bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracoronary and Intravenous Adenosine 5′-Triphosphate, Adenosine, Papaverine, and Contrast Medium to Assess Fractional Flow Reserve in Humans
Authors: De Bruyne Bernard , Pijls Nico H.J. , Barbato Emanuele , Bartunek Jozef , Bech Jan-Willem , Wijns William , Heyndrickx Guy R.
Published: April 2003

Background—

Inducing both maximal and steady-state coronary hyperemia is of clinical importance to take full advantage of fractional flow reserve measurements. The present study compares different dosages and routes of administration of adenosine 5′-triphosphate (ATP), adenosine, contrast medium, and papaverine regarding their potential to achieve both maximal and steady-state hyperemia.

Methods and Results—

In 21 patients with an isolated coronary stenosis, coronary vasodilation was induced successively by papaverine (20 mg intracoronary), adenosine (20 and 40 μg intracoronary), ATP (20 and 40 μg intracoronary), iohexol (6 mL intracoronary), adenosine or ATP through an antecubital vein (140 and 180 μg · kg
−
1
· min
−
1
), or adenosine or ATP through a femoral vein (140 and 180 μg · kg
−
1
· min
−
1
). Because vessel dimensions did not change, the ratio of distal coronary pressure (P
d
) to aortic pressure (P
a
) was used as an index of myocardial resistance. P
d
/P
a
was 0.77±0.21 at rest and decreased to 0.61±0.21 after papaverine. P
d
/P
a
decreased to a similar level with all other vasodilators, except with contrast medium (0.68±0.21;
P
<0.01 versus papaverine). Steady-state hyperemia could only be obtained by intracoronary papaverine and by intravenous ATP or adenosine. In another 23 patients, an intravenous infusion of ATP was varied from 0 to 280 μg · kg
−
1
· min
−
1
. At doses >140 μg · kg
−
1
· min
−
1
, there was neither a further decrease in P
d
/P
a
ratio nor a further increase in coronary flow velocities.

Conclusion—

Provided sufficient dosages are used, ATP, adenosine, and papaverine (but not contrast medium) induce maximal hyperemia and are therefore suitable to assess fractional flow reserve. Only intracoronary papaverine and intravenous ATP or adenosine induce steady-state hyperemia enabling a pressure pullback maneuver that is useful in assessing diffuse coronary atherosclerosis.
Fish and Long-Chain ω-3 Fatty Acid Intake and Risk of Coronary Heart Disease and Total Mortality in Diabetic Women
Authors: Hu Frank B. , Cho Eunyoung , Rexrode Kathryn M. , Albert Christine M. , Manson JoAnn E.
Published: April 2003

Background—

Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients.

Methods and Results—

We examined prospectively the association between intake of fish and ω-3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (
P
for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for ≥5 times per week [
P
for trend=0.005]). Higher consumption of long-chain ω-3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03],
P
for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88],
P
for trend=0.02).

Conclusions—

A higher consumption of fish and long-chain ω-3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women.
Influence of the Bypass Angioplasty Revascularization Investigation National Heart, Lung, and Blood Institute Diabetic Clinical Alert on Practice Patterns
Authors: McGuire Darren K. , Anstrom Kevin J. , Peterson Eric D.
Published: April 2003

Background—

In 1995, the Bypass Angioplasty Revascularization Investigation (BARI) found that patients with diabetes had a survival benefit when treated with surgical revascularization versus balloon angioplasty, prompting a National Heart Lung and Blood Institute (NHLBI) “Clinical Alert.” The influence of the BARI findings and of the Clinical Alert on practice patterns is unknown.

Methods and Results—

The practice patterns of coronary revascularization among patients with diabetes and multivessel coronary artery disease (CAD) were analyzed using data collected in 1994 to 1997 from 13 centers participating in the National Cardiovascular Network. The study population included patients with diabetes and multivessel CAD who underwent elective coronary revascularization (n=9619). Over the 4 years of the study, the Clinical Alert had no significant impact on the proportion of diabetic patients undergoing percutaneous revascularization (28.6% before versus 26.8% after the Clinical Alert;
P
=0.06). Among individual hospitals, the probability of diabetic patients receiving percutaneous revascularization varied by >13-fold (4.3% to 56.6%). Adjusting for clinical factors and the BARI Clinical Alert did not alter this variability. Among the investigators surveyed, although 91% were aware of the Clinical Alert and 76% felt the findings were valid, >50% felt the Clinical Alert had limited or no impact on their personal or institution’s care patterns.

Conclusions—

Limited consensus exists regarding the most appropriate method of revascularization for diabetic patients with multivessel CAD. The results from a large, randomized, clinical trial and subsequent Clinical Alert had no measurable impact on this practice variability.
Modeling and Risk Prediction in the Current Era of Interventional Cardiology
Authors: Holmes David R. , Selzer Faith , Johnston Janet M. , Kelsey Sheryl F. , Holubkov Richard , Cohen Howard A. , Williams David O. , Detre Katherine M.
Published: April 2003

Background—

Validation of in-hospital mortality models after percutaneous coronary interventions using multicenter data remains limited.

Methods and Results—

This study evaluated whether multivariable mortality models developed during the pre-stent era by New York State, American College of Cardiology (ACC)–National Cardiovascular Data Registry, Northern New England Cooperative Group, Cleveland Clinic Foundation, and the University of Michigan are relevant in patients undergoing percutaneous coronary intervention in the 1997 to 1999 National Heart, Lung, and Blood Institute Dynamic Registry. Of 4448 Dynamic Registry patients, 73% received ≥1 stent and 28% received a IIB/IIIA receptor inhibitor. In-hospital mortality occurred in 64 patients (1.4%). The New York state model predicted mortality in 69 patients (1.5%; 95% confidence bounds [CI], 0.89% to 1.70%); Northern New England predicted mortality in 60 patients (1.3%; 95% CI, 1.0% to 1.7%); and Cleveland Clinic predicted mortality in 76 patients (1.7%; 95% CI, 1.3% to 2.1%). Among high-risk subgroups, with these 3 models, observed and predicted in-hospital mortality rates in general were not different. The other 2 models yielded different results. The University of Michigan predicted fewer deaths (n=47; 1.1%; 95% CI, 0.7% to 1.3%), and the ACC Registry model predicted 603 deaths (13.5%; 95% CI, 12.6% to 14.4%). Using the ACC Registry model, predicted mortality was higher than observed in each subgroup.

Conclusions—

Application of 5 mortality risk models developed from different data sets to patients undergoing percutaneous coronary intervention in the Dynamic Registry predicted, in 3 models, mortality rates that were not significantly different than those observed. In both high and low risk subgroups, the University of Michigan slightly underpredicted mortality, and the ACC Registry predicted significantly higher mortality than that observed.
Reduction of Major Adverse Cardiac Events With Intracoronary Compared With Intravenous Bolus Application of Abciximab in Patients With Acute Myocardial Infarction or Unstable Angina Undergoing Coronary Angioplasty
Authors: Wöhrle Jochen , Grebe Olaf C. , Nusser Thorsten , Al-Khayer Eyas , Schaible Stefan , Kochs Matthias , Hombach Vinzenz , Höher Martin
Published: April 2003

Background—

In patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty, abciximab reduces major adverse cardiac events (MACE). Clinical trials have studied intravenous administration only. Intracoronary bolus application of abciximab causes very high local drug concentrations and may be more effective. We studied whether intracoronary bolus administration of abciximab is associated with a reduced MACE rate compared with the standard intravenous bolus application.

Methods and Results—

We stratified 403 consecutive patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty according to the type of application of abciximab. A 20-mg bolus of abciximab was given intravenously in 109 patients and intracoronarily in 294 patients. There were no differences between the groups with regard to diabetes mellitus, cardiogenic shock, successful intervention, or preprocedural and postprocedural TIMI flow. At 30 days, the incidence of MACE (death, myocardial infarction, urgent revascularization) was significantly lower in the patients with intracoronary compared with intravenous administration of abciximab (10.2% versus 20.2%;
P
<0.008), which was independent from stenting in multivariate analysis. The effect was most pronounced in patients with preprocedural TIMI 0/1 flow (MACE: intracoronary 11.8% versus intravenous 27.5%,
P
<0.002; n=273).

Conclusions—

In patients with acute myocardial infarction or unstable angina undergoing emergency coronary angioplasty, intracoronary bolus application of abciximab is associated with a reduction of MACE compared with the standard intravenous bolus application of abciximab. Prospective, randomized trials are warranted to further assess intracoronary application of abciximab.
GFP Bunny
Authors: Kac Eduardo
Published: April 2003

The author describes his transgenic artwork GFP Bunny and discusses the theoretical and practical implications of creating a new mammal in the context of art. Weaving together insights from philosophy, molecular biology, natural history, cognitive ethology and art, the author places primary emphasis on the welfare of the transgenic rabbit he has created. The author rejects biological determinism and states his goals of developing a dialogical relationship with the bunny based on love and care.
Towards Epistemically Autonomous Robots: Exploiting the Potential of Physical Systems
Authors: Bird Jon , Layzell Paul , Webster Andy , Husbands Phil
Published: April 2003

The authors outline one path towards constructing interactive artworks with the potential for displaying novel behavior. They use Peter Cariani's taxonomy of adaptive robotic systems as a framework for comparing the capabilities of systems that interact with their environments. The authors then describe two examples of structurally autonomous systems that are able to construct their own sensors independently of a human designer. The first device, the evolved radio, is the result of a recent hardware evolution (HE) experiment conducted by the authors. The second device, the electrochemical ear, was constructed almost 50 years ago by the British cybernetician Gordon Pask. The emergent behavior in both systems is only possible because many conventional engineering constraints were relaxed during their construction. Using existing technology, artists have the opportunity to explore the potential of structurally autonomous systems as interactive artworks.
Computer Creativity in the Automatic Design of Robots
Authors: Pollack Jordan B. , Hornby Gregory S. , Lipson Hod , Funes Pablo
Published: April 2003

This article demonstrates the possibility that robotic systems can automatically design robots with complex morphologies and tightly adapted control systems at a low cost. These automatic designs are inspired by nature and achieved through an artificial coevolutionary process to adapt the bodies and brains of artificial life-forms simultaneously through interaction with a simulated reality. Through the use of rapid manufacturing, these evolved designs can be transferred from virtual to true reality. The artificial evolution process embedded in realistic physical simulation can create simple designs often recognizable from the history of biology or engineering. This paper provides a brief review of three generations of these robots, from automatically designed LEGO structures, through the GOLEM project of electromechanical systems based on “truss” structures, to new modular designs that make use of a generative, DNA-like representation.
BRIDGES I: Interdisciplinary Collaboration as Practice
Authors: Pearce Celia , Diamond Sara , Beam Mark
Published: April 2003

Today, a worldwide community of innovators is engaged in the convergence of art, technology and science, as are a number of vital and active organizations, yet there seems to be very little discourse about the process of doing interdisciplinary work. The BRIDGES Consortium seeks to create a collaborative forum for the study and development of interdisciplinary collaboration as a practice. At the first Bridges Summit, held in June 2001, participants discussed a broad range of topics, including: preceding historical developments, the role of language, institutional hurdles to collaboration and the value of art/technology-based research. The event concluded with recommendations for aggregating, validating and strengthening the interdisciplinary community through the creation of a new form of collaborative organization.
Circle Packings and the Sacred Lotus
Authors: Tarnai Tibor , Miyazaki Koji
Published: April 2003

How must n non-overlapping equal circles be packed in a given circle so that the diameter of the circles will be as large as possible? This paper presents an account of this problem and its putative solutions and related configurations in lotus receptacles, classical Japanese mathematics (wasan) and traditional Japanese design. Particular emphasis is placed on the connection between the conjectural solutions of this discrete geometrical problem and the fruit arrangements in the receptacles of lotuses, because in most cases the actual fruit arrangements are identical to the mathematical solutions. As the lotus is an important symbol in Buddhism and lotus decorations are quite common in Japanese Buddhist art, packings of circles in a circle have been represented in Japanese art for centuries.
Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors
Authors: Ottinger Hellmut D. , Ferencik Stanislav , Beelen Dietrich W. , Lindemann Monika , Peceny Rudolf , Elmaagacli Ahmed H. , Hüsing Johannes , Grosse-Wilde Hans
Published: April 2003

Allogeneic hematopoietic stem cell transplantation (HSCT) is a proven curative therapy for many hematologic malignancies. HSCT from HLA-identical sibling donors (ISDs) is still the golden standard. For the remaining 70% of the patients lacking an ISD, alternative (partially) HLA-matched family donors (MFDs) and HLA-matched unrelated donors (MUDs) are now widely accepted. However, it is presently unclear whether outcome after HSCT from an MFD or an MUD is superior. Thus, the classical clinical end points after HSCT from an ISD (n = 138), MFD (n = 86), and MUD (n = 101) were compared by means of univariate and multivariate statistical analyses. MFD transplantations with HLA class II (DRB1 ± DQB1) mismatches in graft-versus-host (GVH) direction showed an increased risk of grades II to IV graft-versus-host disease, and MFD transplantations with more than a single HLA class I (A ± B ± C) mismatch in host-versus-graft (HVG) direction were associated with a higher risk of graft failure. However, no significant difference in overall survival was detectable among the 3 study groups after adjustment for the main predictors of transplantation outcome. Thus, for patients lacking an ISD, an already identified MFD with an HLA-DRB1 ± DQB1 mismatch in GVH or a combined HLA-A ± B ± C mismatch in HVG direction should be accepted only in clinically urgent settings that leave no time to identify an MUD.
Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor
Authors: Selvaraj Suresh K. , Giri Ranjit K. , Perelman Natalya , Johnson Cage , Malik Punam , Kalra Vijay K.
Published: April 2003

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1β [IL-1β]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1β [MIP-1β]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal–regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival
Authors: Zheng Bei , Fiumara Paolo , Li Yang V. , Georgakis Georgios , Snell Virginia , Younes Mamoun , Vauthey Jean Nicolas , Carbone Antonino , Younes Anas
Published: April 2003

The mitogen-activated protein kinase (MAPK) (also called extracellular signal–regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia–1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor–related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappaβ (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study
Authors: Tracey Lorraine , Villuendas Raquel , Dotor Ana Maria , Spiteri Inmaculada , Ortiz Pablo , García Juan F. , Peralto Jose Luis Rodríguez , Lawler Mark , Piris Miguel A.
Published: April 2003

Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma, whose diagnosis and study is hampered by its morphologic similarity to inflammatory dermatoses (ID) and the low proportion of tumoral cells, which often account for only 5% to 10% of the total tissue cells. cDNA microarray studies using the CNIO OncoChip of 29 MF and 11 ID cases revealed a signature of 27 genes implicated in the tumorigenesis of MF, including tumor necrosis factor receptor (TNFR)–dependent apoptosis regulators, STAT4, CD40L, and other oncogenes and apoptosis inhibitors. Subsequently a 6-gene prediction model was constructed that is capable of distinguishing MF and ID cases with unprecedented accuracy. This model correctly predicted the class of 97% of cases in a blind test validation using 24 MF patients with low clinical stages. Unsupervised hierarchic clustering has revealed 2 major subclasses of MF, one of which tends to include more aggressive-type MF cases including tumoral MF forms. Furthermore, signatures associated with abnormal immunophenotype (11 genes) and tumor stage disease (5 genes) were identified.
Factor XI–dependence of surface- and tissue factor–initiated thrombus propagation in primates
Authors: Gruber András , Hanson Stephen R.
Published: April 2003

Thrombin, generated through activation of factor XI (FXI) and/or tissue factor (TF)–factor VIIa, is essential for thrombosis and hemostasis. We investigated the role of FXI-dependent thrombus propagation under arterial flow conditions producing rapid thrombus growth that, after the initiation phase, could limit the availability of TF at the blood/thrombus interface. Thrombosis was initiated by knitted dacron or TF-presenting teflon grafts deployed into arteriovenous shunts in baboons treated with antihuman FXI antibody (aFXI). Although aFXI did not prevent thrombus initiation, it markedly reduced intraluminal thrombus growth on both surfaces. The antithrombotic effect of aFXI was comparable with that of heparin at doses that significantly prolonged the partial thromboplastin time (APTT), prothrombin time (PT), and bleeding time (BT). aFXI also prolonged the APTT, but the PT and BT were unaffected. Thus, antithrombotic targeting of FXI might inhibit thrombosis with relatively modest hemostatic impairment versus strategies targeting other coagulation factors.
Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum
Authors: Rochat T , Pastore FD , Schlegel-Haueter SE , Filthuth I , Auckenthaler R , Belli D , Suter S
Published: April 2003

In cystic fibrosis (CF), large amounts of free leucocyte proteases are present in bronchial secretions, contributing to progressive lung damage. Recombinant, human deoxyribonuclease (rhDNase) is a new therapeutic agent that decreases sputum viscosity. However, deoxyribonuclease has been shown, in vitro, to release cationic enzymes from complexes with deoxyribonucleic acid (DNA). The present study was conducted to assess this effect in vivo. Free human leucocyte elastase (HLE), human leucocyte cathepsin G (HCG), total chemotactic activity, and interleukin-8 (IL-8) were determined in sputum from eight patients before, during and after rhDNase treatment. After 15 days of treatment, HLE activity increased by 81+/-44% (NS), and HCG by 189+/-70% (p<0.05). One week after stopping a 4-6 months treatment, HLE activity decreased by 35+/-18% (p<0.05), and HCG by 43+/-11% (p<0.05). Sputum bacterial density, chemotactic activity, and IL-8 concentration did not change. Thus, treatment with rhDNase can indeed increase the activity of HLE and HCG in the bronchial secretions of CF patients, and this effect is still detectable after several months of treatment. If this can be shown to be clinically relevant, combination therapy of recombinant human deoxyribonuclease with protease inhibitors should be considered as an approach to the problem.
Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients
Authors: Hubert D , Bienvenu T , Desmazes-Dufeu N , Fajac I , Lacronique J , Matran R , Kaplan JC , Dusser DJ
Published: April 2003

In cystic fibrosis (CF), relationships between genotype and phenotype have been shown for pancreatic status but not for pulmonary disease. One hundred and ten adult CF patients were classified according to the expected effect of their mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein: Group 1 (n=48) included deltaF508 homozygotes; Group 2 (n=26), patients with two "severe" mutations and no expected CFTR production; Group 3 (n=17), patients with expected partly functional CFTR corresponding to at least one "mild" mutation; Group 4 (n=19), patients with no mutation identified or only one identified "severe" mutation. As compared to Groups 1 and 2: patients from Groups 3 and 4 had higher arterial oxygen tension (Pa,O2) (9.5+/-1.9 and 9.9+/-1.5 vs 8.8+/-1.5 and 8.3+/-1.7 kPa, respectively p<0.02); and a slower decline in their pulmonary function, estimated by the mean annual loss in forced vital capacity (FVC) (1.2+/-1.0 and 1.5+/-1.1 vs 2.0+/-0.9 and 2.2+/-1.0%, respectively; p<0.01) and in forced expiratory volume in one second (FEV1) (1.7+/-1.1 and 1.9+/-1.3 vs 2.6+/-1.0 and 2.8+/-1.0%, respectively; p<0.005). They had fewer episodes of colonization of the airways by Pseudomonas aeruginosa, and colonization occurred at a more advanced age (median age 25 and 19 vs 15 and 17 yrs, respectively; p<0.01) and required fewer intravenous antibiotic courses (p<0.01). Pancreatic insufficiency was less frequent in Groups 3 (23%) and 4 (63%) than in Groups 1 (100%) and 2 (96%). This study suggests that the phenotype of adult cystic fibrosis patients, including the severity of the lung disease, is related to the severity of the cystic fibrosis transmembrane conductance regulator mutations.
Functional residual capacity in healthy preschool children
Authors: Pauwels JH , Van Bever HP , Desager KN , Willemen MJ , Creten WL , Van Acker KJ , Vermeire PA
Published: April 2003

The purpose of this study was to evaluate the feasibility of routine functional residual capacity (FRC) measurements in healthy preschool children aged 2.7-6.4 yrs. Furthermore, accuracy and reproducibility were investigated and normal values were collected. A mass-produced closed-circuit helium dilution device (rolling seal) was used. Selection of the 113 healthy children (from the 571 measured) was based on an extensive personal and family history questionnaire and on clinical examination before measurements were performed. With three successive attempts it was possible to achieve at least two reproducible measurements in 73% of the children (repeatability coefficient 95.3 mL). The main problems were leakage at the corner of the mouth and irregular breathing pattern. The mean time to perform a measurement was 113 s. Mean FRC was significantly higher in boys than in girls: 778 versus 739 mL for a body length of 110 cm (p<0.05). FRC correlated with height (H) (r=0.69), weight (W) (r=0.56), age (A) (r=0.62) and all three combined (r=0.70): FRC = -534.89 + 1.84 x W (kg) + 10.07 x H (cm) + 2.51 x A (months). When a power or exponential function was used to describe FRC as a function of height, the results were not superior to the linear regression (r=0.69): FRC (mL) = -766.2 + 13.8 x H (cm) (r=0.69) or FRC (L) = 0.620 x H (m)(2.03) (r=0.69) or FRC (mL)= 99.5 x e(0.018xH (cm)) (r=0.69). Among these, we recommend the power function because it will better fit broader height ranges. Reliable functional residual capacity measurements can be routinely performed in preschool children with a mass-produced device. Reference values were collected for children 95-125 cm in height.
Eosinophils and eosinophil-derived proteins in children with moderate asthma
Authors: Hoekstra MO , Hovenga H , Gerritsen J , Kauffman HF
Published: April 2003

Laboratory parameters can contribute to the diagnosis of asthma, which is often a difficult procedure in paediatric patients. The aim of this study was to investigate the value of eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) in the diagnosis of paediatric asthma. The number of eosinophils, serum ECP and EDN, and urinary EDN were determined in 22 children with stable, allergic asthma, aged 4-14 yrs, and in 17 age-matched healthy controls. Symptoms were monitored, the peak expiratory flow rate (PEFR) was recorded in the younger children, and lung function tests (forced expiratory volume in one second (FEV1) and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20)) were performed in the older children. None of the asthmatic children had respiratory symptoms. PEFR was not significantly different in asthmatic children compared to controls. The FEV1 % predicted was significantly lower compared to controls. The number of eosinophils, serum ECP and EDN, and urinary EDN were significantly higher in asthmatic children compared with controls. After correction of serum ECP and EDN, and urinary EDN for the number of eosinophils, the differences between patients and controls disappeared. The nocturnal PEFR and the FEV1 were significantly related to urinary EDN. The results suggest that serum and urinary concentration of eosinophil-derived proteins can be determined instead of the number of eosinophils to support the diagnosis of asthma in childhood. The urinary concentration of eosinophil-derived neurotoxin can be especially valuable in young children, because in this age group quantification of lung function cannot be performed and blood sampling can be difficulty.
Lyso-PAF acetyltransferase activity in neutrophils of patients during acute asthma and after recovery
Authors: Misso NL , Gillon RL , Stewart GA , Thompson PJ
Published: April 2003

The production of platelet-activating factor (PAF) by inflammatory cells is regulated by lyso-PAF acetyltransferase, and the activity of this enzyme is increased in neutrophils of stable asthmatic patients. The aim of this investigation was to determine whether acetyltransferase activity is further upregulated in asthmatic patients experiencing acute symptoms. A radioenzymatic assay was used to measure the enzymatic affinity constant (Km) and maximal enzymatic activity (Vmax) for acetyltransferase from unstimulated and Ca2+ ionophore (A23187)-stimulated neutrophils from 16 patients with acute asthma, and the measurement was repeated at the time of discharge (n=9) and after recovery from the acute episode (n=13). During acute asthma, Km (median 93.8 (interquartile range 64.1-109.7) microM) was lower than that measured in nonasthmatic subjects in a previous study using identical methods (155.1 (122.2-179.9) microM; p=0.0001), and in 10 out of 13 acute patients Km for unstimulated neutrophils increased following recovery. In A23187-stimulated neutrophils, Km during acute asthma (84.3 (73.6-100.2) microM) and at discharge (83.9 (83.1-94.8) microM) were similar, but Km after recovery was increased (115.0 (95.6-119.5) microM; p=0.02). The change in Km following stimulation with A23187 was also significantly less during acute asthma than previously measured in nonasthmatic subjects (p=0.003). Although Vmax during acute asthma (12.9 (interquartile range 10.5-22.5) nmol x min(-1) x mg(-1) protein) did not differ significantly from that at discharge (14.4 (12.3-20.4) nmol x min(-1) x mg(-1)) or after recovery (17.3 (12.3-18.4) nmol x min(-1) x mg(-1)), both median Km and Vmax tended to be lowest during acute asthma and increase at discharge and after recovery. An increase in lyso-PAF acetyltransferase activity alone may not account for increased systemic PAF concentrations during acute asthma. However, the reduction in the enzymatic affinity constant and its smaller change following in vitro stimulation suggest that alterations in the affinity of acetyltransferase for acetylcoenzyme A (CoA) and in the regulation of enzyme activity may be occurring during acute asthma.
Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1)
Authors: Hoekx JC , Hedlin G , Pedersen W , Sorva R , Hollingworth K , Efthimiou J
Published: April 2003

The aim of this study was to compare fluticasone propionate (FP) with budesonide (BUD) at a dose of 400 microg x day(-1) in the treatment of children with asthma. Two hundred and twenty nine children with mild-to-moderate asthma, currently receiving 200-400 microg x day(-1) of inhaled corticosteroid, were randomized to receive either 400 microg x day(-1) of FP from the Diskhaler (registered trade mark of the Glaxo Group of Companies) or 400 microg x day(-1) of BUD from the Turbuhaler (registered trade mark of Astra Pharmaceuticals Ltd) for 8 weeks, in a parallel-group, double-blind, double-dummy study. Primary efficacy was assessed by measurement of daily peak expiratory flow (PEF). In addition, pulmonary function tests were performed at each clinic visit and a self-administered patient-centred questionnaire was completed by one parent of each patient at the start and end of study treatment. Mean morning PEF increased following treatment both with FP and BUD, but was significantly higher following treatment with FP during Weeks 1-4 (p=0.015) and Weeks 1-8 (p=0.019). Similar results were found for mean evening PEF and percentage predicted morning and evening PEF. Children receiving FP experienced significantly less disruption in their physical activities (i.e. sports, games) because of their asthma compared to children treated with BUD (p=0.03). Mean cortisol levels increased in both groups, but the increase was significantly higher in the FP group at 4 weeks (p=0.022). Serum and urine markers of bone formation and resorption changed very little and showed no consistent pattern of change. Fluticasone propionate at a dosage of 400 microg x day(-1) from the Diskhaler provided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 microg day(-1) from the Turbuhaler. Both treatments were well-tolerated, with a similar safety profile.
Voluntary decrease in breathing frequency in exercising asthmatic subjects
Authors: Ceugniet F , Cauchefer F , Gallego J
Published: April 2003

Exercise rehabilitation programmes are increasingly recommended in young asthmatics, but it is unclear whether or not training should incorporate instructions on breathing pattern. In this study, we examined the effects of voluntarily decreasing breathing frequency on their ventilatory equivalents for oxygen and carbon dioxide (minute ventilation (V'E)/oxygen consumption (V'O2) and V'E/CO2 production (V'CO2), respectively), noninvasively determined physiological dead space/tidal volume (VD/VT) and dyspnoea. Fifteen young asthmatic subjects were assigned to two groups: low frequency breathing (LFB) and controls. They first underwent an exercise test at a cardiac frequency of 150 beats x min(-1). They were trained at this level for nine sessions. LFB subjects were instructed to decrease respiratory frequency by 40% during exercise. Control subjects received no instructions. A second test was then performed in the same conditions. LFB subjects decreased V'E/V'O2, V'E/V'CO2 and VD/VT by 22, 19 and 12%, respectively. Arterial oxygen saturation (Sa,O2) fell to 89+/-4% and end-tidal carbon dioxide tension (PET,CO2) rose to 6.5+/-0.7 kPa (49+/-5 mmHg). In controls, these variables were identical in the two tests. Dyspnoea was lower in the second test in all subjects. In conclusion, breathing pattern may be profoundly altered during exercise without concomitant increase in dyspnoea. However, directing breathing patterns for exercise rehabilitation requires an individual assessment of the desired pattern in order to prevent hypercapnia or hypoxia.
Bovine tracheal responsiveness in vitro: role of the epithelium and nitric oxide
Authors: Sadeghi-Hashjin G , Henricks PA , Folkerts G , Verheyen AK , van der Linde HJ , Nijkamp FP
Published: April 2003

Airway epithelium releases inhibitory factors, such as nitric oxide (NO) and prostaglandin E2 (PGE2), which may counteract bronchoconstriction. We investigated whether epithelium-derived inhibitory substances exert a crucial influence on bovine tracheal responsiveness in vitro. Isotonic and isometric contractions in response to histamine of intact and epithelium-denuded tracheal smooth muscle strips were compared. In addition, the effects of L-arginine (L-arg), N(G)-nitro-L-arginine methyl esther (L-NAME), and N(G)-monomethyl L-arginine (L-NMMA) on histamine responsiveness were investigated. The release of NO and PGE2 from tracheal epithelium was measured. Removal of the epithelium from tracheal smooth muscle strips did not change the negative log of the concentration of histamine producing half the maximal effect (pD2) or the maximal effect (Emax). Incubation of the tissues for 25 min with L-arg or L-NAME did not influence basal tone or the contractions induced by histamine. However, incubation with L-NMMA increased the basal tone and caused a slight hyporesponsiveness to histamine. S-nitroso-N-acetyl-penicillamine (SNAP, a direct NO donor) reversed the contraction induced by histamine in a concentration-dependent manner. Stimulation of the epithelial layer by 0.1 microM histamine increased the release of NO 3-4 fold compared to basal levels; this effect was completely inhibited in the presence of L-NMMA. In addition, 1 mM histamine caused a significant increase in the release of PGE2 from the epithelial tissue. In conclusion, no functional inhibitory influence of the epithelium can be identified in bovine airways. The S-nitroso-N-acetyl-penicillamine-induced relaxation demonstrates the presence of a nitric oxide sensitive pathway in bovine airways. However, the amounts of nitric oxide and prostaglandin E2 released from bovine tracheal epithelium are probably too low to exert a significant effect on the histamine-induced contractions.
Mitochondria act as a reservoir for the basic amine HIPDM in the lung
Authors: Miniati M , Paci A , Cocci F , Ciarimboli G , Monti S , Pistolesi M
Published: April 2003

The lungs are a site for the uptake, accumulation, and storage of exogenous basic amines. The compound N-N-N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3 propanediamine (HIPDM) is a basic amine that can be labelled with radioactive iodine and detected by external counting. Intravenously injected 123I-HIPDM is extracted by the human lung, where it is retained in a slowly effluxable pool. In the present study, we measured HIPDM lung kinetics and subcellular distribution in rabbits given i.v. 125I-HIPDM. Rabbits were killed from 2 min to 5 h after injection, and the radioactivity retained in their lungs was measured. Subcellular lung fractions (nuclear, mitochondrial, lysosomal, microsomal and postmicrosomal supernatant) were assayed for HIPDM radioactivity, protein content, and distribution of specific marker enzymes. HIPDM lung clearance in rabbits was nearly identical to that of humans. Virtually all the HIPDM radioactivity in lungs (98+/-1%) was associated with subcellular membranous structures. The highest HIPDM specific radioactivity was found in the mitochondrial fraction, and the subcellular distribution profile closely resembled that of the mitochondrial marker enzyme succinate cytochrome c reductase. No redistribution of HIPDM among subcellular compartments was observed over a 5 h period after injection. The data indicate that mitochondria act as reservoir for HIPDM in the lungs and contribute to the pulmonary persistence of this compound. HIPDM can be used to investigate the pulmonary uptake of basic amines in health and in lung disease.
Pulmonary herpes simplex in burns patients
Authors: Byers RJ , Hasleton PS , Quigley A , Dennett C , Klapper PE , Cleator GM , Faragher EB
Published: April 2003

In this study we aimed to determine the incidence of herpes simplex virus (HSV) in the lungs of burns patients, and its association with the presence of adult respiratory distress syndrome (ARDS) and pneumonia. Haematoxylin and eosin (H&E), and immunohistochemical (IHC) staining for HSV was performed on lung tissue from 54 patients who had died following burn injury and from nine control cases. Polymerase chain reaction (PCR) for HSV deoxyribonucleic acid (DNA) was performed on a subset both of burns cases and controls. No viral inclusions were detected in H&E sections, but 50% of the burns cases were positive for HSV by IHC staining; no control cases were positive. Nuclear and cytoplasmic immunopositivity for HSV was seen in macrophages and epithelial lining cells. HSV was strongly associated with ARDS (p=0.007), but not with pneumonia (p=0.577). The relative risk of HSV infection was higher for cases with ARDS (2.21) than for those with pneumonia (1.26). PCR for HSV DNA was positive in three out of five burns cases, and in one out of five control cases. Immunohistochemical staining is more sensitive for the detection of herpes simplex virus than haematoxylin and eosin staining for detection of viral inclusions. Burns cases have a high incidence of pulmonary herpes simplex virus infection. Polymerase chain reaction results may not be fully representative due to problems of tissue necrosis postmortem. Pulmonary herpes simplex virus is strongly associated with adult respiratory distress syndrome and the two may be causally linked. Early detection and treatment of pulmonary herpes simplex virus in burns patients may reduce pulmonary complications and mortality.
Does long-term oxygen therapy affect quality of life in patients with chronic obstructive pulmonary disease and severe hypoxaemia?
Authors: Okubadejo AA , Paul EA , Jones PW , Wedzicha JA
Published: April 2003

Long-term oxygen therapy (LTOT) improves survival in patients with hypoxaemic chronic obstructive pulmonary disease (COPD), but previous studies using general health measures have shown no effect on quality of life (QoL). In this study, the effect of LTOT on QoL was assessed using a disease-specific health measure, the St George's Respiratory Questionnaire (SGRQ). Twenty three hypoxaemic COPD patients (15 females and 8 males) were studied before and after starting LTOT: median age 71 (range 47-82) yrs, mean (SD) forced expiratory volume in one second (FEV1) 0.75 (0.22) L, arterial oxygen tension (Pa,O2) 6.95 (0.75) kPa, arterial carbon dioxide tension (Pa,CO2) 6.52 (1.21) kPa. A control group comprised 18 COPD patients (6 females and 12 males) with less severe hypoxaemia: median age 72 (range 58-85) yrs, FEV1 0.94 (0.33) L, Pa,O2 8.17 (0.94) kPa, Pa,CO2 6.02 (0.75) kPa. QoL was measured at baseline, 2 weeks, 3 and 6 months. The LTOT group had higher SGRQ total scores than controls (p<0.05) at all visits, implying lower QoL. Repeated measures analysis of variance showed no effect of LTOT on QoL over 6 months (F=0.43, p=0.79). In this study we detected no change in quality of life using a disease-specific health measure in patients with severe chronic obstructive pulmonary disease using an oxygen concentrator to provide long-term oxygen therapy.
Nurse-conducted smoking cessation with minimal intervention in a lung clinic: a randomized controlled study
Authors: Tonnesen P , Mikkelsen K , Markholst C , Ibsen A , Bendixen M , Pedersen L , Fuursted R , Hansen LH , Stensgaard H , Schiotz R , Petersen T , Breman L , Clementsen P , Evald T
Published: April 2003

This study aimed to evaluate the effect of a motivational, minimal intervention approach to smoking cessation in an open, randomized design conducted by nurses as routine work in a lung clinic. Subjects who smoked less than 10 cigarettes x day(-1), and subjects who smoked > or = 10 cigarettes x day(-1) and who had refused to participate in a smoking cessation trial with nicotine replacement therapy, were randomly allocated to a motivational approach to smoking cessation or to a control group. The motivational approach consisted of a nurse-conducted 5 min consultation concerning reasons to quit smoking, brochures about smoking cessation and advice about how to quit. After 4-6 weeks, subjects in the motivational group received a letter encouraging them to quit smoking. After 1 year, all subjects were contacted by phone and smoking status reported. Subjects claiming to be abstinent attended the clinic for carbon monoxide verification. A total of 507 subjects were enrolled, 254 in the motivational group and 253 in the control group. The mean age of the motivational group was 51 yrs, 50% were males and they smoked a mean of 13 cigarettes x day(-1). The mean age of the control group was 53 yrs, 61% were males and they smoked a mean of 12 cigarettes x day(-1). At the 1 year follow-up, the success rate for point prevalence (no smoking at 1 year and during the preceding month) was 8, 7% in the motivational group versus 3.6% in the control group (p=0.025). The 12 months sustained success rate (no smoking at all during the year) was 3.1 versus 1.2% (p=0.22). The point prevalence for light smokers (<10 cigarettes x day(-1)) was 13.9% in the motivational group versus 6.3% in control group (p=0.12), and for heavy smokers (10 or more cigarettes x day(-1)) 5.2% versus 1.9% (p=0.20). In conclusion, the effect of this nurse-conducted, minimal intervention, motivational approach seems promising as the quit rate at 1 year follow-up had doubled.
Objective patient compliance in long-term use of nCPAP
Authors: Fleury B , Rakotonanahary D , Hausser-Hauw C , Lebeau B , Guilleminault C
Published: April 2003

Concerns remain regarding patient compliance with nasal continuous positive airway pressure (nCPAP). Poor objective compliance during the first months of treatment has been reported, but no data are available among chronically treated patients. Use of nCPAP, in 17 chronically treated obstructive sleep apnoea patients (820+/-262 days) was evaluated objectively using a pressure monitor (MC+; Sefam, France). Two consecutive recording periods of 30 sessions of treatment were scheduled at the patient's home. To minimize the potential bias caused by the introduction of the monitor, only the pressure data obtained at the end of the second period of recording (T2) were analysed. During the 28.1+/-2.6 monitored days, the mean effective daily rate of use was 7.1+/-1.1 h, 97% of the rate indicated by the standard in-built time counter. The prescribed pressure was observed during 95% of the machine run time. The nCPAP system was used for 94% of the monitored days. Sixty percent of the patients used their device every day. These preliminary results suggest that, contrary to reported compliance during the early period of the treatment, objective use of nasal continuous positive airway pressure therapy in chronically treated patients is satisfactory.