Markers of inflammation in exhaled breath condensate of young healthy smokers

INTRODUCTION: Although a strong correlation exists between long-term cigarette smoking, pulmonary inflammation, and COPD, efforts to identify populations at risk of acquiring COPD have so far been unsuccessful. To this end, noninvasive detection and monitoring of biomarkers of pulmonary inflammation in young healthy smokers may assist in this task. STUDY OBJECTIVES: The purpose of this study was to determine the concentrations of total protein, nitrites, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, and neutrophil chemotactic activity in exhaled breath condensate (EBC) collected from healthy college student smokers and nonsmokers. DESIGN: EBC was collected from 20 volunteers (9 nonsmokers and 11 smokers) during tidal breathing for 20 min. EBC was also collected from smokers 30 min after smoking one filtered cigarette. The concentrations of total protein, nitrite, IL-1beta, and TNF-alpha in EBC was determined by enzyme-linked immunosorbent assay. Neutrophil chemotactic activity in EBC was determined in vitro using the blind-well technique. RESULTS: The concentrations of total protein and nitrite, and neutrophil chemotactic activity were significantly higher in EBC of smokers in comparison to nonsmokers (p < 0.05). The concentrations of total protein and nitrite in the condensate of smokers did not change significantly after smoking one cigarette. The concentrations of IL-1beta and TNF-alpha in EBC were similar in nonsmokers and smokers. CONCLUSIONS: Concentrations of certain inflammatory mediators and neutrophil chemotactic activity are increased in EBC of young healthy smokers. Collection and analysis of EBC may assist in early detection of cigarette smoke-induced pulmonary inflammation and identifying populations at risk for acquiring COPD.     

Characterization of the human CD4+ T‐cell repertoire specific for major histocompatibility class I‐restricted antigens

While CD4⁺ T lymphocytes usually recognize antigens in the context of major histocompatibility (MHC) class II alleles, occurrence of MHC class‐I restricted CD4⁺ T cells has been reported sporadically. Taking advantage of a highly sensitive MHC tetramer‐based enrichment approach allowing detection and isolation of scarce Ag‐specific T cells, we performed a systematic comparative analysis of HLA‐A*0201‐restricted CD4⁺ and CD8⁺ T‐cell lines directed against several immunodominant viral or tumoral antigens. CD4⁺ T cells directed against every peptide‐MHC class I complexes tested were detected in all donors. These cells yielded strong cytotoxic and T helper 1 cytokine responses when incubated with HLA‐A2⁺ target cells carrying the relevant epitopes. HLA‐A2‐restricted CD4⁺ T cells were seldom expanded in immune HLA‐A2⁺ donors, suggesting that they are not usually engaged in in vivo immune responses against the corresponding peptide‐MHC class I complexes. However, these T cells expressed TCR of very high affinity and were expanded following ex vivo stimulation by relevant tumor cells. Therefore, we describe a versatile and efficient strategy for generation of MHC class‐I restricted T helper cells and high affinity TCR that could be used for adoptive T‐cell transfer‐ or TCR gene transfer‐based immunotherapies.     

Population attributable risk of modifiable risk factors associated with invasive breast cancer in women aged 45–69 years in Queensland,Australia

Objectives

To quantify the population attributable risk of key modifiable risk factors associated with breast cancer incidence in Queensland, Australia.

Study design

Population attributable fractions (PAFs) for high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity were calculated, using prevalence data from a representative survey of women attending mammographic screening at BreastScreen Queensland in 2008 and relative risk estimates sourced from published literature. Attributable cancers were calculated using ‘underlying’ breast cancer incidence data for 2008 based on Poisson regression models, adjusting for the inflation of incidence due to the effects of mammographic screening.

Main outcome measures

Attributable burden of breast cancer due to high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity.

Results

In Queensland women aged 45–69 years, an estimated 12.1% (95% CI: 11.6–12.5%) of invasive breast cancers were attributable to high BMI in post-menopausal women who have never used HRT; 2.8% (95% CI: 2.7–2.9%) to alcohol consumption; 7.6% (95% CI: 7.4–7.9%) to inadequate physical activity in post-menopausal women and 6.2% (95% CI: 5.5–7.0%) to current use of HRT after stratification by BMI and type of HRT used. Combined, just over one quarter (26.0%; 95% CI: 25.4–26.6%) of all invasive breast cancers in Queensland women aged 45–69 years in 2008 were attributable to these modifiable risk factors.

Conclusions

There is benefit in targeting prevention strategies to modify lifestyle behaviours around BMI, physical activity, HRT use and alcohol consumption, as a reduction in these risk factors could decrease invasive breast cancer incidence in the Queensland population.     

Health-related quality of life with tralokinumab in moderate-to-severe atopic dermatitis: A phase 2b randomized study

BackgroundAtopic dermatitis (AD) is associated with a substantial burden on quality of life (QoL).ObjectiveTo evaluate the effects of tralokinumab on health-related QoL in patients with moderate-to-severe AD using patient-reported outcomes.MethodsThis was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study in adults with moderate-to-severe AD. The patients received subcutaneous tralokinumab or placebo (1:1:1:1) every 2 weeks for 12 weeks and class 3 topical corticosteroid cream or ointment at least once daily from the run-in to end of follow-up. Patient-reported outcome end points were change from baseline to week 12 in the Dermatology Life Quality Index (dermatology life quality index (DLQI); prespecified secondary objective), the Short Form 36 Health Survey (SF-36) version 2, and sleep interference numeric rating scale score (prespecified exploratory objectives).ResultsA total of 204 patients were randomized to placebo (n = 51) or tralokinumab (45 mg, n = 50; 150 mg, n = 51; 300 mg, n = 52). Tralokinumab 300 mg every 2 weeks improved total Dermatology Life Quality Index vs placebo at week 12 (placebo-adjusted mean change, ?3.51 [95% confidence interval, ?6.00 to ?1.02]). At week 12, both the mental component summary (4.23 [0.98-7.47]) and the physical component summary (4.26 [1.83-6.69]) and all 8 domains of the Short Form 36 Health Survey were improved in patients treated with tralokinumab 300 mg vs placebo. Sleep interference was improved at week 12 with all tralokinumab doses vs placebo.ConclusionTralokinumab improved health-related QoL in patients with moderate-to-severe atopic dermatitis, providing further evidence of the value of targeting interleukin-13 in such patients.Trial RegistrationClinicalTrials.gov identifier: NCT02347176; https://clinicaltrials.gov/ct2/show/NCT02347176.     

Surprisingly high prevalence of anxiety and depression in chronic breathing disorders

STUDY OBJECTIVES: The objectives of this study were to assess the prevalence, screening, and recognition of depression and anxiety in persons with chronic breathing disorders, including COPD. DESIGN: Cross-sectional study. SETTING: The Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC). PARTICIPANTS: A large sample of 1,334 persons with chronic breathing disorder diagnoses who received care at the MEDVAMC. MEASUREMENTS: The prevalence of anxiety and depression was measured in a large sample of persons with a chronic breathing disorder diagnosis who received care at the MEDVAMC, using the Primary Care Evaluation of Mental Disorders (PRIME-MD) screening questions. The positive predictive value of the PRIME-MD questions was then determined. The prevalence of anxiety and depressive diagnoses in patients determined to have COPD was then measured, using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID). RESULTS: Of patients screened with the PRIME-MD, 80% screened positive for depression, anxiety, or both. The predictive value of a positive phone screen for either depression or anxiety was estimated to be 80%. In the subsample of patients who had COPD and received a diagnosis using the SCID, 65% received an anxiety and/or depressive disorder diagnosis. Of those patients, only 31% were receiving treatment for depression and/or anxiety. CONCLUSIONS: It is troubling that a mere 31% of COPD patients with depression or anxiety are being treated, particularly given their high prevalence in this population. Practical screening instruments may help increase the recognition of anxiety and depression in medical patients, as suggested by the excellent positive predictive value of the PRIME-MD in our study.     

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes

Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities ≤0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era.     

All Men with Vasculogenic Erectile Dysfunction Require a Cardiovascular Workup

An association between erectile dysfunction and cardiovascular disease has long been recognized, and studies suggest that erectile dysfunction is an independent marker of cardiovascular disease risk. Therefore, assessment and management of erectile dysfunction may help identify and reduce the risk of future cardiovascular events, particularly in younger men. The initial erectile dysfunction evaluation should distinguish between predominantly vasculogenic erectile dysfunction and erectile dysfunction of other etiologies. For men believed to have predominantly vasculogenic erectile dysfunction, we recommend that initial cardiovascular risk stratification be based on the Framingham Risk Score. Management of men with erectile dysfunction who are at low risk for cardiovascular disease should focus on risk-factor control; men at high risk, including those with cardiovascular symptoms, should be referred to a cardiologist. Intermediate-risk men should undergo noninvasive evaluation for subclinical atherosclerosis. A growing body of evidence supports the use of emerging prognostic markers to further understand cardiovascular risk in men with erectile dysfunction, but few markers have been prospectively evaluated in this population. In conclusion, we support cardiovascular risk stratification and risk-factor management in all men with vasculogenic erectile dysfunction.