Relationship between prior inhaled corticosteroid use and benefits ofbudesonide/glycopyrronium/formoterol fumarate dihydrate on exacerbations, symptoms, health-related quality of life, and lung function in patients with chronic obstructive pulmonary disease: Analyses from the ETHOS study.

BACKGROUND: In the Phase III ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid (ICS) doses reduced moderate/severe exacerbation rates and improved symptoms, health-related quality of life (HRQoL), and lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) dual therapy in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Here, we assessed whether the benefit for BGF versus GFF was driven by patients who received ICS before randomization to GFF. METHODS: ETHOS was a 52-week, randomized, double-blind, multicenter, parallel-group study in symptomatic patients with COPD and ≥1 moderate/severe exacerbation in the previous year. Patients received BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg twice daily via a single metered dose Aerosphere™ inhaler. In these subgroup analyses, efficacy and safety were assessed in patients with or without prior ICS use in the 30 days before screening. RESULTS: The modified intent-to-treat population comprised 8509 patients (prior ICS use, n = 6810 [80%]; no prior ICS use, n = 1699 [20%]). Moderate/severe exacerbation rates were reduced by 24% and 23% in patients with and without prior ICS use, respectively, with BGF 320 versus GFF. Benefits of BGF 320 versus GFF were also similar in patients with and without prior ICS use across other endpoints relating to exacerbations, symptoms, HRQoL, lung function, and safety. Trends were similar for BGF 160 versus GFF. CONCLUSION: Benefits on exacerbations, symptoms, HRQoL, and lung function with BGF versus GFF were observed, irrespective of prior ICS use in the 30 days before screening.

Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON).

BACKGROUND: The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. METHODS: Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting ß2-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 µg) or medium-dose (150/50/80 µg) o.d. or SAL/FLU high-dose (50/500 µg) b.i.d.+Tio 5 µg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. RESULTS: IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and -0.038, respectively; both p < 0.001). IND/GLY/MF high-dose improved ACQ-7 (Δ: -0.124; p = 0.004), trough FEV1 (Δ: 96 mL; p < 0.001), peak expiratory flow (morning [Δ: 9.56 L/min; p = 0.005], evening [Δ: 9.15 L/min; p = 0.006]) and SGRQ (Δ: -2.00; p = 0.04) versus SAL/FLU high dose + TIO. Improvements in these endpoints were comparable for IND/GLY/MF medium-dose and SAL/FLU high dose + TIO. Adverse events were generally comparable across treatments. CONCLUSIONS: IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study.

BACKGROUND: Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. METHODS: This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 µg, 150 µg) or medium-dose MF-IND (160 µg, 150 µg) once daily via Breezhaler; high-dose MF (800 µg [400 µg twice daily]) or medium-dose MF (400 µg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. FINDINGS: Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. INTERPRETATION: Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. FUNDING: Novartis Pharmaceuticals.

Is allergy immunotherapy with birch sufficient to treat patients allergic to pollen of tree species of the birch homologous group?

Pollen from various Fagales tree species prolongs the season and makes tree pollen allergy a major health problem. Despite involving the same causative allergens, allergy immunotherapy (AIT) treatment habits differ significantly across different geographical regions. Diagnosis and treatment with AIT in patients allergic to tree pollen were discussed by a group of German medical experts who give practical recommendations based on the available data. Regulatory perspective: According to current guidelines on allergen products, birch pollen are the representative allergen source of the birch homologous group including several Fagales trees based on sequence and structural similarity of their allergen proteins. Immunological perspective: A high level of IgE cross-reactivity towards allergens from the birch homologous group has been observed in basic research and clinical trials. Clinical perspective: Clinical trial data show that the efficacy of birch pollen AIT is not only related to birch pollen allergy but extends to pollen from other trees, especially alder, hazel and oak. In order to optimize diagnosis and treatment of tree pollen allergy, the experts recommend to focus diagnosis and respective treatment with AIT primarily to birch as the representative allergen of the Fagales tree homologous group, but further diagnostics may be needed for some patients to determine adequate treatment.

MRI Brain Changes After Marathon Running: Results of the Berlin Beat of Running Study.

Several studies report neurological complications such as brain injury induced by ischemia or edema following exhaustive endurance sport. We aimed to detect the frequency of acute brain lesions after a marathon race. In the prospective observational Berlin Beat of Running study, 110 experienced endurance athletes underwent 3-Tesla brain MRI exams 2-3 days prior and within 2 days after a marathon run. MRI results were compared to an age- and sex-matched control group of 68 non-athletes, including the "Age-Related White Matter Changes" (ARWMC) scale to assess white matter lesions (WML) in the brain. 108 athletes (median age 48 years, 24% female, 8% with hypertension; 0% with diabetes) completed the race. No athlete reported neurological deficits, but a single acute ischemic lesion was detected in diffusion-weighted MRI after the race in one athlete. No other acute brain lesions compared to prior MRI were found. An ARWMC score ≥4 was found in 15% of athletes and 12% of non-athletic controls (p=0.7). Chronic ischemic lesions were not found in athletes but in four controls (6%) (p=0.02). In conclusion, acute ischemic brain lesions may be found in endurance runners. Every seventh endurance athlete and every ninth control showed evidence for substantial white matter lesions.

Structural insights into the stimulation of S. pombe Dnmt2 catalytic efficiency by the tRNA nucleoside queuosine.

Dnmt2 methylates cytosine at position 38 of tRNAAsp in a variety of eukaryotic organisms. A correlation between the presence of the hypermodified nucleoside queuosine (Q) at position 34 of tRNAAsp and the Dnmt2 dependent C38 methylation was recently found in vivo for S. pombe and D. discoideum. We demonstrate a direct effect of the Q-modification on the methyltransferase catalytic efficiency in vitro, as Vmax/K0.5 of purified S. pombe Dnmt2 shows an increase for in vitro transcribed tRNAAsp containing Q34 to 6.27 ∗ 10-3 s-1 µM-1 compared to 1.51 ∗ 10-3 s-1 µM-1 for the unmodified substrate. Q34tRNAAsp exhibits an only slightly increased affinity for Dnmt2 in comparison to unmodified G34tRNA. In order to get insight into the structural basis for the Q-dependency, the crystal structure of S. pombe Dnmt2 was determined at 1.7 Å resolution. It closely resembles the known structures of human and E. histolytica Dnmt2, and contains the entire active site loop. The interaction with tRNA was analyzed by means of mass-spectrometry using UV cross-linked Dnmt2-tRNA complex. These cross-link data and computational docking of Dnmt2 and tRNAAsp reveal Q34 positioned adjacent to the S-adenosylmethionine occupying the active site, suggesting that the observed increase of Dnmt2 catalytic efficiency by queuine originates from optimal positioning of the substrate molecules and residues relevant for methyl transfer.

Marathon running increases circulating endothelial- and thrombocyte-derived microparticles.

Background Acute vascular effects of high intensity physical activity are incompletely characterized. Circulating microparticles are cellular markers for vascular activation and damage. Methods Microparticles were analysed in 99 marathon runners (49 ± 6 years, 22% female) of the prospective Berlin Beat of Running study. Blood samples were taken within three days before, immediately after and within two days after the marathon run. Endothelial-derived microparticles were labelled with CD144, CD31 and CD62E, platelet-derived microparticles with CD62P and CD42b, leukocyte-derived microparticles with CD45 and monocyte-derived microparticles with CD14. Results Marathon running induced leukocytosis (5.9 ± 0.1 to 14.8 ± 0.3 109/l, p < 0.0001) and increased platelet counts (239 ± 4.6 to 281 ± 5.9 109/l, p < 0.0001) immediately after the marathon. Blood monocytes increased and lymphocytes decreased after the run ( p < 0.0001). Endothelial-derived microparticles were acutely increased ( p = 0.008) due to a 23% increase of apoptotic endothelial-derived microparticles ( p = 0.007) and returned to baseline within two days after the marathon. Thrombocyte-derived microparticles acutely increased by 38% accompanied by an increase in activated and apoptotic thrombocyte-derived microparticles ( p ≤ 0.0001) each. Both monocyte- and leukocyte-derived microparticles were decreased immediately after marathon run ( p < 0.0001) and remained below baseline until day 2. Troponin T increased from 12 to 32 ng/l ( p < 0.0001) immediately after the run and returned to baseline after two days. Conclusion Circulating apoptotic endothelial- and thrombocyte-derived microparticles increased after marathon running consistent with an acute pro-thrombotic and pro-inflammatory state. Exercise-induced vascular damage reflected by microparticles could indicate potential mechanisms of post-exertional cardiovascular complications. Further studies are warranted to investigate microparticles as markers to identify individuals prone to such complications.

Frequency of exercise-induced ST-T-segment deviations and cardiac arrhythmias in recreational endurance athletes during a marathon race: results of the prospective observational Berlin Beat of Running study.

OBJECTIVES: While regular physical exercise has many health benefits, strenuous physical exercise may have a negative impact on cardiac function. The 'Berlin Beat of Running' study focused on feasibility and diagnostic value of continuous ECG monitoring in recreational endurance athletes during a marathon race. We hypothesised that cardiac arrhythmias and especially atrial fibrillation are frequently found in a cohort of recreational endurance athletes. The main secondary hypothesis was that pathological laboratory findings in these athletes are (in part) associated with cardiac arrhythmias. DESIGN: Prospective observational cohort study including healthy volunteers. SETTING AND PARTICIPANTS: One hundred and nine experienced marathon runners wore a portable ECG recorder during a marathon race in Berlin, Germany. Athletes underwent blood tests 2-3 days prior, directly after and 1-2 days after the race. RESULTS: Overall, 108 athletes (median 48 years (IQR 45-53), 24% women) completed the marathon in 249±43 min. Blinded ECG analysis revealed abnormal findings during the marathon in 18 (16.8%) athletes. Ten (9.3%) athletes had at least one episode of non-sustained ventricular tachycardia, one of whom had atrial fibrillation; eight (7.5%) individuals showed transient ST-T-segment deviations. Abnormal ECG findings were associated with advanced age (OR 1.11 per year, 95% CI 1.01 to 1.23), while sex and cardiovascular risk profile had no impact. Directly after the race, high-sensitive troponin T was elevated in 18 (16.7%) athletes and associated with ST-T-segment deviation (OR 9.9, 95% CI 1.9 to 51.5), while age, sex and cardiovascular risk profile had no impact. CONCLUSIONS: ECG monitoring during a marathon is feasible. Abnormal ECG findings were present in every sixth athlete. Exercise-induced transient ST-T-segment deviations were associated with elevated high-sensitive troponin T (hsTnT) values. TRIAL REGISTRATION: ClinicalTrials.gov NCT01428778; Results.

Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study.

BACKGROUND: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. METHODS/DESIGN: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. RESULTS: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 ± 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 ± 6.6 marathon races within the last 5 years and a mean of 16 ± 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 ± 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN-MARATHON 2011. DISCUSSION: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage. TRIAL REGISTRATION: clinicaltrials.gov NCT01428778.

Omalizumab treatment and exercise capacity in severe asthmatics - results from a pilot study.

BACKGROUND: In patients with moderate to severe allergic asthma, clinical effectiveness of omalizumab, an approved anti-IgE-reacting substance, is usually assessed by pulmonary function testing (PFT), symptom scores and physicians judgement. AIMS: We postulate that cardiopulmonary exercise testing (CPET) may provide an additional option to verify symptomatic changes in patients with allergic asthma. METHODS: Ten consecutive patients with allergic asthma were treated with omalizumab. Prior to and after 16 weeks of treatment all patients underwent PFT and symptom-limited CPET. Results were compared to 10 asthmatic controls without omalizumab medication. Symptoms were assessed according to investigators judgement (IGETE). RESULTS: All 20 patients showed a significantly impaired exercise capacity at baseline [peak oxygen uptake (VO(2)) 71 ± 16% predicted]. In patients with omalizumab, peakVO(2) increased from 13.8 (8.4-21.4) to 16.8 (11.2-23.9) ml/kg/min (p < 0.05), VO(2) at anaerobic threshold increased by 22% [9.8 (3.3-15.2) to 12.3 (6.7-14.4) ml/kg/min (p < 0.05)]. There was no improvement in the controls. The increase in VO(2) was significantly correlated to the improvement in symptoms. All patients revealed dynamic hyperinflation under exercise with a decreasing extent with omalizumab treatment. CONCLUSION: This study suggests that CPET may provide additional and useful tools to assess and verify the individual clinical response to omalizumab treatment. An improvement in exercise capacity can reliably mirror changes in quality of life and IGETE. Patients with omalizumab experience significant improvements in their initially impaired exercise capacity. CPET can be safely accomplished in patients with severe asthma.

Essential role of mitochondrial antiviral signaling, IFN regulatory factor (IRF)3, and IRF7 in Chlamydophila pneumoniae-mediated IFN-beta response and control of bacterial replication in human endothelial cells.

Chlamydophila pneumoniae infection of the vascular wall as well as activation of the transcription factor IFN regulatory factor (IRF)3 have been linked to development of chronic vascular lesions and atherosclerosis. The innate immune system detects invading pathogens by use of pattern recognition receptors, some of which are able to stimulate IRF3/7 activation and subsequent type I IFN production (e. g., IFN-beta). In this study, we show that infection of human endothelial cells with C. pneumoniae-induced production of IFN-beta, a cytokine that so far has been mainly associated with antiviral immunity. Moreover, C. pneumoniae infection led to IRF3 and IRF7 nuclear translocation in HUVECs and RNA interference experiments showed that IRF3 and IRF7 as well as the mitochondrial antiviral signaling (MAVS) were essential for IFN-beta induction. Finally, C. pneumoniae replication was enhanced in endothelial cells in which IRF3, IRF7, or MAVS expression was inhibited by small interfering RNA and attenuated by IFN-beta treatment. In conclusion, C. pneumoniae infection of endothelial cells activates an MAVS-, IRF3-, and IRF7-dependent signaling, which controls bacterial growth and might modulate development of vascular lesions.

Mature mediastinal teratoma with subtotal unidirectional pancreatic differentiation.

Tumor-like lesions of the mediastinum consisting exclusively of mature pancreatic tissue are rare. Most authors regard these lesions as developmental abnormalities. We report the case of a 17-year-old male who presented with progressive dyspnea due to a large mediastinal tumor with accompanying pericardial effusion. Percutaneous core needle biopsies showed differentiated pancreatic tissue with chronic inflammation and cystic transformation. On this basis, heterotopic pancreatic tissue of the mediastinum, a lesion occasionally reported in the literature, was suspected and the lesion was excised. The histopathological workup of the surgically excised lesion, in the first place, supported the primary diagnosis. However, after extensive sampling of the lesion, the diagnosis had to be changed to mature teratoma with subtotal unidirectional pancreatic differentiation. We hypothesize that at least some of those cases reported in the literature as "heterotopic pancreatic tissue of the mediastinum" may be in fact unidirectionally differentiated teratomas and should therefore be regarded and treated as true neoplasms rather than developmental abnormalities.

A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer.

INTRODUCTION: The combination of docetaxel and cisplatin is an effective first-line regimen in patients with advanced non-small cell lung cancer. However, the recommended three-weekly schedule is associated with frequent neutropenia and infections. Because of the toxicity of cisplatin, patients may need to be hospitalized to ensure adequate hydration. The aim of this study was to assess the efficacy and tolerability of a weekly schedule of docetaxel and cisplatin. PATIENTS AND METHODS: Patients with inoperable stage International Union Against Cancer IIIB (malignant effusion) or IV non-small cell lung cancer received docetaxel (35 mg/m(2), 30 minutes infusion) and cisplatin (25 mg/m(2), 30 minutes infusion) on days 1, 8, and 15, every 4 weeks for 4 to 6 cycles. Ondansetron (8 mg) and dexamethasone (8 mg) were given intravenously before chemotherapy. The patients received oral dexamethasone 2 x 4 mg daily from the day before until the day after chemotherapy. NK1-antagonists were given at the investigator's discretion. The majority of patients was treated in outpatient departments. Safety was assessed using CTCAE v3.0. The primary end point was response rate (RECIST). RESULTS: Forty-four patients were included. Twelve of 44 patients achieved an objective response (11 partial, 1 complete, intent-to-treat response rate 27%). Median time to progression was 4.4 months (95% confidence interval: 4.0-4.7) and median survival 9.6 months (95% confidence interval: 2.9-16.2). Patients received a median of three full cycles. Four patients (9%) required dose reductions. No cases of febrile neutropenia or grade 2 to 4 thrombocytopenia were observed. One patient (2%) experienced grade 3/4 nausea and vomiting. CONCLUSIONS: Weekly docetaxel-cisplatin demonstrated comparable efficacy with three-weekly schedules. Although the frequencies of neutropenia and febrile neutropenia were low, non-neutropenic infections remained a problem. Because of relatively short hydration, the schedule can be safely administered in an outpatient setting.

Beta-PIX and Rac1 GTPase mediate trafficking and negative regulation of NOD2.

The nucleotide-binding domain and leucine-rich repeat containing protein NOD2 serves as a cytoplasmic pattern recognition molecule sensing bacterial muramyl dipeptide (MDP), whereas TLR2 mediates cell surface recognition of bacterial lipopeptides. In this study, we show that NOD2 stimulation activated Rac1 in human THP-1 cells and primary human monocytes. Rac1 inhibition or knock-down, or actin cytoskeleton disruption increased MDP-stimulated IL-8 secretion and NF-kappaB activation, whereas TLR2-dependent cell activation was suppressed by Rac1 inhibition. p21-activated kinase [Pak]-interacting exchange factor (beta-PIX) plays a role in this negative regulation, because knock-down of beta-PIX also led to increased NOD2-mediated but not TLR2-mediated IL-8 secretion, and coimmunoprecipitation experiments demonstrated that NOD2 interacted with beta-PIX as well as Rac1 upon MDP stimulation. Moreover, knock-down of beta-PIX or Rac1 abrogated membrane recruitment of NOD2, and interaction of NOD2 with its negative regulator Erbin. Overall, our data indicate that beta-PIX and Rac1 mediate trafficking and negative regulation of NOD2-dependent signaling which is different from Rac1's positive regulatory role in TLR2 signaling.

[Effects of tobacco use on systemic health: relevant information for dentistry (II)--part 2: cardiovascular diseases and public health issues]. / Effekte des Tabakkonsums auf die Allgemeingesundheit: relevante Kenntnisse für die Zahnmedizin (II). Teil 2: Kardiovaskuläre Erkrankungen und gesundheitspolitische Fragen.

This is the sixth and concluding part of a series of publications from the Swiss task force named "Smoking - Intervention in the private dental office" on the topic "tobacco use and dental medicine". The focus of this review is the effects of smoking for the development of atherosclerosis as pathohistological correlate for acute coronary syndrome (ACS), arterial occlusive disease, and cerebrovascular diseases (stroke). Additionally, a causal relationship between tobacco use and an increased rate for complications during pregnancy and child birth will be discussed. Next to causal therapy of local and systemic diseases in general, an emphasis must be given to tobacco use prevention and cessation. Finally, important public health issues concerning smoking and tobacco use will be demonstrated, and options to improve the current situation will be presented.

[Effects of tobacco use on general health: relevant information for dentistry (I)--part 1: pulmonary diseases and other malignancies]. / Effekte des Tabakkonsums auf die AIIgemeingesundheit: relevante Kenntnisse für die Zahnmedizin (I). Teil 1: Pulmonale Erkrankungen und weitere maligne Erkrankungen.

This fifth part of a series of publications from the Swiss task force named "Smoking--Intervention in the private dental office" on the topic "tobacco use and dental medicine" focuses on the effects of tobacco use on general health. A significant increase of tobacco use associated morbidity and mortality for many cardiovascular and pulmonary diseases has been well documented in the literature. In this review, the epidemiologic background as well as the pathophysiological fundamentals for tobacco-mediated pulmonary diseases is presented, focusing especially on chronic obstructive pulmonary disease (COPD) and lung cancer. In addition, a causal relationship between nicotine abuse and an increased carcinoma incidence for other malignancies but lung cancer will be discussed. Regarding the evidence in the present literature, it is undisputable that smoking is the most preventable cause for COPD and lung cancer.