Reliable consultant level data from an Acute Medical Unit: a powerful tool for improvement.

The development of a novel database interrogating the patient management system in the Acute Medical Unit at Forth Valley Royal Hospital, Scotland, has allowed, for the first time, acquisition of reliable individual consultant-level process and outcome data over a 2-year period. These data have a number of uses, including understanding the level of variation between consultant physicians in AMU across key indicators, such as direct discharge percentage (67.5-44.3%), and readmission percentage (4.0-6.8%). Looking at overnight admissions only effectively excluded case mix as a confounder to identify variation in 30-day mortality (0-2.8%). This has allowed benchmarking, and exploring of relationships between volume of work, physician experience, and patient outcomes. For example, no significant relationship was seen between direct discharge percentage and readmission percentage. Furthermore it is extremely useful for individual clinician appraisal and governance. Finally it has practical uses when designing consultant rotas in order to minimise system variation. A key consideration throughout this work has been clear provenance and local clinical ownership of these data, unlike centrally generated data that may not accurately reflect Acute Medical Unit activity.

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Results of the California Healthy Homes Indoor Air Quality Study of 2011-2013: impact of natural gas appliances on air pollutant concentrations.

This study was conducted to assess the current impact of natural gas appliances on air quality in California homes. Data were collected via telephone interviews and measurements inside and outside of 352 homes. Passive samplers measured time-resolved CO and time-integrated NOX , NO2 , formaldehyde, and acetaldehyde over ~6-day periods in November 2011 - April 2012 and October 2012 - March 2013. The fraction of indoor NOX and NO2 attributable to indoor sources was estimated. NOX , NO2 , and highest 1-h CO were higher in homes that cooked with gas and increased with amount of gas cooking. NOX and NO2 were higher in homes with cooktop pilot burners, relative to gas cooking without pilots. Homes with a pilot burner on a floor or wall furnace had higher kitchen and bedroom NOX and NO2 compared to homes without a furnace pilot. When scaled to account for varying home size and mixing volume, indoor-attributed bedroom and kitchen NOX and kitchen NO2 were not higher in homes with wall or floor furnace pilot burners, although bedroom NO2 was higher. In homes that cooked 4 h or more with gas, self-reported use of kitchen exhaust was associated with lower NOX , NO2 , and highest 1-h CO. Gas appliances were not associated with higher concentrations of formaldehyde or acetaldehyde.

Morphologic and cytogenetic variables affect the flow cytometric recovery of plasma cell myeloma cells in bone marrow aspirates.

INTRODUCTION: It is widely recognized that plasma cells (PCs) are under-represented in flow cytometry (FC) studies, but the causes of this phenomenon are poorly understood. We sought to study potential variables that affect PC recovery by flow cytometry (FC) in the analysis of plasma cell myeloma (PCM). METHODS: We retrospectively performed PC differential counts and morphologic assessment on PCM peripheral blood (PB) smears, bone marrow (BM) aspirate smears and posterythrocyte lysis cytospins. PCs were enumerated by FC, excluding erythroid events/debris, and were defined as CD38(bright+), CD45(dim to negative) events. PC recovery was calculated as follows: cytospin/aspirate, FC/aspirate, and FC/cytospin. RESULTS: Sixty-four BM analyses from 42 patients showed a mean aspirate PC% of 32.9 ± 23.2%. The mean PC% decreased in both the cytospin (10.9%) and by FC (8.2%). The difference between PC% in the cytospin and by FC was statistically significant (P < 0.03). Mature PC morphology and lower aspirate PC% had poorer recovery (P < 0.05) but higher-risk cytogenetics (deletions of 13q and TP53) was associated with increased PC recovery. Immunophenotype, heavy chain type, and treatment did not affect PC recovery. PB specimens had superior recovery compared with BM samples. CONCLUSIONS: Similar to prior reports, the greatest loss of PC in BM evaluation occurs between the aspirate and postlysis specimens; however, a small amount occurs from further processing. Additional morphologic and cytogenetic factors also appear to influence recovery in addition to overall PC%.

Arachidonic acid metabolites and enzyme transcripts in asthma are altered by cigarette smoking.

BACKGROUND: Arachidonic acid metabolites are implicated in the pathogenesis of asthma although only limited information is available on the impact of current smoking history on these metabolites. The aim of the study was to examine the effect of smoking status on urinary, sputum, and plasma eicosanoid concentrations and relevant enzyme transcripts in asthma. METHODS: In 108 smokers and never smokers with asthma and 45 healthy controls [smokers and never smokers], we measured urinary tetranor prostaglandin (PG)D2 (PGDM) and leukotriene (LT)E4 , induced sputum fluid LTB4 , LTE4 , PGD2 , and PGE2 , plasma secretory phospholipase A2 (sPLA2 ), and 11ß prostaglandin F2α (11ßPGF2α ), and, in a subgroup with severe asthma, airway leukocyte and epithelial cell mRNA expression levels of arachidonic acid metabolic enzymes. RESULTS: Smokers with asthma had higher urinary LTE4 ; 83 (59, 130) vs 59 (40, 90) pg/mg creatinine, P = 0.008, and PGDM; 60 (35, 100) vs 41 (28, 59) ng/mg creatinine, P = 0.012 concentrations, respectively, and lower sputum PGE2 concentrations 80 (46, 157) vs 192 (91, 301) pg/ml, P = 0.001 than never smokers with asthma. Sputum LTB4 (P = 0.013), and plasma 11ßPGF2α (P = 0.032), concentrations, respectively, were increased in smokers with asthma compared with healthy smokers. Asthma-specific and smoking-related increases (>1.5-fold expression) in arachidonate 15-lipoxygenase and gamma-glutamyltransferase transcripts were demonstrated. CONCLUSIONS: Several arachidonic acid metabolites and enzyme transcripts involving both lipoxygenase and cyclooxygenase pathways are increased in smokers with asthma and differ from never smokers with asthma. Possibly targeting specific lipoxygenase and cyclooxygenase pathways that are activated by asthma and cigarette smoking may optimize therapeutic responses.

A cluster randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of classroom-based cognitive-behavioural therapy (CBT) in reducing symptoms of depression in high-risk adolescents.

BACKGROUND: Depression in adolescents is a significant problem that impairs everyday functioning and increases the risk of severe mental health disorders in adulthood. Although this is a major problem, relatively few adolescents with, or at risk of developing, depression are identified and referred for treatment. This suggests the need to investigate alternative approaches whereby preventative interventions are made widely available in schools. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of classroom-based cognitive-behavioural therapy (CBT) in reducing symptoms of depression in high-risk adolescents. DESIGN: Cluster randomised controlled trial. Year groups ( n = 28) randomly allocated on a 1 : 1 : 1 basis to one of three trial arms once all schools were recruited and balanced for number of classes, number of students, Personal, Social and Health Education (PSHE) lesson frequency, and scheduling of PSHE. SETTING: Year groups 8 to 11 (ages 12-16 years) in mixed-sex secondary schools in the UK. Data were collected between 2009 and 2011. PARTICIPANTS: Young people who attended PSHE at participating schools were eligible ( n = 5503). Of the 5030 who agreed to participate, 1064 (21.2%) were classified as 'high risk': 392 in the classroom-based CBT arm, 374 in the attention control PSHE arm and 298 in the usual PSHE arm. Primary outcome data on the high-risk group at 12 months were available for classroom-based CBT ( n = 296), attention control PSHE ( n = 308) and usual PSHE ( n = 242). INTERVENTIONS: The Resourceful Adolescent Programme (RAP) is a focused CBT-based intervention adapted for the UK (RAP-UK) and delivered by two facilitators external to the school. Control groups were usual PSHE (usual school curriculum delivered by teachers) and attention control (usual school PSHE with additional support from two facilitators). Interventions were delivered universally to whole classes. PRIMARY OUTCOMES: Clinical effectiveness: symptoms of depression [Short Mood and Feelings Questionnaire (SMFQ)] in adolescents at high risk of depression 12 months from baseline. Cost-effectiveness: incremental cost-effectiveness ratios (ICERs) based on SMFQ score and quality-adjusted life-years (from European Quality of Life-5 Dimensions scores) between baseline and 12 months. Process evaluation: reach, attrition and qualitative feedback from service recipients and providers. RESULTS: SMFQ scores had decreased for high-risk adolescents in all trial arms at 12 months, but there was no difference between arms [classroom-based CBT vs. usual PSHE adjusted difference in means 0.97, 95% confidence interval (CI) -0.34 to 2.28; classroom-based CBT vs. attention control PSHE -0.63, 95% CI -1.99 to 0.73]. Costs of interventions per child were estimated at £41.96 for classroom-based CBT and £34.45 for attention control PSHE. Fieller's method was used to obtain a parametric estimate of the 95% CI for the ICERs and construct the cost-effectiveness acceptability curve, confirming that classroom-based CBT was not cost-effective relative to the controls. Reach of classroom-based CBT was good and attrition was low (median 80% attending ≥ 60% of sessions), but feedback indicated some difficulties with acceptability and sustainability. CONCLUSIONS: Classroom-based CBT, attention control PSHE and usual PSHE produced similar outcomes. Classroom-based CBT may result in increased self-awareness and reporting of depressive symptoms. Classroom-based CBT was not shown to be cost-effective. While schools are a convenient way of reaching a wide range of young people, implementing classroom-based CBT within schools is challenging, particularly with regard to fitting programmes into a busy timetable, the lack of value placed on PSHE, and difficulties engaging with teachers and young people. Wider use of classroom-based depression prevention programmes should not be undertaken without further research. If universal preventative approaches are to be pursued, their clinical effectiveness and cost-effectiveness with younger children (aged 10-11 years), before the incidence of depression increases, should be investigated. Alternatively, the clinical effectiveness of indicated school-based programmes targeting those already displaying symptoms of depression should be investigated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19083628. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 47. See the HTA programme website for further project information.

Association of classroom ventilation with reduced illness absence: a prospective study in California elementary schools.

Limited evidence associates inadequate classroom ventilation rates (VRs) with increased illness absence (IA). We investigated relationships between VRs and IA in California elementary schools over two school years in 162 3rd-5th-grade classrooms in 28 schools in three school districts: South Coast (SC), Bay Area (BA), and Central Valley (CV). We estimated relationships between daily IA and VR (estimated from two year daily real-time carbon dioxide in each classroom) in zero-inflated negative binomial models. We also compared IA benefits and energy costs of increased VRs. All school districts had median VRs below the 7.1 l/s-person California standard. For each additional 1 l/s-person of VR, IA was reduced significantly (p<0.05) in models for combined districts (-1.6%) and for SC (-1.2%), and nonsignificantly for districts providing less data: BA (-1.5%) and CV (-1.0%). Assuming associations were causal and generalizable, increasing classroom VRs from the California average (4 l/s-person) to the State standard would decrease IA by 3.4%, increase attendance-linked funding to schools by $33 million annually, and increase costs by only $4 million. Further increasing VRs would provide additional benefits. These findings, while requiring confirmation, suggest that increasing classroom VRs above the State standard would substantially decrease illness absence and produce economic benefits.

The immunophenotypic stability of plasma cell myeloma by flow cytometry.

INTRODUCTION: Flow cytometry (FC) has become increasingly utilized in the diagnosis and monitoring of plasma cell myeloma (PCM), though few studies have evaluated the longitudinal stability of antigen expression. METHODS: We studied 45 PCM patients by four-color FC for shifts in CD19, CD20, CD38, CD45, CD56, and cytoplasmic light chain expression, between diagnostic/first encounter and positive follow-up analyses. An immunophenotypic (IP) change was defined as gain, loss, or ½ log shift of antigen expression. RESULTS: An IP change was observed in 14/45 (31%) patients, with single IP changes in 9/14, two changes in 2/14, and three changes in 3/14. 3/14 reverted from an aberrant to a normal plasma cell IP, while remaining light chain-restricted. Changes in expression of CD45 occurred in 9/45 (20%), CD19 in 5/45 (11.1%), CD20 in 2/45 (4.4%), and CD56 in 5/45 (11.1%). CONCLUSION: Approximately 1/3 of PCM cases show IP changes over time, with CD45 the least stable antigen. Recognition of this relative instability is important to avoid narrow targeting of follow-up FC analyses, especially for minimal residual disease monitoring.

Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma.

BACKGROUND: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. OBJECTIVE: Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. METHODS: Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. RESULTS: Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320)

In situ quantification of HER2-protein tyrosine kinase 6 (PTK6) protein-protein complexes in paraffin sections from breast cancer tissues.

BACKGROUND: Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2. METHOD AND RESULTS: In this study, we used the proximity ligation assay (PLA) technique on formalin-fixed paraffin sections from eighty invasive breast carcinoma tissue specimens to locate PTK6-HER2 protein-protein complexes. Proximity ligation assay signals from protein complexes were assessed quantitatively, and expression levels showed a statistically significant association with tumour size (P=0.015) and course of the cancer disease (P=0.012). CONCLUSION: Protein tyrosine kinase 6 forms protein complexes with HER2 in primary breast cancer tissues, which can be visualised by use of the PLA technique. Human epidermal growth factor receptor 2-PTK6 complexes are of prognostic relevance.

Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma.

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

Type I receptor tyrosine kinases as predictive or prognostic markers in early breast cancer.

The type I receptor tyrosine kinase (RTK) family of proteins play an essential role in the progression of early breast cancer. Our understanding of the role of these proteins has increased over the last 20 years, however, as yet, there are still a number of unanswered questions regarding their position in endocrine resistance, chemotherapy resistance and in the biology of breast cancer. There have been, and are currently, a number of clinical trials that have examined the use of anticancer therapy such as cytotoxic drugs, and treatments that target the RTKs and signaling pathways that have been identified. There is clear evidence that molecular subtypes of cancer respond differently to different therapeutic options, which challenges the 'one size fits all' approach to chemotherapy. Here we review the human epidermal growth factor receptor family of proteins and their potential predictive or prognostic role in early breast cancer.

Role of symptoms and lung function in determining asthma control in smokers with asthma.

BACKGROUND: Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known. AIM OF THE STUDY: The aim of this study was to compare asthma control in smokers vs never-smokers with asthma, using the validated Juniper asthma control questionnaire (ACQ), and assess if any difference was because of a particular symptom or the forced expiratory volume in one second (FEV(1)) value. METHODS: This was a cross-sectional study of 134 asthmatics (74 never-smokers and 60 smokers) with >or=15% reversibility in FEV(1) after salbutamol. All subjects completed the ACQ, recording FEV(1) and asthma symptoms (night awakening, morning symptoms, dyspnoea, wheeze, activity limitation and use of reliever inhaler). RESULTS: Compared with the never-smokers, smokers with asthma had significantly worse median (IQR) total asthma control score [1.6 (1.1-2.3) vs 2.8 (1.7-3.4); (P < 0.0001)] and in each of the six individual symptom question scores (P < 0.001), but no difference in FEV(1) levels (P = 0.908). CONCLUSION: Asthma control is significantly worse in asthmatics who smoke compared with never-smokers, with all symptoms related to asthma control uniformly worse in smokers, independent of FEV(1).

Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease.

Inhaled corticosteroids are the most effective therapy for chronic persistent asthma and have a role in the treatment of chronic obstructive pulmonary disease (COPD). However, corticosteroids have reduced efficacy in some patients with asthma and fail to halt the progressive deterioration in lung function characteristic of COPD. Additional or alternative drug treatments to corticosteroids are required to improve control of inflammation in patients with therapy resistant airway disease. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have displayed potent anti-inflammatory properties in experimental models of asthma and other airway diseases and as a result have the potential to become an additional treatment for asthma and COPD. We review the evidence from these experimental models and their applicability to asthma and COPD and the requirements for future clinical and experimental research.

Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants.

Using electron microscopy, we investigated the effect of (i) a dilute surfactant and of water alone on the ultrastructure of stratum corneum lipids in pig skin exposed in vitro at 46 degrees C, and (ii) of water alone on human skin exposed in vivo at ambient temperature. For pig skin, the surfactant sodium dodecyl sulfate disrupts stratum corneum intercellular lamellar bilayers, leading to bilayer delamination and "roll-up" in a water milieu after 1 h, extensive bilayer disruption after 6 h, and nearly complete dissociation of corneocytes after 24 h. Corneodesmosomes show progressive degradation with exposure time. Water alone also disrupts the stratum corneum, but with a slower onset. Alterations in intercellular lamellar bilayers, but not intercellular lamellar bilayer roll-up, are detected after 2 h. Intercellular lamellar bilayer roll-up occurs after 6 h. Extensive dissociation of corneocytes occurs after 24 h of water exposure. Unlike sodium dodecyl sulfate, water exposure results in the formation of amorphous intercellular lipid. Corneodesmosome degradation parallels intercellular lamellar bilayer disruption; calcium appears to offer some protection. Similar disruption of intercellular lamellar bilayers occurs in human skin in vivo at ambient temperature. Our studies show that water can directly disrupt the barrier lipids and are consistent with surfactant-induced intercellular lamellar bilayer disruption being due at least in part to the deleterious action of water. Intercellular lamellar bilayer disruption by water would be expected to enhance permeability and susceptibility to irritants; accordingly, increased attention should be given to the potential dangers of prolonged water contact. For common in vitro procedures, such as skin permeation studies or isolation of stratum corneum sheets, exposure to water should also be minimized.