bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-γ: a molecular basis for priming and synergism with bacterial lipopolysaccharide
Authors: Bosisio Daniela , Polentarutti Nadia , Sironi Marina , Bernasconi Sergio , Miyake Kensuke , Webb Ginette R. , Martin Michael U. , Mantovani Alberto , Muzio Marta
Published: October 2002

In human monocytes and macrophages, interferon-γ (IFNγ) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNγ counteracted the LPS-induced downregulation of TLR4. IFNγ-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor–associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor α [TNFα] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNγ of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.
Erythrocyte survival is promoted by plasma and suppressed by a Bak-derived BH3 peptide that interacts with membrane-associated Bcl-XL
Authors: Walsh Melanie , Lutz Robert J. , Cotter Thomas G. , O'Connor Rosemary
Published: October 2002

Erythrocytes have a defined lifespan in vivo, and the signals that maintain their survival in circulation or trigger their death are unknown. Here, we investigated the control of erythrocyte survival and death in an in vitro culture system where erythrocytes survived for 10 days in serum-free medium in the presence or absence of bovine serum. Death of the cells in culture was correlated with increased exposure of phosphatidylserine and increased levels of intracellular calcium. Cell death could be suppressed by supplementing the medium with human plasma or serum, resulting in a doubling of the lifespan to 20 days. Freshly isolated erythrocytes and cultured erythrocytes were both found to express Bcl-XL and, to a lesser extent, Bak in membrane protein extracts. Treatment of the cells with a Bak-derived BH3 peptide fused to the internalization sequence of the antennapedia protein, which has previously been shown to enter cells by diffusion and antagonize Bcl-XL, resulted in substantial cell death in erythrocyte cultures. BH3-induced death was accompanied by an immediate increase in accumulation of intracellular calcium and could be suppressed by plasma, but not by the caspase inhibitor zVAD. A BH3 peptide mutated at amino acid 78 of full-length Bak required for heterodimerization with Bcl-XL had no effect on cell viability or calcium levels. We conclude that the BH3 peptide accelerates erythrocyte death through antagonization of Bcl-XL. The data suggest that erythrocyte survival is promoted by survival factors in plasma and by membrane-associated Bcl-XL.
The voluntary drive to breathe is not decreased in hypercapnic patients with severe COPD
Authors: Topeli A. , Laghi F. , Tobin M.J.
Published: October 2002

How do the respiratory centres of patients with chronic obstructive pulmonary disease (COPD) and hypercapnia respond to acute increases in inspiratory load? A depressed respiratory motor output has long been postulated, but studies on this issue have yielded inconsistent results, partly due to limitations of investigative techniques. Many of these limitations can be overcome by the twitch interpolation technique, which is capable of accurately quantifying the degree of diaphragmatic activation, termed the voluntary drive to breathe. The hypothesis that patients with COPD and hypercapnia compensate for an acute increase in mechanical load on the inspiratory muscles with a lower voluntary drive to breathe than is the case with normocapnic patients was tested.

Measurements were obtained in 15 patients with COPD, six of whom displayed hypercapnia and nine normocapnia. The maximum degree of diaphragmatic activation, expressed as a voluntary activation index (mean±sem), was higher in hypercapnic than in normocapnic patients (98.7±0.7versus94.5±0.9% (p=0.006)), as was the mean value (94.5±0.7versus88.5±1.9% (p=0.01)). Within-patient values of the index were also less variable in the hypercapnic patients (coefficients of variation, 3.4±0.3versus6.1±0.9%, p=0.01). Multiple regression analysis revealed the ratio of dynamic elastance to maximum transdiaphragmatic pressure, an index of inspiratory muscle loading, and pH as the only variables that correlated with maximum voluntary activation index (r2=0.69, p=0.02 for each variable).

Contrary to the hypothesis, it was concluded that voluntary activation of the diaphragm was greater and less variable in hypercapnic patients than normocapnic patients with severe chronic obstructive pulmonary disease during an acute increase in inspiratory mechanical load. Whether greater diaphragmatic recruitment during episodes of a severe exacerbation of chronic obstructive pulmonary disease provides a survival advantage for hypercapnic patients with chronic obstructive pulmonary disease remains to be determined.
Partial liquid ventilation improves lung function in ventilation-induced lung injury
Authors: Vazquez de Anda G.F. , Lachmann R.A. , Verbrugge S.J.C. , Gommers D. , Haitsma J.J. , Lachmann B.
Published: October 2002

Disturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish lung function after ventilation-induced lung injury.

Adult rats were exposed to high PIP without PEEP for 20 min. Thereafter, the animals were randomly divided into five groups. The first group was killed immediately after randomization and used as an untreated control. The second group received only sham treatment and ventilation, and three groups received treatment with perfluorocarbon (10 mL·kg−1, 20 mL·kg−1, and 20 ml·kg−1plus an additional 5 mL·kg−1after 1 h). The four groups were maintained on mechanical ventilation for a further 2-h observation period. Blood gases, lung mechanics, total protein concentration, minimal surface tension, and small/large surfactant aggregates ratio were determined.

The results show that in ventilation-induced lung injury, partial liquid ventilation with different amounts of perflubron improves gas exchange and pulmonary function, when compared to a group of animals treated with standard respiratory care. These effects have been observed despite the presence of a high intra-alveolar protein concentration, especially in those groups treated with 10 and 20 mL of perflubron.

The data suggest that replacement of perfluorocarbon, lost over time, is crucial to maintain the constant effects of partial liquid ventilation.
Noninvasive measurement of mean alveolar carbon dioxide tension and Bohr's dead space during tidal breathing
Authors: Koulouris N.G. , Latsi P. , Dimitroulis J. , Jordanoglou B. , Gaga M. , Jordanoglou J.
Published: October 2002

The lack of methodology for measuring the alveolar carbon dioxide tension (PA,CO2) has forced investigators to make several assumptions, such as thatPA,CO2is equal to end-tidal (PET,CO2) and arterial CO2tension (Pa,CO2).

The present study measured the meanPA,CO2and Bohr's dead space ratio (Bohr's dead space/tidal volume (VD,Bohr/VT)) during tidal breathing. The method used is a new, simple and noninvasive technique, based on the analysis of the expired CO2volume per breath (VCO2)versusthe exhaledVT. This curve was analysed in 21 normal, healthy subjects and 35 chronic obstructive pulmonary disease (COPD) patients breathing tidally through a mouthpiece apparatus in the sitting position.

It is shown that: 1)PA,CO2is similar toPa,CO2in normal subjects, whilst it is significantly lower thanPa,CO2in COPD patients; 2)PA,CO2is significantly higher thanPET,CO2in all subjects, especially in COPD patients; 3)VD,Bohr/VTis increased in COPD patients as compared to normal subjects; and 4)VD,Bohr/VTis lower than the “physiological” dead space ratio (VD,phys/VT) in COPD patients.

It is concluded that the expired carbon dioxideversustidal volume curve is a useful tool for research and clinical work, because it permits the noninvasive and accurate measurement of Bohr's dead space and mean alveolar carbon dioxide tension accurately during spontaneous breathing.
Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients
Authors: Linnane S.J. , Thin A.G. , Keatings V.M. , Moynihan J.B. , McLoughlin P. , FitzGerald M.X.
Published: October 2002

In cystic fibrosis (CF), low concentrations of exhaled nitric oxide (NO) and reduced expression of inducible nitric oxide synthase (iNOS) in airway epithelium have been reported. However, abundant iNOS expression has been found in the subepithelial tissues and elevated concentrations of NO metabolites in breath condensate and sputum. These conflicting results may be explained by increased scavenging of NO by superoxide radicals, resulting in rapid conversion to peroxynitrite, so that only a small proportion of the NO produced in the lung tissue reaches the airway lumen. If iNOS were active in the CF lung, exhaled NO would be further reduced by glucocorticoid treatment.

CF patients (n=13) were recruited to a double-blind, placebo-controlled study with crossover. Treatment comprised prednisolone or placebo for 5 days with a 9 day washout. After each treatment, exhaled NO was measured, spirometry performed and blood collected for measurement of serum nitrogen dioxide/nitrous oxide (NO2/NO3).

Ten patients (8 male) completed the study. Following prednisolone treatment (mean±sd) exhaled NO concentration (3.1±1.6 parts per billion (ppb)) was significantly reducedversusplacebo treatment (4.9±4.2 ppb; p<0.05, Wilcoxon signed-rank test). Spirometric indices and serum NO2/NO3concentration were unchanged.

These findings support the hypothesis that glucocorticoids suppress nitric oxide production in cystic fibrosis airways by reducing inducible nitric oxide synthase expression or by inhibiting recruitment of neutrophils, cells which express inducible nitric oxide synthase.
Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids
Authors: Olgart C. , Frossard N.
Published: October 2002

Nerve growth factor (NGF) has recently been suggested to contribute to inflammation and bronchial hyperresponsiveness in asthma. However, the cell types capable of NGF production in the human lung and airways, as well as the regulatory role of pro-inflammatory cytokines and of glucocorticoids on NGF secretion in pulmonary cells, have not been described.

Human pulmonary fibroblasts were cultured in the presence or absence of either interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and/or glucocorticoids. NGF secretion was measured by enzyme-linked immunosorbent assay.

The human pulmonary fibroblasts constitutively secreted NGFin vitro. The rate of NGF secretion was shown to be cell density-dependent, since higher NGF secretion was detected in preconfluent cells,i.e.ones with less established cell-to-cell contact (41.0±5.0 pg·10−6cells at 80% confluence), than cells in higher densities (8.2±3.4 pg·10−6cells at 100% confluence). Stimulation with the pro-inflammatory cytokines IL-1β (0.3–30 U·mL−1) or TNF-α (0.1–30 ng·mL−1) dose- and time-dependently (8–72 h) elevated the NGF secretion (effective concentration causing 50% of the maximum response (EC50)=2.9 U·mL−1and 1.0 ng·mL−1, respectively). Treatment with the glucocorticoid budesonide (10−7 M) markedly reduced the constitutive secretion of NGF by 42%, and attenuated the cytokine-stimulated NGF secretion to the same level.

In conclusion, human lung fibroblasts may serve as a source of nerve growth factor in the lung, positively regulated by the asthma-associated and pro-inflammatory cytokines interleukin-1β and tumour necrosis factor-α, and negatively regulated by the anti-inflammatory glucocorticoids.
Aerosolized PGE1, PGI2and nitroprusside protect against vascular leakage in lung ischaemia-reperfusion
Authors: Schütte H. , Löckinger A. , Seeger W. , Grimminger F.
Published: October 2002

High permeability oedema is an important feature in lung injury secondary to ischaemia-reperfusion. This study investigated the influence of aerosolized prostaglandin E1(PGE1), prostaglandin I2(PGI2) and the nitric oxide (NO)-donor, sodium nitroprusside (SNP) on microvascular barrier function in pulmonary ischaemia-reperfusion.

Buffer-perfused rabbit lungs were exposed to 180 or 210 min of warm ischaemia while maintaining anoxic ventilation and a positive intravascular pressure.

Reperfusion provoked a transient, mostly precapillary elevation of vascular resistance, followed by a severe increase of the capillary filtration coefficient (Kfc)versusnonischaemic controls (3.17±0.34versus0.85±0.05 cm3 s−1·cmH2O−1·g−1·10−4after 30 min of reperfusion), and progressive oedema formation. Short-term aerosolization of SNP, PGE1or PGI2at the beginning of ischaemia largely suppressed the Kfc increase (1.36±0.22, 1.32±0.23 and 1.32±0.22 cm3·s−1·cmH2O−1·g−1·10−4, respectively) and oedema formation. In contrast, application prior to reperfusion was much less effective, with some reduction of Kfc increase by PGI2and SNP and no effect of PGE1(1.79±0.31, 2.2±0.53 and 3.2±0.05 cm3·s−1·cmH2O−1·g−1·10−4, respectively). Haemodynamics, including microvascular pressure, were only marginally affected by the chosen doses of aerosolized vasodilators.

It is concluded that short-term aerosolization of prostaglandin E1, prostaglandin I2and sodium nitroprusside at the onset of ischaemia is highly effective in maintaining endothelial barrier properties in pulmonary ischaemia-reperfusion. This effect is apparently attributable to nonvasodilatory mechanisms exerted by these agents. Alveolar deposition of prostaglandins and/or nitric oxide donors by the aerosol technique may offer pulmonary protection in ischaemia-reperfusion injury.
Effects of formoterol and budesonide on GM-CSF and IL-8 secretion by triggered human bronchial epithelial cells
Authors: Korn S.H. , Jerre A. , Brattsand R.
Published: October 2002

The effect of formoterol, alone and in combination with budesonide, upon tumour necrosis factor-α stimulated (10 ng·mL−1) human bronchial epithelial cells was investigated.

Addition of formoterol (≥10−10 M) reduced granulocyte macrophage-colony stimulating factor (GM-CSF) levels, as assessed by enzyme-linked immunosorbent assay, by 40–50% and increased interleukin (IL)-8 levels by ∼50%. The effects of formoterol were long lasting (23 h). Budesonide (10−8 M) reduced the amounts of both cytokines (GM-CSF and IL-8) by 40%. Simultaneous addition of formoterol and budesonide reduced GM-CSF levels ∼75%, while IL-8 levels were decreased ∼40%, similar to the reduction obtained with budesonide alone. The glucocorticoid receptor (GR) antagonist RU486 did not influence the effect of formoterol, suggesting no involvement of the GR. Formoterol rapidly induced an elevation in intracellular cyclic adenosine monophosphate, which was reduced in the presence of propranolol. In addition, the alterations in cytokine secretion induced by formoterol could be fully blocked by propranolol, demonstrating that these effects are β2-receptor mediated.

In conclusion, the combination of budesonide and formoterol reduces the secretion of granulocyte macrophage-colony stimulating factor to basal levels and counteracts the capacity of formoterol alone to induce interleukin-8 production, modulations which may facilitate improved asthma control.
The effects of pressurization rate on breathing pattern, work of breathing, gas exchange and patient comfort in pressure support ventilation
Authors: Chiumello D. , Pelosi P. , Croci M. , Bigatello L.M. , Gattinoni L.
Published: October 2002

The aim of this study was to investigate the effects of different pressurization rates during pressure support ventilation on breathing pattern, work of breathing, gas exchange and patient comfort in patients with acute lung injury. The pressurization rate modifies the initial pressure ramp by changing the initial peak flow rate: the increase in pressurization rate is associated with a decrease in the time to reach the level of pressure support ventilation by increasing the peak flow rate.

Ten intubated patients (age 64±17 yrs, body mass index 24±17 Kg·m−2, arterial oxygen tension/inspired oxygen fraction 214±59) were studied in random order varying the pressurization rate at 5 and 15 cmH2O of pressure support ventilation. Breathing comfort was evaluated by a visual analogue scale.

Increasing the pressurization rate caused an increase of peak flow rate from 473±141 mL·s−1to 758±302 mL·s−1at pressure support ventilation 5 (p<0.05) and from 481±126 mL·s−1to 1,121±175 mL·s−1at pressure support ventilation 15 (p<0.05). At the lowest pressurization rate the tidal volume was the lowest, the respiratory rate and the work of breathing were the highest (p<0.05) compared with other pressurization rates. Excluding the lowest pressurization rate, in all the other pressurization rates tested the breathing pattern and the work of breathing did not change. The lowest and the highest pressurization rates caused the worst patient comfort (p<0.05). The gas exchange was stable throughout the study.

The presented results suggest: 1) the lowest pressurization rate caused the lowest tidal volume, highest respiratory rate and highest work of breathing; 2) at the other pressurization rates no differences in breathing pattern and work of breathing were observed; and 3) the patient's comfort was worse at the lowest and highest pressurization rates.
Herpesvirus type 1–8 in BAL fluid from HIV-1-infected patients with suspected pneumonia and from healthy individuals
Authors: Tarp B. , Jensen-Fangel S. , Dahl R. , Obel N.
Published: October 2002

Pneumonia is still a major problem in human immunodeficiency virus (HIV)-infected patients, and despite extensive investigation the aetiology remains unknown in many cases. The prevalence of the eight human herpesviruses was determined by polymerase chain reaction in 91 samples of bronchoalveolar lavage (BAL) fluid from 72 HIV-infected patients with 91 episodes of suspected pneumonia. The presence of herpesviruses was related to clinical and immunological findings and the prevalence of herpesviruses in HIV-infected patients was compared with the prevalence in BAL fluid from 50 healthy, immunocompetent individuals.

Epstein-Barr virus, cytomegalovirus and human herpesvirus-8 (HHV8) were found in 5.5%, 36%, and 5.5% of BAL fluid samples from HIV-infected patients. No herpesviruses were detectable in BAL fluid from healthy, immunocompetent individuals. The herpesviruses occurred mainly in patients with CD4+ counts <200×106 L−1. All patients with herpesviruses recovered without specific antiviral treatment. Two patients with HHV8 had the diagnosis of Kaposi's sarcoma.

It is concluded that cytomegalovirus, Epstein-Barr virus, and human herpesvirus-8 are frequently present in bronchoalveolar lavage fluid from severely immunocompromised human immunodeficiency virus-infected patients with pulmonary symptoms. In bronchoalveolar lavage fluid from healthy, immunocompetent individuals, herpesviruses are absent. Apart from human herpesvirus-8, the present results indicate that the herpesviruses do not play a serious pathogenic role in the development of pulmonary symptoms in human immunodeficiency virus-infected patients.
The effect of sulphur dioxide exposure on indices of heart rate variability in normal and asthmatic adults
Authors: Tunnicliffe W.S. , Hilton M.F. , Harrison R.M. , Ayres J.G.
Published: October 2002

Sulphur dioxide (SO2) is an important air pollutant and causes bronchoconstriction in normal and asthmatic adults. This paper has explored the autonomic consequences of SO2exposure using the spectral analysis of heart rate variability.

Electrocardiogram recordings were made in 12 normal and 12 asthmatic adults undergoing pollutant exposures. Exposures were of a 1 h duration, double blind, in random order, ≥2 weeks apart and included air and 200 parts per billion SO2. Spectral analysis of R-R intervals was performed.

SO2exposure was associated with an increase in total power (TP) and high (HF) and low frequency (LF) power in the normal subjects, and a reduction in these indices in the subjects with asthma. The difference in TP with SO2exposure compared to air was +1730 ms2in the normal group and −1021 ms2asthmatic group (p<0.003). For HF the respective values were +964 ms2and −539 ms2(p=0.02) and for LF, +43 7 ms2and −57 2 ms2(p=0.01). No change in lung function or symptoms was observed in either group.

This suggests that SO2exposure at concentrations which are frequently encountered during air pollution episodes can influence the autonomic nervous system. This may be important in understanding the mechanisms involved in SO2induced bronchoconstriction, and of the cardiovascular effects of air pollution.
Pulmonary function, inflammation, exercise capacity and quality of life in cystic fibrosis
Authors: Bradley J. , McAlister O. , Elborn S.
Published: October 2002

The aim of the study was to determine the extent to which treatment induced changes in exercise capacity and quality of life (QoL) are related to spirometric measures of lung function and other measures of disease impairment.

Twenty patients admitted to hospital with an exacerbation of pulmonary disease were recruited. Measures of disease impairment, disability and QoL were obtained at the beginning and end of an intravenous course of antibiotic therapy.

Intravenousantibiotic treatment resulted in a significant improvement in all measures of disease impairment, disability and handicap. The only significant predictor of treatment induced change in exercise capacity was C-reactive protein (CRP) and this explained 28% of the variance in change in exercise capacity. In the case of QoL, two predictors (change in exercise capacity and sputum output) contributed significantly to the change in QoL and collectively explained 54% of the variance in QoL.

Lung function provides a limited index of treatment outcome. Exercise capacity and quality of life assessment have the potential to make a significant contribution to the decision making process regarding treatment choices in cystic fibrosis and should be measured directly if a comprehensive evaluation of the effect of treatment is required.
Sleep fragmentation: comparison of two definitions of short arousals during sleep in OSAS patients
Authors: Smurra M.V. , Dury M. , Aubert G. , Rodenstein D.O. , Liistro G.
Published: October 2002

The measurement of arousals during sleep is useful to quantify sleep fragmentation. The criteria for electroencephalography (EEG) arousals defined by the American Sleep Disorders Association (ASDA) have recently been criticized because of lack of interobserver agreement. The authors have adopted a scoring method that associates the increase in chin electromyography (EMG) with the occurrence of an α-rhythm in all sleep stages (Université Catholique de Louvain (UCL) definition of arousals). The aim of the present study was to compare the two scoring definitions in terms of agreement and repeatability and the time taken for scoring in patients with obstructive sleep apnoea syndrome (OSAS) of varying severity.

Two readers using both ASDA and UCL definitions scored twenty polysomnographies (PSGs) each on two occasions. The PSGs were chosen retrospectively to represent a wide range of arousal index (from 6–82) in OSAS patients.

There was no difference in the arousal indices between readers and between scoring methods. The mean±sd difference between the two definitions (the bias) was 1.1±3.76 (95% confidence interval: −0.66–2.86). There was a strong linear relationship between the arousal index scored with the two definitions (r=0.981, p<0.001). Mean±sd scoring duration was significantly shorter for UCL than for ASDA definitions (18.5±5.4versus25.3±6.6 min, p<0.001).

In conclusion, it has been found that in obstructive sleep apnoea syndrome patients, the American Sleep Disorders Association and Université Catholique de Louvain definitions were comparable in terms of agreement and repeatability.
Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnoea syndrome
Authors: Guilleminault C. , Do Kim Y. , Chowdhuri S. , Horita M. , Ohayon M. , Kushida C.
Published: October 2002

This study has investigated differences in the nocturnal sleep and daytime sleepiness among patients with obstructive sleep apnoea syndrome (OSAS), upper airway resistance (UARS), sleep hypopnoea syndrome, and normal control subjects, using sleep scoring and spectral activity analysis of the electroencephalogram (EEG).

Twelve nonobese males with UARS aged 30–60 yrs were recruited. These subjects were strictly matched for age and body mass index with twelve OSAS patients, 12 sleep hypopnoea syndrome patients, and 12 normal controls, all male. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT). The macrostructure of sleep was determined using international criteria and spectral analysis of the sleep EEG was obtained from a central lead.

The sleep macrostructure of OSAS and UARS patients was significantly different from that of controls. These patients were also sleepier during the daytime than controls. Complaints of tiredness and daytime sleepiness, ESS and MSLT scores were similar in the different patient groups. Mild dysmorphia was present in all three patient groups. However, nocturnal sleep was significantly different among the different groups. OSAS patients had significantly more awake time during sleep than the UARS patients. The spectral activity of the total sleep time of the patient groups also differed significantly from that of controls. When the sleep spectral activity of UARS and OSAS patients were compared, OSAS patients had less slow wave sleep activity than UARS patients. UARS patients had a significantly higher absolute power in the 7–9 Hz bandwidth than OSAS patients. The absolute delta power over the different sleep cycles was also different between controls and patients, and between UARS and OSAS patients.

There are clear differences in the macrostructure and spectral activity of sleep between upper airway resistance and obstructive sleep apnoea syndrome patients, demonstrated by differences in the cortical activity recorded in the central lead during sleep. Despite these nocturnal sleep differences, the tests of subjective daytime sleepiness are not significantly different.
Comparison of the acute effects of salbutamol and terbutaline on heart rate variability in adult asthmatic patients
Authors: Eryonucu B. , Uzun K. , Güler N. , Bilge M.
Published: October 2002

This study investigated the effects of β2-adrenergic agonist therapy on heart rate variability (HRV) in adult asthmatic patients by using frequency domain measures of HRV.

A randomized crossover design was used. Twenty adult patients with asthma were studied. All patients showed a mild-to-moderate decrease in baseline forced expiratory volume in one second. Any diseases that might have influenced the autonomic function were excluded. All patients had a complete physical examination and medical history that revealed no cardiovascular disease or medication. The study used 200 µg inhaled salbutamol and 500 µg inhaled terbutaline. HRV analysis was performed for each 5-min segment, 5 min before inhalation of the study drug and 5, 10, 15, 20, 25 and 30 min after inhalation. Total power (TP: <0.40 Hz), high-frequency power (HF: 0.15–0.40 Hz), low-frequency power (LF: 0.04–0.15 Hz) and LF/HF ratio were calculated.

The LF and LF/HF ratio increased and TP decreased at 5, 10, 15 and 20 min after the salbutamol and the terbutaline inhalation, HF did not change significantly after the salbutamol and terbutaline inhalation.

Acute salbutamol and terbutaline inhalation produce similar effects on heart rate variability and increase sympathetic modulation in the cardiac autonomic activity.
Natural history of sensitization, symptoms and occupational diseases in apprentices exposed to laboratory animals
Authors: Gautrin D. , Ghezzo H. , Infante-Rivard C. , Malo J-L.
Published: October 2002

The natural history of the development of sensitization and disease due to high-molecular-weight allergens is not well characterized. This study describes the time-course of the incidence of work-related symptoms, skin reactivity and occupational rhinoconjunctivitis (RC) and asthma (OA); and assesses the predictive value of skin testing and RC symptoms in apprentices exposed to laboratory animals, in a 3–4-yr programme.

Four-hundred and seventeen apprentices at five institutions were assessed prospectively with questionnaire, skin-testing with animal-derived allergens, spirometry and airway responsiveness (n=373). Depending on the school, students were seen 8 (n=136), 20 (n=345), 32 (n=355) and 44 (n=98) months after starting the programme.

At all visits, the incidence was greater for work-related RC symptoms followed in order by skin reactivity, occupational RC, and, almost equally, OA and work-related respiratory symptoms. The incidence-density figures were comparable for each follow-up period and for most indices up to 32 months after entry into the study and then tended to decrease. The positive predictive values (PPVs) of skin reactivity to work-related allergens for the development of work-related RC and respiratory symptoms were 30% and 9.0%, respectively, while the PPVs of work-related RC for the development of OA was 11.4%.

Sensitization, symptoms and diseases occur maximally in the first 2–3 yrs after starting exposure to laboratory animals. Skin reactivity to work-related allergens and rhinoconjuctivitis symptoms have low positive predictive values.
Observer variation in computed tomography of pleural lesions in subjects exposed to indoor asbestos
Authors: De Raeve H. , Verschakelen J.A. , Gevenois P.A. , Mahieu P. , Moens G. , Nemery B.
Published: October 2002

To assess the reliability of computed tomography (CT) in detecting discrete pleural lesions, the interobserver and intra-observer variability in reading the conventional and high-resolution CT (HRCT) scans of 100 volunteers, who had worked for ≥10 yrs in a building with known asbestos contamination, was evaluated.

In the first session, pleural abnormalities were detected by a single radiologist (A1) in 13 subjects. In the second session, the scans were read again independently by the same radiologist (A2) and two other experienced radiologists (B, C). The final decision for the presence of pleural lesions was made in a final consensus reading.

This gave a diagnosis of pleural abnormalities in 18 subjects, of whom eight (44%) had been detected by all three readers, five (28%) by two readers and four (22%) by only one reader; one scan, rated normal by all readers during the second session, was reconsidered because pleural abnormalities had been noted at the first reading (A1). The intra-observer agreement for reader A was good (kappa (κ) 0.68) but the interobserver agreement between the readers was only fair to moderate (weighted κ: A2-B=0.43, A2-C=0.45, B-C=0.26) in the second reading session.

In conclusion, when looking for the prevalence of pleural lesions in indoor asbestos exposed subjects, the potential lack of consistency in reporting the presence of small pleural abnormalities must be borne in mind and strict precautions must be taken.
Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis
Authors: Miravitlles M. , Murio C. , Guerrero T.
Published: October 2002

This study aimed to identify the risk factors for relapse after ambulatory treatment of acute exacerbations of chronic bronchitis (AECB) that can easily be used in a primary care setting.

Data were prospectively collected on 2,414 ambulatory patients with AECB from 268 general practices located throughout Spain. A multivariate model to identify risk factors independently associated with failures was developed and validated from the information recorded at the inclusion visit and at 30-days follow-up visit.

A total of 507 patients relapsed (21%); of these, 84 required admission (16.5%). The multivariate model for prediction of the risk of relapse included 2,414 cases: 1,689 for the developmental sample and 725 in the validation sample. The model obtained contained three readily-obtainable variables: ischaemic heart disease (odds ratio (OR)=1.63; 95% confidence interval (CI)=1.07–2.47), degree of dyspnoea (OR=1.31; 1.14–1.50) and number of visits to the general practitioner the previous year (OR=1.07; 1.04–1.10). The model calibrated well in developmental and validation samples (goodness-of-fit tests: p=0.295 and p=0.637, respectively). Severity of the exacerbation was not associated with increased risk of relapse in either univariate or multivariate analysis.

The present results suggest that baseline characteristics of the patients such as degree of dyspnoea, coexisting ischaemic heart disease and number of previous visits to the general practitioner for respiratory problems are strongly associated with increased risk of relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. In contrast, exacerbation severity was not associated with clinical failure. Guidelines for management of acute exacerbations of chronic bronchitis should consider such risk factors and advocate intensive broad spectrum treatment and closer follow-up of patients exhibiting them.
Endothelin-1-induced airway and parenchymal mechanical responses in guinea-pigs: the roles of ETA and ETB receptors
Authors: Adamicza Á. , Peták F. , Asztalos T. , Tiszlavicz L. , Boros M. , Hantos Z.
Published: October 2002

Endothelin-1 (ET-1) has been shown to have a constrictor effect on the airways and parenchyma; however, the roles of the ETAand ETBreceptors in the ET-1-induced changes in the airway and tissue compartments have not been fully explored.

Low-frequency pulmonary impedance (ZL) was measured in anaesthetized, paralysed, open-chest guinea-pigs.ZLspectra were fitted by a model to estimate airway resistance (Raw) and inertance (Iaw), and coefficients of tissue damping (G) and elastance (H), and hysteresivity (η=G/H).

Two successive doses of ET-1 (0.05 and 0.2 nmol·kg−1) each evoked significant dose-related increases inRaw, G, H and η. Pretreatment with 20 nmol·kg−1BQ-610 (a highly selective ETAreceptor antagonist) resulted in a significantly decreased elevation only in H after the lower dose of ET-1. However, all parameters changed significantly less on the administration of ET-1 after pretreatment with 80 nmol·kg−1BQ-610, with 20 nmol·kg−1ETR-P1/fl (a novel ETAreceptor antagonist) or with 20 nmol·kg−1IRL 1038 (an ETBreceptor antagonist).

The results of the separate assessments of the airway and tissue mechanics demonstrate that endothelin-1 induces airway and parenchymal constrictionviastimulation of both receptor types in both compartments.
Surfactant apoprotein A modulates interleukin-8 and monocyte chemotactic peptide-1 production
Authors: Meloni F. , Alberti A. , Bulgheroni A. , Lupi A. , Paschetto E. , Marone Bianco A. , Rodi G. , Fietta A. , Luisetti M. , Baritussio A.
Published: October 2002

Previous studies have shown that surfactant apoprotein A (SP-A) and natural or synthetic surfactant can modulate the release of pro-inflammatory cytokines from alveolar mononuclear phagocytes.

The aim of this study was to assess whether SP-A or Surfactant (Surf) from patients with pulmonary alveolar proteinosis (PAP) can affect the release of two chemokines (interleukin (IL)-8 and monocyte chemtactic peptide (MCP)-1) from human monocytes and rat lung type-II cells. In addition IL-8 and MCP-1 levels were assessed in the brochoalveolar lavage fluid (BALF) of seven patients with PAP and compared with those in a group of control subjects (n=5).

SP-A, tested over a wide range of concentrations, significantly increased IL-8 and MCP-1 release from monocytes. SP-A retained its activity after collagenase digestion, but was not active after heat treatment. The release of IL-8 by monocytes was also stimulated by Surf. Finally, median BALF IL-8 and MCP-1 levels in PAP patients were significantly higher than in controls (9.50 and 9.51 pg·mL−1in controlsversus151.95 and 563.70 pg·mL−1in PAP, respectively) and significantly correlated with SP-A concentrations in BALF.

Overall the results of this study support the view that the high content of alveolar surfactant apoprotein A may contribute to the upregulation of chemokine release in pulmonary alveolar proteinosis, thus contributing to airway inflammation.
Role of alveolar epithelial ICAM-1 in lipopolysaccharide-induced lung inflammation
Authors: Beck-Schimmer B. , Madjdpour C. , Kneller S. , Ziegler U. , Pasch T. , Wüthrich R.P. , Ward P.A. , Schimmer R.C.
Published: October 2002

Intercellular adhesion molecule-1 (ICAM-1) is known to play a central role in lung inflammation. Limited information, however, is available regarding the expression and biological function of ICAM-1 in the alveolar epithelial compartment. The current report analyses the expression pattern of ICAM-1 in primary cultures of rat alveolar epithelial cells (AECs) and in the rat lung following instillation of bacterial endotoxin (lipopolysaccharide (LPS)) in order to better define the role of alveolar epithelial ICAM-1.

AECs stimulatedin vitrowith LPS were evaluated for ICAM-1 and ICAM-1 messenger ribonucleic acid content. Adherence assays with neutrophils and macrophages were performed. Endotoxin-induced ICAM-1 upregulation on AECs was demonstratedin vivoby immunofluorescence staining. In addition, the effect of intratracheally-instilled anti-ICAM-1 was assessed.

Significant upregulation of ICAM-1 occurredin vitroandin vivoon AECs after LPS stimulation. Adherence assays showed a 114% increase in adhesion of neutrophils to AECs. Antibody directed against ICAM-1 reduced this adhesion by 40%. A significant reduction in the number of neutrophils in bronchoalveolar lavage fluid and whole lung was seen under airway ICAM-1 blockade.

These data indicate that intercellular adhesion molecule-1 participates in the inflammatory response to lipopolysaccharide-induced lung injury in the distal airways by interacting mainly with neutrophils.
Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics
Authors: Walmrath D. , Grimminger F. , Pappert D. , Knothe C. , Obertacke U. , Benzing A. , Günther A. , Schmehl T. , Leuchte H. , Seeger W.
Published: October 2002

The aim of the present study was to investigate the feasibility and efficacy of bronchoscopic surfactant administration in a noncontrolled multicentre study in five university centres.

A total number of 27 patients, suffering from severe acute respiratory distress syndrome (mean±sem lung injury score: 3.15±0.06) and septic shock (Acute Physiology and Chronic Health Evaluation (APACHE) II score at study entry 33.2±1.3, lactate 4.3±0.6 mmol·L−1) were studied. The patients were ventilated with a mean tidal volume of 11.0±0.5 mL·kg−1body weight (bw), either volume or pressure controlled, with 16.3±2.8 cmH2O positive end-expiratory pressure, for an average of 3.5±0.3 days at study entry. A natural bovine surfactant extract (300 mg·kg−1bw Alveofact®; mean total volume 378 mL) was delivered in divided doses to each segment of the lungsviaflexible bronchoscope within ∼45 min.

No untoward effects on gas exchange, lung mechanics and haemodynamics were noted during the procedure of surfactant administration. Within 12 h the oxygen tension in arterial blood/inspiratory oxygen fraction increased from a mean of 109±8 mmHg to 210±20 mmHg (p<0.001). In seven patients, in whom gas exchange again deteriorated with further progression of the disease, a second surfactant dose of 200 mg·kg−1was administered 18–24 h after the first application, again improving arterial oxygenation. A total of 15 patients survived the 28-day study period (mortality rate 44.4%, compared to a calculated risk of death for the given APACHE II scores of 74.0±3.5%), with all causes of death being nonrespiratory. The bronchoscopic application of a high dose of natural surfactant in patients with severe acute respiratory distress syndrome and septic shock is both feasible and safe, resulting in a pronounced improvement in gas exchange.
Lung emptying in patients with acute respiratory distress syndrome: effects of positive end-expiratory pressure
Authors: Kondili E. , Prinianakis G. , Athanasakis H. , Georgopoulos D.
Published: October 2002

The pattern of lung emptying was studied in 10 mechanically-ventilated patients with acute respiratory distress syndrome.

At four levels of positive end-expiratory pressure (PEEP) (0, 5, 10 and 15 cmH2O) tracheal (Ptr) and airway pressures (Paw), flow (V′) and volume (V) were continuously recorded. Tidal volume was set between 0.5–0.6 L andV′/Vcurves during passive expiration were obtained. Expired volume was divided into five equal volume slices and the time constant (τe) and effective deflation compliance (Crseff) of each slice was calculated by regression analysis ofV/V′ and postocclusionV/Ptrrelationships, respectively. In each slice, the presence or absence of flow limitation was examined by comparingV′/Vcurves with and without decreasingPaw. For a given slice, total expiratory resistance (Rtot) (consisting of the respiratory system (Rrs), endotracheal tube (Rtube) and ventilator circuit (Rvent)) was calculated as the τe/Crseffratio. In the absence of flow limitationRrswas obtained by subtractingRtubeandRventfromRtot, while in the presence of flow limitationRrsequaledRtot. The τe of the pure respiratory system (τers) was calculated as the product ofRrsandCrseff.

At zero PEEP, τersincreased significantly towards the end of expiration (52±31%) due to a significant increase inRrs(46±36%). Application of PEEP significantly decreasedRrsat the end of expiration and resulted in a faster and relatively constant rate of lung emptying.

In conclusion, without positive end-expiratory pressure the respiratory system in patients with acute respiratory distress syndrome deflates with a rate that progressively decreases, due to a considerable increase in expiratory resistance at low lung volumes. Application of positive end-expiratory pressure decreases the expiratory resistance, probably by preventing airway closure, and as a result modifies the pattern of lung emptying.
Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler®
Authors: Johnell O. , Pauwels R. , Löfdahl C-G. , Laitinen L.A. , Postma D.S. , Pride N.B. , Ohlsson S.V.
Published: October 2002

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD).

Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1) 77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized to receive budesonide 400 µg, or placebo twice dailyviaTurbuhaler®. BMD was measured at the L2–L4 vertebrae and the femoral neck, trochanter and Ward's triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653).

Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients, compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin.

In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 µg·day−1viaTurbuhaler® had no clinically significant effects on bone mineral density or fracture rates.
Role of biomarkers for early detection of lung cancer and chemoprevention
Authors: Hirsch F.R. , Merrick D.T. , Franklin W.A.
Published: October 2002

Lung cancer is the leading cause of cancer deaths in developed countries. The poor prognosis associated with this disease is closely related to the fact that most lung cancer patients are not identified until their malignancy has reached an advanced stage.

Recent advances have added to the understanding of the morphological and molecular characteristics of preinvasive bronchial lesions and early lung cancers. Such information is being used to provide new tests for the detection of lung cancer at early or preinvasive stages, and for identifying targets for therapeutic intervention that can prevent progression to advanced disease. Laser induced fluorescence endoscope bronchoscopy has improved the sensitivity with which preinvasive dysplastic bronchial lesions and early invasive malignancies can be detected. Morphological features of such lesions have been described and can be monitored by follow-up bronchoscopies in order to validate potential chemoprevention treatments.

Distinct morphological characteristics such as angiogenic squamous dysplasia also suggest that processes like angiogenesis are present early in the development of lung cancer. Furthermore, tissue obtained from these early lesions has been used to describe alterations in the expression of a number of factors that distinguish these early lesions from normal bronchial epithelium. This could provide molecular markers and targets for the detection and treatment of early lung cancer. Studies to detect these alterations by polymerase chain reaction and/or immunhistochemical analyses of easily obtained specimens such as sputa are helping identifing molecular markers that could be utilized in effective screening programmes.

The current article reviews new findings regarding the molecular biology of preinvasive bronchial lesions and early lung cancers, and describes new developments regarding their application in the early detection and chemoprevention of lung cancer.
Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients
Authors: Miron MJ , Perrier A , Bounameaux H , de Moerloose P , Slosman DO , Didier D , Junod A
Published: October 2002

The effectiveness of new diagnostic tools for suspected pulmonary embolism (PE), such as clinical probability assessment, plasma D-dimer (DD) measurement and lower limb venous compression ultrasonography (US), has not been specifically studied in patients with a suspected PE occurring during hospital stay. This study applied a sequential, decision analysis-based strategy adding these instruments to a ventilation/perfusion lung scan in a cohort of 114 consecutive inpatients clinically suspected of PE in order to establish in how many patients a pulmonary angiogram could thereby be avoided. A definitive diagnosis could be established by the noninvasive protocol in 61% of these patients: normal/near-normal lung scan, 14%; high probability lung scan, 19%; clinical probability combined with lung scan result, 18%; and US, 8%. Specificity of DD was only 7% and contributed to the exclusion of PE in only two patients. Pulmonary angiography was required in 39% of patients. The 3-month thromboembolic risk in patients in whom PE was excluded by the diagnostic process was 0% (95% confidence interval 0-4.9%). In conclusion, a noninvasive work-up for suspected pulmonary embolism is effective in hospitalized patients, allowing to forego angiography in 61% of them, and it appears to be safe, although this should be further investigated. In contrast to outpatients, D-dimer measurement appears to be useless in hospitalized patients.