Massimo Caruso

EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as Tobacco Cigarettes Substitute: A Prospective 12-Month Randomized Control Design Study

Background Electronic cigarettes (e-cigarettes) are becoming increasingly popular with smokers worldwide. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco withdrawal symptoms, and to continue having a ‘smoking’ experience, but with reduced health risks. Research on e-cigarettes is urgently needed in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science. Methods ECLAT is a prospective 12-month randomized, controlled trial that evaluates smoking reduction/abstinence in 300 smokers not intending to quit experimenting two different nicotine strengths of a popular e-cigarette model (‘Categoria’; Arbi Group Srl, Italy) compared to its non-nicotine choice. GroupA (n = 100) received 7.2 mg nicotine cartridges for 12 weeks; GroupB (n = 100), a 6-week 7.2 mg nicotine cartridges followed by a further 6-week 5.4 mg nicotine cartridges; GroupC (n = 100) received no-nicotine cartridges for 12 weeks. The study consisted of nine visits during which cig/day use and exhaled carbon monoxide (eCO) levels were measured. Smoking reduction and abstinence rates were calculated. Adverse events and product preferences were also reviewed. Results Declines in cig/day use and eCO levels were observed at each study visits in all three study groups (p<0.001 vs baseline), with no consistent differences among study groups. Smoking reduction was documented in 22.3% and 10.3% at week-12 and week-52 respectively. Complete abstinence from tobacco smoking was documented in 10.7% and 8.7% at week-12 and week-52 respectively. A substantial decrease in adverse events from baseline was observed and withdrawal symptoms were infrequently reported during the study. Participants’ perception and acceptance of the product under investigation was satisfactory. Conclusion In smokers not intending to quit, the use of e-cigarettes, with or without nicotine, decreased cigarette consumption and elicited enduring tobacco abstinence without causing significant side effects. Trial Registration ClinicalTrials.gov NCT01164072 NCT01164072

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach. This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements. Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids. Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach. Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

Effect of Smoking Abstinence and Reduction in Asthmatic Smokers Switching to Electronic Cigarettes: Evidence for Harm Reversal

Electronic cigarettes (e-cigs) are marketed as safer alternatives to tobacco cigarettes and have shown to reduce their consumption. Here we report for the first time the effects of e-cigs on subjective and objective asthma parameters as well as tolerability in asthmatic smokers who quit or reduced their tobacco consumption by switching to these products. We retrospectively reviewed changes in spirometry data, airway hyper-responsiveness (AHR), asthma exacerbations and subjective asthma control in smoking asthmatics who switched to regular e-cig use. Measurements were taken prior to switching (baseline) and at two consecutive visits (Follow-up/1 at 6 (±1) and Follow-up/2 at 12 (±2) months). Eighteen smoking asthmatics (10 single users, eight dual users) were identified. Overall there were significant improvements in spirometry data, asthma control and AHR. These positive outcomes were noted in single and dual users. Reduction in exacerbation rates was reported, but was not significant. No severe adverse events were noted. This small retrospective study indicates that regular use of e-cigs to substitute smoking is associated with objective and subjective improvements in asthma outcomes. Considering that e-cig use is reportedly less harmful than conventional smoking and can lead to reduced cigarette consumption with subsequent improvements in asthma outcomes, this study shows that e-cigs can be a valid option for asthmatic patients who cannot quit smoking by other methods.

Changes in breathomics from a 1‐year randomized smoking cessation trial of electronic cigarettes

Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long‐term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs.

Preventing Progression of Allergic Rhinitis to Asthma

The prevalence of allergic rhinitis (AR) is on the increase and this condition is frequently associated with asthma, thus leading to the concept that these two conditions are different aspects of the same disease. There is now accumulating evidence that AR often precedes the onset of asthmatic symptoms. This notion has important implications, not only for the diagnosis and management of these common allergic conditions but also for the potential progression of disease. Very little is known about the risk factors responsible for the progression of AR to asthma; current treatment options can control symptoms but do not prevent or cure the disease. However, there are recent data supporting the notion that it is possible to prevent new asthma cases by modifying the immune response and clinical outcome with allergen immunotherapy. This review article evaluates the impact of AR on the development of asthma, examines putative predictors for the progression of AR to asthma, and reviews recent, promising literature suggesting that early treatment of allergic individuals with immunotherapy may aid in asthma prevention.

Impact of air quality on lung health: myth or reality?

The respiratory system is a primary target of the harmful effects of key air pollutants of health concern. Several air pollutants have been implicated including particulate matter (PM), ozone (O3), nitrogen dioxide (NO2) polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). It is well known that episodes of exposure to high concentrations of outdoor air pollutants can cause acute respiratory exacerbations. However, there is now increasing evidence suggesting that significant exposure to outdoor air pollutants may be also associated with development of lung cancer and with incident cases of chronic obstructive pulmonary disease (COPD) and respiratory allergies. Here we provide a critical appraisal of the impact of air pollution on respiratory diseases and discuss strategies for preventing excessive exposure to harmful air pollutants. However, the evidence that significant exposure to air pollutants is causing COPD, lung cancer or respiratory allergies is not conclusive and therefore regulators must be aware that execution of clean air policies may not be that cost-effective and may lead to unintended consequences. Addressing the lung health effects of air pollution must be considered work in progress.

Evaluation of Post Cessation Weight Gain in a 1-Year Randomized Smoking Cessation Trial of Electronic Cigarettes

Stop smoking it is often associated to weight gain that is one of the most important causes for relapse. This is the first study to describe long-term changes in body weight in smokers invited to quit or reduce smoking by switching to ECs. Conventional cigarettes consumption and body weight were measured prospectively in a randomized controlled trial of smokers invited to switch to ECs. Post cessation weight changes from baseline at week-12, -24 and -52 were compared among 1) high, medium and zero nicotine strength products and 2) pooled continuous smoking failure, smoking reduction and abstinence phenotypes. Saliva cotinine levels and appetite levels were also measured. No significant changes in body weight were observed among high, medium and zero nicotine strength products. Differences among continuous smoking phenotypes were significant only at week-12 (p = 0.010) and week-24 (p = 0.012) with quitters gaining 2.4{plus minus}4.3 Kg and 2.9{plus minus}4.4 Kg respectively. However, weight gain at week-52 (1.5{plus minus}5.0 Kg) was no longer significant compared to Failures and Reducers. No confounding factors could explain the significant changes in body weight. Smokers who quit smoking by switching to ECs may limit their post-cessation weight gain, with substantial reversal in weight gain being manifest at late time points.

Effect of ischemia-reperfusion on renal expression and activity of N(G)-N(G)-dimethylarginine dimethylaminohydrolases.

Background:Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. It is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Methods:Rats (n = 50) underwent to 45 min of renal ischemia followed by 30 min, 1 h, and 3 h of reperfusion. Expression of endothelial nitric oxide synthase, inducible nitric oxide synthase, DDAH-1, DDAH-2, renal DDAH activity, plasma NO2−/NO3−, and ADMA levels were evaluated. Results:Inducible nitric oxide synthase expression increased, as confirmed by both plasma (11.89 ± 1.02, 15.56 ± 0.93, 11.82 ± 0.86, 35.05 ± 1.28, and 43.89 ± 1.63 nmol/ml in the control, ischemic, 30-min, 1-h, and 3-h groups, respectively) and renal (4.81 ± 0.4, 4.85 ± 1, 9.42 ± 0.7, 15.42 ± 0.85, and 22.03 ± 1.11 nmol/mg protein) formations of NO2−/NO3−. DDAH-1 expression decreased after reperfusion, whereas DDAH-2 increased after 30 min, returning to basal levels after 3 h. Total DDAH activity was reduced during all times of reperfusion. Both plasma (0.41 ± 0.03, 0.43 ± 0.05, 0.62 ± 0.02, 0.71 ± 0.02, and 0.41 ± 0.01 nmol/ml in the control, ischemic, 30-min, 1-h, and 3-h groups, respectively) and renal (1.51 ± 0.01, 1.5 ± 0.01, 1.53 ± 0.01, 2.52 ± 0.04, and 4.48 ± 0.03 nmol/mg protein in the control, ischemic, 30-min, 1-h, and 3-h groups, respectively) concentrations of ADMA increased. Conclusions:Results suggest that ischemia–reperfusion injury leads to reduced DDAH activity and modification of different DDAH isoform expression, thus leading to increased ADMA levels, which may lead to increased cardiovascular risk.

Biologic therapy for atopic asthma and beyond.

Purpose of reviewMost asthma patients are easily managed with a standard combination of therapies consisting of inhaled controller and reliever drugs, but there remains a large unmet need at the severe end of the disease spectrum. For these patients, development of safer and more effective therapies for asthmatic patients with severe refractory disease remains a top priority. Here, drugs in development for the severe asthma sufferers and their specific mechanism-based pharmacological rationale will be reviewed with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Recent findingsDespite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics have been largely disappointing. However, there is scope for their specific role in distinctively targeted subpopulations of severe asthmatic patients. SummaryIt is clear that more efforts should be devoted towards establishing new and more efficient key targets. A closer interaction between industry, academia and health workers will be required to achieve this goal effectively.

Interaction between human lung fibroblasts and T-lymphocytes prevents activation of CD4+ cells

BackgroundT lymphocytes are demonstrated to play an important role in several chronic pulmonary inflammatory diseases. In this study we provide evidence that human lung fibroblasts are capable of mutually interacting with T-lymphocytes leading to functionally significant responses by T-cells and fibroblasts.MethodsHuman lung fibroblast were co-cultured with PMA-ionomycin activated T-CD4 lymphocytes for 36 hours. Surface as well as intracellular proteins expression, relevant to fibroblasts and lymphocytes activation, were evaluated by means of flow cytometry and RT-PCR. Proliferative responses of T lymphocytes to concanavalin A were evaluated by the MTT assay.ResultsIn lung fibroblasts, activated lymphocytes promote an increase of expression of cyclooxygenase-2 and ICAM-1, expressed as mean fluorescence intensity (MFI), from 5.4 ± 0.9 and 0.7 ± 0.15 to 9.1 ± 1.5 and 38.6 ± 7.8, respectively. Fibroblasts, in turn, induce a significant reduction of transcription and protein expression of CD69, LFA-1 and CD28 in activated lymphocytes and CD3 in resting lymphocytes. In activated T lymphocytes, LFA-1, CD28 and CD69 expression was 16.6 ± 0.7, 18.9 ± 1.9 and 6.6 ± 1.3, respectively, and was significantly reduced by fibroblasts to 9.4 ± 0.7, 9.4 ± 1.4 and 3.5 ± 1.0. CD3 expression in resting lymphocytes was 11.9 ± 1.4 and was significantly reduced by fibroblasts to 6.4 ± 1.1. Intracellular cytokines, TNF-alpha and IL-10, were evaluated in T lymphocytes. Co-incubation with fibroblasts reduced the number of TNF-alpha positive lymphocytes from 54,4% ± 6.12 to 30.8 ± 2.8, while IL-10 positive cells were unaffected. Finally, co-culture with fibroblasts significantly reduced Con A proliferative response of T lymphocytes, measured as MTT absorbance, from 0.24 ± 0.02 nm to 0.16 ± 0.02 nm. Interestingly, while the activation of fibroblasts is mediated by a soluble factor, a cognate interaction ICAM-1 mediated was demonstrated to be responsible for the modulation of LFA-1, CD28 and CD69.ConclusionFindings from this study suggest that fibroblasts play a role in the local regulation of the immune response, being able to modulate effector functions of cells recruited into sites of inflammation.