Adolescent↗

PubMed2000

The effect of clinical pathway implementation on total hospital costs for thyroidectomy and parathyroidectomy patients.

Clinical pathways have long been used to guide the delivery of patient care in varied practice settings. There is little information in the literature to document the effectiveness of pathway implementation in general surgical populations. This study reports the effect of clinical pathway implementation in two general surgical patient groups, thyroidectomy and parathyroidectomy. Clinical pathways were implemented to serve patients undergoing thyroidectomy and parathyroidectomy surgery. The effects of both clinical pathways on total hospital costs, length of hospitalization, variances, and outcomes were collected and evaluated from July 1998 through July 1999. These data were compared to data from the previous year. The average length of stay for parathyroidectomy patients decreased from 2.4 to 1.5 days (P = 0.26) for pathway patients as compared to prepathway patients. The average cost per case decreased from $5071 to $4291 (P = 0.50) for parathyroidectomy pathway versus prepathway patients. The average length of stay decrease for thyroidectomy patients was 1.4 to 1.2 (P = 0.16) for the pathway to prepathway comparison. The average cost per case decrease was minor at $4117 to $4111. Pharmacy costs and laboratory utilization were effectively reduced. Perioperative costs rose dramatically during this period, operating room/central sterile supply cost per case rose 12 per cent, anesthesia supply cost per case rose 15 per cent, and surgical pathology costs increased 110 per cent overall for both patient groups. Clinical pathway implementation has allowed us to reduce or maintain total hospital costs in the face of rising perioperative costs. We conclude that implementation of these clinical pathways has allowed us to improve consistency with which we deliver care while maintaining the quality of patient outcomes and reducing the costs of care and length of hospital stay.

Adolescent↗

PubMed2002

Improving treatment outcomes with a clinical pathway for hysterectomy and myomectomy.

OBJECTIVE: To determine if using a postoperative clinical pathway for women having hysterectomy or myomectomy would improve clinical care. STUDY DESIGN: Data from the literature and patient focus groups guided development of a clinical pathway. Nurses, pharmacists and physicians participated in the development process. Implementation relied on accepted quality improvement methods. We used a case-control design to compare administrative and clinical data for patients managed with (n = 28) and without (n = 28) the aid of the clinical pathway between June 1997 and January 1998. RESULTS: Case and control groups did not differ in age, race, payer status, severity of illness or procedure type. Clinical differences between pathway and nonpathway patients included a mean six-hour-shorter period of indwelling bladder catheters (P = .019), mean 11-hour more rapid return to regular diet (P = .014) and more pain assessments among pathway patients (mean, five vs. two; P < .001). There was no significant difference in length of stay between groups. Clinicians used the pathway for approximately one year, but with personnel changes the pathway gradually fell out of use. CONCLUSION: Clinical pathways can improve quality of care, even if they do not reduce length of stay. A team approach that focuses on patient concerns during pathway development may help ensure that quality improvement, rather than simply cost reduction, arises from the use of clinical pathways.

Adult↗

PubMed1990

Clinical implications of parallel visual pathways.

Visual information travels from the retina to visual cortical areas along at least two parallel pathways. In this paper, anatomical and physiological evidence is presented to demonstrate the existence of, and trace these two pathways throughout the visual systems of the cat, primate, and human. Physiological and behavioral experiments are discussed which establish that these two pathways are differentially sensitive to stimuli that vary in spatial and temporal frequency. One pathway (M-pathway) is more sensitive to coarse visual form that is modulated or moving at fast rates, whereas the other pathway (P-pathway) is more sensitive to spatial detail that is stationary or moving at slow rates. This difference between the M- and P-pathways is related to some spatial and temporal effects observed in humans. Furthermore, evidence is presented that certain diseases selectively comprise the functioning of M- or P-pathways (i.e., glaucoma, Alzheimer's disease, and anisometropic amblyopia), and some of the spatial and temporal deficits observed in these patients are presented within the context of the dysfunction of the M- or P-pathway.

Animals↗

PubMed1988

Intracranial visual pathway gliomas in children with neurofibromatosis.

The association between neurofibromatosis and visual pathway gliomas is well documented. The introduction of computed tomography and magnetic resonance imaging has heralded a new era in the understanding of visual pathway gliomas. Both of these noninvasive neuroinvestigative techniques have demonstrated extensive abnormalities throughout the visual pathway in children with visual pathway gliomas, especially in those with neurofibromatosis. The clinical significance of these abnormal areas of brain, especially in asymptomatic patients, is unknown. In an attempt to clarify the incidence, natural history, and clinical course of patients with neurofibromatosis and visual pathway lesions, we reviewed our experience with 24 patients managed consecutively at Children's Hospital of Philadelphia over the past 12 years. The patients in this series were compared to 29 children with visual pathway gliomas without neurofibromatosis who were evaluated at our institution over the same period of time. Visual pathway gliomas in children with neurofibromatosis differ from those in children without neurofibromatosis. In general, lesions tended to be more extensive in patients with neurofibromatosis and the clinical course of these patients is more variable. Twelve of the 24 patients with neurofibromatosis in our series had symptoms of progressive disease at the time of diagnosis and underwent treatment with variable results. Twelve children with neurofibromatosis and visual pathway lesions had static lesions at the time of diagnosis and, to date, 3 have developed progressive disease. From our review we can make some recommendations concerning the management of children with neurofibromatosis and visual pathway gliomas, but many questions remain unanswered. Sequential follow-up of a large cohort of both asymptomatic and symptomatic children with neurofibromatosis and visual pathway lesions is needed to more definitively outline the best management approach for these patients.

Adolescent↗

PubMed1985

Prevention of immune precipitation by purified components of the alternative pathway.

The role of the alternative pathway in complement-mediated prevention of immune precipitation has been investigated by the use of BSA-anti-BSA immune complex (IC) purified components. For immune precipitation to be prevented all six alternative pathway components (C3, factors B D, P, H and I) were required. In the absence of one or both of the control proteins H and I, excessive fluid phase turnover of C3 occurred with precipitation of IC. Kinetic studies showed that in the presence of the control proteins, an initial phase of precipitation occurred, and was followed by a phase of resolubilization of IC. When the efficiency of classical and alternative pathways in the prevention of immune precipitation was compared it was found that the classical pathway proteins were more effective than the alternative pathway components. A reaction mixture containing the components of both pathways was no better than the classical pathway protein alone. 125I-C3 was bound to IC which had been rendered soluble in the presence of classical or alternative pathway components. A molar ratio of two molecules C3b:five molecules IgG was calculated. Other complement components which were bound to IC which had been formed in the presence of serum were C1q, C4, C2, C3, C5, P and H. Factors B and I were not detected. Our findings suggest that the alternative pathway is of secondary importance to the classical pathway in the prevention of immune precipitation.

Antigen-Antibody Complex↗

PubMed1993

Developmental changes produced in the retinofugal pathways of rats and ferrets by early monocular enucleations: the effects of age and the differences between normal and albino animals.

Early monocular enucleations were done in rats, either at embryonic day 16 (E16) or on the day of birth, and the surviving uncrossed pathway was studied either at birth for some of the animals enucleated prenatally, or in the adult for all of the other animals. The uncrossed pathways were studied by using HRP as a retrograde tracer. The neonatal enucleations showed the increase of the surviving uncrossed component previously documented by others. In contrast to this, a prenatal enucleation produced a significant reduction in the surviving uncrossed pathway at birth. If these animals survived to be adults, then the surviving uncrossed pathway was slightly increased relative to normal. We conclude that two quite distinct mechanisms have been exposed by these experiments, one acting prenatally and producing a reduction in the uncrossed pathway, and the other acting postnatally and producing an increase. The postnatal effect, which is due to a decrease of the normally occurring ganglion cell death, thus neutralizes the prenatal effect, so that the most effective demonstration of the prenatal effect is to be seen before the period of cell death (early postnatal in rats and ferrets). The same methods were applied to prenatal ferrets at E26-E28 and, in order to see the maximum prenatal effects, the uncrossed pathways were studied at birth in all of these animals. There was a severe reduction of the uncrossed pathway throughout, and this was greatest in the animals with the earliest enucleations. Since the uncrossed pathway in normally reared albino animals is abnormally small, the effects of an early prenatal enucleation in albino rats and ferrets were compared with the effects in normally pigmented animals in order to determine whether the early enucleation was producing an abnormality comparable to the albino abnormality. Prenatal enucleations reduced the uncrossed pathway not only in normally pigmented but also in albino neonatal rats and ferrets. Further, the characteristic position of the nasal border of the temporal retina, which is abnormal in albino animals, was unaffected by the enucleation in either the albino or the pigmented animals, except where, in ferrets, enucleations produced a complete loss of the temporal concentration of ipsilaterally projecting ganglion cells (the temporal crescent). The earlier enucleations showed a greater tendency to produce such a complete loss of the temporal crescent. We conclude that the developmental mechanisms affected by the early enucleations are distinct from those that act to produce the albino abnormality even though both produce an abnormally small uncrossed pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Albinism↗

PubMed1995

Isolation and interaction of ON and OFF pathways in human vision: pattern--polarity effects on contrast discrimination.

To activate selectively cortical ON and OFF pathways, I measured pattern contrast discrimination functions and manipulated contrast polarity (positive and negative) of base contrast (C) and added contrast (delta C). C was a large, long-duration cosine mask and delta C was a brief, localized, spatially narrow-band "D6" pattern. For same polarity C and delta C, contrast discrimination followed a "dipper" pattern: threshold facilitation at low C and a power relation (exponent < 1.0) at high C. The facilitation is predicted from the low-contrast response of cortical neurons and seems to represent isolation of an ON or OFF pathway. Opposite polarity C and delta C give a monotonic function. delta C increases at low base C and remaining higher than the same-polarity function at higher C values. This represents interaction between ON and OFF pathways. Pathway isolation also occurs: a positive test is detected as a contrast increment if masked by negative contrast and a negative test is detected as a contrast decrement if masked by positive contrast. Quantitative aspects of the data suggest a subtractive interaction at low C values and a divisive interaction between pathways at high C values. Test contrast thresholds upon uniform fields of varying luminance show that both the dipper effect and most of the rise in delta C with C are mediated in pattern-selective pathways rather than at a site of luminance adaptation. The pattern-polarity effects on contrast discrimination rule out the "channel uncertainty" explanation for the facilitation dipper. My results suggest that parallel ON and OFF pathways evolved because stimulus-produced decreases in the response of a single pathway are potentially confounded with the effects of contrast adaptation. Thus transient decreases in response in either pathway are not processed and both decreases and increases in contrast are expressed as response increases in separate pathways.

Contrast Sensitivity↗

PubMed2006

Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement.

C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.

Complement C1 Inhibitor Protein↗

PubMed1999

Emergency department thrombolysis critical pathway reduces door-to-drug times in acute myocardial infarction.

BACKGROUND: Rapid time to treatment with thrombolytic therapy is an important determinant of survival in acute myocardial infarction (AMI). HYPOTHESIS: We hypothesized that establishment of an AMI thrombolysis critical pathway in the Emergency Department could successfully reduce the "door-to-drug" time, the time between patient arrival and start of thrombolysis. METHODS AND RESULTS: Before establishment of the AMI critical pathway, median door-to-drug time was 73 min, which was reduced to 37 min after critical pathway implementation (p < 0.05). The percentage of patients treated within 30 min rose from 0% prior to establishment of the pathway to 43% (p = 0.03). Similarly, the percentage treated in within 45 min rose from 0 to 67% (p = 0.0005). Door-to-drug times were longer for women than for men (median 105 min for women vs. 70 min for men before pathway implementation). The pathway reduced door-to-drug time for both genders, but the median door-to-drug times were higher for women than for men (Mann-Whitney p = 0.013). The difference between men and women was 35 min before establishment of the pathway to 10 min by the end of the study period. CONCLUSIONS: Our critical pathway was successful in reducing door-to-drug times. We observed a "gender gap" in door-to-drug times, with longer mean times for women, which was reduced by the AMI critical pathway. Thus, our data provide support for the use of critical pathways to reduce door-to-drug times, as recommended by the National Heart Attack Alert Program.

Critical Care↗

PubMed1989

Distribution of delta-aminolevulinic acid biosynthetic pathways among phototrophic bacterial groups.

Two biosynthetic pathways are known for the universal tetrapyrrole precursor, delta-aminolevulinic acid (ALA). In the ALA synthase pathway which was first described in animal and some bacterial cells, the pyridoxal phosphate-dependent enzyme ALA synthase catalyzes condensation of glycine and succinyl-CoA to form ALA with the loss of C-1 of glycine as CO2. In the five-carbon pathway which was first described in plant and algal cells, the carbon skeleton of glutamate is converted intact to ALA in a proposed reaction sequence that requires three enzymes, tRNA(Glu), ATP, Mg2+, NADPH, and pyridoxal phosphate. We have examined the distribution of the two ALA biosynthetic pathways among various genera, using cell-free extracts obtained from representative organisms. Evidence for the operation of the five-carbon pathway was obtained by the measurement of RNase-sensitive label incorporation from glutamate into ALA, using 3,4-[3H]glutamate or 1-[14C]glutamate as substrate. ALA synthase activity was indicated by RNase-insensitive incorporation of label from 2-[14C]glycine into ALA. The distribution of the two pathways among the bacteria tested was in general agreement with their previously established phylogenetic relationships and clearly indicates that the five-carbon pathway is the more ancient process, whereas the pathway utilizing ALA synthase probably evolved much later. The five-carbon pathway is apparently the more widely utilized one among bacteria, while the ALA synthase pathway seems to be limited to the alpha subgroup of purple bacteria.

Aminolevulinic Acid↗

PubMed1992

The RAS-adenylate cyclase pathway and cell cycle control in Saccharomyces cerevisiae.

The cell cycle of Saccharomyces cerevisiae contains a decision point in G1 called 'start', which is composed of two specific sites. Nutrient-starved cells arrest at the first site while pheromone-treated cells arrest at the second site. Functioning of the RAS-adenylate cyclase pathway is required for progression over the nutrient-starvation site while overactivation of the pathway renders the cells unable to arrest at this site. However, progression of cycling cells over the nutrient-starvation site does not appear to be triggered by the RAS-adenylate cyclase pathway in response to a specific stimulus, such as an exogenous nutrient. The essential function of the pathway appears to be limited to provision of a basal level of cAMP. cAMP-dependent protein kinase rather than cAMP might be the universal integrator of nutrient availability in yeast. On the other hand stimulation of the pathway in glucose-derepressed yeast cells by rapidly-fermented sugars, such as glucose, is well documented and might play a role in the control of the transition from gluconeogenic growth to fermentative growth. The initial trigger of this signalling pathway is proposed to reside in a 'glucose sensing complex' which has both a function in controlling the influx of glucose into the cell and in activating in addition to the RAS-adenylate cyclase pathway all other glucose-induced regulatory pathways in yeast. Two crucial problems remaining to be solved with respect to cell cycle control are the nature of the connection between the RAS-adenylate cyclase pathway and nitrogen-source induced progression over the nutrient-starvation site of 'start' and second the nature of the downstream processes linking the RAS-adenylate cyclase pathway to Cyclin/CDC28 controlled progression over the pheromone site of 'start'.

Adenylyl Cyclases↗

PubMed2006

The Wnt-dependent signaling pathways as target in oncology drug discovery.

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer's disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways.

Animals↗

PubMed1993

Recurrent conduction in accessory pathway and possible new arrhythmias after radiofrequency catheter ablation.

Radiofrequency catheter ablation was performed in 142 patients with 166 accessory pathways. One hundred thirty-six patients with 160 accessory pathways underwent successful ablation in the first ablation session. Serial follow-up electrophysiologic studies were performed immediately (30 minutes), early (5 to 7 days), and late (3 to 6 months) after successful ablation to determine the recurrent accessory pathway conduction and possible new arrhythmias. After a minimum follow-up period of 6 months (mean, 14 +/- 3 months), accessory pathway conduction recurred in 13 patients (9.6%), with recurrent tachycardia in three patients (2.2%). Five of the recurrent accessory pathways had decremental conduction properties. Incidence of recurrent accessory pathway conduction was similar in different accessory pathway locations (6.4% to 9.0%). Patients with concealed accessory pathways (12.2 vs 2.9%; p < 0.05), and patients without accessory pathway potentials in the ablation site (15.5% vs 2.2%; p < 0.05) had a higher recurrence rate. Patients without tachycardia in the late electrophysiologic study did not have recurrent tachycardia during follow-up. New arrhythmias, including atrial and ventricular arrhythmias, which were detected by 24-hour Holter monitoring, were apparent only on the first day after ablation. The findings indicate that the overall incidence of recurrent accessory pathway conduction was low and that possible new arrhythmias were rare in the late follow-up period.

Adult↗

PubMed1992

Electrocardiographic and electrophysiologic characteristics of anterior, midseptal and right anterior free wall accessory pathways.

OBJECTIVES: The objective of this study was to define the electrocardiographic (ECG) and electrophysiologic characteristics of midseptal, anteroseptal and right anterior free wall accessory pathways. METHODS: The fully pre-excited 12-lead surface ECGs and ECGs during orthodromic atrioventricular (AV) reentrant tachycardia were compared for 13 patients with an anteroseptal, 7 with a midseptal and 7 with a right free wall accessory pathway. Routine electrophysiologic studies were performed in all and stimulation of the right ventricular summit during tachycardia was accomplished in 10 patients. RESULTS: Differences in the surface ECGs were not sufficiently sensitive to distinguish among accessory pathway locations. Premature ventricular complexes induced from the right ventricular septal summit during ventricular activation either advanced the succeeding atrial depolarization or terminated the tachycardia in three of six patients with a septal pathway and in none of the four with a right anterior pathway. The change in ventriculoatrial (VA) interval with the development of right bundle branch block during orthodromic AV tachycardia proved most helpful in distinguishing these pathways. Patients with a right anterior free wall pathway showed a change in VA interval > or = 40 ms, whereas those with an anteroseptal pathway showed changes of 20 to 30 ms and those with a midseptal pathway showed no change. CONCLUSIONS: Anteroseptal, midseptal and right anterior free wall pathways may be distinguished by using programmed stimulation of the summit of the right ventricular septum and especially with changes in the VA interval with development of right bundle branch block during orthodromic AV reentrant tachycardia.

Adolescent↗