Interventional management of recurrent paroxysmal atrial fibrillation despite isolated pulmonary veins: impact of an ablation strategy targeting inducible atrial tachyarrhythmias

AIMS Pulmonary vein isolation (PVI) is an effective treatment option for paroxysmal atrial fibrillation (PAF). Reconnection of pulmonary veins (PVs) is the predominant cause for recurrence of PAF. However, treatment of patients with recurrence of PAF despite isolated PV in the absence of extra-PV foci remains challenging. METHODS AND RESULTS Of 265 patients undergoing repeat catheter ablation (CA) for recurrence of PAF 21 (8%) patients (14 men, age 58 ± 14 years) showed no reconnection of PV. Therefore, inducibility of sustained atrial arrhythmias was tested. If sustained atrial fibrillation (AF) or sustained atrial tachycardia (AT) was induced, patients underwent CA. During follow-up (FU), Holter- and Tele-electrocardiogram were performed. In 19 (91%) of 21 patients, sustained atrial arrhythmias [16 (84%) AF; 3 (15%) patients AT] were induced. One patient showed PAF. Eighteen patients underwent CA aiming for termination of induced arrhythmia. In 14 (77%) patients, termination into sinus rhythm was achieved. Despite extensive CA, three (16%) patients were externally cardioverted. No periprocedural complications occurred. During 21.2 ± 6.8-month FU, 10 (53%) patients were free of any arrhythmia. Paroxysmal atrial fibrillation recurred in 4 (21%) and AT in 5 (26%) patients. One patient showed persistent AF. Repeat CA was scheduled and successfully performed for these patients. CONCLUSION In patients with recurrence of PAF despite isolated PV, termination of induced atrial arrhythmias can be achieved in most patients by defragmentation and AT ablation. Moreover, this ablation strategy results in favourable mid-term outcome results.

Ultraviolet radiation modulates the immune system through the platelet -activating factor receptor

Ultraviolet radiation plays a critical role in the induction of non-melanoma skin cancer. UV radiation is also immune suppressive. Moreover, UV-induced systemic immune suppression is a major risk factor for skin cancer induction. Previous work had shown that UV exposure in vivo activates a cytokine cascade involving PGE2, IL-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV-exposure, especially those upstream of PGE2, were not well defined. To determine the initial events and mediators that lead to immune suppression after a pathological dose of UV, mouse keratinocytes were analyzed after sunlamp irradiation. It is known that UV-irradiated keratinocytes secrete the phospholipid mediator of inflammation, platelet-activating factor (PAF). Since PAF stimulates the production of immunomodulatory compounds, including PGE2, the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression was tested. Both UV and PAF activated the transcription of cyclooxygenase (COX)-2 and IL-10 reporter gene constructs. A PAF receptor antagonist blocked UV-induced IL, 10 and COX-2 transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH), and immune suppression was blocked when UV-irradiated mice were injected with a PAF receptor antagonist. This work shows that UV generates PAF-like oxidized lipids, that signal through the PAF receptor, activate cytokine transcription, and induce systemic immune suppression. ^

Simulación de maniobras de buques con sistemas de propulsión no convencional en aguas poco profundas

Los requisitos cada vez más exigentes en cuanto a misiones, limitaciones operacionales y ambientales así como nuevas tecnologías, imponen permanentemente retos a los arquitectos navales para generar alternativas de buques y valorar su bondad en las primeras etapas del proyecto. Este es el caso de los Buques Patrulleros de Apoyo Fluvial Pesados PAF-P, que por requerimiento de la Armada Nacional de Colombia ha diseñado y construido COTECMAR. Los PAF-P, son buques fluviales cuya relación Manga-Calado excede la mayoría de los buques existentes (B/T=9,5), debido principalmente a las restricciones en el calado a consecuencia de la escasa profundidad de los ríos. Estos buques están equipados con sistemas de propulsión acimutales tipo “Pum-Jet”. Las particularidades del buque y del ambiente operacional, caracterizado por ríos tropicales con una variabilidad de profundidad dependiente del régimen de lluvias y sequía, así como la falta de canalización y la corriente, hacen que la maniobrabilidad y controlabilidad sean fundamentales para el cumplimiento de su misión; adicionalmente, no existen modelos matemáticos validados que permitan predecir en las primeras etapas del diseño la maniobrabilidad de este tipo de buques con los efectos asociados por profundidad. La presente tesis doctoral aborda el desarrollo de un modelo matemático para simulación de maniobrabilidad en aguas poco profundas de buques con relación manga-calado alta y con propulsores acimutales tipo “Pump-Jet”, cuyo chorro además de entregar el empuje necesario para el avance del buque, genera la fuerza de gobierno en función del ángulo de orientación del mismo, eliminando la necesidad de timones. El modelo matemático ha sido validado mediante los resultados obtenidos en las pruebas de maniobrabilidad a escala real del PAF-P, a través de la comparación de trayectorias, series temporales de las variables de estado más significativas y parámetros del círculo evolutivo como son diámetro de giro, diámetro táctico, avance y transferencia. El plan de pruebas se basó en técnicas de Diseño de Experimentos “DOE” para racionalizar el número de corridas en diferentes condiciones de profundidad, velocidad y orientación del chorro (ángulo de timón). En el marco de la presente investigación y para minimizar los errores por efectos ambientales y por inexactitud en los instrumentos de medición, se desarrolló un sistema de adquisición y procesamiento de datos de acuerdo con los lineamientos de ITTC. La literatura existente describe los efectos negativos de la profundidad en los parámetros de maniobrabilidad de buques convencionales (Efecto tipo S), principalmente las trayectorias descritas en los círculos evolutivos aumentan en la medida que disminuye la profundidad; no obstante, en buques de alta relación manga-calado, B/T=7,51 (Yoshimura, y otros, 1.988) y B/T=6,38 (Yasukawa, y otros, 1.995) ha sido reportado el efecto contrario (Efecto tipo NS Non Standart). Este último efecto sin embargo, ha sido observado mediante experimentación con modelos a escala pero no ha sido validado en pruebas de buques a escala real. El efecto tipo NS en buques dotados con hélice y timones, se atribuye al mayor incremento de la fuerza del timón comparativamente con las fuerzas del casco en la medida que disminuye la profundidad; en el caso de estudio, el fenómeno está asociado a la mejor eficiencia de la bomba de agua “Pump-Jet”, debido a la resistencia añadida en el casco por efecto de la disminución de la profundidad. Los resultados de las pruebas con buque a escala real validan el excelente desempeño de esta clase de buques, cumpliendo en exceso los criterios de maniobrabilidad existentes y muestran que el diámetro de giro y otras características de maniobrabilidad mejoran con la disminución de la profundidad en buques con alta relación manga-calado. ABSTRACT The increasingly demanding requirements in terms of missions, operational and environmental constraints as well as new technologies, constantly impose challenges to naval architects to generate alternatives and asses their performance in the early stages of design. That is the case of Riverine Support Patrol Vessel (RSPV), designed and built by COTECMAR for the Colombian Navy. RSPV are riverine ships with a Beam-Draft ratio exceeding most of existing ships (B/T=9,5), mainly due to the restrictions in draft as a result of shallow water environment. The ships are equipped with azimuthal propulsion system of the “Pump-Jet” type. The peculiarities of the ship and the operational environment, characterized by tropical rivers of variable depth depending on the rain and dry seasons, as well as the lack channels and the effect of water current, make manoeuvrability and controllability fundamental to fulfill its mission; on the other hand, there are not validated mathematical models available to predict the manoeuvrability of such ships with the associated water depth effects in the early stages of design. This dissertation addresses the development of a mathematical model for shallow waters’ manoeuvrability simulation of ships with high Beam-Draft ratio and azimuthal propulsion systems type “Pump-Jet”, whose stream generates the thrust required by the ship to advance and also the steering force depending on the orientation angle, eliminating the need of rudders. The mathematical model has been validated with the results of RSPV’s full scale manoeuvring tests, through a comparison of paths, time series of state variables and other parameters taken from turning tests, such as turning diameter, tactical diameter, advance and transfer. The test plan was developed applying techniques of Design of Experiments “DOE”, in order to rationalize the number of runs in different conditions of water depth, ship speed and jet stream orientation (rudder angle). A data acquisition and processing system was developed, following the guidelines of ITTC, as part of this research effort, in order to minimize errors by environmental effects and inaccuracy in measurement instruments, The negative effects of depth on manoeuvrability parameters for conventional ships (Effect Type S: the path described by the ship during turning test increase with decrease of water depth), has been documented in the open literature; however for wide-beam ships, B/T=7,51 (Yoshimura, y otros, 1.988) and B/T=6,38 (Yasukawa, y otros, 1.995) has been reported the opposite effect (Type NS). The latter effect has been observed thru model testing but until now had not been validated with full-scale results. In ships with propellers and rudders, type NS effect is due to the fact that increment of rudder force becomes larger than hull force with decrease of water depth; in the study case, the phenomenon is associated with better efficiency of the Pump-Jet once the vessel speed becomes lower, due to hull added resistance by the effect of the decrease of water depth. The results of full scale tests validates the excellent performance of this class of ships, fulfilling the manoeuvrability criteria in excess and showing that turning diameter and other parameters in high beam-draft ratio vessels do improve with the decrease of depth.

Use of ovary culture techniques in reproductive toxicology

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgements The author's studies in this field are supported by MRC grants G1002118 (NS and RAA) and G110357 (RAA), MR/L010011/1 (PAF), the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 212885 (PAF) and the Wellcome Trust (080388 to PAF). AS was funded by a BBSRC CASE Studentship co-funded by AstraZeneca.

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements: We thank Ms Margaret Fraser, Ms Samantha Flannigan, and Dr Wing Yee Kwong for their expert assistance. The staff at Grampian NHS Pregnancy Counselling Service were essential for collecting fetuses. We thank Professor Geoffrey Hammond and Dr Marc Simard, University of British Colombia for helpful comments on the manuscript. Supported by grants as follows: Scottish Senior Clinical Fellowship (AJD); Chief Scientist Office (Scottish Executive, CZG/1/109 to PAF, & CZG/4/742 (PAF & PJOS); NHS Grampian Endowments 08/02 (PAF, SB & PJOS); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 (PAF & SMR); the Medical Research Council grants MR/L010011/1 (PAF & PJOS) and MR/K018310/1 (AJD). None of the funding bodies played any role in the design, collection, analysis, and interpretation of data, in the writing of the manuscript, nor in the decision to submit the manuscript for publication

Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization

Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.

Tissue-specific response of the human platelet-activating factor receptor gene to retinoic acid and thyroid hormone by alternative promoter usage.

We have studied the effects of retinoic acid (RA) and thyroid hormone (3,3',5-triiodothyronine; T3) on platelet-activating factor receptor (PAFR) gene expression in intact rats and the ability of two human PAFR gene promoters (PAFR promoters 1 and 2) to generate two transcripts (PAFR transcripts 1 and 2). Northern blotting showed that RA and T3 regulated PAFR gene expression only in rat tissues that express PAFR transcript 2. Functional analysis of the human PAFR promoter 2 revealed that responsiveness to RA and T3 was conferred through a 24-bp element [PAFR-hormone response element (HRE) located from -67 to -44 bp of the transcription start site, whereas PAFR promoter 1 did not respond to these hormones. The PAFR-HRE is composed of three direct repeated TGACCT-like hexamer motifs with 2-and 4-bp spaces, and the two upstream and two downstream motifs were identified as response elements for RA and T3. Thus, the PAF-PAFR pathway is regulated by the PAFR level altered by a tissue-specific response to RA and T3 through the PAFR-HRE of the PAFR promoter 2.

Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task.

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), which is thought to be a retrograde messenger in long-term potentiation (LTP), enhances glutamate release and LTP through an action on presynaptic nerve endings. The PAF antagonist BN 52021 blocks CA1 LTP in hippocampal slices, and, when infused into rat dorsal hippocampus pre- or posttraining, blocks retention of inhibitory avoidance. Here we report that memory is affected by pre- or posttraining infusion of the PAF analog 1-O-hexadecyl-2-N-methylcarbamoyl-sn-glycerol-3-phosphocholine (mc-PAF) into either rat dorsal hippocampus, amygdala, or entorhinal cortex. Male Wistar rats were implanted bilaterally with cannulae in these brain regions. After recovery from surgery, the animals were trained in step-down inhibitory avoidance or in a spatial habituation task and tested for retention 24 h later. mc-PAF (1.0 microgram per side) enhanced retention test performance of the two tasks when infused into the hippocampus before training without altering training session performance. In addition, mc-PAF enhanced retention test performance of the avoidance task when infused into (i) the hippocampus 0 but not 60 min after training; (ii) the amygdala immediately after training; and (iii) the entorhinal cortex 100 but not 0 or 300 min after training. In confirmation of previous findings, BN 52021 (0.5 microgram per side) was found to be amnestic for the avoidance task when infused into the hippocampus or the amygdala immediately but not 30 or more minutes after training or into the entorhinal cortex 100 but not 0 or 300 min after training. These findings support the hypothesis that memory involves PAF-regulated events, possibly LTP, generated at the time of training in hippocampus and amygdala and 100 min later in the entorhinal cortex.

Avaliação do efeito de polimorfismos genéticos com a dependência à nicotina

Introdução: A identificação de variantes genéticas que predispõem a maior susceptibilidade à dependência à nicotina pode ser importante para a prevenção e o tratamento do tabagismo. No contexto de medicina personalizada, os principais objetivos do presente estudo foram avaliar se polimorfismos nos genes CHRNA2, CHRNA3, CHRNA5 e CHRNB3 estão associados com o nível de dependência em indivíduos fumantes e com o resultado do tratamento antitabágico. Métodos: Estudo de coorte com 1049 pacientes fumantes que receberam tratamento farmacológico (vareniclina, vareniclina e bupropiona, bupropiona e/ou terapia de reposição nicotínica). O sucesso na cessação tabágica foi considerado para os pacientes que completaram 6 meses de abstinência contínua. O teste de Fagerström para a dependência à nicotina (FTND) e o escore de consumo situacional Issa foram utilizados para avaliar a dependência à nicotina. A escala de conforto PAF foi utilizada para avaliar o conforto do paciente durante o tratamento. Os polimorfismos CHRNA2 rs2472553, CHRNA3 rs1051730, CHRNA5 rs16969968, CHRNA5 rs2036527 e CHRNB3 rs6474413 foram genotipados pela análise da curva de melting. Resultados: As mulheres portadoras dos genótipos GA e AA para os polimorfismos CHRNA5 rs16969968 e rs2036527 obtiveram maior taxa de sucesso no tratamento antitabagismo: 44,0% e 56,3% (rs16969968), 41,5% e 56,5% (rs2036527), respectivamente; em comparação com as mulheres portadoras do genótipo GG: 35,7% (rs16969968) e 34,8% (rs2036527), (P=0,03; n=389; P=0,01; n=391). Os genótipos GA ou AA para os rs16969968 e rs2036527 foram associados com maior OR para o sucesso em mulheres (OR=1,63; IC 95%=1,04-2,54; P=0,03 e OR=1,59; IC 95%=1,02-2,48; P=0,04; respectivamente), em um modelo multivariado. Não foi encontrada associação dos polimorfismos no gene CHRNA5 com o escore de FTND. Para os polimorfismos CHRNA2 rs2472553, CHRNA3 rs1051730 e CHRNB3 rs6474413 não foram encontradas associações significativas com os fenótipos estudados. Conclusão: Os polimorfismos rs16969968 e rs2036527 no gene CHRNA5 foram associados com maior taxa de sucesso no tratamento antitabagismo em mulheres. Estes resultados podem contribuir com avanços na terapêutica baseada em medicina personalizada

Platelet-activating factor downregulates the expression of liver X receptor-α and its target genes in human neutrophils

Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less well known. It has been reported that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions have also been reported. In this study, we investigated the effect of platelet-activating factor (PAF), a proinflammatory molecule, on LXRα signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRα, ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and sterol response element binding protein 1c. This negative action was mediated by the PAF receptor, and was dependent on the release of reactive oxygen species elicited by PAF, as it was enhanced by pro-oxidant treatment and reversed by antioxidants. Current data also support the idea that PAF induces phosphorylation of the LXRα molecule in an extracellular signal-regulated kinase 1/2-mediated fashion. These results suggest that a possible mechanism by which PAF exerts its proinflammatory effect is through the downregulation of LXRα and its related genes, which supports the notion that LXRα ligands exert a modulatory role in the neutrophil-mediated inflammatory response.

Reliability and Validity Evidence of Scores on the French Version of the Questionnaire about Interpersonal Difficulties for Adolescents

This study examined the reliability and validity evidence drawn from the scores of the French version of the Questionnaire about Interpersonal Difficulties for Adolescents (QIDA) in a sample of 957 adolescents (48.5% boys) ranging in age from 11 to 18 years (M = 14.48, SD = 1.85). A principal axis factoring (PAF) and confirmatory factor analyses (CFA) were performed to determine the fit of the factor structure of scores on the QIDA. PAF and CFA replicated the previously identified correlated five-factor structure of the QIDA: Assertiveness, Heterosexual Relationships, Public Speaking, Family Relationships, and Close Friendships. The QIDA yielded acceptable reliability scores for French adolescents. Validity evidence of QIDA was also established through correlations with scores on the School Anxiety Inventory and the Social Anxiety Scale for Adolescents. Most of the correlations were positive and exceeded the established criteria of statistical significance, but the magnitude of these varied according to the scales of the QIDA. Results supported the reliability and validity evidence drawn from the scores of the French version of the QIDA.

Markers for silent atrial fibrillation in esophageal long-term electrocardiography.

PURPOSE Paroxysmal atrial fibrillation (PAF) often remains undiagnosed. Long-term surface ECG is used for screening, but has limitations. Esophageal ECG (eECG) allows recording high quality atrial signals, which were used to identify markers for PAF. METHODS In 50 patients (25 patients with PAF; 25 controls) an eECG and surface ECG was recorded simultaneously. Partially A-V blocked atrial runs (PBARs) were quantified, atrial signal duration in eECG was measured. RESULTS eECG revealed 1.8‰ of atrial premature beats in patients with known PAF to be PBARs with a median duration of 853ms (interquartile range (IQR) 813-1836ms) and a median atrial cycle length of 366ms (IQR 282-432ms). Even during a short recording duration of 2.1h (IQR 1.2-17.2h), PBARs occurred in 20% of PAF patients but not in controls (p=0.05). Left atrial signal duration was predictive for PAF (72% sensitivity, 80% specificity). CONCLUSIONS eECG reveals partially blocked atrial runs and prolonged left atrial signal duration - two novel surrogate markers for PAF.

The fraction of ischaemic heart disease and stroke attributable to smoking in the WHO Pacific and South-East Asian regions

Background: Tobacco will soon be the biggest cause of death worldwide, with the greatest burden being borne by low and middle-income countries where 8/10 smokers now live. Objective: This study aimed to quantify the direct burden of smoking for cardiovascular diseases (CVD) by calculating the population attributable fractions (PAF) for fatal ischaemic heart disease (IHD) and stroke (haemorrhagic and ischaemic) for all 38 countries in the World Health Organization Western Pacific and South East Asian regions. Design and subjects: Sex-specific prevalence of smoking was obtained from existing data. Estimates of the hazard ratio (HR) for IHD and stroke with smoking as an independent risk factor were obtained from the,600 000 adult subjects in the Asia Pacific Cohort Studies Collaboration (APCSC). HR estimates and prevalence were then used to calculate sex-specific PAF for IHD and stroke by country. Results: The prevalence of smoking in the 33 countries, for which relevant data could be obtained, ranged from 28-82% in males and from 1-65% in females. The fraction of IHD attributable to smoking ranged from 13-33% in males and from < 1-28% in females. The percentage of haemorrhagic stroke attributable to smoking ranged from 4-12% in males and from < 1-9% in females. Corresponding figures for ischaemic stroke were 11-27% in males and < 1-22% in females. Conclusions: Up to 30% of some cardiovascular fatalities can be attributed to smoking. This is likely an underestimate of the current burden of smoking on CVD, given that the smoking epidemic has developed further since many of the studies were conducted.

Using QFD for e-business planning and analysis in a micro-sized enterprise

Purpose - The purpose of this paper is to show how QFD can be used as part of a structured planning and analysis framework for micro-sized enterprises to build-up their e-business capabilities. Design/methodology/approach - This case study has been produced using a new framework which integrates the balanced scorecard, value chain and quality function deployment techniques into an integrated framework known as the E-Business Planning and Analysis Framework (E-PAF). It has been produced using an action research approach. Findings - A new framework with a supporting case study is provided. This case study has demonstrated that the framework can be applied successfully to micro-sized enterprises (those with less than ten employees) to successfully plan new strategic and technical developments. This will enhance the online service that the company is able to provide. Research limitations/implications - This paper presents a single case study. The technical recommendations are currently being implemented. Originality/value - Such analytical techniques are most commonly associated with large organisations, and are not specifically associated with e-business planning. This paper provides a new framework that will be of general applicability to other similarly sized enterprises that are looking to improve e-business capabilities. © Emerald Group Publishing Limited.

The central role of the neutrophil in ischaemic/reperfusion injury

Inadequate blood flow to an organ, ischaemia, may lead to both local and remote tissue injury characterized by oedema, increased microvascular permeability to protein and degradation of connective tissue components. This damage is probably caused by the accumulation and inappropriate activation of neutrophils which occurs when the tissue is reperfused. To test this hypothesis a number of in vitro models of the sequential stages of ischaemia/reperfusion injury were examined. Methods were initially developed to examine the adhesion of neutrophils to monolayers of a cultured endothelial cell line (ECV304) after periods of hypoxia and reoxygenation. Neutrophil migration in response to factors secreted by the treated endothelial cells was then assessed. The genesis of an inappropriate oxidative burst by the neutrophil upon exposure to endothelial chemoattractants and adhesion molecules was also measured. Finally to appraise how tissue function might be affected by endothelial cell hypoxia the contractility of vascular smooth muscle was examined. Neutrophil adhesion to ECV304 cells, which had been hypoxic for 4 hours and then reoxygenated for 30 minutes, was significantly increased. This response was probably initiated by reactive oxygen species (ROS) generated by the endothelial cells. Blockage of their production by allopurinol reduced the heightened adhesion. Similarly removal of ROS by superoxide dismutase or catalase also attenuated adhesion. ROS generation in turn caused the release of a soluble factor (s) which induced a conformational change on the neutrophil surface allowing it to bind to the intercellular adhesion molecule 1 (ICAM-1) on the endothelial cell. Soluble factor (s) from hypoxia/reoxygenated endothelial cells also had a powerful neutrophil chemoattractant ability. When neutrophils were exposed to both hypoxic/reoxygenated endothelial cells and the soluble factor (s) released by them a large oxidative burst was elicited. This response was greatest immediately after reoxygenation and one hour later was diminishing suggesting at least one of the components involved was labile. Analysis of the supernatant from hypoxic/reoxygenated endothelial cell cultures and studies using inhibitors of secretion suggested platelet activating factor (PAF) may be a major component in this overall sequence of events. Lesser roles for IL-8, TNF and LTB4 were also suggested. The secretory products from hypoxia/reoxygenated endothelial cells also affected smooth muscle contractility having an anti-vasoconstrictor or relaxation property, similar to that exerted by PAF.