bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a biomarker for lung inflammation in COPD through analysis of labelled leukocyte transit through the lung circulation
Authors: Baker EmmaH. , Irwin Andrew , Brennan AmandaL. , Trost Brian , Britten Alan , Heenan Sue , Peterson Barry
Published: September 2008

Measurement of pulmonary leukocyte margination could be a useful biomarker of lung inflammation in COPD, but analysis is complicated by recirculation of labeled leukocytes.

15 minutes of planar nuclear images were obtained after injecting autologous99mTc-labeled leukocytes in 4 never-smoked controls, 6 stable mild/moderate and 2 exacerbating COPD patients. COPD patients were also imaged for 10 minutes afterin vivored blood cell (RBC) labeling with99mTc and were re-imaged 2 weeks later to determine reproducibility. Activity as a function of time was measured in regions of interest over lungs and heart.

A multi-compartment mathematical model was used to correct for recirculation but failed to provide a biomarker that clearly separated controls from COPD. A simpler model for activity in lungs and heart as a function of time (A(t)) was applied only to time points before recirculation: [A(t) = X1x (1-exp(-X2x t)) x exp(-X3x t), where Xiare adjusted to match the data]. The ratio (R) of X3(downslope of curve) in the lungs to X3in the heart was investigated as a biomarker of margination. Values of R were reasonable (1.06±0.08 (SE)) for RBC (i.e.no margination) and 0.76±0.10 for controls (∼25% margination). In stable COPD patients R was significantly smaller (0.19±0.09, p<0.01) than controls and was reproducible (0.25±0.10). R during exacerbation was surprisingly large (0.88±0.22), possibly due to steroid treatment, but R was similar to stable COPD patients 2 weeks later (0.09±0.04).

R requires only 2–3 minutes of imaging and may be a useful biomarker of margination. However it remains to be shown whether R truly reflects inflammation in COPD.
Role of purinergic receptors in the activation of human airway smooth muscle cells by the antimicrobial peptide LL-37
Authors: Zuyderduyn Suzanne , Ninaber DennisK. , Hiemstra PieterS. , Rabe KlausF.
Published: September 2008

Inflammatory cells that infiltrate and surround the airway smooth muscle (ASM) layer express antimicrobial peptides including the cathelicidin LL-37. LL-37 has been shown to activate epithelial cells by transactivation of the epidermal growth factor receptor (EGFR). Previously, we have shown that LL-37-induced IL-8 release by ASM cells was not dependent on either formyl peptide receptors or the EGFR (ATS 2005). In monocytes LL-37 induces processing of IL-1β through activation of the purinergic P2X7receptor. Therefore, the aim of our study was to evaluate the role of purinergic receptors in LL-37-induced activation of ASM cells, and to explore the involvement of several intracellular signalling pathways.

ASM cells were cultured and serum-deprived 24 hours before stimulation with LL-37 (10 μg·ml−1). The purinergic receptor antagonist suramin and inhibitors of ERK1/2, p38, Src and PI3K were preincubated for one hour. ERK1/2 phosphorylation was assessed by Western Blot, and IL-8 release was determined in supernatants using a sandwich ELISA. RT-PCR was performed for P2X7on untreated ASM cells. LL-37 induced ERK1/2 phosphorylation and IL-8 release; both were inhibited by suramin (IL-8: 86%). Inhibitors of ERK1/2, p38 and Src signalling also reduced LL-37-induced IL-8 release (by 67%, 63% and 76%, respectively), suggesting a role for these pathways. P2X7mRNA was expressed in ASM cells.

These data show that LL-37-induced IL-8 release is mediated via purinergic receptors, ERK1/2 activation, p38 and Src signalling. Our PCR data are in line with the hypothesis that also in ASM P2X7is the purinergic receptor involved in LL-37 signalling, although this needs further investigation.
The effects of ELTGOL on mucociliary clearance in patients with COPD
Authors: Martins JocimarA. , Andrade ArmèleD. , Assis RodrigoS. , Lara Rovilson , Parreira VerônicaF.
Published: September 2008

Excessive tracheobronchial secretion is a common complication of chronic obstruction pulmonary disease (COPD) and its presence is associated with lower survival, greater hospitalization and death. Slow expiration with the glottis open in a lateral posture (ELTGOL) is a chest physiotherapy procedure for the removal of lung secretions. Studies which have assessed ELTGOL through pulmonary scintigraphy were not found [1]. The aim this study was to evaluate the effects of ELTGOL on the mucociliary clearance in patients with COPD.

Twelve patients with COPD aged 45 to 75 years were studied. After inhaling 20 mCi of 99mTc-DTPA [2], six posterior static scintigraphy images were taken in intervals of 0, 20, 40, 60, 80 and 120 minutes (figure 1).

The study was carried out in two stages (control and experimental) in a randomized order with a minimum interval of one week between the stages. In the experimental stage, ELTGOL was carried out after the first image. The right lung was studied, comparing the percentage of retention [3] of radioactive aerosol obtained during the control stage with the experimental condition, for each interval studied. The study was approved by the local ethics committee and all patients gave their written consent participate. The t test was used for data analysis with a significance level of α<0.05.

As shown in figure 2, significant differences between groups were found between all time intervals.

The present results showed the ELTGOL significantly increased the mucociliary clearance suggesting that ELTGOL is an effective technique to improve secretion removal in patients with COPD.
A Disintegrin and Metalloprotease 33polymorphisms and lung function decline in the general population
Authors: van Diemen CleoC. , Postma DirkjeS. , Vonk JudithM. , Bruinenberg Marcel , Schouten JanP. , Marike Boezen H.
Published: September 2008

ADAM33(A Disintegrin and Metalloprotease 33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excess decline of lung function in asthmatics.

To assess whether SNPs inADAM33are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD).

We have collected DNA from subjects of the Vlagtwedde/Vlaardingen cohort participating in the last survey in 1989/1990 after a follow up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. 1390 subjects from the cohort were genotyped for the following SNPs inADAM33: F+1, Q−1, S_1, S_2, T_1, T_2, V_4, ST+5. Differences in prevalence of SNPs were analyzed with chi-square tests. Linear mixed effects models were used to analyze FEV1decline according to genotype.

In the whole population mean adjusted decline was 18.7 and 12.7 ml·y−1in females and males respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q−1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV1of respectively 4.9, 9.6 and 3.6 ml·y−1compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2 and T_2 in subjects with COPD.

We demonstrated that SNPs inADAM33are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.
Diminished peroxisome proliferator-activated receptor (PPAR) regulation as a potential mechanism for the persistent inflammation in chronic obstructive pulmonary disease
Authors: Drost E. M. , Poland C. A. , Donaldson K. , MacNee W.
Published: September 2008

Persistent inflammation is the main pathological process that underlies COPD. Understanding this inflammatory response is a key focus of COPD research with the aim of discovering new therapeutic targets. The nuclear hormone receptor, PPAR is now a recognised modulator of inflammation in various chronic inflammatory conditions, but its role in the persistent airways inflammation in COPD has not been examined. Control of the inflammatory response by PPARα has been shown by antagonising inflammatory signalling pathways, such as NF-κB and AP-1.

PPARα protein levels in lung tissue from patients with COPD were assessed by Western blot.In vitroassays using the human type II alveolar epithelial cell line were performed to assess the effect of PPARα agonist treatment on inflammatory cytokine generation.

An increase in PPARα protein levels was seen for healthy smokers compared with non-smokers (Ratio to β-actin loading control, non-smokers 0.61±0.1, n = 10; healthy smokers 0.97±0.3, n = 11, p>0.05). No increase was seen for current smoker or ex-smoker COPD patients (0.36±0.08, n = 12; 0.49±0.1, n = 8 respectively).In vitroexperiments with a human type II alveolar epithelial cell line demonstrated a diminished inflammatory response to TNFα, as measured by the generation of the pro-inflammatory cytokine IL-8, following pre-treatment with the PPARα agonist, WY-14643 (IL-8 generation, control 823±22 pg·ml−1, TNFα 7491±530 pg·ml−1p<0.001, WY-14643 2559±46 pg·ml−1p<0.05, n = 3).

We propose PPAR agonists as a potential therapy for reducing the NF-κB-regulated inflammation in COPD airways.

Supported by GlaxoSmithKline
How different measures of cold weather affect chronic obstructive pulmonary disease (COPD) hospital admissions in London
Authors: Marno P. , Bryden C. , Bird W. , Watkin H. A.
Published: September 2008

Many COPD sufferers find that their symptoms become worse during colder weather, which can lead to an exacerbation resulting in hospital admission. This study investigates different measures of cold, assessing which most strongly relate to COPD admissions and whether they can be used to forecast risk of exacerbation.

COPD admissions (ICD10 J40–J44) for the five Strategic Health Authorities (SHAs) in London and corresponding meteorological data were extracted for October–March 1997–2003. Correlations and regressions were used to compare the effects on admissions of:

daily mean, maximum and minimum temperature;

significant drops in temperature;

weekly average maximum temperature;

“cumulative cold”, summing the number of degrees the daily maximum temperature was below a threshold across a week;

different windchill indices.

All measures of cold showed significant negative correlations with COPD admissions. Daily relationships were weaker than weekly ones (R =  −0.19, p<0.001 for daily maximum temperature, R =  −0.36, p<0.001 for weekly average maximum temperature) but are most significant with an 8-day lag. Windchill had the strongest correlation with one-week lag (R =  −0.397, p<0.001) accounting for 20% of the variation in admissions. “Cumulative cold” is also significant at p<0.001, ranging from R = 0.28 for a 3°C threshold to R = 0.36 for 18°C.

Cold measures explain sufficient variation in COPD hospital admissions to be used in a forecast model of risk of exacerbation. The Met Office uses such a model in a health forecasting and anticipatory care service in England.
Suppressed pulmonary expression of leptin in lipopolysaccharide-induced acute and chronic lung inflammation
Authors: Vernooy J. H. J. , Cloots R. H. E. , Dentener M. A. , Wouters E. F. M.
Published: September 2008

Leptin, originally described as an adipocyte-derived hormone regulating energy expenditure, is now classified as a type I cytokine. We and others recently demonstrated that the lung is an additional source of leptin. The aim of the present study was to investigate the effect of acute and chronic inflammation on pulmonary expression of leptin in male Swiss mice. Acute lung inflammation was induced by a single intratracheal (IT) dose of 5 μg LPS (E.coli O55:B5), and mice were killed 4h, 24h and 72h postexposure. Chronic lung inflammation was induced by repeated LPS exposure (twice a week for 12 wks) and mice were killed after a 1-wk or 8-wks recovery period. Lungs were removed to assess cellular influx, leptin protein (immunohistochemistry) and mRNA (RT-PCR). Acute LPS exposure induced a transient neutrophilia (Vernooy, J.et al.AJRCMB 2001; 24:569–576). Chronic LPS exposure resulted in persistent accumulation of macrophages and CD8+ T-cells and emphysema (Vernooy, J.et al.AJRCMB 2002; 26:152–159). Control mice displayed positive leptin staining in bronchiolar epithelium and alveolar macrophages. Both acute (4h, 24h, 72h) and chronic (1-wk) inflammation was associated with complete suppression of pulmonary leptin expression at protein and mRNA level. Leptin expression was fully restored after 8-wks of recovery. Lungs of mice displayed constitutive leptin expression in bronchiolar epithelium and alveolar macrophages. Acute and chronic lung inflammation resulted in complete suppression of pulmonary leptin expression. Our data suggest that downregulation of leptin expression in lung may contribute to chronic pulmonary inflammation.
Multiple flow rate modelling of nitric oxide in COPD – methodological concerns
Authors: Roy Kay , Borrill Zoe , Hazel Andrew , Vestbo Jorgen , Singh Dave
Published: September 2008

Multiple flow rates FeNOdata two-compartment mathematical modelling can estimate NO airway wall concentration (CawNO), airway wall diffusing capacity (DawNO), alveolar concentration (CalvNO) and maximal NO flux (JawNO). To compare modelling based on linear, non linear and mixed linear and non linear analyses in COPD. FeNOwas measured using the Niox analyser (Aerocrine) at flow rates: 10, 30, 50, 100 and 200ml/s in 50 COPD patients and the data applied to 4 different methods. All methods showed that current smoking reduced CawNO. JawNOdata differed between methods (Table 1). All the methods showed that current smoking did not affect CalvNOor DawNO. Comparison of the methods showed that CalvNOand DawNOdata were significantly different between all methods, JawNOwas different for most between method comparisons, while there was agreement between all the methods for CawNO. Smoking in COPD reduces CawNO ,but not CalvNOand DawNO. JawNO,CalvNOand DawNOdata are model dependent parameters. CawNOfindings were model independent, and hence the most robust modelled parameter.
Mannose binding lectin (MBL) levels predict lung function decline in severe asthma
Authors: van Veen IlonkaH. , Hiemstra PieterS. , ten Brinke Anneke , Roos Anja , Verhoosel RenateM. , Sont JaapK. , Sterk PeterJ. , Rabe KlausF. , Bel ElisabethH.
Published: September 2008

There is increasing evidence that activation of the complement system in asthma contributes to ongoing inflammation, tissue damage and airway remodeling. Mannose binding lectin (MBL) is a pattern recognition molecule that serves as the key mediator of the lectin pathway of complement activation. MBL levels are genetically determined and vary widely amongst individuals. In the present study we hypothesized that high MBL levels in asthma are associated with increased loss of lung function over time, as a consequence of inflammatory tissue damage. We measured serum MBL levels by ELISA in 68 patients with severe asthma and prospectively determined the change in post-bronchodilator (pb) FEV1 over a mean period of 5.7 years. The relationship between MBL and change in pbFEV1 (ΔFEV1) was analysed using (multiple) regression analysis and corrected for possible confounders (age, sex, age of onset, asthma duration, and pbFEV1). The median (range) MBL level was 332 (10.8-3587) ng·ml−1. MBL was significantly associated with ΔFEV1 (p<0.04). Patients with a high MBL level (≥332 ng·ml−1) had an increased risk of lung function decline compared to those with low MBL levels (OR (CI): 3.16 (1.14-8.79), p = 0.027); the excess decline being 42 ml·yr−1(p = 0.01). We conclude that a high MBL level is associated with an increased decline in lung function in patients with severe asthma. MBL might provide a clue towards better understanding of the pathophysiology of ongoing inflammation and subsequent decline in lung function of patients with severe asthma.
Relationship of airway dimensions with airflow limitation or lung volumes in chronic obstructive pulmonary disease (COPD)
Authors: Hasegawa Masaru , Nasuhara Yasuyuki , Onodera Yuya , Makita Hironi , Betsuyaku Tomoko , Nishimura Masaharu
Published: September 2008

We have recently developed new software to obtain longitudinal images and accurate short axis images of airways with an inner diameter > 2 mm located anywhere in the lung, using curved multiplanar reconstruction. Using this software, we demonstrated in patients with COPD that FEV1 (%predicted) was highly correlated with airway dimensions and the correlation coefficients improved as the airway became smaller in size (3). In this study, our aims are to further confirm the significant relationship between airway dimensions and airflow limitation in larger number of subjects, and to examine the relationship of airway dimensions with lung volumes in 95 patients with COPD (stage 0, 10; stage I, 23; stage II, 35; stage III, 24; stage IV, 3). We analyzed the airway dimensions from the 3rdto the 6thgenerations of the apical bronchus (B1) of the right upper lobe and the anterior basal bronchus (B8) of the right lower lobe. Lung volumes were measured by the helium closed circuit method. Both airway luminal area (Ai) and wall area percent (WA%) of all the generations, except a few, from the two bronchi were significantly correlated with RV and RV/TLC, but not with TLC or FRC. More importantly, the correlation coefficients (r) between airway dimensions and RV/TLC improved as the airways became smaller in size from the 3rdto 6thgenerations in both bronchi (r =  −0.483, −0482, −0.553, −0.624 for Ai of B8; r = 0.316, 0.380, 0.499, 0.551 for WA% of B8). These findings provide further evidence that distal (small) airways rather than proximal (large) airways are the determinants for airflow limitation in COPD.
Challenging cases in PH
Authors: Hoeper M. M. , Laenger F.
Published: September 2008

The requirement for a timely diagnosis of pulmonary arterial hypertension (PAH) to maximise the benefits achieved with appropriate therapy is hampered by the insidious nature of the disease and consequently the late presentation of the majority of patients. Therefore, it is critical to maintain a high index of suspicion in cases of unexplained dyspnoea and to employ a structured and systematic diagnostic strategy.

Pulmonary hypertension (PH) has been classified clinically into PAH, PH associated with left heart diseases, PH associated with hypoxaemia or disorders of the respiratory system, PH caused by chronic thrombotic or embolic disease and PH caused by disorders of the pulmonary vasculature, such as sarcoidosis. These different classes of diseases may have similar presentations despite differing physiologies and aetiologies. Moreover, in some cases, incorrect diagnosis and instigation of an inappropriate course of action can have serious consequences.

This paper illustrates two particularly challenging clinical cases that can be encountered in patients with pulmonary hypertension.
Pharmacokinetic optimisation of β-lactams for the treatment of ventilator-associated pneumonia
Authors: Drusano G. L.
Published: September 2008

Rational therapy of ventilator-associated pneumonia requires choosing the right drug at the right dose. The choice of dose depends on the microbiological goal, the range of minimum inhibitory concentrations (MICs) for likely pathogens, the extent of the drug's protein binding and, in humans, pharmacokinetics.

If protein binding and the distribution of pharmacokinetic parameters are known, as well as the likely pathogens and MICs in a given setting, Monte Carlo simulations can be used to calculate the likelihood that a given dose will attain an identified microbiological goal. For β-lactams, the antibacterial effect depends on the percentage of time (%T) during the dosing interval that the free (nonprotein bound) antibiotic concentration remains above the MIC (%T >MIC); the required values are smaller for carbapenems than for penicillins or cephalosporins.

Data show that infusion of ani.v.β-lactam over an extended period may greatly increase %T >MIC, and hence efficacy, at a given dose. Alternatively, it may provide the same efficacy at a lower total dose, reducing cost and potential toxicity. In a real-life setting, a 4-h infusion of 3.375 g piperacillin-tazobactamq8 h(every 8 h; 3 times daily); proved more effective for severePseudomonas aeruginosainfections than a 30-min infusion of 3.375 gq6 h(every 6 h; 4 times daily) orq4 h(every 4 h; 6 times daily).

Data for doripenem, an investigational carbapenem, suggest that its stability following reconstitution may render it particularly suitable for extended infusion.
The rationale for treating allergic asthma with anti-IgE
Authors: Hamelmann E.
Published: September 2008

An estimated two-thirds of asthma is allergic and >50% of severe asthma has an allergic component. An increased immunoglobulin (Ig)E production in response to environmental allergens (atopy) is the strongest detectable predisposing factor for the development of asthma, particularly when sensitisation occurs early in life.

IgE binds to high-affinity receptors (FcϵRI) on effector cells, such as mast cells and basophils. Allergen binds to IgE and initiates an inflammatory cascade resulting in release of pro-inflammatory mediators that contribute to the acute and chronic symptoms of allergic airway diseases. By reducing serum IgE levels and FcϵRI receptor expression on key cells in the inflammatory cascade, omalizumab blocks the release of inflammatory mediators from mast cells and reduces the infiltration of inflammatory cells, notably eosinophils, into the airway. In patients with allergic asthma, omalizumab inhibits both the early and late asthmatic response and several other markers of inflammation, including the requirement for inhaled or oral corticosteroids.

The anti-inflammatory effects of omalizumab provide proof-of-concept of the key role played by immunoglobulin E in allergic respiratory disease. Omalizumab represents a novel approach to the treatment of asthma, inhibiting the inflammatory cascade before it starts.
Which patients should be treated with anti-IgE?
Authors: -M. Beeh K.
Published: September 2008

In the European Union, omalizumab is indicated as add-on therapy to improve asthma control in adult and adolescent patients (≥12 yrs of age) with severe persistent allergic asthma who have a positive skin test orin vitroreactivity to a perennial aeroallergen, and who, despite receiving daily high-dose inhaled corticosteroids and a long-acting β2-agonist, have the following characteristics: reduced lung function (forced expiratory volume in one second <80%); frequent daytime symptoms or night-time awakenings; and multiple documented severe asthma exacerbations. Omalizumab is indicated for patients with baseline total immunoglobulin E levels of 30–700 IU·mL−1. Patients who receive omalizumab should be assessed by their physician after 16 weeks and treatment continued only if there has been a marked improvement in asthma control. Omalizumab is administered by subcutaneous injection every 2 or 4 weeks at a dosage determined using a dosing table based on the patient's pre-treatment serum total immunoglobulin E levels and body weight.
Inflammation in COPD: a link to systemic comorbidities
Authors: Rennard S. I.
Published: September 2008

Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable disease characterised by progressive airflow limitation that is not fully reversible and associated with an abnormal inflammatory response in the lungs.

Results from a large number of recent studies have characterised the inflammatory processes underlying COPD. Inflammatory cells, most notably CD8+ T-lymphocytes, macrophages and neutrophils, as well as a large number of chemokines, cytokines and proteinases, are believed to play a role.

The inflammatory processes in COPD contribute to remodelling of pulmonary tissues, leading to the irreversible airflow limitation characteristic of this disease. Inflammation may also contribute to the comorbidities often observed in COPD patients. Patients with COPD often have cardiovascular disease, changes in body composition, osteoporosis and anaemia. The same inflammatory processes that characterise COPD are also risk factors for these comorbidities.

Ongoing studies are evaluating a wide range of new therapies for chronic obstructive pulmonary disease. Some of these have the potential to blunt the inflammatory processes underlying chronic obstructive pulmonary disease and potentially the associated comorbid conditions. These therapies may significantly improve survival, function and quality of life for patients with this disease.
Where current pharmacological therapies fall short in COPD: symptom control is not enough
Authors: Roche N.
Published: September 2008

Chronic obstructive pulmonary disease (COPD) is a common and progressive condition that is currently the fourth leading cause of death worldwide. There is now a large body of evidence indicating that both pulmonary and systemic inflammation are present in patients with stable COPD and may underlie both respiratory symptoms and common comorbidities of this disease. Smoking cessation and long-term oxygen therapy have been shown to change the course of COPD and recent results obtained with the combination of fluticasone and salmeterol have indicated that it could decrease mortality and slow the decline in lung function in patients with this disease. However, some pharmacological treatments can significantly improve dyspnoea, exercise tolerance, limitations in activity, rate of exacerbations and quality of life (e.g.long-acting bronchodilators and inhaled corticosteroids combined with a long-acting β2-agonist). The ability of these agents to modify the rate of disease progression remains to be firmly established in large-scale, long-term trials.

The concept of disease modification itself in COPD may need to be revisited and more precisely defined in terms of markers and clinical outcomes, including extrarespiratory manifestations: agents that durably affect symptoms, activities, exacerbations and quality of life should probably be considered as disease modifiers. It is also reasonable to suggest that early diagnosis and treatment of patients with COPD might be the first and potentially most important disease-modifying intervention.

There is clearly a need for new therapies that directly target the specific inflammatory processes underlying chronic obstructive pulmonary disease and its pulmonary and extrapulmonary manifestations.
Ventilatory support and pharmacological treatment of patients with central apnoea or hypoventilation during sleep: FIGURE 1.
Authors: Pevernagie D. , Janssens J. P. , De Backer W. , Elliott M. , Pepperell J. , Andreas S.
Published: September 2008

The concept of central sleep apnoea or hypoventilation encompasses hypercapnic central hypoventilation, such as obesity hypoventilation syndrome and eucapnic or hypocapnic central sleep apnoea.

Among subjects with eucapnic or hypocapnic central sleep apnoea, several therapeutic options are available for those with Cheyne–Stokes respiration (CSR). CSR is frequent in patients with New York Heart Association stage III and IV chronic heart failure, and in various neurological disorders. In these patients, treatment modalities include optimising cardiac condition and drugs, such as theophylline, acetazolamide and/or oxygen. Ventilatory support, such as nasal continuous positive airway pressure (CPAP), bi-level pressure support, or adaptive servo-ventilation (ASV), has been shown to improve CSR in patients with cardiac failure; however, convincing evidence that nasal CPAP improves life expectancy in these patients is lacking. Nevertheless, the treatment of associated obstructive sleep-disordered breathing is indicatedper se, as it may improve cardiac function.

There is currently no proof that bi-level ventilation is superior to nasal CPAP. The few available studies that have focused on ASV have shown satisfactory control of CSR in cardiac failure patients. While ASV is not a first-line treatment choice, it appears to be superior to oxygen, CPAP and bi-level pressure ventilation in controlling the apnoea/hypopnea index and probably sleep fragmentation. As yet there are no data on mortality and, as such, firm conclusions cannot be drawn as to the role of ASV in the management of cardiac failure patients suffering from CSR.

Obesity-related hypoventilation has increased dramatically over recent decades due to the epidemic increase in obesity in the developed countries. Obesity hypoventilation syndrome predisposes to the development of pulmonary hypertension and cor pulmonale. Noninvasive home ventilation is increasingly applied in obese patients with hypercapnic respiratory failure, however, initial mechanical ventilatory support can be reduced to nasal continuous positive airway pressure in only a subset of these individuals.
Sleep apnoea, hypertension and vascular disease: where are we now?
Authors: Buyse B. , Hedner J.
Published: September 2008

The objective of the present article was to explore the relationship between obstructive sleep apnoea (OSA) and hypertension (HT) and/or arterial vascular disease (VD), including stroke and ischaemic coronary disease.

Epidemiological and interventional studies on these relationships provide compelling evidence that OSA is causally related to HT. The causal relationship between OSA and VD other than HT has not been firmly established.

A number of pathophysiological mechanisms that could potentially provide a causal link between obstructive sleep apnoea and hypertension, as well as vascular disease, have been identified. Available data on such mechanisms include sustained daytime sympathetic activation, oxidative stress, promotion of vascular inflammation and endothelial dysfunction.
Sleep apnoea and driving: how can this be dealt with?
Authors: Krieger J.
Published: September 2008

Excessive daytime sleepiness has long been known to be associated with an increased risk of often particularly severe traffic accidents. Obstructive sleep apnoea (OSA) is among the most prevalent conditions leading to excessive daytime sleepiness, in addition to impaired cognitive function, both of which are likely to impair driving ability.

An increased risk of traffic accidents has been demonstrated repeatedly, in association with OSA, as well its normalisation with effective treatment. However, it seems that not all patients are at equal risk, but it is not clear how to identify when and how at-risk patients can be identified.

Nevertheless, some European countries have made specific regulations concerning OSA and/or excessive daytime sleepiness and the capacity to obtain or to keep a driving license. Most countries have the general rule that “a driving license should not be given or renewed to any candidate or license holder suffering from a disorder … likely to compromise safety on the road”, without a specific mention of sleepiness and/or sleep apnoea. However, the way in which such a statement is applied and the measures taken to identify unfit drivers vary greatly from country to country. In addition, in those countries that have made specific regulations, no evaluation of their efficacy in reducing sleepiness-related accidents is available.

In practice, it is the physician's responsibility to inform the untreated obstructive sleep apnoea patient about the risk associated with their condition, and about the regulations that prevail in their country, if relevant; only in a few countries, is the physician allowed (or compelled) to report the unfit patient to the licensing authorities. Although it is generally accepted that the treated patient may be allowed to drive, the specific treatment conditions that eliminate the risk are not clearly established.
Mortality in sleep apnoea syndrome: a review of the evidence
Authors: Lavie P.
Published: September 2008

Sleep apnoea syndrome is associated with cardiovascular morbidity, but it is less clear if it is also associated with increased mortality.

Studies investigating mortality in sleep apnoea have 1) compared mortality rates of patients with different levels of severity of the syndrome relying on sleep laboratory populations, 2) compared treated and untreated patients, 3) examined the effect of co-existing cardiovascular diseases on survival and 4) investigated the effect of sleep-disordered breathing on mortality in the elderly.

In spite of methodological limitations, the accumulated data generally support an increased risk of mortality in patients with severe sleep apnoea in comparison with mild or no sleep apnoea, and indicate that efficient treatment decreases mortality. Surprisingly, several studies have shown that the highest risk of mortality in sleep apnoea occurs in patients younger than 50 yrs of age, that risk tends to decline with age and that the occurrence of disordered breathing in sleep in the elderly does not affect mortality. It is as yet unclear if this finding represents a selection bias, differences in apnoea severity or in compliance with treatment between young and old patients, or an adaptation to the syndrome with age.

There is conflicting evidence as to whether the occurrence of sleep apnoea in patients with existing cardiovascular diseases increases the risk of mortality beyond that associated with the cardiovascular diseases themselves.
Results of endoscopic surgery and intralesional steroid therapy for airway compromise due to tracheobronchial Wegener's granulomatosis
Authors: Nouraei S. A. R. , Obholzer R. , Ind P. W. , Salama A. D. , Pusey C. D. , Porter F. , Howard D. J. , Sandhu G. S.
Published: September 2008

Background: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's Granulomatosis (WG). There is at present no consensus on the optimal management of this life-threatening condition.

Objective: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery, and dilatation in managing obstructive tracheobronchial WG.

Methods: Records of eighteen previously-untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006 were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis.

Results: There were nine males and the average age at presentation was 40 (16) years [range 13–74]. There were thirteen patients with tracheal, and five patients with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions respectively. Mean intervention-free interval following minimally-invasive treatment was 26 (2.8) months. Following endobronchial therapy the median intervention-free interval was 22 months (p>0.8 vs. tracheal lesions). No patient required a tracheostomy or endoluminal stenting.

Conclusions: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG, obviating the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG.
Objective evaluation of patient–ventilator interactions during noninvasive ventilation (NIV)
Authors: Rabarimanantsoa Herinaina , Achour Linda , Letellier Christophe , Muir Jean-Francois , Cuvelier Antoine
Published: September 2008

The success of NIV depends on patient–ventilator interactions. These interactions are evaluated with the subjective comfort score which is not always reliable. An objective evaluation is thus required. To evaluate these interactions, we use a statistical measure of the variability of a physiological signal, i.e the Shannon entropy. Our purpose is to show whether estimating Shannon entropy from airway pressure (SP) and from the total duration of ventilatory cycles (ST) may evaluate objectively the patient–ventilator interactions during NIV.

Pressure support NIV was applied to 4 COPD patients, 4 OHS patients in stable state and 4 healthy subjects during six successive 10-min periods with various inspiratory pressure. The flow and the airway pressure signals were recorded with sensors located near the mask. Good patient–ventilator interactions were assumed to correspond to patient well synchronized (low ineffective efforts) and with low ventilatory variability. All the subjects were awaked and both Shannon entropies SPand STwere computed for each ventilatory tracing.

The incidence of ineffective efforts (IE) varied from 0 to 64.7 %. SPappeared to be strongly correlated to this incidence (r = 0.91). STquantified precisely the ventilatory variability. When SPwas plotted versus ST, 4 distinct groups of patients were distinguished as follows:

SP<1 and ST<1: IE<10% but no ventilatory variability

SP<1 and ST>1: IE <10% with high ventilatory variability

SP>1 and ST<1: IE >10% but no ventilatory variability

SP>1 and ST>1: IE > 10% with high ventilatory variability

Shannon entropies objectively evaluate the patient–ventilator interactions in terms of ineffective efforts and ventilatory variability. Good patient–ventilator interactions occur when there is only few ineffective efforts (SP<1) and a low ventilatory variability (ST<1).
Rapid corticosteroid effect on long-acting β2-agonist disposal by smooth muscle cells in the airway: a new paradigm of inhaled combination therapy
Authors: Horvath Gabor , Mendes Eliana S. , Schmid Nathalie , Schmid Andreas , Conner Gregory E. , Salathe Matthias , Wanner Adam
Published: September 2008

Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. Forin vitrofunctional studies, [¶H]-formoterol (FORM) and [¶H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48±0.09, 1.88±0.24, 4.48±0.31 μmol·l−1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5±1.3% vs. 27.4±3.1%, respectively; p<0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4±1.7 vs. 327.5±13.7 pmol·mg−1protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma.
Virtual respiratory system for interactive e-learning of spirometry
Authors: Tomalak W. , Gólczewski T. , Michnikowski M. , Darowski M.
Published: September 2008

Progress in computer simulation technology offers new possibilities for modern medicine. On one hand – virtual organs can help to create animal or human models for research, on the other hand – e-learning or distant learning through Internet is now possible. The aim of our work was to create a system for interactive learning of spirometry (SILS), enabling students or physicians to observe spirometric measurements (flow-volume) modified by setting level and kind of abnormalities within the respiratory system. SILS is based on a virtual respiratory system presented previously in several papers. Its main features are: separation of the lungs and chest; anatomical division of the lungs; division of airway resistance into transmural pressure dependent (Rp) and lung volume dependent (Rv) parts. The one mathematical formula that represents Rpdescribes both flow limitation (forced expiration) and dependence of Raw on lungs volume (small airflows). The output of system are spirometric parameters (as FEV1, FVC, FEV1%FVC) and a flow–volume loop constructed according to results of simulation of forced expiration for the chosen abnormality kind and level.

As a result – this system may be used in teaching process in medical schools and postgraduate education. We offer access to a basic version of SILS for students and physicians at:www.spirometry.ibib.waw.plandwww.zpigichp.edu.pl. As we expect feedback from users, it is possible to modify user interface or model features to comply with users' requests.
Relationship between respiratory muscle strength, functional capacity and quality of life in pre-operative cardiac surgery patients
Authors: Saglam Melda , Arikan Hulya , Savci Sema , Inal-Ince Deniz , Bosnak-Guclu Meral , Degirmence Betul , Nur Turan Hatice , Demircin Metin
Published: September 2008

The aim of this study was to investigate the relationship between respiratory muscle strength, functional capacity, physical activity, and quality of life in preoperative cardiac surgery patients.

Forty eight preoperative cardiac surgery patients (mean age 59.79±10.29 years, 40 M, 8 F, FEV1: 79.52±17.02%) participated in this study. Pulmonary function tests and respiratory muscle strength (MIP and MEP) were performed. Physical activity level was measured using International Physical Activity Questionnaire (IPAQ). Quality of life was determined using Nottingham Health Profile (NHP). Functional capacity was assessed using six-minute walk test (6MWT).

The MIP was significantly correlated with 6MWT distance (r = 0.31, p<0.05). Respiratory muscle strength was not significantly correlated with quality of life and physical activity level (p>0.05). Total physical activity level was significantly related with NHP total score (r =  -0.35, p<0.05), NHP emotional stress dimension (r =  -0.32, p<0.05), NHP pain dimension (r =  -0.35, p<0.05), NHP energy dimension (r =  -0.29, p<0.05), NHP physical activity dimension (r =  -0.37, p<0.05). The NHP physical activity dimension was significantly correlated with 6MWT distance (r =  -0.29, p<0.05).

Inspiratory muscle strength is related to functional capacity in preoperative cardiac surgery patients. Quality of life is related with physical activity level and functional capacity in these patients.
Towards new antituberculotic targets: biochemical characterisation of mycobacterial RNase E/G
Authors: Csanadi Agnes , Zeller Mirijam-Elisabeth , Miczak Andras , Rose Thierry , Bizebard Thierry , Kaberdin Vladimir R.
Published: September 2008

The World Health Organization estimates that each year 3 million people die from tuberculosis (TB) and 8 million people become infected. No new anti-TB drugs have been introduced in the past 30 years, even though their development becomes increasingly important to face new challenges posed by multidrug-resistant and extensively drug-resistant strains and by acute infection withM. tuberculosisof HIV positive patients. Owing to its apparently important role in RNA metabolism, the RNase E/G family of endoribonucleases can be considered as a promising target for antimicrobial drugs. This consideration promted us to characterise biochemical properties of theM. tuberculosisRNase E/G homologue.

To learn more about specific properties of RNase E/G homologues aM. tuberculosisRNase E/G (MycRne) was overexpressed inE. coliand purified as a 6His-tagged polypeptide.To characterise MycRne,we usedin vitrocleavage assays and primer extension analysis of total RNA extracted from mycobacteria.

We show that affinity purified MycRne has an endoribonucleolytic activity, which is dependent on the 5′-phosphorylation status of RNA. We could also show that RNase E/G has Mg2+dependent activity and similar toE. coliRNase E, MycRne was able to cleave in an intercistronic region of the putative 9S precursor of 5S rRNA.

Although, similar toE. coliRNase E, the mycobacterial RNase E/G homologue plays a role in rRNA processing, the substrate specificities of these enzymes show differences. This suggests that RNase E/G can be used as a promising target for antimicrobial drugs that can be optimized to specifically target pathogenic species.
The epithelial integrity is preserved during particle exchange across the epithelium by macrophages and dendritic cells
Authors: Blank F. , Wehrli M. , Baum O. , Gehr P. , Rothen-Rutishauser B.
Published: September 2008

The epithelium of the human airway wall serves as structural and functional barrier against inhaled and deposited particulate antigen. Recently we have shown that human blood monocyte-derived dendritic cells (MDDC) and human blood monocytes derived macrophages (MDM) collaborate as sentinels against foreign particulate antigen by building a transepithelial interacting cellular network. Although the tight junction belt was penetrated by processes of MDDC and MDM to transfer particles across the epithelium, the monolayer integrity of the epithelial cells was not affected. These results brought up two main questions: (1) How is the epithelial integrity preserved? (2) If MDM and MDDC make a direct contact by their processes can they exchange particles?

The presence of tight junction and adherens junction mRNA and proteins in MDM and MDDC monocultures was determined by RT-PCR, and immunofluorescence. Living co-cultures of MDM and MDDC exposed to particles (1 mm in diameter) were investigated by laser scanning microscopy.

We found that MDDC as well as MDM express adherens junction and tight junction mRNA and proteins as shown by RT-PCR and SDS-Page. Furthermore, performing live cell experiments we have seen that MDDC and MDM moved towards each other and that particles were transferred from MDM to MDDC. Interestingly, MDDC also made contacts with other MDDC and we observed particle exchange between them as well.

We may conclude from these findings that MDM and MDDC can form tight junction and adherens junction-like structures with epithelial cells to preserve the epithelial integrity during particle translocation across the epithelium. In addition, we demonstrate an exchange of particles from MDM to MDDC and MDDC to MDDC which supports our hypothesis that MDM and MDDC collaborate as sentinels.