Pre- and post-bronchodilator lung function as predictors of mortality in the Lung Health Study

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is supposed to be classified on the basis of post-bronchodilator lung function. Most longitudinal studies of COPD, though, do not have post-bronchodilator lung function available. We used pre-and post bronchodilator lung function data from the Lung Health Study to determine whether these measures differ in their ability to predict mortality. METHODS: We limited our analysis to subjects who were of black or white race, on whom we had complete data, and who participated at either the 1 year or the 5 year follow-up visit. We classified subjects based on their baseline lung function, according to COPD Classification criteria using both pre- and post-bronchodilator lung function. We conducted a survival analysis and logistic regression predicting death and controlling for age, sex, race, treatment group, smoking status, and measures of lung function (either pre- or post-bronchodilator. We calculated hazard ratios (HR) with 95% confidence intervals (CI) and also calculated area under the curve for the logistic regression models. RESULTS: By year 15 of the study, 721 of the original 5,887 study subjects had died. In the year 1 sample survival models, a higher FEV1 % predicted lower mortality in both the pre-bronchodilator (HR 0.87, 95% CI 0.81, 0.94 per 10% increase) and post-bronchodilator (HR 0.84, 95% CI 0.77, 0.90) models. The area under the curve for the respective models was 69.2% and 69.4%. Similarly, using categories, when compared to people with normal lung function, subjects with Stage 3 or 4 disease had similar mortality in both the pre- (HR 1.51, 95% CI 0.75, 3.03) and post-bronchodilator (HR 1.45, 95% CI 0.41, 5.15) models. In the year 5 sample, when a larger proportion of subjects had Stage 3 or 4 disease (6.4% in the pre-bronchodilator group), mortality was significantly increased in both the pre- (HR 2.68, 95% CI 1.51, 4.75) and post-bronchodilator (HR 2.46, 95% CI 1.63, 3.73) models. CONCLUSIONS: Both pre- and post-bronchodilator lung function predicted mortality in this analysis with a similar degree of accuracy. Post-bronchodilator lung function may not be needed in population studies that predict long-term outcomes

Establishing a method to monitor replicative polymerase usage genome-wide in human cells

The majority of DNA replication in eukaryotic cells is carried out by two replicative DNA polymerases: polymerases δ and ε (Pols δ and ε). Whilst both polymerases exhibit high specificity for deoxyribonucleotides, both frequently misincorporate ribonucleotides (rNTPs) which are rapidly removed via ribonucleotide excision repair (RER) by the heterotrimeric enzyme RNase H2. In yeast, using mutant polymerases that incorporate elevated levels of rNTPs (and in the absence of the catalytic subunit of RNase H2 (RNase H2A)) unrepaired rNTPs serve as a molecular footprint of the replicative polymerases. This allows the determination of genome‐wide polymerase usage using a deep sequencing methodology that we have termed polymerase usage sequencing (Pu‐seq). The aim of this project is to develop cell lines that can be used for Pu-­‐seq in human cells. Ultimately, this system could then be used to monitor DNA replication dynamics in human cells to aid in the study of replication stress responses. As in yeast, the development of the Pu‐seq system in human cells requires an absence of RNase H2 activity and mutant alleles of Pol δ and Polε that result in excess ribonucleotide incorporation. This thesis describes the steps taken towards developing Pu‐seq in human cell lines; firstly, by establishing that in human cells expressing normal levels of p53, RNase H2A is an essential gene, then by developing mechanisms that allow for the shutoff of RNase H2 activity through the targeted downregulation of one of its accessory subunits, RNase H2C. Attempts to develop a novel method of quantifying genomic ribonucleotides are described in addition to showing that previously published protocols for assessing overall RNase H2 activity and genomic ribonucleotide presence provide the sensitivity required to screen candidate human Pu‐seq cell lines. Finally, progress made in screening mutations in Pols δ and ε that may cause increased ribonucleotide incorporation is described

Subjects with Discordant Airways Obstruction: Lost between Spirometric Definitions of COPD

Background. Since the FEV1/FVC ratio declines with age, using the fixed ratio of 0.70 leads to overdiagnosis of COPD in older populations and underdiagnosis among young adults. Objective. To evaluate whether discordant obstructive cases (FEV1/FVC < 0.70 but ≥LLN) are a healthy population or have clinical features that would place them at increased risk. Methods. We used post-bronchodilator spirometry data from the population-based Austrian Burden of Obstructive Lung Disease (BOLD) study. Those with post-bronchodilator FEV1/FVC ratio <LLN and <0.70 were defined as concordant obstructive cases. Participants with post-bronchodilator FEV1/FVC ratio ≥LLN but <0.70 were defined as discordant obstructive cases. Results. Discordant obstructive cases were more likely to be older, male and never-smokers. Additionally they had less respiratory symptoms and less severe impairment of FEV1. However, discordant obstructive cases reported significantly more often a diagnosis of heart disease than subjects with normal lung function (27.2% vs 7.3%, P = .015). Conclusion. The clinical profile of discordant obstructive cases includes potentially important comorbid disease

The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs

What stops hospital clinical staff from following protocols? An analysis of the incidence and factors behind the failure of bedside clinical staff to activate the rapid response system in a multi-campus Australian metropolitan healthcare service

OBJECTIVE: To explore the causes of failure to activate the rapid response system (RRS). The organisation has a recognised incidence of staff failing to act when confronted with a deteriorating patient and leading to adverse outcomes. DESIGN: A multi-method study using the following: a point prevalence survey to determine the incidence of abnormal simple bedside observations and activation of the rapid response team by clinical staff; a prospective audit of all patients experiencing a cardiac arrest, unplanned intensive care unit admission or death over an 8-week period; structured interviews of staff to explore cognitive and sociocultural barriers to activating the RRS. SETTING: Southern Health is a comprehensive healthcare network with 570 adult in-patient beds across four metropolitan teaching hospitals in the south-eastern sector of Melbourne. MEASUREMENTS: Frequency of physiological instability and outcomes within the in-patient hospital population. Qualitative data from staff interviews were thematically coded. RESULTS: The incidence of physiological instability in the acute adult population was 4.04%. Nearly half of these patients (42%) did not receive an appropriate clinical response from the staff, despite most (69.2%) recognising their patient met physiological criteria for activating the RRS, and being 'quite', or 'very' concerned about their patient (75.8%). Structured interviews with 91 staff members identified predominantly sociocultural reasons for failure to activate the RRS. CONCLUSIONS: Despite an organisational commitment to the RRS, clinical staff act on local cultural rules within the clinical environment that are usually not explicit. Better understanding of these informal rules may lead to more appropriate activation of the RRS

Salt and ionic cocrystalline forms of amides: protonation of carbamazepine in aqueous media

The products of reactions of the pharmaceutical amide carbamazepine (CBZ) with strong acids under aqueous conditions were investigated by both powder and single crystal X-ray diffraction. Despite previous claims to the contrary, it was found that salt forms with CBZ protonated at the amide O atom could be isolated from reactions with both HCl and HBr. These forms include the newly identified hydrate phase [CBZ(H)][Cl]·H O. Reactions with other mineral acids (HI and HBF ) gave ionic cocrystalline (ICC) forms (CBZ· [acridinium][I ]·2.5I and CBZ·[H O ] [BF ] ·H O) as well as the salt form CBZ·[CBZ(H)][BF ]·0.5H O. Reaction 2 4 3 2 5 2 0.25 4 0.25 2 4 2 of CBZ with a series of sulfonic acids also gave salt forms, namely, [CBZ(H)][O SC H ], [CBZ(H)][O SC H (OH)]· 3 6 5 3 6 4 0.5H O, [CBZ(H)] [O SCH CH SO ], and [CBZ(H)][O SC H (OH) (COOH)]·H O. CBZ and protonated CBZ(H) 2 2 3 2 2 3 3 6 3 2 moieties can be differentiated in the solid state both by changes to molecular geometry and by differing packing preference

Gender Specific Differences in the Pros and Cons of Smoking among Current Smokers in Eastern Kentucky: Implications for Future Smoking Cessation Interventions

This study investigated gender differences in the perceived “pros” and “cons” of smoking using the constructs of decisional balance (DB) and stage of change from the Transtheoretical Model. The population distribution for stage of change among a population-based, cross-sectional survey of 155 current smokers over 40 years was: precontemplation (22.6%), contemplation (41.9%), preparation (35.5%). Results of stepwise regression models indicated significant gender differences in DB were in the preparation stage of change; scores on the DB measure increased 3.94 points (95% CI: 1.94, 5.93) for male smokers. Interventions targeting the “pros” and “cons” of smoking may need to be gender specific

Worldwide patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Criteria for a clinically significant bronchodilator response (BDR) are mainly based on studies in patients with obstructive lung diseases. Little is known about the BDR in healthy general populations, and even less about the worldwide patterns. 10 360 adults aged 40 years and older from 14 countries in North America, Europe, Africa and Asia participated in the Burden of Obstructive Lung Disease study. Spirometry was used before and after an inhaled bronchodilator to determine the distribution of the BDR in population-based samples of healthy non-smokers and individuals with airflow obstruction. In 3922 healthy never smokers, the weighted pooled estimate of the 95th percentiles (95% CI) for bronchodilator response were 284 ml (263 to 305) absolute change in forced expiratory volume in 1 s from baseline (ΔFEV(1)); 12.0% (11.2% to 12.8%) change relative to initial value (%ΔFEV(1i)); and 10.0% (9.5% to 10.5%) change relative to predicted value (%ΔFEV(1p)). The corresponding mean changes in forced vital capacity (FVC) were 322 ml (271 to 373) absolute change from baseline (ΔFVC); 10.5% (8.9% to 12.0%) change relative to initial value (ΔFVC(i)); and 9.2% (7.9% to 10.5%) change relative to predicted value (ΔFVC(p)). The proportion who exceeded the above threshold values in the subgroup with spirometrically defined Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher (FEV(1)/FVC <0.7 and FEV(1)% predicted <80%) were 11.1%, 30.8% and 12.9% respectively for the FEV(1)-based thresholds and 22.6%, 28.6% and 22.1% respectively for the FVC-based thresholds. The results provide reference values for bronchodilator responses worldwide that confirm guideline estimates for a clinically significant level of BDR in bronchodilator testing.ALTANA Aventis AstraZeneca Boehringer-Ingelheim Chiesi GlaxoSmithKline Merck Novartis Pfizer Schering-Plough Sepracor University of Kentucky Boehringer Ingelheim Schering Ploug