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PubMed1992

The optic lobe of Drosophila melanogaster. II. Sorting of retinotopic pathways in the medulla.

We present a quantitative evaluation of Golgi-impregnated columnar neurons in the optic lobe of wild-type Drosophila melanogaster. This analysis reveals the overall connectivity pattern between the 10 neuropil layers of the medulla and demonstrates the existence of at least three major visual pathways. Pathway 1 connects medulla layer M10 to the lobula plate. Input layers of this pathway are M1 and M5. Pathway 2 connects M9 to shallow layers of the lobula, which in turn are tightly linked to the lobula plate. This pathway gets major input via M2. Pathways 1 and 2 receive input from retinula cells R1-6, either via the lamina monopolar cell L1 (terminating in M1 and M5) or via L2 and T1 (terminating in M2). Neurons of these pathways typically have small dendritic fields. We discuss evidence that pathways 1 and 2 may play a major role in motion detection. Pathway 3 connects M8 to deep layers of the lobula. In M8 information converges that is derived either from M3 (pathway 3a) or from M4 and M6 (pathway 3b), layers that get their major input from L3 and R8 or L4 and R7, respectively. Some neurons of pathway 3 have large dendritic fields. We suggest that they may be involved in the computation of form and colour. Possible analogies to the organization of pathways in the visual system of vertebrates are discussed.

Animals↗
PubMed1986

Functional organization of the spinal reflex pathways from forelimb afferents to hindlimb motoneurones in the cat. II. Conditions of the interneuronal connections.

The interneuronal conditions of the descending pathways from forelimb afferents to hindlimb motoneurones were investigated by testing spatial interactions in these pathways and between these pathways and segmental lumbar reflex pathways. In high spinal unanaesthetized cats hindlimb motoneurones were intracellularly recorded and spatial interactions were tested between effects evoked by stimulation of pairs of ipsi- and contralateral forelimb nerves or pairs of a forelimb and an ipsilateral hindlimb nerve. The excitatory and late inhibitory pathways from forelimb afferents projecting to most of the hindlimb motoneurone pools, showed an interactive pattern which was distinctly different to the fast inhibitory pathway projecting specifically from ipsilateral forelimb afferents to flexor digitorum and hallucis longus (FDHL) motoneurones. Stimulation of homonymous or heteronymous pairs of two forelimb nerves of both sides evoked generally a distinct spatial facilitation of the excitatory and late inhibitory effects, while the specific early IPSPs to FDHL motoneurones were not facilitated. Paired stimulation of two forelimb nerves of one side only produced spatial facilitation of EPSPs or late IPSPs if low strength stimuli were used, using higher strength which induced larger effects, generally caused occlusion instead. In case of large IPSPs this may be due to the vicinity to the equilibrium potential. Except for an inhibition of cutaneous reflex pathways, the spatial interaction of the excitatory and late inhibitory pathways onto segmental lumbar reflex pathways was weak and variable. The fast inhibitory pathway to FDHL motoneurones showed a partial spatial facilitatory interaction with lumbar reflex pathways from cutaneous and group II muscle afferents. The second IPSP wave evoked by this pathway was inhibited by antidromic stimulation of the ventral root L7S1 and of the alpha-efferents of the antagonistic peroneal nerve. From the results conclusions are drawn on the interneuronal organization of the descending pathways from forelimb afferents to hindlimb motoneurones.

Animals↗
PubMed2000

Implementation and evaluation of a clinical pathway for TRAM breast reconstruction.

Among strategies recently proposed to reduce practice variation, promote quality, and control costs in health care delivery, the concept of the clinical pathway has received considerable attention. Because transverse rectus abdominis musculocutaneous (TRAM) breast reconstruction is a common and often costly intervention, this institution sought to evaluate cost and quality outcomes of a clinical pathways program for this procedure. The TRAM reconstruction clinical pathway was implemented in April of 1996 to standardize postoperative care in this patient population. Outcomes of consecutive pathway cases for the first 14 months of the program were assessed in a retrospective cohort design, by using all nonpathway TRAM cases from the 18 months immediately before pathway implementation as controls. Outcomes assessed included length of hospital stay, postoperative complications, total postoperative charges, and total postoperative costs in relative value units. Data on these dependent variables were collected from hospital charts and billing records. The effects of pathway implementation on the outcomes of interest were analyzed by using analysis of covariance to control for potential confounding by other independent variables, including surgical site (unilateral versus bilateral reconstructions), technique (pedicle versus free TRAMs), timing (immediate versus delayed reconstructions), and patient age. Finally, a comparison of variances in the outcomes of interest between the two groups was analyzed by using an Ftest. For all statistical tests, p values of < or = 0.05 were considered significant. Twenty-nine patients were treated in the TRAM pathway group, whereas the control population included 40 nonpathway patients. After implementation of the TRAM pathway, length of stay decreased from 6.0 to 5.2 days; total postoperative charges were reduced from $8587 to $7744; and total postoperative relative value unit utilization declined from 1686 to 1104. Analysis of covariance showed that the decreases in length of hospital stay and relative value units in the TRAM pathway were statistically significant (p = 0.05 and p = 0.007, respectively). By contrast, no significant increase in complications was observed after pathway implementation. Variability in the TRAM pathway group, as measured by SD, decreased significantly for both length of hospital stay (p = 0.039) and relative value units (p = 0.023). Implementation of the TRAM reconstruction clinical pathway resulted in significant declines in length of hospital stay and total costs. These decreases in resource utilization had no significant effect on postoperative complication rates. Although additional research is needed to further assess the impact of clinical pathways, this approach offers considerable promise for improving the cost-effectiveness of health care.

Adult↗
PubMed2006

Defining pathways.

AIMS AND BACKGROUND: The term 'clinical pathway' is internationally accepted in all settings of healthcare management. The way in which clinical pathways have been developed in the United Kingdom differs from that in the USA. Besides the international differences in the purpose, many alternative names also can be found. These have led to confusion. There is no single, widely accepted definition of a clinical pathway. The aim of the study was to survey the definitions used in describing the concept and to derive key characteristics of clinical pathways. METHOD: Using the PubMed, we conducted a review of literature published between January 2000 and December 2003 using the following terms: critical pathway, clinical pathway, integrated care pathway, care pathway and care map. All reports reviewed had to use the concept, as defined by the Medical Subject Headings term, to be considered. To assess all definitions, the concept analysis method was used. RESULTS: In 82 of the 263 eligible articles, the definition of pathway was given. Totally, we found 84 different definitions. Each definition was rephrased by taking into consideration the following three features inherent to pathways: nouns, characteristics and aims and outcomes. Every feature was further divided into categories. CONCLUSIONS: A clinical pathway is a method for the patient-care management of a well-defined group of patients during a well-defined period of time. A clinical pathway explicitly states the goals and key elements of care based on Evidence Based Medicine (EBM) guidelines, best practice and patient expectations by facilitating the communication, coordinating roles and sequencing the activities of the multidisciplinary care team, patients and their relatives; by documenting, monitoring and evaluating variances; and by providing the necessary resources and outcomes. The aim of a clinical pathway is to improve the quality of care, reduce risks, increase patient satisfaction and increase the efficiency in the use of resources.

Critical Pathways↗
PubMed2006

Clinical pathway audit tools: a systematic review.

AIM: To determine whether clinical/care pathway audit tools can identify the characteristics of well-organized care processes. BACKGROUND: Although pathways are used worldwide, confusion exists about the concept and impact. Evaluation Search of OVID-Medline, Cinahl, British Nursing Index; manual search of the Journal of Integrated Care Pathways; contact with Smartgroup on Clinical Pathways and board members of the European Pathway Association and Google search. KEY ISSUES: We selected seven of 15 clinical pathway audit tools for this review. Through content analysis, we identified 17 characteristics and grouped them using the realistic evaluation paradigm. The Integrated Care Pathway Appraisal Tool is the most appropriate audit tool to assess clinical pathway documents. CONCLUSIONS: It is astonishing that so little research on clinical pathway audit tools has been underwent, given the prevalent use of clinical pathways. Because the concept of clinical pathways remains unclear, a variety of audit tools are needed to help clarify the concept. Further research on the construct and criterion validity of pathway audit tools is necessary to fully understand why and under which circumstances pathways lead to improved care.

Critical Pathways↗
PubMed1994

Radiofrequency catheter ablation of septal accessory atrioventricular pathways.

OBJECTIVE: Septal accessory atrioventricular pathways are recognised as being more difficult to ablate than pathways in other locations. This paper describes an experience of 48 consecutive patients with septal accessory pathways who had catheter ablation with radiofrequency current. PATIENTS AND METHODS: There were 28 male and 20 female patients, mean (SD) age 35 (17). 43 patients had a single accessory pathway and 5 patients had multiple accessory pathways. Pre-excitation was present in 37 patients, and 11 patients had concealed accessory pathways. 21 patients had had a previous electrophysiological study. Catheter ablation was undertaken with radiofrequency current delivered by a standard unipolar technique or by delivery of current across the septum (the bipolar technique). RESULTS: The median total procedure time was 167 (83) minutes including a 30-40 minute observation period after the abolition of conduction by the accessory pathway. The median total fluoroscopic time was 56 (30) minutes. 42 (88%) out of 48 patients had successful ablation of the pathway during the first session. In the six patients in whom the procedure failed, five had a midseptal pathway and one had a right anteroseptal pathway. A second attempt at ablation was made in two patients and succeeded in both. In total, 49 accessory pathways were successfully ablated in 44 (92%) out of 48 patients. The bipolar technique was used in 11 patients and succeeded in 10 patients. Standard unipolar current delivery had previously failed in seven of the 11 patients. Complications developed in two patients with a mid septal pathway (one with complete atrioventricular block and the other with a small pericardial effusion). CONCLUSION: Radiofrequency catheter ablation of septal accessory pathways is efficacious and safe. The procedure time can be shortened and success rate can be increased after improvement of the technique--that is, consideration of a bipolar approach for energy delivery in difficult cases.

Adolescent↗
PubMed1984

Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum.

We have developed a new, specific, and highly sensitive enzyme-linked immunosorbent assay (ELISA) which quantitates activation of the alternative pathway in human serum, plasma, or on the surface of activators. The ELISA detects the third component of complement (C3b), proteolytic fragment of complement Factor B (Bb), and properdin (P) complex or its derivative product, C3b,P. In the method, activator-plasma mixtures, plasma containing an activated alternative pathway, or other samples are added to the wells of microtitration plates precoated with antibody to P. C3b, Bb,P or C3b,P complexes which become bound are quantitated by subsequently added, enzyme-labeled, anti-C3. The resulting hydrolysis of the chromogenic substrate is expressed as nanograms of C3b by reference to a C3 standard curve. In addition to absolute specificity for activation of the pathway because of the nature of the complex detected by the assay, the ELISA is highly sensitive and able to reproducibly detect 10-20 ng/ml of C3b,P complexes in serum. This value corresponds to 0.0015% of the C3 in serum. In a series of studies to validate the parameters of the ELISA, reactivity was found to be dependent on the presence of alternative pathway proteins, the functional integrity of the pathway, and on the presence of magnesium. Sheep erythrocytes were converted to activators by treatment with neuraminidase. By using a variety of activators, the kinetics of activation and the numbers of bound C3b molecules quantitated by the ELISA were very similar to those measured by C3b deposition. The ELISA also detected identical activation kinetics when MgEGTA-serum and a mixture of the purified alternative pathway proteins were used as sources of the pathway. ELISA reaction kinetics also correlated with the restriction index, a measure of alternative pathway-activating ability. These studies cumulatively validate the ELISA as a direct and quantitative assay for alternative pathway activation. The sensitivity of the ELISA has permitted its use to detect direct alternative pathway activation by several viruses. The ELISA has also shown that certain classical pathway activators trigger the amplification loop of the alternative pathway while others do not. In addition, stable ELISA reactive complexes appeared in the supernatant of mixtures of serum with certain, but not other activators. The ability of the ELISA to detect activation which has already occurred and the stability of the reactive complexes permits studies of clinical sera. Normal human sera (20) contained low levels (5-20 ng/ml) of ELISA-reactive complexes. A proportion of sera from individuals with the adult respiratory distress syndrome (9-10), typhoid fever (8-10), malaria (3-5), gram-negative sepsis (9 of 47), acute trauma and shock (6 f 25), and systemic lupus erythematosus (3 of 29) showed elevated levels of complexes reactive in the alternative pathway ELISA. In contrast, nine sera from patients with circulating C3 nephritic factor were not reactive in the ELISA.

Animals↗
PubMed2000

Clinical pathways--an evaluation of its impact on the quality of care in an acute care general hospital in Singapore.

A critical or clinical pathway defines the optimal care process, sequencing and timing of interventions by healthcare professionals for a particular diagnosis or procedure. It is a relatively new clinical process improvement tool that has been gaining popularity across hospitals and various healthcare organisations in many parts of the world. It is now slowly gaining momentum and popularity in Asia and Singapore. Clinical pathways are developed through collaborative efforts of clinicians, case managers, nurses, and other allied healthcare professionals with the aim of improving the quality of patient care, while minimising cost to the patient. Clinical pathways have been shown to reduce unnecessary variation in patient care, reduce delays in discharge through more efficient discharge planning, and improve the cost-effectiveness of clinical services. The approach and objectives of clinical pathways are consistent with those of total quality management (TQM) and continuous clinical quality improvement (CQI), and is essentially the application of these principles at the patient's bedside. However, despite the growing popularity of pathways, their impact on clinical outcomes and their clinical effectiveness remains largely untested and unproven through rigorous clinical trials. This paper begins with an overview of the nature of clinical pathways and the analysis of variances from the pathway, their benefits to the healthcare organisation, their application as a tool for CQI activities in direct relation to patient care, and their effectiveness in a variety of healthcare settings. The paper describes an evaluation of the impact of a clinical pathway on the quality of care for patients admitted for uncomplicated acute myocardial infarction (AMI) through an analysis of variances. The author carried out a one year evaluation of a clinical pathway on uncomplicated AMI in Changi General Hospital (CGH) to determine its effectiveness and impact on a defined set of outcomes. A before and after nonrandomized study of two groups of patients admitted to the Hospital for uncomplicated AMI was done. A total of 169 patients were managed on the clinical pathway compared to 100 patients in the control (historical comparison) group. Outcomes were compared between the two groups of patients. Restriction and matching of study subjects in both groups ensured that the patients selected were comparable in terms of severity of illness. The results showed that the patients on the clinical pathway and the comparison group were similar with respect to demographic variables, prevalence of risk factors and comorbidities. There was a statistically significant reduction in the average length of stay after implementation of the clinical pathway. This was achieved without any adverse effect on short term clinical outcomes such as in-hospital mortality, complication rate and morbidity. There were no significant difference in readmission rates at 6 months after discharge. The paper concludes that clinical pathways, implemented in the context of an acute care general hospital, is able to significantly improve care processes through better collaboration among healthcare professionals and improvements in work systems.

Analysis of Variance↗
PubMed2002

[Implementation of a clinical pathway for transurethral resection in benign prostatic hyperplasia].

OBJECTIVE: Clinical pathways constitute a powerful tool for reducing the variability that occurs in clinical practice. The results obtained with the use of a clinical pathway for patients undergoing transurethral resection for benign hyperplasia of the prostate (BPH) are presented. METHODS: A prospective study was carried out on a cohort of 80 consecutive patients that had undergone transurethral resection for BPH after the application of a clinical pathway (5 days hospitalization) and compared with the results of a historical cohort of 80 consecutive patients that had been treated before the application of the clinical pathway. The exclusion criteria were diabetes mellitus, anticoagulation therapy with dicoumarin and other pathologies that changed the length of the preoperative stay established in the clinical pathway. For the evaluation of the degree of satisfaction, patients were asked to fill out a questionnaire included in the pathway documents. RESULTS: 73 patients met the inclusion criteria of the clinical pathway. 67 of the 80 patients that underwent surgery before the application of the clinical pathway were valid for comparative analysis. No statistically significant differences were found between both groups for age, prostate volume measured by DRE and US, previous treatment for prostatism, anesthetic risk and weight of the resected specimen. With the application of the pathway, the mean duration of hospital stay was reduced from 6 (SD 1.7; range 4-15) to 4.9 (SD 1.4; range 3-13) days (p < 0.0001) and the duration of urethral catheterization from 4.5 (SD 1.4; range 3-13) to 3.8 (SD 1.3; range 2-11) days (p < 0.01). Statistically significant differences were found before and after the application of the clinical pathway for degree of compliance of the preestablished antimicrobial prophylaxis guidelines during hospitalisation and after discharge, and thromboembolic prophylaxis. The relative risk of complications after discharge was less after the application of the clinical pathway (RR = 0.66), although it was not statistically significant (CI: 0.41-1.05). 63 of the 73 patients included in the clinical pathway submitted the questionnaire without identifying themselves. Duration of hospitalization was considered adequate by 89%, and coincided with the programmed and actual duration according to 82.5%. CONCLUSIONS: The application of a clinical pathway for patients undergoing transurethral resection for BPH has reduced costs by reducing the length of hospital stay and adverse effects. Furthermore, reducing the variability of medical care has improved its quality.

Aged↗
PubMed2025

Pathway-specific genomic alterations in pancreatic cancer across diverse cohorts.

BACKGROUND/OBJECTIVES: Pancreatic cancer (PC) is an aggressive malignancy with rising incidence and poor survival rates. While Hispanic/Latino (H/L) patients have a lower overall incidence compared to Non-Hispanic White (NHW) patients, they are diagnosed at younger ages, often present with more advanced disease, and experience worse survival outcomes. The molecular drivers underlying these disparities remain poorly understood. Key oncogenic pathways, including TP53, WNT, PI3K, TGF-Beta, and RTK/RAS, play crucial roles in tumor progression, therapy resistance, and response to targeted treatments. However, their ethnicity-specific alterations and prognostic implications in PC remain largely unexplored. This study aims to characterize pathway-specific mutations in PC among H/L and NHW patients, assess tumor mutation burden, and identify ethnicity-specific oncogenic drivers using publicly available datasets. The findings may provide critical insights to optimize precision medicine strategies and enhance targeted therapies for underrepresented populations. METHODS: A bioinformatics analysis was performed using publicly available PC datasets to evaluate mutation frequencies in genes associated with the TGF-Beta, RTK/RAS, WNT, PI3K, and TP53 pathways. The study included 4,248 patients, with 407 identified as H/L and 3,841 as NHW. Patients were stratified by ethnicity to assess differences in mutation prevalence. Chi-squared tests were conducted to compare mutation rates between groups, while Kaplan-Meier survival analysis was performed to evaluate overall survival differences based on pathway-specific alterations. RESULTS: Significant differences were observed in the TGF-Beta pathway between H/L and NHW patients. TGF-Beta mutations were less prevalent in H/L patients (18.4% vs. 24.4%, p = 8.6e-3). Additionally, genes related to the TGF-Beta pathway showed significant alterations, with SMAD2 (1.5% vs. 0.4%, p = 6.3e-3) and SMAD4 (15% vs. 19.9%, p = 0.02) exhibiting notable differences. Although RTK/RAS, WNT, PI3K, and TP53 pathway mutations were not statistically significant overall, borderline significance was observed in genes associated with these pathways, including ERBB4 (3.4% vs. 1.8%, p = 0.03), ALK (2.7% vs. 1.1%, p = 0.01), HRAS (1.2% vs. 0.1%, p = 1.3e-4), and RIT1 (0.7% vs. 0.1%, p = 0.03) in the RTK/RAS pathway, as well as CTNNB1 (2.9% vs. 1.3%, p = 0.01) in the WNT pathway. Survival analysis revealed no significant differences in overall survival among H/L patients. However, NHW patients with TP53 pathway alterations exhibited borderline significant differences in survival outcomes.

PI3K pathway↗
PubMed2004

Proteome analysis of Pseudomonas sp. K82 biodegradation pathways.

Pseudomonas sp. K82 is a soil bacterium that can degrade and use monocyclic aromatic compounds including aniline, 3-methylaniline, 4-methylaniline, benzoate and p-hydroxybenzoate as its sole carbon and energy sources. In order to understand the impact of these aromatic compounds on metabolic pathways in Pseudomonas sp. K82, proteomes obtained from cultures exposed to different substrates were displayed by two-dimensional gel electrophoresis and were compared to search for differentially induced metabolic enzymes. Column separations of active fractions were performed to identify major biodegradation enzymes. More than thirty proteins involved in biodegradation and other types of metabolism were identified by electrospray ionization-quadrupole time of flight mass spectrometry. The proteome analysis suggested that Pseudomonas sp. K82 has three main metabolic pathways to degrade these aromatic compounds and induces specific metabolic pathways for each compound. The catechol 2,3-dioxygenase (CD2,3) pathway was the major pathway and the catechol 1,2-dioxygenase (beta-ketoadipate) pathway was the secondary pathway induced by aniline (aniline analogues) exposure. On the other hand, the catechol 1,2-dioxygenase pathway was the major pathway induced by benzoate exposure. For the degradation of p-hydroxybenzoate, the protocatechuate 4,5-dioxygenase pathway was the major degradation pathway induced. The nuclear magnetic resonance analysis of substrates demonstrated that Pseudomonas sp. K82 metabolizes some aromatic compounds more rapidly than others (benzoate > p-hydroxybenzoate > aniline) and that when combined, p-hydroxybenzoate metabolism is repressed by the presence of benzoate or aniline. These results suggest that proteome analysis can be useful in the high throughput study of bacterial metabolic pathways, including that of biodegradation, and that inter-relationships exist with respect to the metabolic pathways of aromatic compounds in Pseudomonas sp. K82.

Aniline Compounds↗
PubMed1993

Recognition and catheter ablation of subepicardial accessory pathways.

OBJECTIVES: The purpose of this study was to characterize left-sided accessory pathways that traverse the atrioventricular (AV) groove subepicardially and to describe results of radiofrequency catheter ablation within the coronary sinus in the patients studied. BACKGROUND: Radiofrequency catheter ablation has proved to be a safe and effective method for treatment of accessory pathways; however, subepicardial accessory pathways may account for some of the failures encountered during endocardial ablation. METHODS: The study group comprised 51 consecutive patients with a left-sided accessory pathway who were undergoing radio-frequency catheter ablation. Initially, the ablation catheter was introduced into a femoral artery and positioned on the ventricular aspect of the mitral annulus. If this endocardial approach was unsuccessful, the ablation catheter was introduced into the coronary sinus and energy applied at sites with shorter activation times than those recorded from the endocardium. RESULTS: Five (10%) of 51 patients with a left-sided accessory pathway could not have accessory pathway conduction interrupted with a median of 18 endocardial radiofrequency energy applications. Accessory pathway potentials were less frequent during endocardial mapping in these 5 patients than in the 46 patients whose accessory pathway was successfully ablated from the endocardial surface. All five of these patients later had successful ablation using one or two applications of radiofrequency energy from within the coronary sinus. Effective target site electrograms in the coronary sinus were characterized by an accessory pathway potential that was larger than the corresponding atrial or ventricular electrogram. There were no complications or recurrences after ablation within the coronary sinus. CONCLUSIONS: Some left-sided accessory pathways may be difficult to ablate from the endocardial surface because they traverse the AV groove subepicardially. The absence of an accessory pathway potential during endocardial mapping in combination with a relatively large accessory pathway potential within the coronary sinus may be a useful marker of a subepicardial pathway. In this select group of patients, radiofrequency catheter ablation from within the coronary sinus appears to enhance efficacy.

Action Potentials↗
PubMed1993

Radiofrequency ablation for atrioventricular node reentrant tachycardia: comparison between fast (anterior) and slow (posterior) pathway ablation.

OBJECTIVES: We compared the electrophysiologic effects on atrioventricular (AV) node physiology of selective "fast" versus selective "slow" pathway radiofrequency ablation in 42 patients with drug-resistant AV node reentrant tachycardia who underwent 51 ablation attempts to prevent tachycardia recurrence while preserving AV conduction. BACKGROUND: The recent introduction of radiofrequency ablation to treat AV node reentrant tachycardia allows the opportunity to study the effects of selective elimination of the different limbs involved in AV node reentrant tachycardia. METHODS: Selective fast pathway ablation was attempted in 13 patients by delivering radiofrequency energy anteriorly across the tricuspid valve anulus. Selective slow pathway ablation was attempted in 29 patients by delivering radiofrequency energy posteriorly across the tricuspid valve anulus at sites where putative slow pathway potentials were recorded. RESULTS: Selective fast pathway ablation eliminated AV node reentrant tachycardia without AV block in 6 (46%) of 13 patients after one ablation session and in an additional 3 patients (69% of total) after repeat ablation sessions. Slow pathway ablation eliminated AV node reentrant tachycardia without AV block in 26 (90%) of 29 patients after one radiofrequency ablation session and in an additional 2 patients (97% of total) after repeat ablation sessions. Selective fast pathway ablation increased the PR interval (140 to 220 ms, p = 0.0001) and AH interval (66 to 153 ms, p = 0.0001), whereas slow pathway ablation did not change these intervals. Fast pathway radiofrequency ablation caused retrograde block in 7 (64%) of 11 patients, whereas no patients undergoing slow pathway ablation developed selective retrograde block. Single AV node echo beats were commonly induced after slow but not fast pathway ablation (17 of 29 patients vs. 1 of 11 patients, respectively, p = 0.01) and did not predict recurrence of AV node reentrant tachycardia. CONCLUSIONS: Successful selective radiofrequency ablation of fast or slow pathways in patients with AV node reentrant tachycardia resulted in different electrophysiologic properties after ablation. Slow pathway ablation produced more successful outcomes, with a decreased prevalence of recurrent AV node reentrant tachycardia or AV block.

Atrioventricular Node↗
PubMed2005

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Animals↗
PubMed2003

MAPK pathways in radiation responses.

Within the last 15 years, multiple new signal transduction pathways within cells have been discovered. Many of these pathways belong to what is now termed 'the mitogen-activated protein kinase (MAPK) superfamily.' These pathways have been linked to the growth factor-mediated regulation of diverse cellular events such as proliferation, senescence, differentiation and apoptosis. Based on currently available data, exposure of cells to ionizing radiation and a variety of other toxic stresses induces simultaneous compensatory activation of multiple MAPK pathways. These signals play critical roles in controlling cell survival and repopulation effects following irradiation, in a cell-type-dependent manner. Some of the signaling pathways activated following radiation exposure are those normally activated by mitogens, such as the 'classical' MAPK (also known as the ERK) pathway. Other MAPK pathways activated by radiation include those downstream of death receptors and procaspases, and DNA-damage signals, including the JNK and P38 MAPK pathways. The expression and release of autocrine growth factor ligands, such as (transforming growth factor alpha) and TNF-alpha, following irradiation can also enhance the responses of MAPK pathways in cells and, consequently, of bystander cells. Thus, the ability of radiation to activate MAPK signaling pathways may depend on the expression of multiple growth factor receptors, autocrine factors and Ras mutation. Enhanced basal signaling by proto-oncogenes such as K-/H-/N-RAS may provide a radioprotective and growth-promoting signal. In many cell types, this may be via the PI3K pathway; in others, this may occur through nuclear factor-kappa B or multiple MAPK pathways. This review will describe the enzymes within the known MAPK signaling pathways and discuss their activation and roles in cellular radiation responses.

Animals↗
PubMed1996

Reduction pathway of cis-5 unsaturated fatty acids in intact rat-liver and rat-heart mitochondria: assessment with stable-isotype-labelled substrates.

Besides the conventional isomerase-mediated pathway, unsaturated fatty acids with old-numbered double bonds are also metabolized by reduction pathways with NADPH as cofactor. The relative contributions of these pathways were measured in intact rat-liver and rat-heart mitochondria with a novel stable isotope tracer technique. A mixture of equal amounts of unlabelled cis-5-enoyl-CoA and 13C4-labelled acyl-CoA of equal chain lengths was incubated with mitochondria. The isotope distribution of 3-hydroxy fatty acids produced from the first cycle of beta-oxidation was analysed with selected ion monitoring by gas chromatograph-mass spectrometer. 3-Hydroxy fatty acids produced from the reduction pathway of unsaturated fatty acids were unlabelled (m + 0) whereas those produced from saturated fatty acids were labelled (m + 4). The m + 0 content serves to indicate the extent of reduction pathway. Rotenone treatment was used to switch the pathway completely to reduction. The extent of m + 0 enrichment in untreated mitochondria normalized to the m + 0 enrichment of rotenone-treated mitochondria was the percentage of reduction pathway. With this technique, cis-4-decenoate was found to be metabolized completely by the reduction pathway in both liver and heart mitochondria. cis-5-Dodecenoate was metabolized essentially by the reduction pathway in liver mitochondria, but only to 75% in heart mitochondria. When the chain length was extended to cis-5-tetradecenoate, the reduction pathway in liver mitochondria decreased to 86% and that in heart mitochondria to 65%. The effects of carnitine, clofibrate and other conditions on the reduction pathway were also studied. Enrichments of the label on saturated fatty acids and 3-hydroxy fatty acids indicated that the major pathway of reduction was not by the direct reduction of the cis-5 double bond. Instead, it is most probably by a pathway that does not involve forming a reduced saturated fatty acid first.

Animals↗
PubMed1996

Control of metabolic flux through the quinate pathway in Aspergillus nidulans.

The quinic acid ulitization (qut) pathway in Aspergillus nidulans is a dispensable carbon utilization pathway that catabolizes quinate to protocatechuate via dehydroquinate and dehydroshikimate(DHS). At the usual in vitro growth pH of 6.5, quinate enters the mycelium by means of a specific permease and is converted into PCA by the sequential action of the enzymes quinate dehydrogenase, 3-dehydroquinase and DHS dehydratase. The extent of control on metabolic flux exerted by the permease and the three pathway enzymes was investigated by applying the techniques of Metabolic Control Analysis. The flux control coefficients for each of the three quinate pathway enzymes were determined empirically, and the flux control coefficient of the quinate permease was inferred by use of the summation theorem. There measurements implied that, under the standard growth conditions used, the values for the flux control coefficients of the components of the quinate pathway were: quinate permease, 0.43; quinate dehydrogenase, 0.36; dehydroquinase, 0.18; DHS dehydratase, <0,03. Attempts to partially decouple quinate permease from the control over flux by measuring flux at pH 3.5 (when a significant percentage of the soluble quinate is protonated and able to enter the mycelium without the aid of a permease) led to an increase of approx. 50% in the flux control coefficient for dehydroquinase. Taken together with the fact that A. nidulans has a very efficient pH homeostasis mechanism, these experiments are consistent with the view that quinate permease exerts a high degree of control over pathway flux under the standard laboratory growth conditions at pH 6.5. The enzymes quinate dehydrogenase and 3-dehydroquinase have previously been overproduced in Escherichia coli, and protocols for their purification published. The remaining qut pathway enzyme DHS dehydratase was overproduced in E. coli and a purification protocol established. The purified DHS dehydratase was shown to have a K(m) of 530 microM for its substrate DHS and a requirement for bivalent metal cations that could be fulfilled by Mg(2+), Mn(2+) or Zn(2+). All three qut pathway enzymes were purified in bulk and their elasticity coefficients with respect to the three quinate pathway intermediates were derived over a range of concentrations in a core tricine/NaOH buffer, augmented with necessary cofactors and bivalent cations as appropriate. Using these empirically determined relative values, in conjunction with the connectivity theorem, the relative ratios of the flux control coefficients for the various quinate pathway enzymes, and how this control shifts between them, was determined over a range of possible metabolic concentrations. These calculations, although clearly subject to caveates about the relationswhip between kinetic measurements in vitro and the situation in vivo, were able to successfully predict the hiearchy of control observed under the standard laboratory growth conditions. The calculations imply that the hierarchy of control exerted by the quinate pathway enzymes is stable and relatively insensitive to changing metabolite concentrations in the ranges most likely to correspond to those found in vivo. The effects of substituting the type I 3-dehydroquinases from Salmonella typhi and the A. nidulans AROM protein (a pentadomain protein catalysing the conversion of 3-deoxy-D-arabinoheptulosonic acid 7-phosphate into 5-enolpyruvylshikimate 3 phosphate), and the Mycobacterium tuberculosis type II 3-dehydroquinase, in the quinate pathway were investigated and found to have an effect. In the case of S. typhi and A. nidulans, overproduction of heterologous dehydroquinase led to a diminuation of pathway flux caused by a lowering of in vivo quinate dehydrogenase levels increased above those of the wild type. We speculate that these changes in qu

Alcohol Oxidoreductases↗
PubMed2002

Contribution of the mevalonate and methylerythritol phosphate pathways to the biosynthesis of gibberellins in Arabidopsis.

Gibberellins (GAs) are diterpene plant hormones essential for many developmental processes. Although the GA biosynthesis pathway has been well studied, our knowledge on its early stage is still limited. There are two possible routes for the biosynthesis of isoprenoids leading to GAs, the mevalonate (MVA) pathway in the cytosol and the methylerythritol phosphate (MEP) pathway in plastids. To distinguish these possibilities, metabolites from each isoprenoid pathway were selectively labeled with (13)C in Arabidopsis seedlings. Efficient (13)C-labeling was achieved by blocking the endogenous pathway chemically or genetically during the feed of a (13)C-labeled precursor specific to the MVA or MEP pathways. Gas chromatography-mass spectrometry analyses demonstrated that both MVA and MEP pathways can contribute to the biosyntheses of GAs and campesterol, a cytosolic sterol, in Arabidopsis seedlings. While GAs are predominantly synthesized through the MEP pathway, the MVA pathway plays a major role in the biosynthesis of campesterol. Consistent with some crossover between the two pathways, phenotypic defects caused by the block of the MVA and MEP pathways were partially rescued by exogenous application of the MEP and MVA precursors, respectively. We also provide evidence to suggest that the MVA pathway still contributes to GA biosynthesis when this pathway is limiting.

Arabidopsis↗