bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient mortality of active pulmonary tuberculosis requiring mechanical ventilation
Authors: Lee P.L. , Jerng J.S. , Chang Y.L. , Chen C.F. , Hsueh P.R. , Yu C.J. , Yang P.C. , Luh K.T.
Published: June 2003

Mortality remains high among patients with pulmonary tuberculosis requiring mechanical ventilation (TBMV). This study was carried out to establish the mortality rates of TBMV and to identify factors that contribute to in-hospital mortality.

From January 1996–April 2001, there were 825 patients with active pulmonary tuberculosis at the National Taiwan University Hospital, Taipei, Taiwan. Of these, 41 suffered acute respiratory failure and required mechanical ventilation in the intensive care unit (ICU). Of these 41 patients, 38 were followed up for 180 days. In-hospital deaths were documented in the medical records and all possible parameters contributing to mortality were collected.

Of the 41 patients, 27 died in the hospital and 14 were discharged alive (in-hospital mortality rate 65.9%), with (mean±sd) 40.7±35.4 admission days before death. Of the 27 that died, 25 died during ICU admission and two died after being transferred to the ward. The mortality rate for the 180-day monitoring period was 79%. Factors contributing to in-hospital mortality included consolidations on chest radiographs and multiple organ failure.

The mortality rate in the patients with pulmonary tuberculosis requiring mechanical ventilation is very high, with two factors affecting in-hospital mortality. These factors were multiple organ failure and consolidation on chest radiographs.
Sleep-disordered breathing and hormones
Authors: Saaresranta T. , Polo O.
Published: June 2003

Sleep-disordered breathing (SDB) is not only a problem of the upper airway but is a systemic condition with endocrine and metabolic interactions. The accumulating body of evidence shows that SDB induces changes in the serum levels or secretory patterns of several hormones. Conversely, various endocrine disorders and hormone therapies may induce, exacerbate or alleviate SDB.

Much of the understanding of the interactions between hormones and sleep-disordered breathing derive from intervention studies with nasal continuous positive airway pressure therapy. Better understanding of hormones and breathing may open new perspectives in developing strategies to prevent, alleviate or cure sleep-disordered breathing and its systemic consequences.
Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers
Authors: Neurohr C. , Lenz A-G. , Ding I. , Leuchte H. , Kolbe T. , Behr J.
Published: June 2003

The antioxidant glutathione (GSH) is increased in the epithelial lining fluid (ELF) of chronic smokers. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), also known as γ‐glutamylcysteine synthetase, consisting of a heavy, catalytic (GCLC) and a light, modulatory (GCLM) subunit.

To determine the contribution of bronchoalveolar lavage (BAL) cells to GSH levels in ELF, BAL was performed in eight smokers and eight never-smokers. Intra- and extracellular total glutathione (GSHt) levels and GCL subunit expression were assessed.

GSHtwas increased in ELF from smokers (1,090.1±163.0 µMversus559.2±48.2 µM). GSHtcontent of BAL cells (nmol·mg protein−1) was decreased in smokers without differences reaching statistical significance (8.0±1.4versus12.4±2.6). GCLM expression was also reduced in smokers (0.6±0.1versus2.8±0.4) and correlated with intracellular GSHtcontent. There was no significant difference in GCLC expression and in differential cell counts in BAL fluid.

The authors conclude that smoking does increase glutathione levels in the epithelial lining fluid but not intracellular levels in bronchoalveolar lavage cells. The data suggest that the intracellular glutathione concentration of bronchoalveolar lavage cells (predominately alveolar macrophages) is regulated by the modulatory glutamate-cysteine ligase subunit rather than the catalytic subunit.
Decreased computed tomographic lung density during exacerbation of asthma
Authors: Mitsunobu F. , Ashida K. , Hosaki Y. , Tsugeno H. , Okamoto M. , Nishida N. , Nagata T. , Takata S. , Tanizaki Y.
Published: June 2003

Recently, it was shown that both mean lung density (MLD) and the relative lung area with an attenuation of <-950 HU (RA950) are related to severity of asthma in nonsmoking asthmatics. The aim of the present study was to examine whether reduced computed tomography (CT) lung density during exacerbation could change after treatment.

A cross-sectional study was performed to compare CT lung density in 30 stable asthmatics, 30 unstable asthmatics and 25 control subjects. In order to investigate longitudinally the effect of treatment on decreased CT lung density, 17 asthmatics with an exacerbation were followed at the initiation of treatment and 2 months after relief.

The MLD was significantly lower and the RA950significantly higher in unstable asthmatics than in controls and stable asthmatics. Both MLD and RA950changed significantly with administration of systemic glucocorticoid therapy. The changes in forced expiratory volume in one second correlated significantly with those in both MLD and RA950. The changes in residual volume also correlated significantly with those in both MLD and RA950.

It was concluded that decreased computed tomographic lung density during an asthma exacerbation is at least partially reversible, and changes in mean lung density and the relative lung area with a radiation attenuation of <−950 HU are related to the change in forced expiratory volume in one second and residual volume.
Helium-3 MRI diffusion coefficient: correlation to morphometry in a model of mild emphysema
Authors: Peces-Barba G. , Ruiz-Cabello J. , Cremillieux Y. , Rodríguez I. , Dupuich D. , Callot V. , Ortega M. , Rubio Arbo M.L. , Cortijo M. , Gonzalez-Mangado N.
Published: June 2003

Hyperpolarised gases have been most recently used in magnetic resonance imaging to demonstrate new image-derived pulmonary function parameters. One of these parameters is the apparent diffusion coefficient, which reflects the sizes of the structures that compartmentalise gas within the lung (i.e.alveolar space). In the present study, noninvasive parameters were compared to microscopic measurements (mean linear intercept and mean alveolar internal area).

Nonselective helium‐3 gas density coronalex vivoimages and apparent diffusion maps were acquired in control and elastase-induced panacinar emphysema rats. Total lung capacity was considered the reference for both imaging experiments and lung fixation.

A mild degree of emphysema was found based on mean linear intercept (134±25 µm)versuscontrol (85±14 µm). The apparent diffusion coefficients were significantly different between the two groups (0.18±0.02 and 0.15±0.01 cm2·s−1for elastase and control, respectively).

A significant correlation between the apparent diffusion coefficient and corresponding morphometric parameters in mild emphysema was demonstrated for the first time. This study opens the possibility of estimating absolute airspace size using noninvasive techniques.
Idiopathic chronic eosinophilic pneumonia and asthma: how do they influence each other?
Authors: Marchand E. , Etienne-Mastroianni B. , Chanez P. , Lauque D. , Leclerc P. , Cordier J.F. ,   the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires (GERM“O”P)
Published: June 2003

Since idiopathic chronic eosinophilic pneumonia (ICEP) and asthma are frequently associated, their possible reciprocal influence on clinical presentation and evolution were investigated.

The clinical and follow-up features of 53 cases of ICEP, of which 41 (77%) had asthma, were reviewed retrospectively. Asthma preceded the diagnosis of ICEP in 26 patients, was contemporaneous in eight patients, and developed 17±12 months after ICEP in seven patients.

Presentation of ICEP was similar in asthmatics and nonasthmatics with the exception of a higher level of total immunoglobulin E in the former group. Patients with asthma at the time of diagnosis of ICEP were more likely to remain free of relapse of ICEP (56versus23%) and had a lower number of relapses per year of follow-up (median 0versus0.24). Moreover, they were treated more frequently with long-term inhaled corticosteroids (88versus31%) at last follow-up. Asthma got worse after the diagnosis of ICEP and frequently required long-term oral corticosteroids.

To conclude, among patients with idiopathic chronic eosinophilic pneumonia, asthmatics have a lower frequency of relapse than nonasthmatics, possibly because of a higher use of inhaled corticosteroids. The occurrence of idiopathic chronic eosinophilic pneumonia in asthmatics is often associated with the development of severe asthma.
Uncoupling protein‐3 content is decreased in peripheral skeletal muscle of patients with COPD
Authors: Gosker H.R. , Schrauwen P. , Hesselink M.K.C. , Schaart G. , van der Vusse G.J. , Wouters E.F.M. , Schols A.M.W.J.
Published: June 2003

Mechanical efficiency is reduced in patients with chronic obstructive pulmonary disease (COPD). Furthermore, altered fibre-type distribution and metabolic profile has been observed in peripheral skeletal muscle of COPD patients. Since skeletal muscular uncoupling protein‐3 (UCP3) has been implicated in the regulation of energy metabolism, the aim of this study was to assess UCP3 in peripheral skeletal muscle of COPD patients and healthy controls.

A total of 16 COPD patients and 11 healthy age-matched control subjects were studied. Mechanical efficiency was measured by means of cycle ergometry. Biopsies were taken from the vastus lateralis, and UCP3 and cytochromec(as a marker for mitochondrial content) levels were assessed by Western blotting. Muscle fibre types and metabolic profile were examined histochemically. UCP3 levels were markedly decreased in COPD compared to controls. In COPD patients, there was a positive correlation between UCP3 content and the forced expiratory volume in one second. UCP3 content was not related to mechanical efficiency, or other muscular data such as fibre types, markers of oxidative/glycolytic energy metabolism or cytochromec.

The authors of this study conclude that uncoupling protein‐3 content is decreased in peripheral skeletal muscle of patients with chronic obstructive pulmonary disease and is related to disease severity, but not to mechanical efficiency. The low uncoupling protein‐3 content is independent of the loss of oxidative capacity observed in these patients.
Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome
Authors: Meslier N. , Gagnadoux F. , Giraud P. , Person C. , Ouksel H. , Urban T. , Racineux J-L.
Published: June 2003

The aim of this cross-sectional study was to evaluate the frequency of type‐2 diabetes and impaired glucose tolerance (IGT) in a large clinic-based male population presenting various degrees of obstructive sleep apnoea syndrome (OSAS) and to analyse the relationship between OSAS and glucose-insulin metabolism.

Male patients (n=595) with suspected OSAS underwent both nocturnal polysomnography and a 2‐h oral glucose-tolerance test with measurements of fasting and postload blood glucose and plasma insulin. Insulin sensitivity was evaluated by the ratio of fasting glucose to fasting insulin.

OSAS was diagnosed in 494 patients, while 101 patients were nonapnoeic snorers. Type‐2 diabetes was present in 30.1% of OSAS patients and 13.9% of nonapnoeic snorers. IGT was diagnosed in 20.0% of OSAS patients and 13.9% of nonapnoeic snorers. Fasting and postload blood glucose increased with severity of sleep apnoea. Insulin sensitivity decreased with increasing severity of sleep apnoea. In addition to body mass index and age, the apnoea/hypopnoea index independently influenced postload blood glucose and insulin sensitivity.

The authors conclude that in a clinic-based sample of patients, obstructive sleep apnoea syndrome is associated with a high frequency of type‐2 diabetes and impaired glucose tolerance. The relationship between sleep-disordered breathing and impaired glucose-insulin metabolism is independent of obesity and age.
Airway response to deep inspiration: role of nitric oxide
Authors: Brown R.H. , Mitzner W.
Published: June 2003

Deep inspirations (DI) have been shown to have both bronchoprotective and bronchodilator effects in healthy subjects. The bronchodilator effects of a DI appear to be impaired in asthmatics compared with healthy subjects. This study investigated the role of nitric oxide (NO) in the bronchodilator role of a DI.

In five anaesthetised and ventilated dogs, high-resolution computed tomography was used to measure the changes in airway size after a small (25 cmH2O) and large (45 cmH2O) DI before and after administeringNG-nitro‐l‐arginine methyl ester to block NO synthesis.

The depth of the inspiratory manoeuvre during a deep inspiration determined the subsequent qualitative behaviour of the airway response. Inflation to relatively high pressure resulted in airway dilation, whereas one to lower pressure leads to airway constriction. WhenNG-nitro‐L‐arginine methyl ester was administered, both a large and a small deep inspiration resulted in subsequent airway constriction. These results support the idea that nitric oxide may be a potential bronchoprotective agent in the airways.
Airway epithelial inflammatory responses and clinical parameters in COPD
Authors: Patel I.S. , Roberts N.J. , Lloyd-Owen S.J. , Sapsford R.J. , Wedzicha J.A.
Published: June 2003

This study examined inflammatory responses from primary cultured human bronchial epithelial cells in chronic obstructive pulmonary disease (COPD) and the clinical factors modulating them.

Epithelial cells from bronchoscopic biopsies from 14 patients with COPD ((mean±sd) age 74.6±5.7 yrs, forced expiratory volume in one second (FEV1) 1.21±0.36 L, FEV1% predicted 51.1±15.8%, 51.5±24.0 pack-yrs of smoking, inhaled steroid dosage 1237.5±671.0 µg·day−1, Medical Research Council (MRC) dyspnoea score 3.18±1.33) and eight current/exsmokers with normal pulmonary function (age 60.4±13.5 yrs, FEV12.66±1.27 L, FEV1% pred 89.6±17.7%, 49±44 pack-yrs of smoking, MRC dyspnoea score 1±0) were grown in primary culture and exposed to 50 ng·mL−1tumour necrosis factor‐α.

Stimulated COPD cells produced significantly more interleukin (IL)‐6 at 24 and 48 h, and IL‐8 at 6 and 24 h than unstimulated COPD cells. This response was not seen in cells from current/exsmokers. IL‐6 and IL‐8 production was lower in COPD patients taking inhaled steroids.

Following an inflammatory stimulus, bronchial epithelial cells in chronic obstructive pulmonary disease show a significant cytokine response not seen in smokers with normal pulmonary function and this may be modified by inhaled steroid therapy.
A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels
Authors: Wright J.L. , Farmer S.G. , Churg A.
Published: June 2003

Cigarette smoking produces pulmonary hypertension (PHT) through unknown mechanisms. In animal models acute smoke exposure induces cell proliferation in the small arteries adjacent to the alveolar ducts, and chronic exposure results in muscularisation of these vessels, with changes related to the development of PHT. Studies indicate that serine-elastase inhibitors can prevent experimental monocrotaline-induced PHT. This study examined whether they could also prevent cigarette smoke-induced pulmonary vascular disease.

Guinea-pigs were exposed to cigarette smoke or air for 6 months. Some animals also received ZD0892, an orally active, synthetic, selective, serine-elastase inhibitor. The percentage of muscularised, small, pulmonary arteries was determined by morphometric analysis of histological sections and vascular cell proliferation by proliferating cell nuclear antigen staining.

Vascular cell proliferation was markedly increased in the smoke-exposed animals and the percentage of completely muscularised small vessels was increased four-fold. Cell proliferation indices correlated with muscularisation indices. In the animals treated with ZD0892, the number of completely muscularised vessels was reduced by 50% and cell proliferation was reduced by 61%.

These data suggest that smoke-induced cell proliferation leads to pulmonary arterial muscularisation. Serine-elastase inhibitors appear to be able to reduce cell proliferation and vascular remodelling.
Development of the Satisfaction with Inhaled Asthma Treatment Questionnaire
Authors: Campbell J.L. , Kiebert G.M. , Partridge M.R.
Published: June 2003

For the management of a condition such as asthma, patients should feel confident with their medication, feel that the treatment is adequate in controlling symptoms and that side-effects of the treatment are minimal.

As no comprehensive instrument to measure patient satisfaction with inhaled asthma medication existed, the Satisfaction with Asthma Treatment Questionnaire was developed. The procedures that were used are described, and the initial validation and reliability tests are reported. The study involved focus group meetings, development, testing and modification of a preliminary instrument, and testing of the revised instrument using different samples of patients with asthma.

Factor analysis of the 26‐item questionnaire identified four domains reflecting four aspects of satisfaction: effectiveness of treatment, ease of use, medication burden, and side-effects and worries. Cronbach's alpha showed evidence of internal consistency reliability. Test/retest reliability ranged from 0.66–0.74. Interscale correlations were moderate-to-high. Significant correlations were found between domain and overall scale scores and patients' overall level of satisfaction.

The Satisfaction with Asthma Treatment Questionnaire is potentially a useful instrument for gaining insight into patient satisfaction with inhaled treatment for asthma.
Acute lung injury as a possible adverse drug reaction related to gefitinib
Authors: Ieki R. , Saitoh E. , Shibuya M.
Published: June 2003

Gefitinib is a potent drug used in the treatment of nonsmall-cell lung cancer (NSCLC).

Gefitinib acts by inhibition of the epidermal growth factor receptor tyrosine kinase. Clinical trials have confirmed the efficacy of gefitinib for NSCLC. Adverse drug reactions, although frequent, are mild, and include acne-like skin rash and diarrhoea.

The present study describes the case of a 56-yr-old male with NSCLC who, 4 weeks after treatment with gefitinib, suffered from a severe alveolar haemorrhage diagnosed by bronchoalveolar lavage.

This is the first case report of an acute life-threatening lung injury in a patient with nonsmall-cell lung cancer who had been given gefitinib.
Low lung volume alters contractile properties of airway smooth muscle in sheep
Authors: McClean M.A. , Matheson M.J. , McKay K. , Johnson P.R.A. , Rynell A-C. , Ammit A.J. , Black J.L. , Berend N.
Published: June 2003

Breathing at volumes lower than functional residual capacity (FRC) can induce changes in nonasthmatic airways consistent with the behaviour of asthmatic airways. This study investigated the chronic effect of breathing at volumes lower than FRC on the contractility of airway smooth muscle and myosin light chain kinase (MLCK) content and activity.

Sheep of three age groups (neonate, adolescent and adult) had their FRC reduced by ∼25% for 4 weeks using a leather corset. Contractile responses to carbachol were then recorded in isolated tracheal strips and bronchial rings. MLCK content and activity were assessed by immunoblotting.

The rate of stress generation increased in the bronchial smooth muscle of both adult and adolescent but not neonatal corseted sheep: adolescent corsetedversuscontrol, 65.0±4.1versus103.4±7.0 s (to reach 50% maximum stress), respectively; and adult corsetedversuscontrol, 57.0±6.4versus93.4±8.2 s, respectively. This was not due to increases in either bronchial or tracheal smooth muscle amount or MLCK content and activity.

The present results indicate that chronic breathing at low lung volumes increases the rate of stress generation in airway smooth muscle.
Pet- and pollen-induced upper airway symptoms in farmers and in nonfarmers
Authors: Koskela H.O. , Iivanainen K.K. , Remes S.T. , Pekkanen J.
Published: June 2003

The effect of farming on the risk of upper airway symptoms is not clear. In this cross-sectional, population-based study, 198 female farmers, 50 nonfarmers living on a farm, and 218 nonfarmers not living on a farm, filled in a symptom questionnaire and underwent skin-prick testing with common and agricultural allergens. In the logistic regression analysis, the latter group served as a control. Several adjustments were made, including childhood farming environment.

Current farming was found to decrease the risks of pet- and pollen-induced upper airway symptoms, dose-dependently with the intensity and duration of animal husbandry. Including skin-test positivity to pets in the regression models did not affect the negative association between farming and pet-induced symptoms. In contrast, animal husbandry increased the risk of farm work-induced upper airway symptoms.

Animal husbandry often induces work-related upper airway symptoms. However, the present study among female adults suggests that it may also decrease the risk of pet- and pollen-induced upper airway symptoms.
Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury
Authors: Rocco P.R.M. , Momesso D.P. , Figueira R.C. , Ferreira H.C. , Cadete R.A. , Légora-Machado A. , Koatz V.L.G. , Lima L.M. , Barreiro E.J. , Zin W.A.
Published: June 2003

The effects of LASSBio596, a phosphodiesterase type‐4 and ‐5 inhibitor, were tested inEscherichia colilipopolysaccharide (LPS)-induced acute lung injury.

Twenty-four BALB/c mice were randomly divided into four groups. In the control group, saline (0.05 mL) was injected intratracheally (i.t.). The LPS group received LPS (10 µgi.t., 0.05 mL). In the LASSBio596 groups, LASSBio596 (10 mg·kg−1, 0.2 mL) was injected intraperitoneally 1 h before or 6 h after LPS administration. After 24 h,in vivo(lung resistive and viscoelastic pressures, and static and dynamic elastances) andin vitro(tissue resistance, elastance and hysteresivity) pulmonary mechanics, lung morphometry and collagenous fibre content were computed. Neutrophils and tumour necrosis factor (TNF)‐α levels were evaluated in the bronchoalveolar lavage fluid.

LASSBio596 prevented the changes in lung mechanics, and inhibited neutrophilic recruitment, TNF‐α release, bronchoconstriction, alveolar collapse and the increment of collagen fibre content induced by LPS, independently of the moment of injection.

In conclusion, LASSBio596 modulated the lung inflammatory process and had the potential to block fibroproliferation. Thus, agents that inhibit phosphodiesterase 4 and 5 simultaneously may be a useful adjunct therapy for acute lung injury.
Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players
Authors: Lumme A. , Haahtela T. , Öunap J. , Rytilä P. , Obase Y. , Helenius M. , Remes V. , Helenius I.
Published: June 2003

There is little information of lower respiratory symptoms, bronchial hyperresponsiveness and airway inflammation in elite ice hockey players.

A total of 88 highly trained ice hockey players and 47 control subjects were studied. All the subjects were subjected to skin-prick tests, resting spirometry examinations and histamine-challenge tests. Adequate induced sputum samples were obtained from 68 of the ice hockey players and from 18 symptom-free control subjects on a separate day.

Bronchial hyperresponsiveness in a histamine-challenge test was found in 21 (24%) of the athletes and in five (11%) of the controls. Current asthma (current asthmatic symptoms and increased bronchial responsiveness) was observed in 13 (15%) of the athletes and in one (2%) of the control subjects. Total asthma (current asthma or previously physician-diagnosed asthma) occurred in 19 (22%) of the athletes and in two (4%) of the controls. Atopy, according to skin-prick tests, was observed in 51 (58%) of the athletes and 17 (36%) of the control subjects. The differential cell counts of eosinophils (2.6versus0.2%) and neutrophils (80.9versus29.9%) in the sputum samples of the ice hockey players were significantly higher than in those of the control subjects.

Asthma is common in elite ice hockey players and they show signs of a mixed type of neutrophilic and eosinophilic airway inflammation. Inhalation of cold air associated with exposure to indoor pollutants during intensive training is a possible causative factor.
Mortality during hospitalisation for pneumonia in Alberta, Canada, is associated with physician volume
Authors: Marrie T.J. , Carriere K.C. , Jin Y. , Johnson D.H.
Published: June 2003

The association of mortality with patient factors (severity of illness, comorbidity), physician factors (specialty training, prehospitalisation visit, in-hospital consultation, volume of patients seen per physician) and healthcare organisation factors (patient-travel distances, regional beds per capita, admitting hospital-bed occupancy, admitting hospital-bed turnover, hospital location, volume of pneumonia cases per hospital) after hospital admission with community-acquired pneumonia was investigated using administrative data from Alberta, Canada from April 1, 1994–March 31, 1999.

During the 5‐yr study period there were 43,642 pneumonia hospitalisations, with an 11% in-hospital and 26% 1‐yr mortality. Patient severity of illness and comorbidity were the strongest predictors of increased mortality. Physicians with the highest in-hospital pneumonia patient volume (>27 patients·yr−1) cared for patients with greater severity/comorbidity, but with decreased odds of in-hospital mortality, compared with the lowest volume physicians (less than seven patients per year).

The effects of internal medicine specialist or subspecialist care were mixed, with a reduction in deaths for the first 72 h and an increase in in-hospital deaths. Pre-hospitalisation visit by a physician was associated with decreased mortality. Healthcare organisation factors were the least strong predictor of mortality, demonstrating an effect only for 1‐yr mortality in those discharged alive from hospital. Admissions to larger volume or metropolitan hospitals were associated with a decrease in mortality.

Severity of illness and comorbidity had the strongest association with mortality. The first association of high-volume physician and pre-hospital care with decreased in-hospital mortality for community-acquired pneumonia is reported.
Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects
Authors: Salome C.M. , Thorpe C.W. , Diba C. , Brown N.J. , Berend N. , King G.G.
Published: June 2003

After bronchoconstriction, deep inspiration (DI) causes dilatation followed by airway re-narrowing. Re-narrowing may be faster in asthmatic than nonasthmatic subjects. This study investigated the relationship between re-narrowing and the magnitude of both DI-induced dilatation and the volume-dependence of respiratory system resistance (Rrs) during tidal breathing.

In 25 asthmatic and 18 nonasthmatic subjects the forced oscillation technique was used to measureRrsat baseline and after methacholine challenge, during 1 min of tidal breathing, followed by DI to total lung capacity (TLC) and passive return to functional residual capacity (FRC). Dilatation was measured as the decrease inRrsbetween end tidal inspiration and TLC, re-narrowing asRrsat FRC immediately after DI, as per centRrsat end-tidal expiration, and volume dependent tidal fluctuation as the difference between meanRrsat end-expiration and end-inspiration.

Asthmatic subjects had greater re-narrowing, less dilatation, and greater tidal fluctuations both at baseline and after challenge. Re-narrowing correlated with baseline tidal fluctuation and inversely with dilatation. Both baseline tidal fluctuation and dilatation were significant independent predictors of re-narrowing.

Following deep inspiration-induced dilatation, faster airway re-narrowing in asthmatic than nonasthmatic subjects is associated not only with reduced deep inspiration-induced dilatation but also with some property of the airways that is detectable prior to challenge as an increased volume dependence of resistance.
Increased ventilation with NiIPPV does not necessarily improve exercise capacity in COPD
Authors: Highcock M.P. , Shneerson J.M. , Smith I.E.
Published: June 2003

Evidence that noninvasive intermittent positive-pressure ventilation (NiIPPV) improves exercise capacity in chronic obstructive pulmonary disease (COPD) is limited. The effectiveness of different ventilators in this setting has not been studied.

Three bilevel pressure support ventilators (Bipap S/T 30, Nippy2 and Vpap II ST), appliedviaa mouthpiece, were compared during submaximal treadmill exercise in eight subjects with COPD. Subjects walked to exhaustion with each of the ventilators and while breathing through the mouthpiece alone, in random order. In addition, four unencumbered walks were performed.

The unencumbered distance (mean±sd) walked was 259±123 m. With the mouthpiece alone this decreased to 211±96 m and fell further to 145±76 m with NiIPPV. There was no difference between the brands of ventilator. At the break-point of exercise, significant increases were seen in tidal volume and minute ventilation in the ventilator walks compared with the mouthpiece alone.

Noninvasive intermittent positive-pressure ventilation increased ventilation but did not improve exercise capacity in the subjects in this study. No significant differences were seen between the ventilators. The effectiveness of this technique and the optimal method of assistance require further clarification.
RNA analysis of B cell lines arrested at defined stages of differentiation allows for an approximation of gene expression patterns during B cell development
Authors: Tsapogas Panagiotis , Breslin Thomas , Bilke Sven , Lagergren Anna , Månsson Robert , Liberg David , Peterson Carsten , Sigvardsson Mikael
Published: June 2003

The development of a mature B lymphocyte from a bone marrow stem cell is a highly ordered process involving stages with defined features and gene expression patterns. To obtain a deeper understanding of the molecular genetics of this process, we have performed RNA expression analysis of a set of mouse B lineage cell lines representing defined stages of B cell development using Affymetrix™ microarrays. The cells were grouped based on their previously defined phenotypic features, and a gene expression pattern for each group of cell lines was established. The data indicated that the cell lines representing a defined stage generally presented a high similarity in overall expression profiles. Numerous genes could be identified as expressed with a restricted pattern using dCHIP-based, quantitative comparisons or presence/absence-based, probabilistic state analysis. These experiments provide a model for gene expression during B cell development, and the correctly identified expression patterns of a number of control genes suggest that a series of cell lines can be useful tools in the elucidation of the molecular genetics of a complex differentiation process.
G protein-coupled receptors in natural killer cells
Authors: Maghazachi Azzam A
Published: June 2003

Natural killer (NK) cells are capable of killing tumor as well as virally infected cells. How these cells migrate toward the infected sites in the body is not completely understood. Chemokine receptors that belong to the heptahelical family of receptors and characteristically bind heterotrimeric G proteins are present in most NK cells. Recent results showed that resting NK cells highly express constitutive chemokine receptors (CCR4, CCR7, CXCR4, and CX3CR1) with low expression of a limited repertoire of inflammatory chemokine receptors (CCR1 and CXCR3). However, only a subset of these cells expressing the CD56dim and adhesion moleculehigh phenotype is capable of in vivo binding to vascular endothelium. Under pathological conditions where inflammatory cytokines are present, these cells are induced to express inflammatory chemokine receptors. Resting as well as activated NK cells also express receptors for another member of the heptahelical family of receptors that bind phosphorylated or glycosylated lysolipids. These include sphingosine 1-phosphate (S1P)1, S1P4, and S1P5, the receptors for S1P; lysophosphatidic acid (LPA)1, LPA2, and LPA3, the receptors for LPA; and T cell death-associated gene 8, the receptor for psychosine. Similar to chemokines, S1P, LPA, and psychosine induce the chemotaxis of NK cells through heterotrimeric G proteins. However, in contrast to chemokines, which enhance the cytotoxicity of NK cells, lysolipids inhibit this function. We hope that gaining knowledge regarding the distribution of activated NK cells toward the sites of tumor growth or virally infected sites will give an advantage in designing strategies using these cells as tools for the prevention and treatment of immunodeficiencies.
Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas
Authors: Phillips Teresa A , Ni Jian , Hunt Joan S
Published: June 2003

Apoptosis-inducing tumor necrosis factor (TNF) ligands and receptors have been reported in human placentas, but the expression patterns of family members lacking this function [a proliferation-inducing ligand (APRIL), B lymphocyte stimulator (BLyS), CD30L/CD153, CD40L/CD154, TNF-related activation-induced cytokine, CD27L/CD70, OX40L, activation-inducible TNF receptor ligand (AITRL)] are incompletely documented or unknown. We therefore investigated expression of these eight ligands and nine of their receptors (B cell maturation antigen, transmembrane activator and calcium-modulator and cyclophilin ligand-interactor, CD30, CD40, receptor activator of nuclear factor-κB, osteoprotegerin, CD27, OX40/CD134, AITR). Analysis by reverse transcriptase-polymerase chain reaction revealed mRNAs encoding only three of the ligands (APRIL, BLyS, CD30L/CD153). Immunoblots demonstrated all three proteins in first-trimester and term placentas, and immunohistochemical experiments showed that expression was cell-specific and gestation-related. Although mRNAs encoding receptors for the three expressed ligands were absent, those encoding receptors for all of the unexpressed ligands were detectable. Collectively, the results are consistent with the postulate that nonapoptosis-inducing, placenta-derived TNF superfamily cytokines contribute to the T helper cell type 2 bias required for successful pregnancy. Patterns of placental expression of receptors suggest bidirectional maternal–fetal cytokine communication.
Composition of MHC class II-enriched lipid microdomains is modified during maturation of primary dendritic cells
Authors: Setterblad Niclas , Roucard Corinne , Bocaccio Claire , Abastado Jean-Pierre , Charron Dominique , Mooney Nuala
Published: June 2003

Dendritic cells (DCs) are the most potent antigen presenting cells. Major histocompatibility complex (MHC) class II molecule expression changes with maturation; immature DCs concentrate MHC class II molecules intracellularly, whereas maturation increases surface expression of MHC class II and costimulatory molecules to optimize antigen presentation. Signal transduction via MHC class II molecules localized in lipid microdomains has been described in B lymphocytes and in the THP-1 monocyte cell line. We have characterized MHC class II molecules throughout human DC maturation with particular attention to their localization in lipid-rich microdomains. Only immature DCs expressed empty MHC class II molecules, and maturation increased the level of peptide-bound heterodimers. Ligand binding to surface human leukocyte antigen (HLA)-DR induced rapid internalization in immature DCs. The proportion of cell-surface detergent-insoluble glycosphingolipid-enriched microdomain-clustered HLA-DR was higher in immature DCs despite the higher surface expression of HLA-DR in mature DCs. Constituents of HLA-DR containing microdomains included the src kinase Lyn and the cytoskeletal protein tubulin in immature DCs. Maturation modified the composition of the HLA-DR-containing microdomains to include protein kinase C (PKC)-δ, Lyn, and the cytoskeletal protein actin, accompanied by the loss of tubulin. Signaling via HLA-DR redistributed HLA-DR and -DM and PKC-δ as well as enriching the actin content of mature DC microdomains. The increased expression of HLA-DR as a result of DC maturation was therefore accompanied by modification of the spatial organization of HLA-DR. Such regulation could contribute to the distinct responses induced by ligand binding to MHC class II molecules in immature versus mature DCs.
PU.1 regulates glutathione peroxidase expression in neutrophils
Authors: Throm Stacy L , Klemsz Michael J
Published: June 2003

Based on knockout models, the transcription factor PU.1 has been shown to be important for the maturation of neutrophils. As the list of genes PU.1 directly regulates in neutrophils is still quite limited, defining PU.1 target genes for this lineage will provide valuable insight into how this factor regulates neutrophil development and terminal function. Using the combined techniques of representational difference analysis and a cDNA library screen, we identified four genes that were differentially expressed in the PU.1-expressing 503PU myeloid cell line but not the PU.1 null parent cell line 503. Two of these genes, glutathione peroxidase (GPx) and serine leukoprotease inhibitor, are involved in protecting neutrophils from the products they make to destroy pathogens and were analyzed further to determine if PU.1 directly regulates their expression. These studies showed that PU.1 directly regulated the expression of only the GPx gene through binding sites in the promoter and a 3′ regulatory region. Thus, PU.1 not only regulates the expression of molecules involved in the production of reactive oxygen species but also a gene that protects the neutrophils from these same destructive enzymes.
Proteinase-3 directly activates MMP-2 and degrades gelatin and Matrigel; differential inhibition by (−)epigallocatechin-3-gallate
Authors: Pezzato Elga , Donà Massimo , Sartor Luigi , Dell’Aica Isabella , Benelli Roberto , Albini Adriana , Garbisa Spiridione
Published: June 2003

Proteinase-3 (PR-3), a serine-proteinase mainly expressed by polymorphonuclear leukocytes (PMNs), can degrade a variety of extracellular matrix proteins and may contribute to a number of inflammation-triggered diseases. Here, we show that in addition to Matrigel™ components, PR-3 is also able to degrade denatured collagen and directly activate secreted but not membrane-bound pro-MMP-2, a matrix metallo-proteinase instrumental to cellular invasion. In contrast, following addition of purified PR-3 or PMNs to HT1080 tumor cells, dose-dependent inhibition of in vitro Matrigel™ invasion is registered. (−)Epigallocatechin-3-gallate (EGCG), the main flavanol in green tea and known to inhibit inflammation and tumor invasion, exerts dose-dependent inhibition of degradation of gelatin (IC50<20 μM) and casein, which is directly triggered by PR-3. The presence of EGCG does not modify the colocalization of MMP-2 and exogenous PR-3 at the cell surface and does not restrain secreted pro-MMP-2 and pro-MMP-9 activation or degradation of a specific, synthetic peptide by PR-3. These results add new activities to the list of those exerted by PR-3 and indicate a differential inhibition as a result of EGCG.
Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2K
b –tsA58 mice
Authors: Dory Daniel , Echchannaoui Hakim , Letiembre Maryse , Ferracin Fabrizia , Pieters Jean , Adachi Yoshiyuki , Akashi Sachiko , Zimmerli Werner , Landmann Regine
Published: June 2003

Murine Kupffer cells (KCs) are heterogeneous and survive only for a short time in vitro. Here, a clonal, murine KC line was generated from transgenic mice, expressing the thermolabile mutant tsA58 of the Simian virus 40 large T antigen under the control of the H-2Kb promoter. Thirty-three degrees Celsius and 37°C but not 39°C have been permissive for growth of the clone; it required conditioned media from hepatocytes and endothelial cells for proliferation. In contrast to primary cells, the cells of the clone were uniform, survived detachment, and could therefore be analyzed by cytofluorimetry. The clone, as primary KCs, constitutively expressed nonspecific esterase, peroxidase, MOMA-2, BM8, scavenger receptor A, CD14, and Toll-like receptor 4 (TLR4); the antigen-presenting molecules CD40, CD80, and CD1d; and endocytosed dextran–fluorescein isothiocyanate. It lacked complement, Fc receptors, F4/80 marker, and the phagosomal coat protein tryptophan aspartate-containing coat protein (TACO). The clone exhibited CD14- and TLR4/MD2-independent, plasma-dependent lipopolysaccharide (LPS) binding, Escherichia coli and Streptococcus pneumoniae phagocytosis, and LPS- and interferon-γ-induced NO production but no tumor necrosis factor α, interleukin (IL)-6, or IL-10 release. The large size, surface-marker expression, and capacity to clear gram-negative and -positive bacteria indicate that the clone was derived from the periportal, large KC subpopulation. The clone allows molecular studies of anti-infective and immune functions of KCs.
Expression of and functional responses to protease-activated receptors on human eosinophils
Authors: Bolton Sarah J , McNulty Clare A , Thomas Rebecca J , Hewitt Colin R A , Wardlaw Andrew J
Published: June 2003

Eosinophil recruitment to airway tissue is a key feature of asthma, and release of a wide variety of toxic mediators from eosinophils leads to the tissue damage that is a hallmark of asthma pathology. Factors that control the release of these toxic mediators are targets for potential therapeutic intervention. Protease-activated receptors (PARs) are a novel class of receptors that are activated by cleavage of the N terminus of the receptor by proteases such as thrombin or trypsin-like enzymes. To date, PAR1–4 have been identified, and there are several studies that have demonstrated the expression of PARs in airway tissue, particularly the respiratory epithelium. We have investigated whether eosinophils express PARs and if activation of these receptors will then trigger a functional response. Using a combination of reverse transcriptase-polymerase chain reaction, Western blotting, and flow cytometry analysis, we have demonstrated that eosinophils express PAR1 and PAR2. FACS analysis showed that PAR1 could be clearly detected on the surface of the cells, whereas PAR2 appeared to be primarily intracellular. Trypsin and the PAR2 agonist peptide were seen in trigger shape change, release of cysteinyl leukotrienes, and most obviously, generation of reactive oxygen species. In contrast, thrombin had no effect on eosinophil function. The PAR1 agonist peptide did have a minor effect on eosinophil function, but this was most likely down to its ability to activate PAR1 and PAR2. These results demonstrate that PAR2 is the major PAR receptor that is capable of modulating eosinophil function.
Disparate functions of immature and mature human myeloid dendritic cells: implications for dendritic cell-based vaccines
Authors: Tschoep Katharina , Manning Thomas C , Harlin Helena , George Christopher , Johnson Melissa , Gajewski Thomas F
Published: June 2003

Although antigen-loaded dendritic cells (DC) are being investigated as antitumor vaccines, which DC differentiation state is most effective is not clear. Three DC functions that may be critical for immunization potential are expression of CD80/86, cytokine production following CD40 engagement, and migration to chemokine receptor 7-binding chemokines. We therefore examined highly purified human monocyte-derived immature and mature DC for these properties from normal donors and cancer patients. Although high expression of CD80/86 and migration to 6Ckine + macrophage-inflammatory protein-3β were properties of mature DC, cytokine production following CD40 ligation was superior by immature DC. Loss of cytokine secretion occurred with multiple maturation conditions, was not apparently reversible, and was also seen with lipopolysaccharide stimulation in correlation with down-regulated Toll-like receptor expression. Our results suggest that the functions thought to contribute to optimal T cell priming are not coexpressed by the same DC population and that immature and mature DC likely possess distinct CD40-mediated signaling events.
The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization
Authors: Tsutsumi Chikako , Sonoda Koh-Hei , Egashira Kensuke , Qiao Hong , Hisatomi Toshio , Nakao Shintaro , Ishibashi Minako , Charo Israel F , Sakamoto Taiji , Murata Toshinori , Ishibashi Tatsuro
Published: June 2003

Choroidal neovascularization (CNV) is directly related to visual loss in some eye diseases, such as age-related macular degeneration. Although several human histological studies have suggested the participation of macrophages in CNV formation, the precise mechanisms are still not fully understood. In this study, we elucidated the role of ocular-infiltrating macrophages in experimental CNV using CCR2 knockout (KO) mice, wild-type mice, and C57BL/6 (B6) mice. CCR2 is the receptor of monocyte chemoattractant protein-1, and the number of infiltrating macrophage and the area of CNV were significantly reduced in CCR2 KO mice. Enriched ocular-infiltrating macrophages from B6 mice actually showed angiogenic ability in a dorsal air sac assay. Moreover, their expression of class II, CD40, B7-1 and B7-2 molecules, and the mRNA for potential angiogenic factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and tumor necrosis factor α, was also observed. Collectively, we conclude that ocular-infiltrating macrophages play an important role in CNV generation.
Activation by prion peptide PrP106–126 induces a NF-κB-driven proinflammatory response in human monocyte-derived dendritic cells
Authors: Bacot Silvia M , Lenz Petra , Frazier-Jessen Michelle R , Feldman Gerald M
Published: June 2003

Specific prion peptides have been shown to mimic the pathologic isoform of the prion protein (PrP) and to induce a neurotoxic effect in vitro and in vivo. As monocytic cells are thought to play a role in the transmission and pathogenesis of prion disease, the use of these peptides in regulating monocytic cell function is under intense investigation. In the current study, we characterize the ability of prion peptide PrP106–126 to activate specific signaling pathways in human monocyte-derived dendritic cells (DCs). Electrophoretic mobility shift assays establish the activation of transcription factor nuclear factor-κB within 15 min of exposure, with as little as 25 μM peptide. This signaling cascade results in the up-regulation of inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α) at the mRNA and protein levels. Phenotypic activation of DCs exposed to PrP106–126 is partly a result of an autocrine TNF-α response and results in an increased ability of these cells to induce lymphocyte proliferation. The effects of PrP106–126 on DCs were elicited through a receptor complex distinct from that used by human monocytes, demonstrating the ability of this peptide to interact with a multiplicity of receptors on various cell types. Together, these data suggest an involvement of DCs in prion disease pathogenesis.