bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing cholinergic constriction: the major reversible mechanism in COPD
Authors: Brusasco V.
Published: September 2008

The airway narrowing in chronic obstructive pulmonary disease (COPD) has often been misunderstood as being irreversible. However, a large proportion of patients with COPD do respond to bronchodilator agents with significant changes in lung function.

Unlike in asthma, abnormalities in airway smooth muscle structure or function are not believed to play a key role in COPD airway narrowing. Although there are only limited data suggesting that cholinergic tone may be increased in COPD, the well-documented efficacy of antimuscarinic agents in increasing airway calibre suggests that cholinergic tone represents the major reversible component of airflow obstruction in these patients. Airway wall thickening and loss of airway-to-parenchyma interdependence are nonreversible components of airflow obstruction in COPD that may amplify the effect of changes in airway smooth muscle tone. Thus, keeping airway smooth muscle tone to a minimum might offer patients long-lasting airway patency and protection against breathlessness, which is the major complaint of patients with COPD.

Receptor antagonism by anticholinergic agents can achieve effective relaxation of airway smooth muscle in COPD. According to a classical view of cholinergic receptor function and distribution, the ideal anticholinergic bronchodilator would be one that blocks both M1and M3receptors, which mediate airway smooth muscle contraction, but not the M2receptor, stimulation of which reduces acetylcholine release from vagus nerve endings and prevents the airway smooth muscle from contracting by excessive increments.

Agents with such pharmacodynamic selectivity are not available, but effective and prolonged inhibition of airway smooth muscle tone has been obtained with tiotropium, which binds to all three major muscarinic receptor subtypes, but for much longer to M3than to M2receptors. Recent data show that long-term treatment with tiotropium for 1 yr helps sustain 24-h airway patency. This sustained effect may help to explain the improvements in both exacerbation rate and lung function observed in chronic obstructive pulmonary disease patients treated with tiotropium.
Impacting patient-centred outcomes in COPD: deconditioning
Authors: Casaburi R.
Published: September 2008

Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from exercise intolerance, leading to a reduced ability to participate in activities of daily life and, therefore, to a reduced health-related quality of life (HRQoL). An important determinant of exercise intolerance is the loss of muscle mass.

Although the mechanism for loss of muscle function is multi-factorial, deconditioning appears to play a primary role in many patients. COPD patients often have decreased fat-free mass compared with healthy counterparts and reduced muscle cross-sectional area. It seems, then, that a cycle of decline often characterises COPD, in which inactivity results in muscle weakness, which in turn acts as a further deterrent to exercise. Such deconditioning can be reversed by pulmonary rehabilitation, leading to significant improvements in exercise tolerance and HRQoL.

Recent research suggests that the effectiveness of pulmonary rehabilitation can be amplified with concomitant administration of tiotropium (a long-acting bronchodilator) or supplemental oxygen. This suggests that facilitating higher training work-rates can enhance the anabolic effects of training.

Patients should be encouraged to maintain activity levels in the follow-up period after training, in order to retain the benefits of rehabilitation.
Tiotropium as essential maintenance therapy in COPD
Authors: Decramer M.
Published: September 2008

Over the past decade, several large-scale clinical trials have been performed to assess the impact of pharmacological treatments on patient-centred outcomes such as dyspnoea, exercise tolerance, exacerbations and health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD).

Tiotropium, a once-daily inhaled anticholinergic agent that works through prolonged muscarinic M3receptor blockade, has consistently been shown to provide sustained improvements in lung function parameters. Furthermore, several prospective trials have shown that tiotropium improves exercise tolerance and augments the beneficial effects of pulmonary rehabilitation. Beyond these important physiological outcomes, tiotropium has been shown to reduce dyspnoea, decrease the frequency of exacerbations and improve HRQoL in studies of ≤1 yr in duration. Such improvements in patient-centred outcomes may allow patients to increase their activity levels, thereby interrupting the downward spiral of chronic inactivity that leads to physical deconditioning and further reductions in exercise tolerance.

Recently, combination therapies of two long-acting bronchodilators have been examined more closely regarding their potential to provide patients with superior symptom relief compared with that provided by single-agent therapy.

Because maintenance treatment with tiotropium provides consistent and sustained improvements in many relevant clinical outcomes of chronic obstructive pulmonary disease, it may reduce the progression of the disease. This hypothesis is being tested in the ongoing Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial.
Physiology and consequences of lung hyperinflation in COPD
Authors: O'Donnell D. E. , Laveneziana P.
Published: September 2008

Lung hyperinflation commonly accompanies expiratory flow limitation in patients with chronic obstructive pulmonary disease (COPD) and contributes importantly to morbidity and an impoverished quality of life. It is not surprising, therefore, that lung hyperinflation has become an important therapeutic target in symptomatic COPD patients. Acute dynamic increases in lung hyperinflation under conditions of worsening expiratory flow limitation and increased ventilatory demand (or both) can seriously stress cardiopulmonary reserves in patients with more advanced disease. The present understanding of the physiological mechanisms of dynamic hyperinflation during exacerbations of COPD and during physical activity continues to grow, together with an appreciation of its negative mechanical and sensory consequences. In this brief overview, definitions and measurement of lung hyperinflation during rest and exercise will be discussed and its potential clinical importance will be considered. The focus will mainly be on current concepts of the mechanisms of air trapping and its role in inducing respiratory discomfort and activity limitation in COPD.
Circulatory effects of expiratory flow-limited exercise, dynamic hyperinflation and expiratory muscle pressure
Authors: Macklem P. T.
Published: September 2008

This article reviews recent research in normal subjects exercising with and without expiratory flow limitation at ∼1 L·s−1imposed by a Starling resistor in the expiratory line, and in patients with chronic obstructive pulmonary disease (COPD), using optoelectronic plethysmography to measure respiratory kinematics, combined with mouth, pleural and abdominal pressure measurements, to assess work of breathing and respiratory muscle performance.

In normal subjects, flow-limited exercise resulted in the following: 1) Impaired exercise performance due to intolerable dyspnoea; 2) hypercapnia; 3) excessive respiratory muscle recruitment; 4) blood shifts from trunk to extremities; 5) a 10% reduction in cardiac output and a 5% reduction in arterial oxygen saturation, decreasing energy supplies to working respiratory and locomotor muscles. In both normal subjects and in COPD patients, dynamic hyperinflation did not always occur. Those patients that hyperinflated had worse lung function and less work of breathing, but better exercise performance than the others, in whom expiratory muscle recruitment prevented dynamic hyperinflation at the cost of increased work of breathing and excessive oxygen cost of breathing. This established an early competition between respiratory and locomotor muscles for available energy supplies.

Dynamic hyperinflation is a better exercise strategy in chronic obstructive pulmonary disease than expiratory muscle recruitment, but the benefit it confers is small.
Nonpharmacological modulation of dynamic hyperinflation
Authors: Wouters E. F. M.
Published: September 2008

Expiratory flow limitation is the pathophysiological hallmark of chronic obstructive pulmonary disease (COPD), but dyspnoea is the most prominent and distressing symptom. Acute dynamic hyperinflation (DH), which refers to the temporary increase in operating lung volumes above their resting value, is a key mechanistic consequence of expiratory flow limitation and has serious mechanical and sensory consequences. In flow-limited patients, pharmacological interventions using bronchodilating agents act by improving dynamic airway function: enhancing lung emptying and reducing lung hyperinflation. Besides bronchodilators, other factors that reduce the ventilatory demand at a given level of exercise or interventions that aim to improve lung emptying or to reduce resting levels of hyperinflation decrease the rate of development of DH in COPD patients. The different nonpharmacological intervention strategies that aim to reduce lung hyperinflation are summarised in the present article, as well as the different underlying mechanisms contributing to lung deflation. The following interventions are systematically reviewed in the present article: breathing supplemental oxygen or low-density gas mixtures of helium and oxygen, pulmonary rehabilitation and noninvasive positive pressure ventilation. Pulmonary rehabilitation and noninvasive pressure ventilation reduce the DH; the effects of heliox-breathing and hyperoxia are more variable. These nonpharmacological interventions have importantly contributed to the present understanding of the role of hyperinflation in COPD patients.
Bronchoscopic lung volume reduction
Authors: Polkey M. I. , Hopkinson N. S.
Published: September 2008

Surgical lung volume reduction can improve exercise performance and forced expiratory volume in one second in patients with emphysema. However, the procedure is associated with a 5% mortality rate and a nonresponse rate of ∼25%. Accordingly, interest has focused on alternative ways of reducing lung volume. Two principle approaches are used: collapse of the diseased area using blockers placed endobronchially and the creation of extrapulmonary pathways. Preliminary data from the former approach suggest that it can be successful and that the magnitude of success is related to reduction in dynamic hyperinflation.
Sampling for stereology in lungs
Authors: Nyengaard J. R. , Gundersen H. J. G.
Published: September 2008

The present article reviews the relevant stereological estimators for obtaining reliable quantitative structural data from the lungs. Stereological sampling achieves reliable, quantitative information either about the whole lung or complete lobes, whilst minimising the workload. Studies have used systematic random sampling, which has fixed and constant sampling probabilities on all blocks, sections and fields of view. For an estimation of total lung or lobe volume, the Cavalieri principle can be used, but it is not useful in estimating individual cell volume due to various effects from over- or underprojection. If the number of certain structures is required, two methods can be used: the disector and the fractionator.

The disector method is a three-dimensional stereological probe for sampling objects according to their number. However, it may be affected on tissue deformation and, therefore, the fractionator method is often the preferred sampling principle. In this method, a known and predetermined fraction of an object is sampled in one or more steps, with the final step estimating the number. Both methods can be performed in a physical and optical manner, therefore enabling cells and larger lung structure numbers (e.g.number of alveoli) to be estimated. Some estimators also require randomisation of orientation, so that all directions have an equal chance of being chosen. Using such isotropic sections, surface area, length, and diameter can be estimated on a Cavalieri set of sections.

Stereology can also illustrate the potential for transport between two compartments by analysing the barrier width. Estimating the individual volume of cells can be achieved by local stereology using a two-step procedure that first samples lung cells using the disector and then introduces individual volume estimation of the sampled cells.

The coefficient of error of most unbiased stereological estimators is a combination of variance from blocks, sections, fields of view, and noise due to random positioning of the probes. This can be decreased by increasing the number of units from the element causing the most variance. Overall, stereology provides lung scientists with efficient tools for estimating structural components correctly.
Stereological analysis of acute lung injury
Authors: Ochs M.
Published: September 2008

Acute lung injury is associated with a variety of histopathological alterations, such as oedema formation, damage to the components of the blood–air barrier and impairment of the surfactant system. Stereological methods are indispensable tools with which to properly quantitate these structural alterations at the light and electron microscopic level. The stereological parameters that are relevant for the analysis of acute lung injury are reviewed in the present article.
Animal models of pulmonary emphysema: a stereologist's perspective
Authors: Fehrenbach H.
Published: September 2008

A variety of animal models have been suggested as models of pulmonary emphysema; these are critically discussed in the present article from a stereologist's perspective. In addition, a stereological design for the quantification of experimentally induced emphysema is proposed.

On the basis of the widely accepted definition of pulmonary emphysema being an “abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls,” quantitative morphology is the only method with which to reliably assess the presence of emphysema. Recognising this, careful inspection of animal models that are based on instillation of elastase, genetic alterations, inhalation of cigarette smoke or induction of apoptosis, reveals that both criteria of emphysema definition were demonstrated in surprisingly few of them.

Several aspects are suggested to be critical for the understanding of animal models of human emphysema. For example, genetic models that rely on the inhibition of the formation of alveoli during post-natal alveolarisation should clearly be distinguished from models that rely on the loss of mature alveoli after alveolarisation is complete. Furthermore, inhalation models that are characterised by exposed animals exhibiting a severe loss of body weight should carefully examine the relative contribution of intervention and weight loss, respectively. Models that rely on the exposure of juvenile animals for several weeks or even months should take into account the effects of normal lung growth and ageing.

Stereology offers appropriate tools with which to quantify the parameters relevant to assess development and the regeneration of emphysema. Stereologists continue to develop tools that will help ascertain the reliability of established and new models. If inappropriate parameters continue to be used for the evaluation of animal models of emphysema, thinking and resources are likely to be misdirected and the models may limit rather than expand the understanding of human emphysema and the development of new therapies.
Quantitative morphology of compensatory lung growth
Authors: Hsia C. C. W.
Published: September 2008

Compensatory lung growth is defined by the absolute increases in the quantity of functioning lung tissue in response to injury and/or disease, leading to a positive impact on functional outcome. The pneumonectomy model is used as an example to illustrate the salient features of compensatory growth and the specific considerations in its morphological quantification, including techniques of sampling and analysis, resolution of ultrastructural details, selection of markers for measurement, and interpretation of results in the context of organ architecture and physiology. The potential for structure–function dissociation is described in the present article. The current paper will discuss the application of high-resolution computed tomography to noninvasively quantify regional anatomy as well as temporal evolution of lung growth.
The molecular controls of resolution of inflammation: what can we learn from zebrafish?
Authors: Renshaw StephenA. , Loynes CatherineA. , Trushell DanielM. , Ingham PhilipW. , Whyte MoiraK. B.
Published: September 2008

Although we are separated from zebrafish by 160 million years of evolution, we share many features of the innate and adaptive immune systems. In addition, we can manipulate the genome of zebrafish, and observe the effects on inflammation
in vivo
as they are transparent in their larval stages. This has exciting implications for the study of inflammatory diseases.

We have established a model of inflammation in the zebrafish tail, in which caspase dependent cell death is required for resolution. For example, addition of the pan-caspase inhibitor zVD added at 4 hours after tailfin injury increases the number of neutrophils present from 6.0+/-1.0 to 28.9+/- 3.3 (mean +/- s.e.m. p<0.001 n = 3).

The transparency of the larvae makes these an ideal model for the study of
in vivo
inflammation, and we have generated fluorescent systems for the easy visualisation of neutrophilic inflammation and resolution
in vivo
.

We are also performing an unbiased forward genetic screen for mutants with defective resolution of inflammation, and to date have identified 38 putative mutants. These techniques allow new approaches to understanding the molecular controls of inflammation resolution.
Molecular mechanisms of the synergy between cysteinyl-leukotrienes and receptor tyrosine kinase growth factors on human bronchial fibroblast proliferation
Authors: Yoshisue Hajime , Holgate StephenT. , Davies DonnaE. , Sampson AnthonyP.
Published: September 2008

We have reported that cysteinyl-leukotrienes (cys-LTs) synergise not only with epidermal growth factor (EGF) but also with platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) to induce mitogenesis in human bronchial fibroblasts. We now describe the molecular mechanisms underlying this synergism. Mitogenesis was assessed by incorporation of [3H]thymidine into DNA and changes in protein phosphorylation by Western blotting. Surprisingly, no CysLT receptor antagonists (MK-571, montelukast, BAY u9773) prevented the synergistic mitogenesis. LTD4did not cause phosphorylation of EGFR nor did it augment EGF-induced phosphorylation of EGFR, and the synergy between LTD4and EGF was not blocked by the metalloproteinase inhibitor GM6001 or by an HB-EGF neutralising antibody. The EGFR-selective kinase inhibitor, AG1478, suppressed the synergy by LTD4and EGF, but had no effect on the synergy with PDGF and FGF. While inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase and protein kinase C (PKC) prevented the synergy, these drugs also inhibited mitogenesis elicited by EGF alone. In contrast, pertussis toxin (PTX) efficiently inhibited the potentiating effect of LTD4on EGF-induced mitogenesis, as well as that provoked by PDGF or FGF, but had no effect on mitogenesis elicited by the growth factors alone. Whereas LTD4alone did not augment phosphorylation of extracellular signal-regulated kinase (Erk)-1/2 and Akt, it increased phosphorylation of PKC in a Gαi-dependent manner. Addition of LTD4prolonged the duration of EGF-induced phosphorylation of Erk-1/2 and Akt, both of which were sensitive to PTX. The effect of cys-LTs involves a PTX-sensitive and PKC-mediated intracellular pathway leading to sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt.
Dual effect of neutrophils on secretory component production by human bronchial epithelial cells
Authors: Pilette C. , Detry B. , Guisset A. , Sibille Y.
Published: September 2008

A decreased bronchial expression of secretory component (SC) was demonstrated in severe COPD, and correlated with neutrophils. Mechanisms of epithelial cell/neutrophils interactions remain however poorly understood.

Calu-3 (human bronchial epithelial) cells were incubated after confluence (in triplicate conditions) with various ratios of activated neutrophils (0.5:1 to 15:1, neutrophils: Calu-3 cells). After 48hrs of co-culture supernatants were assayed for SC by ELISA.

SC production by Calu-3 cells increased at intermediate neutrophil numbers (316±32versus193±19ng·ml−1, ratio of 5:1versuscontrol, mean±SEM of 3 experiments, p = 0.05). In contrast, a trend for decrease in SC was observed with high neutrophil numbers (111±19versus193±19ng·ml−1, ratio of 15:1versuscontrol, p = 0.06). The addition of secretory leukocyte protease inhibitor further increased SC upregulation at intermediate ratios, and inhibited the SC decrease at high neutrophil numbers. The mechanism of SC up-regulation by neutrophils did not implicate TNF-α or IL-1β.

This study provides direct evidence of a dual effect of neutrophils on epithelial SC. Our data suggest that neutrophils could differently affect epithelial immune secretory function according to the extent of neutrophil influx and/or to the reactivity of airway epithelial cells.
A stop codon polymorphism of toll-like receptor 5 is associated with a stable course of chronic obstructive lung disease
Authors: Pabst Stefan , Yenice Vildan , Lennarz Martina , Baumgarten Georg , Knuefermann Pascal , Hecht Bettina , Gillissen Adrian , Vetter Hans , Grohe Christian
Published: September 2008

The etiology of chronic obstructive lung disease (COPD) is unclear. It is supposed to be the product of an exogenous antigenic stimulus, such as tobacco smoke, and an endogenous genetic susceptibility. Toll-like receptors (TLR) are signal molecules, essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS) binds to TLR4 and two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have recently been described. TLR5 is the receptor for flagellin, aconstituent of Gram-positive and -negative bacterial flagella. A functional relevant TLR5 polymorphism (TLR5392STOP) has already been identified. The coactivation of both TLR4 and 5 seems to play an important role in the mediation of host-defense mechanisms. We genotyped 138 Caucasian patients with COPD and 135 healthy controls for the TLR5 polymorphism TLR5392STOP respectively for Asp299Gly and Thr399Ile polymorphisms in theTLR4gene. Among COPD patients the prevalence for the TLR5 mutant allele was 9.42% (26/276). The prevalence for each Asp299Gly and Thr399Ile mutant allele was 4.71% (13/276). In the control group the TLR5 mutation prevalence was 5.19% (14/270) (P = 0.138), the prevalence of each TLR4 polymorphism was 2.96% (8/270) (p = 0.279). In the subgroup of 54 patients with a stable course of COPD, defined as less than three hospitalizations over the last three years due to COPD, we found a significant association with the TLR5392STOP gene polymorphism (P = 0.026). These data suggest that the TLR5392STOP polymorphism is associated with a stable course of COPD, whereas TLR4 polymorphisms have no impact neither on the onset nor on the course of COPD.
Extracellular superoxide dismutase (EC-SOD) as a protective factor for risk of chronic obstructive pulmonary disease
Authors: Bowler R. P. , Hokanson J. , Taylor M. , Levy S. , Canaham E. M. , Regan E. , Wheeler C. , Nicks M. , Chan E. , Crapo J. D.
Published: September 2008

Tobacco smoke contains a high concentration of oxidants and is the primary cause of chronic obstructive pulmonary disease (COPD). Extracellular superoxide dismutase (EC-SOD) is the major antioxidant enzyme in the extracellular space of the lung and is part of the lung defense against these oxidants. We hypothesized that EC-SOD is a risk factor for COPD. We found that EC-SOD plasma levels were significantly higher (p<0.001) in 337 patients with COPD (147±7 ng·ml−1) versus 343 controls (96±9 ng·ml−1) and that lower FEV1s were associated with lower EC-SOD levels. To identify whether the EC-SOD gene was associated with COPD, we resequenced a subset of 188 subjects and identified 33 novel SNPs. Two of these SNPs (rs8192287 and rs8192288) were associated with a reduced odds of having COPD (OR 0.05 and 0.34; P<0.05). Haplotype analysis using a total of 5 EC-SOD SNPs (Table 1) further identified a protective haplotype (TTCGC) that was found in 11.4% of controls, but only 2.1% of subjects with COPD (P<0.001). These data indicate that EC-SOD genotype may partially predict whether smokers are resistant to the effects smoking.
Base excess, a marker of chronic hypercapnic respiratory failure and predictor of survival in COPD
Authors: Budweiser Stephan , Jörres RudolfA. , Riedl Theresa , Heinemann Frank , Pfeifer Michael
Published: September 2008

We studied the role of base excess (BE) as marker of chronic hypercapnia and survival in patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnic respiratory failure (CHRF). Moreover, it was investigated whether the effects of non-invasive positive pressure ventilation (NPPV) on CHRF were reflected in BE and survival.

In 240 (160 without exacerbation) patients with COPD (mean±sdFEV1 30.7±9.7 %pred; PaCO256.9±9.9 mmHg) body-mass index (BMI), lung function, respiratory muscle function, blood gases and 6-minute walking distance (6-MWD) were assessed prior to initiation of NPPV. In addition, the changes of risk factors 6.3±2.9 months after initiation of NPPV were evaluated.

Overall mortality during the follow-up time (26.0±24.5 months) was 34.6%. Deaths resulted predominantly from respiratory causes (65.1%); among those, respiratory failure was most frequent (85.2%). Univariate analysis revealed BMI, FEV1, maximal inspiratory pressure (PImax), inspiratory load (P0.1), haemoglobin, 6-MWD, hyperinflation (IC/TLC, RV/TLC), blood gases and BE to be associated (p<0.05 each) with prognosis. In multivariate analyses, however, only BMI, RV/TLC and BE turned out to be independent cross-sectional predictors (p<0.05). Kaplan-Meier analyses showed that BE had predictive value particularly in patients with BMI≥25 kg·m−2, RV/TLC≥70 % and PaCO2≥57 mmHg. Furthermore, changes of BMI, RV/TLC and BE (p<0.01) were associated with improved prognosis in severe hypercapnic COPD.

In patients with COPD and CHRF, BE was a prognostic marker for mortality, that was independent from other factors, particularly PaCO2. In addition, reversal of CHRF was reflected in BE and appeared to have an impact on prognosis.
Noninvasive markers of airway inflammation and redox biochemistry applied to asthma
Authors: Carraro S.
Published: September 2008

At the European Respiratory Society (ERS) Annual Congress 2006, I received the ERS Annual Award for Pediatric Respiratory Research in Europe for my research work on noninvasive markers of airway inflammation. Most of the studies in which I have been involved were conducted at the University of Padova, Padova, Italy. We have studied asthmatic children, and have demonstrated that some markers of inflammation (e.g cysteinyl leukotrienes) and oxidative stress (e.g.8-isoprostane and malondialdehyde) are increased in their exhaled breath condensate, while antioxidant products, such as glutathione, are reduced. In addition, while I was working in the laboratory of Dr Benjamin Gaston at the University of Virginia, Charlottesville, VA, USA, I conducted some basic research studies. A first group of experiments was aimed at investigating the role of rhinovirus infection in airway acidification. A second group of experiments was conducted to investigate the mechanisms involved in the regulation of expressionS-nitrosoglutathione reductase (GSNOR), an enzyme that has a role in asthma pathogenesis, breaking down the endogenous bronchodilator GSNO.
The effect of entrainment site and inspiratory pressure on the delivery of oxygen therapy during non-invasive mechanical ventilation (NIMV) in acute COPD patients
Authors: Kaul Sundeep , Stell IanM. , Chinn S. , Polkey M. , Moxham J.
Published: September 2008

Supplemental O2is frequently added to bi-level non-invasive ventilation circuits to maintain Sa,O2>90%. Oxygen can be added at several points & in the presence of different inspiratory pressures. The effect of varying entrainment sites and inspiratory pressures (IPAP) on PO2, PCO2, Fio2, inspiratory triggering and expiratory triggering in COPD patients is unknown.

18 patients with stable COPD (mean FEV1 47%) participated in the study. Oxygen was added at 4 sites in the ventilatory circuit (site 1: between mask and exhalation port; site 2: just distal to exhalation port; site 3: at ventilator outlet; site 4: directly into the mask via an inlet). The effect of varying entrainment sites and inspiratory pressures on arterial PO2, PCO2, FIO2, was recorded at 3 mins. The same full face mask (Respironics, Image 3) & ventilator (Respironics, BIPAP ST 30) was used.

Results for PO2 are shown at IPAP 10/EPAP 4 [table 1].

Anova was used to analyse the data.

Site 4 (via mask) was associated with a significantly higher PO2 at all flow rates compared with sites 1, 2 and 3 (P<0.001).

Site 3 (at ventilator outlet) was associated with the lowest PO2 at all flow rates, particularly at 15 L min (P<0.001).

Adding oxygen to the mask at lower IPAPs result in higher oxygen delivery.
The effect of continuous positive airway pressure on glucose excursions in diabetics with sleep-disordered breathing: the results of continuous glucose monitoring
Authors: Pallayova M. , Donic V. , Donicova V. , Tomori Z. , Gresova S.
Published: September 2008

Sleep-disordered breathing (SDB) is often associated with impaired glucose metabolism. The study aimed at assessing immediate effect of CPAP on glucose excursions in type 2 diabetic patients with SDB measured with 72-hour continuous glucose monitoring system (CGMS).

8 type 2 diabetic patients with SDB (men, age 48,13±4,91 years, BMI 34,06±7,41 kg·m−2, HbA1c 7,3±1,4%) underwent 2 overnight polysomnographic examinations including diagnostic night and CPAP night. CGMS was applied on both occasions. Statistical analyses included paired Student's t-test.

CPAP decreased apnoea-hypopnoea index (AHI) from 57,64±9,64·h−1to 8,05±4,42·h−1(p<0,0001) with significant improvement of saturation. Frequent episodes of sleep apnoea/hypopnoea and severe oxygen desaturation were followed by significant rise in blood glucose of up to 12,3 mmol·l−1. Duration of post-hypoxic hyperglycemia was 50±10,79 min and its climax tended to be appeared up to 45min post-hypoxia. Nocturnal hyperglycemia strongly correlated with severe oxygen desaturation. Nocturnal glucose values were significantly higher during diagnostic night than during CPAP night (8,19±0,99 mmol·l−1versus 6,77±1,47 mmol·l−1; p<0,0001). CGMS also showed improved preprandial and 1,5-hour postprandial glucose levels for breakfast after CPAP night. The improvement in overall glucose levels was much greater in patients with BMI<30 kg·m−2than in more obese patients.

The results suggest that nocturnal hyperglycemia is closely related to desaturation and CPAP treatment may have an immediate decreasing effect on blood glucose in type 2 diabetic patients with SDB.
Exhaled nitric oxide in childhood asthma: methodological issues and clinical applications
Authors: Pijnenburg Mariëlle
Published: September 2008

The work described herein was presented as an oral, invited presentation at the European Respiratory Society (ERS) Congress 2006 and was awarded the European Respiratory Society Annual Award for Paediatric Respiratory Research in Europe; the work consists of two parts. The first part is on methodological issues of measuring exhaled nitric oxide fraction (Fe,NO) in children. The second part includes four studies on clinical applications ofFe,NOmeasurements in asthmatic children.
Predictors of elevated tumour necrosis factor α level in obstructive sleep apnoea syndrome
Authors: Ryan Silke , Taylor CormacT. , McNicholas WalterT.
Published: September 2008

Circulating levels of TNF-α are elevated in Obstructive Sleep Apnoea Syndrome (OSAS) and likely contribute to associated cardiovascular diseases. Furthermore, TNF-α has been suggested as a mediator of excessive daytime sleepiness (EDS). We investigated the predictors of TNF-α in OSAS in large, well-selected patient and control cohorts.

We undertook a prospective study of 30 non-OSAS (including 22 non-sleepy controls and 8 sleepy non-apnoeic snorers), 36 mild-moderate OSAS and 31 severe OSAS male subjects. All groups were closely matched in age, BMI, smoking status, blood pressure and lipid profile. All subjects were free of other disease and were not taking regular medication. Serum for TNF-α assay was drawn following polysomnography (PSG) in all subjects. 49 patients were commenced on CPAP therapy within one week following PSG; sleep studies and TNF-α measurements were repeated 6 weeks later.

TNF-α was higher in OSAS patients than controls (p<0.001). In multivariate analysis, TNF-α was independently associated with the desaturation index (r = 0.399, p<0.001), the Epworth Sleepiness Score (ESS) (r = 0.243, p = 0.005) and total cholesterol (r = 0.216, p = 0.018). Furthermore, levels were higher in sleepy non-OSAS patients than in controls (4.49[3.35,6.94] pg·ml−1vs 2.46[1.66,3.40]; p = 0.002) but lower than in severe OSAS patients (6.32[5.70,8.17]; p = 0.03). CPAP significantly lowered TNF-α (from 5.56±2.10 to 4.13±2.99 pg·ml−1; p = 0.004).

The severity of intermittent hypoxia is the strongest predictor of TNF-α level supporting a key role of inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF-α is independently associated with EDS.
Diagnostic value of procalcitonin, CRP, leukocytes and BAL neutrophils for pulmonary complications in the immunocompromised host
Authors: Stolz Daiana , Stulz Andreas , Mueller Beat , Tamm Michael
Published: September 2008

We evaluated the diagnostic accuracy of laboratory biomarkers and BAL differential cell count for the diagnosis of bacterial infection in severe immunosuppressed patients. One-hundred and seven consecutive patients undergoing bronchoscopy for suspected pulmonary infection were included in this study. Assessment included history, clinical examination, chest image studies, CRP, procalcitonin (ProCT), leukocyte counts, and BAL results. Patients were classified as having proven, possible, and non-bacterial infection.
Plasticity of vascular progenitor cells: Implications in pulmonary vascular remodelling in COPD
Authors: Díez M. , Peinado V. I. , Ferrer E. , Ramírez J. , Roca J. , Rodriguez-Roisin R. , Barberà J. A.
Published: September 2008

Vascular progenitor cells (VPC) have shownin vitroandin vivotheir ability to differentiate into endothelial cells (EC). Some evidence suggests that the plasticity of these cells to differentiate into other cell types might contribute not only to angiogenesis but also to perpetuate vascular lesions. Studies done in pulmonary arteries (PA) of patients with COPD have demonstrated the presence of VPC infiltrating the intima. Since intimal thickening is mainly constituted by smooth muscle cells (SMC), we asked whether VPC could play a role in wall thickening. Accordingly, the objective was to evaluatein vitrothe plasticity of VPC to differentiate into SMC and EC of human PA. G-CSF-mobilized peripheral blood CD133+ cells from a commercial primary line were expanded and labelled with acetylated-LDL-DiI for tracking cell purposes. Then, cells were co-cultured with commercial primary lines of human PA EC or SMC (n = 3). As control, CD133+ cells were cultured alone, with minimal medium with or without VEGF (50ng·ml−1). After 6 and 12 days of growth, the phenotype of cultures was characterized by immunofluorescence with: lectin, α-actin and CD31. Cells were also evaluated morphologically. After 6 days, VPC acquired the morphology and the phenotype of the cells with which they were co-cultured, EC (lectin+, CD31+, α-actin-) or SMC (α-actin+, lectin-, CD31-). VPC cultured 12 days alone or with VEGF did not acquire typical morphology and markers of mature EC or SMC of PA. We conclude that VPC have the potential to differentiatein vitrointo SMC, and that this plasticity could contribute to perpetuate pulmonary vascular remodelling in COPD.
Making a diagnosis in PAH
Authors: Gibbs J. S. R.
Published: September 2008

Poor survival among patients with untreated pulmonary arterial hypertension (PAH) means that timely and accurate diagnosis is of paramount importance. However, the nonspecific nature of PAH symptoms, which include breathlessness and fatigue, make PAH a considerable diagnostic challenge. As a result, many patients are passed among different physicians and are only correctly diagnosed at relatively advanced stages of disease, when they are already significantly compromised and are finding even the basic activities of daily living difficult. Over recent years, the advent of targeted therapies has changed PAH from a rapidly fatal disease to a serious but treatable condition. This makes the need for obtaining a rapid and accurate diagnosis all the more urgent.

The diagnostic process itself requires a reason for clinical suspicion and a series of investigations that are intended to confirm the diagnosis, to establish the cause of pulmonary hypertension and to determine the severity. The present paper reviews the routine investigations available to the physician to diagnose PAH, including electrocardiography, chest radiography, transthoracic Doppler echocardiography and right heart catheterisation, and highlights some of the diagnostic pitfalls encountereden routeto an accurate diagnosis of PAH.
Dual endothelin receptor antagonism: setting standards in PAH
Authors: Humbert M.
Published: September 2008

Endothelin (ET) has emerged as a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). The effects of ET are mediated by its binding to two receptors on endothelial and pulmonary smooth muscle cells: ETAand ETB. Blockade of both these receptors with the oral dual ET receptor antagonist, bosentan, represents an attractive treatment option for these severely compromised patients.

The efficacy of bosentan in PAH has been demonstrated in randomised controlled trials in idiopathic PAH, and PAH associated with connective tissue diseases and congenital heart disease.

In addition, an open-label study has shown clinical and haemodynamic effects in PAH associated with HIV infection. In these trials, bosentan has been shown to improve haemodynamics, increase functional capacity, improve time to clinical worsening, which is a surrogate marker of survival, and to improve patients' quality of life; in longer-term studies, it has been shown to improve patient outcome.

The current article will present these key data from randomised controlled trials on bosentan as well as experiences from everyday clinical practice.
Blocking endothelin: breaking new ground
Authors: du Bois R. M.
Published: September 2008

Endothelin is one of a number of profibrotic cytokines and growth factors, along with transforming growth factor-β, connective tissue growth factor and tumour necrosis factor-α, thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases characterised by fibrosis, including IPF-related pulmonary hypertension.

A growing body of evidence has supported a mitogenic effect of endothelin on fibroblasts and demonstrated that endothelin can reduce collagen breakdown and induce the synthesis of extracellular matrix components, all contributing to fibrosis. These findings, together with the detection of elevated levels of endothelin in the plasma and bronchoalveolar lavage fluid of patients, provide a sound rationale for dual endothelin receptor antagonism as a potential therapy for IPF and other fibrotic lung diseases.

The randomised controlled trial of Bosentan Use in Interstitial Lung Disease (BUILD)-1 investigated the potential of bosentan for the treatment of idiopathic pulmonary fibrosis. Although bosentan did not improve exercise capacity, encouraging trends were seen in the pre-defined clinically relevant end-point of disease progression or death, as well as dyspnoea and quality of life measures. The potential efficacy of bosentan, a well-established pathogenic mediator in pulmonary arterial hypertension, will continue to be evaluated in the treatment of idiopathic pulmonary fibrosis.
Importance of appropriate initial antibiotic therapy and de-escalation in the treatment of nosocomial pneumonia
Authors: Rello J.
Published: September 2008

Inappropriate initial antibiotic therapy in nosocomial pneumonia is associated with higher mortality, longer hospital stays and increased healthcare costs. The key pathogens associated with these adverse outcomes includePseudomonas aeruginosa, methicillin-resistantStaphylococcus aureusandAcinetobacter baumannii.

Due to the increasing rates of resistance, a new paradigm is needed for treating nosocomial infections in the intensive care unit (ICU). Optimal initial therapy consists of a broad-spectrum antibiotic started in a timely manner and administered at the correct dose andviathe correct route.

Because pathogen aetiology and resistance patterns vary from one ICU to another, recommendations for initial therapy should be tailored to each institution. Selection of the broad-spectrum antibiotic should be based on the patient's risk factors (including comorbidities, duration of ventilation and recent antibiotic exposure), suspected pathogen and up-to-date local resistance patterns.

After 48–72 h, the patient should be reassessed and antibiotic therapy de-escalated based on the microbiological results and the clinical response.
Examining the unmet need in adults with severe asthma
Authors: Partridge M. R.
Published: September 2008

Asthma currently affects an estimated 300 million people worldwide and the number is expected to rise to 400 million by 2025. Asthma morbidity remains high and the economic burden is significant. Approximately 20% of patients have severe persistent asthma. As patients with severe asthma often have a variety of conditions that may coexist with or be mistaken for asthma, careful diagnosis and management are essential, and adhering to a protocol for investigations is helpful.

For patients with severe persistent asthma, the Global Initiative for Asthma 2005 guidelines recommend the use of high-dose inhaled corticosteroids in combination with a long-acting β2-agonist, with one or more additional controller medications if required (step 4 therapy). However, recent studies have shown that asthma remains inadequately controlled in many patients with severe asthma, despite treatment in accordance with guidelines.

Patients with severe asthma have the highest healthcare utilisation and mortality, and there is clearly an unmet need for the effective and safe treatment of patients with severe persistent allergic asthma who remain symptomatic despite optimised standard treatment. The latest guidelines suggest that omalizumab may address this unmet need.
Anti-IgE: lessons from clinical trials in patients with severe allergic asthma symptomatic despite optimised therapy
Authors: Buhl R.
Published: September 2008

The efficacy of omalizumab has been extensively investigated in clinical trials in patients with severe persistent allergic (pre-treatment total immunoglobulin E 30–700 IU·mL−1) asthma including the Investigation of Omalizumab in Severe Asthma Treatment (INNOVATE) study, which enrolled patients with inadequately controlled severe persistent allergic asthma despite receiving high-dose inhaled corticosteroid in combination with a long-acting β2-agonist, and also additional controller medication if required.

In the INNOVATE study, add-on omalizumab significantly reduced clinically significant exacerbation rates by 26% (0.68versus0.91), severe exacerbation rates by 50% (0.24versus0.48) and emergency visit rates by 44% (0.24versus0.43) and significantly improved asthma-related quality of life (QoL) compared with placebo. In a pooled analysis of data from seven studies, add-on omalizumab significantly reduced asthma exacerbation rates by 38% (0.91versus1.47) and total emergency visits by 47% (0.332versus0.623). In addition, omalizumab significantly improved QoLversuscurrent asthma therapy in a pooled analysis of data from six studies.

Omalizumab has demonstrated a good safety and tolerability profile in completed phase-I, -II and -III studies involving >7,500 patients with asthma, rhinitis or related conditions. Omalizumab represents a major advance for the treatment of severe persistent allergic asthma that is inadequately controlled despite treatment with inhaled corticosteroids and a long-acting β2-agonist.
How to evaluate a patient's response to anti-IgE
Authors: Holgate S. T.
Published: September 2008

Omalizumab, an anti-immunoglobulin E antibody, is indicated in the European Union (EU) as add-on therapy for patients with severe persistent allergic asthma whose symptoms persist, despite receiving optimised treatment with high-dose inhaled corticosteroids and a long-acting β2-agonist. In an attempt to further optimise the use of omalizumab, studies have been performed to investigate whether patient selection for omalizumab therapy could be further enhanced.

Analyses of pre-treatment baseline variables have shown there is no reliable way to predict which patients within the label population will achieve a greater response to omalizumab. However, a physician's overall assessment can easily and reliably identify patients who respond to omalizumab. All patients eligible for omalizumab treatment should receive a 16-week trial and treatment should only be continued if the physician judges that a marked improvement in asthma control has been achieved, as specified in the EU label.

By continuing treatment only in patients who respond to omalizumab therapy, unwarranted drug exposure is minimised, while treatment benefit and cost effectiveness of the therapy are maximised.
Alternatives for OSAHS treatment: selection of patients for upper airway surgery and oral appliances
Authors: Boudewyns A. , Marklund M. , Hochban W.
Published: September 2008

Although continuous positive airway pressure (CPAP) is considered to represent the standard treatment for patients with moderate-to-severe obstructive sleep apnoea/hypopnoea syndrome (OSAHS), poor treatment compliance and/or refusal is an issue in ∼20–30% of these patients.

As an alternative to life-long CPAP treatment, conservative procedures exist with dental appliances for mandibular advancement, as well as curative surgical techniques.

Surgical treatment of OSAHS can be divided into the following two main groups: 1) upper airway surgery by soft tissue resection (uvulopalatopharyngoplasty,etc.), and 2) skeletal procedures, such as maxillo-mandibular advancement. Proper selection of patients for the different treatment modalities is the key for full treatment success.

Patient-related factors, such as the site of upper airway collapse, craniofacial characteristics, dental health, obesity, age, profession and positional dependence, as well as treatment-related factors, should be evaluated before a final proposal for these treatment alternatives is formulated.