bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.
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.
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.
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.
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.