| Achieving asthma control with ICS/LABA: A review of strategies for asthma management and prevention |
Maintenance treatment with an inhaled corticosteroid (ICS) and a long-acting beta2-agonist (LABA) is recommended for patients whose asthma is not controlled with a low-to-moderate dose of ICS alone; a separate reliever medication is used on an as-needed basis. The Gaining Optimal Asthma ControL (GOAL) study demonstrated that salmeterol/fluticasone maintenance treatment can improve asthma control and reduce future risk compared with fluticasone alone, although the dose escalation design of this study meant that most patients treated with salmeterol/fluticasone were receiving the highest dose of ICS at the end of the study. Similarly, budesonide/formoterol maintenance therapy improved asthma control and reduced future risk compared with budesonide alone in the Formoterol and Corticosteroids Establishing Therapy (FACET) study. An alternative approach to asthma management is to use an ICS/LABA for both maintenance and reliever therapy. A large body of clinical evidence has shown that the use of budesonide/formoterol in this way improves both current control and reduces future risk compared with ICS/LABA plus as-needed short-acting beta2-agonist (SABA), even when patients receive lower maintenance doses of ICS as part of the maintenance and reliever therapy regimen. In addition, one study has shown that beclometasone/formoterol maintenance and reliever therapy reduces exacerbations more effectively than beclometasone/formoterol plus as-needed SABA. The use of ICS/LABA as both maintenance and reliever therapy ensures that an increase in reliever use in response to worsening symptoms is automatically matched by an increase in ICS.
- Aalbers, R.; Vogelmeier, C.; Kuna, P.
Keywords
- Administration, Inhalation
- Adrenal Cortex Hormones/*therapeutic use
- Adrenergic beta-2 Receptor Agonists/*therapeutic use
- Asthma/*drug therapy/prevention & control
- Bronchodilator Agents/*therapeutic use
- Budesonide/*therapeutic use
- Drug Therapy, Combination
- Formoterol Fumarate/*therapeutic use
- Humans
- Asthma
- Beclometasone
- Budesonide
- Formoterol
- Ics/laba
- Maintenance and reliever therapy
|
10.1016/j.rmed.2015.11.002 |
Respir Med |
AA |
UMR |
UGMLC |
Review |
2016 |
| BRAF Inhibition in a Lung Transplant Recipient With Metastatic Melanoma |
- Afshar, K.; David, S.; Fuehner, T.; Gottlieb, J.; Gutzmer, R.
Keywords
- Female
- Humans
- Immunosuppressive Agents/*administration & dosage/pharmacology
- Indoles/administration & dosage/pharmacology
- *Lung Transplantation
- Melanoma/*drug therapy/pathology
- Middle Aged
- Neoplasm Metastasis
- Proto-Oncogene Proteins B-raf/*antagonists & inhibitors
- Sulfonamides/administration & dosage/pharmacology
|
10.1001/jamadermatol.2015.2910 |
JAMA Dermatol |
ROR, LC |
MHH |
BREATH |
Original |
2016 |
| alpha-Linoleic acid enhances the capacity of alpha-1 antitrypsin to inhibit lipopolysaccharide induced IL-1beta in human blood neutrophils |
Alpha1-antitrypsin (A1AT, SERPINA1), a major circulating inhibitor of neutrophil elastase (NE) and proteinase-3 (PR3), has been proposed to reduce the processing and release of IL-1beta. Since the anti-inflammatory properties of A1AT are influenced by the presence of polyunsaturated fatty acids, we compared effects of fatty acid-free (A1AT-0) and alpha-linoleic acid bound (A1AT-LA) forms of A1AT on lipopolysaccharide (LPS)-induced synthesis of IL-1beta precursor and the release of IL-1beta from human blood neutrophils. The presence of A1AT-LA or A1AT-0 significantly reduced LPS induced release of mature IL-1beta. However, only A1AT-LA reduced both steady state mRNA levels of IL-1beta and the secretion of mature IL-1beta. In LPS-stimulated neutrophils, mRNA levels of TLR2/4, NFKBIA, P2RX7, NLRP3, and CASP1 decreased significantly in the presence of A1AT-LA but not A1AT-0. A1AT-0 and A1AT-LA did not inhibit the direct enzymatic activity of caspase-1, but we observed complexes of either form of A1AT with NE and PR3. Consistent with the effect on TLR and IL-1beta gene expression, only A1AT-LA inhibited LPS-induced gene expression of NE and PR3. Increased gene expression of PPAR-gamma was observed in A1AT-LA treated neutrophils without of LPS stimulation, and the selective PPAR-gamma antagonist (GW9662) prevented the reduction in IL-1beta by A1AT-LA. We conclude from our data, that the ability of A1AT to reduce TLR and IL-1beta gene expression depends on its association with LA. Moreover, the anti-inflammatory properties of A1AT-LA are likely to be mediated by the activation of PPAR-gamma.
- Aggarwal, N.
- Korenbaum, E.
- Mahadeva, R.
- Immenschuh, S.
- Grau, V.
- Dinarello, C. A.
- Welte, T.
- Janciauskiene, S.
Keywords
- Lps
- Serpina1
- alpha1 antitrypsin
- fatty acids
- human neutrophils
- inflammasome
- alpha-linoleic acid
|
10.2119/molmed.2016.00119 |
Mol Med |
ROR |
JLU, MHH |
BREATH, UGMLC |
Original |
2016 |
| Alpha-1 Antitrypsin Regulates Transcriptional Levels of Serine Proteases in Blood Mononuclear Cells |
- Aggarwal, N.; Koepke, J.; Matamala, N.; Martinez-Delgado, B.; Martinez, M. T.; Golpon, H.; Stolk, J.; Janciauskiene, S.; Koczulla, R.
|
10.1164/rccm.201510-2062LE |
Am J Respir Crit Care Med |
LC |
MHH |
BREATH |
Original |
2016 |
| Treatable traits: toward precision medicine of chronic airway diseases |
Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway diseases that have a high personal and social impact. They likely represent a continuum of different diseases that may share biological mechanisms (i.e. endotypes), and present similar clinical, functional, imaging and/or biological features that can be observed (i.e. phenotypes) which require individualised treatment. Precision medicine is defined as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations". In this Perspective, we propose a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular.
- Agusti, A.; Bel, E.; Thomas, M.; Vogelmeier, C.; Brusselle, G.; Holgate, S.; Humbert, M.; Jones, P.; Gibson, P. G.; Vestbo, J.; Beasley, R.; Pavord, I. D.
Keywords
- Asthma/*drug therapy/immunology/physiopathology
- Humans
- Inflammation
- Phenotype
- Precision Medicine/*methods
- Pulmonary Disease, Chronic Obstructive/*drug therapy/immunology/physiopathology
|
10.1183/13993003.01359-2015 |
Eur Respir J |
AA |
UMR |
UGMLC |
Review |
2016 |
| Highlights and hot topics in the management of COPD: where are we heading? |
- Agusti, A.; Jones, P. W.; Vogelmeier, C.
Keywords
- Humans
- Predictive Value of Tests
- Prognosis
- *Pulmonary Disease, Chronic Obstructive/diagnosis/drug
- therapy/epidemiology/physiopathology
- Risk Factors
|
10.2147/COPD.S85975 |
Int J Chron Obstruct Pulmon Dis |
COPD |
UMR |
UGMLC |
Other |
2016 |
| PROGRESS - prospective observational study on hospitalized community acquired pneumonia |
BACKGROUND: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION: The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.
- Ahnert, P.; Creutz, P.; Scholz, M.; Schutte, H.; Engel, C.; Hossain, H.; Chakraborty, T.; Bauer, M.; Kiehntopf, M.; Volker, U.; Hammerschmidt, S.; Loeffler, M.; Suttorp, N.; Progress study group
Keywords
- Biobank
- Biomarkers
- Data base
- Disease progression
- Innate immunity
- Pneumonia
- Prospective observational study
- Sepsis
|
10.1186/s12890-016-0255-8 |
BMC Pulm Med |
PLB |
JLU, PROGRESS |
UGMLC |
Original |
2016 |
| MAP1LC3B overexpression protects against Hermansky-Pudlak syndrome type-1-induced defective autophagy in vitro |
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, and some patients with HPS develop pulmonary fibrosis, known as HPS-associated interstitial pneumonia (HPSIP). We have previously reported that HPSIP is associated with severe surfactant accumulation, lysosomal stress, and alveolar epithelial cell type II (AECII) apoptosis. Here, we hypothesized that defective autophagy might result in excessive lysosomal stress in HPSIP. Key autophagy proteins, including LC3B lipidation and p62, were increased in HPS1/2 mice lungs. Electron microscopy demonstrated a preferable binding of LC3B to the interior of lamellar bodies in the AECII of HPS1/2 mice, whereas in wild-type mice it was present on the limiting membrane in addition to the interior of the lamellar bodies. Similar observations were noted in human HPS1 lung sections. In vitro knockdown of HPS1 revealed increased LC3B lipidation and p62 accumulation, associated with an increase in proapoptotic caspases. Overexpression of LC3B decreased the HPS1 knockdown-induced p62 accumulation, whereas rapamycin treatment did not show the same effect. We conclude that loss of HPS1 protein results in impaired autophagy that is restored by exogenous LC3B and that defective autophagy might therefore play a critical role in the development and progression of HPSIP.
- Ahuja, S.
- Knudsen, L.
- Chillappagari, S.
- Henneke, I.
- Ruppert, C.
- Korfei, M.
- Gochuico, B. R.
- Bellusci, S.
- Seeger, W.
- Ochs, M.
- Guenther, A.
- Mahavadi, P.
Keywords
- Alveolar Epithelial Cells/*physiology
- Animals
- Apoptosis Regulatory Proteins/metabolism
- *Autophagy
- Cell Line, Tumor
- Female
- Hermanski-Pudlak Syndrome/*metabolism/pathology
- Humans
- Lung/metabolism/pathology
- Male
- Membrane Proteins/genetics
- Mice, Inbred C57BL
- Microtubule-Associated Proteins/genetics/*metabolism
- Hermansky-Pudlak syndrome
- Hermansky-Pudlak syndrome-associated interstitial pneumonia
- alveolar epithelial cells
- apoptosis
- autophagy
- lung fibrosis
|
10.1152/ajplung.00213.2015 |
Am J Physiol Lung Cell Mol Physiol |
CFBE |
JLU, MHH |
BREATH, UGMLC |
Original |
2016 |
| Should all adult cystic fibrosis patients with repeated nontuberculous mycobacteria cultures receive specific treatment? A 10-year case-control study |
- Albrecht, C.; Ringshausen, F.; Ott, S.; Wagner, D.; Rademacher, J.; Schneider, M.; Welte, T.; Pletz, M. W.
|
10.1183/13993003.01239-2015 |
Eur Respir J |
CFBE |
MHH |
BREATH |
Original |
2016 |
| Measurement of exhaled volatile organic compounds from patients with chronic obstructive pulmonary disease (COPD) using closed gas loop GC-IMS and GC-APCI-MS |
Due to its high sensitivity, compact size and low cost ion mobility spectrometry (IMS) has the potential to become a point-of-care breath analyzer. Therefore, we developed a prototype of a compact, closed gas loop IMS with gas chromatographic (GC) pre-separation and high resolving power of R = 90. In this study, we evaluated the performance of this GC-IMS under clinical conditions in a COPD study to find correlations between VOCs (10 ppbv to 1 ppmv) and COPD. Furthermore, in order to investigate possible correlations between ultra-low concentrated breath VOCs (0.1 pptv to 1 ppbv) and COPD, a modified mass spectrometer (MS) with atmospheric pressure chemical ionization (APCI) and GC pre-separation (GC-APCI-MS) was used. The GC-IMS has been used in 58 subjects (21 smokers with moderate COPD, 12 ex-smokers with COPD, 16 healthy smokers and 9 non-smokers). GC-APCI-MS data were available for 94 subjects (21 smokers with moderate COPD, 25 ex-smokers with COPD, 25 healthy smokers and 23 non-smokers). For 44 subjects, a comparison between GC-IMS and GC-APCI-MS data could be performed. Due to service intervals, subject availability and corrupt data, patient numbers were different for GC-APCI-MS and GC-IMS measurements. Using GC-IMS, three VOCs have been found showing a significant difference between healthy controls and patients with COPD. In the GC-APCI-MS data, we only observed one distinctive VOC, which has been identified as 2-pentanone. This proof-of-principle study shows the potential of our high-resolution GC-IMS in the clinical environment. Due to different linear dynamic response ranges, the data of GC-IMS and GC-APCI-MS were only comparable to a limited extent.
- Allers, M.; Langejuergen, J.; Gaida, A.; Holz, O.; Schuchardt, S.; Hohlfeld, J. M.; Zimmermann, S.
Keywords
- Adult
- Aged
- Breath Tests/*methods
- Chromatography, Gas/*methods
- Exhalation
- Female
- Humans
- Male
- Mass Spectrometry/*methods
- Middle Aged
- Point-of-Care Systems
- Pulmonary Disease, Chronic Obstructive/*physiopathology
- Volatile Organic Compounds/*analysis
- Young Adult
|
10.1088/1752-7155/10/2/026004 |
J Breath Res |
COPD |
ITEM |
BREATH |
Original |
2016 |
| The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study |
Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity.
- Altmaier, E.
- Menni, C.
- Heier, M.
- Meisinger, C.
- Thorand, B.
- Quell, J.
- Kobl, M.
- Romisch-Margl, W.
- Valdes, A. M.
- Mangino, M.
- Waldenberger, M.
- Strauch, K.
- Illig, T.
- Adamski, J.
- Spector, T.
- Gieger, C.
- Suhre, K.
- Kastenmuller, G.
Keywords
- Adult
- Aged
- Angiotensin-Converting Enzyme Inhibitors/*therapeutic use
- Antihypertensive Agents/therapeutic use
- Blood Pressure/drug effects/genetics
- Dipeptides/metabolism
- Female
- Genetic Variation/drug effects/genetics
- Genotype
- Humans
- Hypertension/drug therapy/genetics/metabolism
- Male
- Metabolome/*drug effects/*genetics
- Metabolomics/methods
- Middle Aged
- Oligopeptides/metabolism
- Peptidyl-Dipeptidase A/*genetics/*metabolism
- Pharmacogenetics/methods
|
10.1371/journal.pone.0153163 |
PLoS One |
PLB |
HMGU, LMU, MHH |
BREATH, CPC-M |
Original |
2016 |
| Searching for better animal models of BPD: a perspective |
There have been many efforts to develop good animal models of bronchopulmonary dysplasia (BPD) to better understand the pathophysiology and mechanisms underlying development of BPD as well as to test potential strategies for its prevention and treatment. This Perspectives summarizes the features of common animal models of BPD and the strengths and limitations of such models. Potential optimal approaches to development of animal models are indicated, with the underlying concepts that require emphasis.
- Ambalavanan, N.; Morty, R. E.
Keywords
- Animals
- Bronchopulmonary Dysplasia/*pathology/therapy
- *Disease Models, Animal
- Humans
- Infant, Newborn
- Lung/embryology/pathology
- animal models
- bronchopulmonary dysplasia
- diseases
- infant
- lung development
- lung injury
- premature
|
10.1152/ajplung.00355.2016 |
Am J Physiol Lung Cell Mol Physiol |
DPLD |
MPI-BN |
UGMLC |
Other |
2016 |
| Social/economic costs and health-related quality of life in patients with epidermolysis bullosa in Europe |
BACKGROUND: The aim of this study was to determine the social/economic costs and health-related quality of life (HRQOL) of patients with epidermolysis bullosa (EB) in eight EU member states. METHODS: We conducted a cross-sectional study of patients with EB from Bulgaria, France, Germany, Hungary, Italy, Spain, Sweden and the United Kingdom. Data on demographic characteristics, health resource utilisation, informal care, labour productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. RESULTS: A total of 204 patients completed the questionnaire. Average annual costs varied from country to country, and ranged from euro9509 to euro49,233 (reference year 2012). Estimated direct healthcare costs ranged from euro419 to euro10,688; direct non-healthcare costs ranged from euro7449 to euro37,451 and labour productivity losses ranged from euro0 to euro7259. The average annual cost per patient across all countries was estimated at euro31,390, out of which euro5646 accounted for direct health costs (18.0 %), euro23,483 accounted for direct non-healthcare costs (74.8 %), and euro2261 accounted for indirect costs (7.2 %). Costs were shown to vary across patients with different disability but also between children and adults. The mean EQ-5D score for adult EB patients was estimated at between 0.49 and 0.71 and the mean EQ-5D visual analogue scale score was estimated at between 62 and 77. CONCLUSION: In addition to its negative impact on patient HRQOL, our study indicates the substantial social/economic burden of EB in Europe, attributable mostly to high direct non-healthcare costs.
- Angelis, A.; Kanavos, P.; Lopez-Bastida, J.; Linertova, R.; Oliva-Moreno, J.; Serrano-Aguilar, P.; Posada-de-la-Paz, M.; Taruscio, D.; Schieppati, A.; Iskrov, G.; Brodszky, V.; von der Schulenburg, J. M.; Chevreul, K.; Persson, U.; Fattore, G.; Burqol-Rd Research Network
Keywords
- Adolescent
- Adult
- Caregivers
- Child
- *Cost of Illness
- Cross-Sectional Studies
- Epidermolysis Bullosa/*economics/psychology
- Europe
- European Union
- Female
- *Health Care Costs/statistics & numerical data
- Humans
- Male
- Middle Aged
- Patient Care/economics
- *Quality of Life
- Sick Leave/economics/statistics & numerical data
- Sickness Impact Profile
- Socioeconomic Factors
- Surveys and Questionnaires
- United Kingdom
- Young Adult
- *Cost-of-illness
- *Epidermolysis bullosa
- *European Union
- *Health-related quality of life
- *Rare disease
- *Social cost
|
10.1007/s10198-016-0783-4 |
Eur J Health Econ |
COPD |
LUH |
BREATH |
Original |
2016 |
| Novel method for the generation of tissue-engineered vascular grafts based on a highly compacted fibrin matrix |
UNLABELLED: The generation of tissue-engineered blood vessel substitutes remains an ongoing challenge for cardiovascular tissue engineering. Full biocompatibility and immediate availability have emerged as central issues for clinical use. To address these issues, we developed a technique that allows the generation of highly stable tubular fibrin segments. The process is based on the compaction of fibrin in a custom-made high-speed rotation mold. In an automated process, fibrin is precipitated from plasma by means of the Vivostat(R) system. Following application to the rotating mold, the fibrin was compacted by centrifugal force and excess fluid was pressed out. This compaction results in increasing cross-links between the fibrin fibrils and a corresponding significant increase of biomechanical stability up to a burst strength of 230mm of mercury. The molding process allows for a simultaneous seeding procedure. In a first in vivo evaluation in a sheep model, segments of the carotid artery were replaced by tissue-engineered vascular grafts, generated immediately prior to implantation (n=6). Following subjection to the body's remodeling mechanisms, the segments showed a high structural similarity to a native artery after explantation at 6months. Thus, this technique may represent a powerful tool for the generation of biomechanically stable vascular grafts immediately prior to implantation. STATEMENT OF SIGNIFICANCE: Fibrin has previously been shown to be suitable as a matrix for the seeding of different celltypes and for that reason was widely used as scaffold in different fields of tissue engineering. Nevertheless, fibrin's lack of stability has strongly limited its application. Our study describes a novel moulding technique for the generation of a highly compacted fibrin matrix. Using this approach, it was possible to optimize the engineering process of tubular fibrin segments to provide bioartificial vascular grafts within one hour with sufficient stability for immediate implantation in the arterial system. Thus, this technique may represent a powerful tool to get closer to the ultimate aim of an optimal bioartificial vascular graft.
- Aper, T.; Wilhelmi, M.; Gebhardt, C.; Hoeffler, K.; Benecke, N.; Hilfiker, A.; Haverich, A.
Keywords
- Animals
- *Blood Vessel Prosthesis
- *Carotid Arteries
- Fibrin/*chemistry
- Humans
- Sheep
- Tissue Engineering/*methods
- Tissue Scaffolds/*chemistry
- Arterial tissue engineering
- Biocompatibility
- Cross-linking
- Endothelial cell
- Fibrin
- Progenitor cell
|
10.1016/j.actbio.2015.10.012 |
Acta Biomater |
ROR |
MHH |
BREATH |
Original |
2016 |
| T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4(+) T cells |
The NLRP3 inflammasome controls interleukin-1beta maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1beta secretion, thereby promoting interferon-gamma production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses.
- Arbore, G.
- West, E. E.
- Spolski, R.
- Robertson, A. A. B.
- Klos, A.
- Rheinheimer, C.
- Dutow, P.
- Woodruff, T. M.
- Yu, Z. X.
- O'Neill, L. A.
- Coll, R. C.
- Sher, A.
- Leonard, W. J.
- Kohl, J.
- Monk, P.
- Cooper, M. A.
- Arno, M.
- Afzali, B.
- Lachmann, H. J.
- Cope, A. P.
- Mayer-Barber, K. D.
- Kemper, C.
Keywords
- Adaptive Immunity
- Animals
- Autocrine Communication
- CD4-Positive T-Lymphocytes/*immunology
- Carrier Proteins/genetics/*metabolism
- Complement Activation
- Complement C5a/*immunology
- Cryopyrin-Associated Periodic Syndromes/immunology
- Disease Models, Animal
- HEK293 Cells
- Humans
- Immunity, Innate
- Inflammasomes/*immunology
- Inflammation/immunology
- Interferon-gamma/*biosynthesis
- Membrane Cofactor Protein/immunology
- Mice
- Mice, Mutant Strains
- NLR Family, Pyrin Domain-Containing 3 Protein
- Reactive Oxygen Species/metabolism
- Receptor, Anaphylatoxin C5a/agonists/antagonists & inhibitors/metabolism
- Receptors, Antigen, T-Cell/agonists/metabolism
- Receptors, Chemokine/agonists/antagonists & inhibitors/metabolism
- Th1 Cells/*immunology
|
10.1126/science.aad1210 |
Science |
General Lung and Other |
UzL |
ARCN |
Original |
2016 |
| Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC |
BACKGROUND: Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome. MATERIAL AND METHODS: In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed. RESULTS: At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy. CONCLUSIONS: These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.
- Ardizzoni, A.
- Tiseo, M.
- Boni, L.
- Di Maio, M.
- Buffoni, L.
- Belvedere, O.
- Grossi, F.
- D'Alessandro, V.
- de Marinis, F.
- Barbera, S.
- Caroti, C.
- Favaretto, A.
- Cortinovis, D.
- Morrica, B.
- Tixi, L.
- Ceschia, T.
- Parisi, S.
- Ricardi, U.
- Grimaldi, A.
- Loreggian, L.
- Navarria, P.
- Huber, R. M.
- Belani, C.
- Brunsvig, P. F.
- Scagliotti, G. V.
- Scolaro, T.
Keywords
- Adult
- Aged
- Antineoplastic Agents/*administration & dosage/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Bridged-Ring Compounds/*administration & dosage/therapeutic use
- Carboplatin/*administration & dosage/therapeutic use
- Carcinoma, Non-Small-Cell Lung/*drug therapy/*radiotherapy
- Combined Modality Therapy/*methods
- Female
- Humans
- Induction Chemotherapy
- Male
- *Meta-Analysis as Topic
- Middle Aged
- Neoplasm Staging
- Paclitaxel/*administration & dosage/therapeutic use
- Survival Rate
- Taxoids/*administration & dosage/therapeutic use
- Treatment Outcome
- *Chemotherapy
- *Concurrent treatment
- *nsclc
- *Radiotherapy
- *Stage III
|
10.1016/j.lungcan.2016.07.026 |
Lung Cancer |
LC |
KUM |
CPC-M, TLRC, UGMLC |
Original |
2016 |
| 147P: Level of concordance between EGFR mutation status obtained from tissue/cytology and blood (plasma) for advanced non-small-cell lung cancer in Spain: ASSESS study |
- Arriola, E.
- Paredes, A.
- Gomez, R. G.
- Diz, P.
- Constenla, M.
- Giron, C. G.
- Amador, M.
- Reck, M.
- Vivanco, G. L.
|
10.1016/S1556-0864(16)30257-X |
J Thorac Oncol |
LC |
Ghd |
ARCN |
Other |
2016 |
| Can severe asthmatic patients achieve asthma control? A systematic approach in patients with difficult to control asthma followed in a specialized clinic |
BACKGROUND: Despite advances in asthma treatment, severe asthma (SA) still results in high morbidity and use of health resources. Our hypothesis was that SA patients would achieve adequate control with a systematic protocol, including oral corticosteroids, budesonide/formoterol maintenance and reliever therapy and a multidisciplinary approach to improve adherence. METHODS: Non-controlled (NC) SA patients were enrolled to receive 2 weeks of oral corticosteroids and 12 weeks of formoterol + budesonide. Assessments included asthma control questionnaire (ACQ), asthma control test (ACT), daily symptom diary, lung function and health-related quality of life (HRQoL) questionnaires. RESULTS: Of 51 patients, 13 (25.5%) achieved control. NC patients had higher utilization of health resources and higher exacerbation rates. Both controlled (C) and NC patients had significantly reduced ACQ scores after oral corticosteroid treatment. After 12 weeks, C patients continued improving. NC patients did not have significant changes. A similar pattern was found regarding lung function, use of rescue medication, and days free of symptoms. After 2 weeks of oral corticosteroids, an increase occurred in those who achieved the ACQ cut off; however, 53.8% of C patients had an ACQ < 1.57 versus 21.1% of NC patients (p = 0.03). Both groups had low HRQoL at baseline with improvement after intervention. CONCLUSIONS: Despite rigorous, optimized follow-up treatment, 75% of SA patients did not achieve adequate symptom control and presented with impaired quality of life. Conversely, application of a low-cost, easy to implement systematic protocol can prevent up to 25% of SA patients from up-titrating to new and complex therapies, thus reducing costs and morbidity. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrial.gov on 22 February 2010 ( NCT01089322 ).
- Athanazio, R.
- Carvalho-Pinto, R.
- Fernandes, F. L.
- Rached, S.
- Rabe, K.
- Cukier, A.
- Stelmach, R.
Keywords
- Administration, Inhalation
- Adrenal Cortex Hormones/*administration & dosage
- Adult
- Anti-Asthmatic Agents/*administration & dosage
- Asthma/*drug therapy
- Brazil
- Bronchodilator Agents/*administration & dosage
- Budesonide/*administration & dosage
- Female
- Formoterol Fumarate/*administration & dosage
- Humans
- Logistic Models
- Male
- Middle Aged
- Multivariate Analysis
- Prospective Studies
- *Quality of Life
- Respiratory Function Tests
- Severity of Illness Index
- Surveys and Questionnaires
- Treatment Outcome
- *Asthma
- *Control
- *Difficult to control
- *Health related quality of life
- *Refractory asthma
|
10.1186/s12890-016-0314-1 |
BMC Pulm Med |
AA |
Ghd |
ARCN |
Original |
2016 |
| Treatment-related experiences and preferences of patients with lung cancer: a qualitative analysis |
BACKGROUND: Lung cancer is one of the most common types of cancer worldwide, and it causes significant challenges for patients due to the poor survival rate and treatment-related side-effects. Because of lung cancer's great burden, identification and use of the patients' preferences can help to improve patients' quality of life. OBJECTIVE: Interviews with patients who have lung cancer were used to ascertain a range of experiences and to make recommendations regarding the improvement of treatment based on these patients' preferences. Because chemotherapy is the common treatment option for lung cancer, we focused on this treatment. The interviews were audio-taped, verbally transcribed and evaluated via content analysis. SETTING AND PARTICIPANTS: A total of 18 participants (11 men and 7 women) with small or non-small-cell lung cancer who were receiving chemotherapy in one clinic were interviewed between June and July 2013. RESULTS: Two main aspects with different subthemes were identified during the interviews. One main aspect focused on organizational context, such as the treatment day process, or experiences with different stakeholders, such as with the health insurance company or physicians. The other category referred to experiences that influenced psychosocial factors, including physical and mental experiences. DISCUSSION AND CONCLUSION: Patients reported different experiences concerning physical, psychological and organizational areas during chemotherapy. Nevertheless, some potential areas for improving care, and therefore the quality of life of patients with lung cancer, could be identified. These improvement measures highlighted that with small, non-time-consuming and inexpensive changes, the treatment for patients with lung cancer can be improved.
- Aumann, I.; Kreis, K.; Damm, K.; Golpon, H.; Welte, T.; Graf von der Schulenburg, J. M.
Keywords
- chemotherapy
- experiences
- lung cancer
- preferences
- qualitative interviews
- treatment
|
10.1111/hex.12417 |
Health Expect |
LC |
MHH, LUH |
BREATH |
Original |
2016 |
| Analysis of Driving Factors of Willingness to Use and Willingness to Pay for Existing Pharmacological Smoking Cessation Aids Among Young and Middle-Aged Adults in Germany |
BACKGROUND: Smoking cessation is a challenging task with a high risk of relapse. Depending on the choice of medication and duration of therapy, the costs of using a smoking cessation aid can be high. Additionally, these costs are not covered by health insurance in Germany. Information on willingness to use (WTU) and willingness to pay (WTP) for smoking cessation aids is valuable for developing different smoking cessation strategies. OBJECTIVES: The study analyses WTU and WTP for three pharmacological smoking cessation aids (nicotine replacement therapy (NRT), bupropion and varenicline) among young and middle-aged adults in Germany and attempts to determine their major driving factors. METHODS: Two cross-sectional internet-based surveys of smokers over 18 years of age were conducted in 2014 and 2015 in Germany. Respondents were asked about smoking-related issues and WTU and WTP for each therapy. The contingent valuation method with payment cards was used to measure WTP. Descriptive statistics, logistical regression and accelerated failure-time regression models were performed. RESULTS: The total sample size is 505. Half of the respondents are willing to use NRT and one-third are willing to use bupropion and/or varenicline. WTU induces positive WTP; however, the magnitude of WTP is beneath the market price. WTU significantly increases with a higher addiction level and if smokers have previously heard about the therapy. CONCLUSION: This study indicates different points to be considered for policy development. Promotion information and improving awareness about medication aids might increase WTU, and development of monetary incentives for young smokers could create a better chance for successful smoking cessation.
- Aumann, I.; Treskova, M.; Hagemann, N.; von der Schulenburg, J. M.
Keywords
- Adult
- Aged
- Bupropion/*economics/therapeutic use
- Cost-Benefit Analysis
- Cross-Sectional Studies
- Dopamine Uptake Inhibitors/economics/therapeutic use
- Female
- Financing, Personal/*economics/statistics & numerical data
- Germany
- Humans
- Logistic Models
- Male
- Middle Aged
- Nicotinic Agonists/economics/therapeutic use
- Patient Acceptance of Health Care/*statistics & numerical data
- Smoking Cessation/*economics/methods
- Tobacco Use Cessation Products/adverse effects/*economics
- Varenicline/*economics/therapeutic use
- Young Adult
|
10.1007/s40258-016-0239-0 |
Appl Health Econ Health Policy |
COPD |
LUH |
BREATH |
Original |
2016 |
| Experiences of COPD patients with existing smoking cessation programs and their preferences for improvement - a qualitative analysis |
BACKGROUND: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). For current smokers who are diagnosed with COPD, their first treatment option is to stop smoking. Motivation is necessary for long-term smoking cessation; therefore, when designing smoking cessation programs, the patients' needs and preferences should be considered. We focused on COPD patients' experiences with existing smoking cessation programs and evaluated their preferences for the improvement of these programs. METHODS: We conducted 18 guideline-based interviews with COPD patients between April and June 2014 in Germany. Each patient with COPD, who was a current or past smoker and had made at least one attempt to quit smoking in the past 5 years, was included in the study. We audiotaped, verbatim transcribed, and evaluated the interviews, using content analysis. RESULTS: The patients had broad and different experiences with pharmaceutical, behavioral, and alternative approaches that supported or negatively influenced the smoking cessation process. Pharmaceuticals were viewed as an expensive alternative with many side effects although they helped to stop cravings for a few moments. Furthermore, the bad structure and impersonal content of the seminars for smoking cessation negatively influenced group cohesion, and therefore degrading the patients' motivation to stop smoking. Alternative methods, such as acupuncture and hypnosis were mostly ineffective in smoking cessation, but in some cases, served as motivational strategies. CONCLUSION: Negative experiences with smoking cessation were explained by the patients' lack of motivation or resolution. Other negative experiences, such as the structure of seminars for smoking cessation and the high price of pharmaceuticals should be addressed through policy changes to increase the patients' motivation to quit smoking.
- Aumann, I.; Tedja, L.; von der Schulenburg, J. M.
Keywords
- Copd
- Chronic obstructive pulmonary disease
- Preferences
- Qualitative interviews
- Smoking cessation
|
10.1186/s12971-016-0097-4 |
Tob Induc Dis |
COPD |
LUH |
BREATH |
Original |
2016 |
| Augmentation of Transient Donor Cell Chimerism and Alloantigen-Specific Regulation of Lung Transplants in Miniature Swine |
Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-gamma production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.
- Avsar, M.; Jansson, K.; Sommer, W.; Kruse, B.; Thissen, S.; Dreckmann, K.; Knoefel, A. K.; Salman, J.; Hafer, C.; Hecker, J.; Buechler, G.; Karstens, J. H.; Jonigk, D.; Langer, F.; Kaever, V.; Falk, C. S.; Hewicker-Trautwein, M.; Ungefroren, H.; Haverich, A.; Struber, M.; Warnecke, G.
|
10.1111/ajt.13629 |
Am J Transplant |
ROR |
MHH |
BREATH |
Original |
2016 |
| Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis |
BACKGROUND: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). OBJECTIVES: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. METHODS: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. RESULTS: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 +/- 140 m; mean SPD 5,017 +/- 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. CONCLUSION: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.
- Bahmer, T.
- Kirsten, A. M.
- Waschki, B.
- Rabe, K. F.
- Magnussen, H.
- Kirsten, D.
- Gramm, M.
- Hummler, S.
- Brunnemer, E.
- Kreuter, M.
- Watz, H.
Keywords
- Aged
- Dyspnea/etiology
- *Exercise
- Exercise Tolerance
- Fatigue/etiology
- Female
- Humans
- Idiopathic Pulmonary Fibrosis/complications/*physiopathology
- Lung/*physiopathology
- Male
- Middle Aged
- Prospective Studies
- Quality of Life
- Respiratory Function Tests
|
10.1159/000446607 |
Respiration |
DPLD |
Ghd |
ARCN, TLRC |
Original |
2016 |
| The use of auto-antibody testing in the evaluation of interstitial lung disease (ILD)--A practical approach for the pulmonologist |
Interstitial lung diseases (ILD), also defined as diffuse parenchymal lung diseases (DPLD) include a heterogeneous group of pulmonary disorders. They may be caused by an underlying connective tissue disease (CTD), Rheumatoid Arthritis (RA) or ANCA-associated Vasculitis (AAV). Pulmonary manifestations of these conditions may also precede systemic onset and therefore, pulmonologists may be confronted with diagnosing a systemic rheumatic disease. For the discrimination of CTD-related ILD and idiopathic interstitial pneumonia (IIP), serological testing is recommended. After careful reviewing the available literature, we suggest a serologic diagnostic algorithm for pulmonologists dealing with ILD-patients. This algorithm depicts the consensus for antibody testing that was reached amongst authors. Obviously this consensus approach requires further validation in everyday practice and leaves room for local adaption of the diagnostic strategy depending on the availability of diagnostic capacity and cost. It is our hope, however, that the rational and stepwise approach of serological testing for ILD will ultimately save unnecessary expenses associated with general laboratory screening. Finally a broader consensus on the strategy for laboratory testing in ILD in general might also improve the detection level of these relatively rare diseases and this will ultimately improve management and care of patients suffering from these complex disorders.
- Bahmer, T.
- Romagnoli, M.
- Girelli, F.
- Claussen, M.
- Rabe, K. F.
Keywords
- Algorithms
- Autoantibodies/chemistry/*immunology
- Early Diagnosis
- Humans
- Lung Diseases, Interstitial/*diagnosis/etiology/immunology
- Pulmonologists
- Sensitivity and Specificity
- ANA fluorescence pattern
- Ctd-ild
- Diagnostic algorithm
- Ipaf
- Ipf
- Serological testing
|
10.1016/j.rmed.2016.01.019 |
Respir Med |
DPLD |
Ghd |
ARCN |
Review |
2016 |
| Evaluation of the prognostic value of electrocardiography parameters and heart rhythm in patients with pulmonary hypertension |
BACKGROUND: Several studies have analyzed arrhythmias in patients with pulmonary hypertension (PH) and increased P-wave duration was identified as a risk factor for development of atrial fibrillation (AF). METHODS: We retrospectively analyzed the incidence of arrhythmias in patients with an initial diagnosis of PH during long-term follow-up and assessed the prognostic value of electrocardiography (ECG) data. Data from 167 patients were analyzed (Dana Point Classification: Group 1: 59 patients, Group 2: 28 patients, Group 3: 39 patients, Group 4: 41 patients). Clinical, 6-min-ute walk distance test, echocardiography and right heart catheterization data were collected, and baseline/follow-up ECGs were analyzed. RESULTS: Baseline ECGs revealed sinus rhythm in 137 patients. Thirteen patients had newly onset AF during follow-up. In 30 patients, baseline ECG showed AF. Patients with baseline AF showed higher atrial diameters and higher right atrial pressure. Patients with P-wave du-ration > 0.11 s had shorter survival. Other ECG parameters (PQ-interval, QRS-width, QT-/ /QTc-interval) were not associated with survival. Mean survival times were 79.4 +/- 5.4 months (sinus rhythm), 64.4 +/- 12.9 months (baseline AF) and 58.8 +/- 8.9 months (newly onset AF during follow-up) (p = 0.565). CONCLUSIONS: Atrial fibrillation predict adverse prognosis in patients with PH and a longer P-wave (> 0.11 s) is associated with shorter survival time.
- Bandorski, D.
- Bogossian, H.
- Ecke, A.
- Wiedenroth, C.
- Gruenig, E.
- Benjamin, N.
- Arlt, M.
- Seeger, W.
- Mayer, E.
- Ghofrani, A.
- Hoeltgen, R.
- Gall, H.
Keywords
- Atrial Fibrillation/epidemiology/*etiology/physiopathology
- *Electrocardiography
- Exercise Test
- Female
- Germany/epidemiology
- Heart Atria/physiopathology
- Humans
- Hypertension, Pulmonary/*complications/physiopathology
- Incidence
- Male
- Middle Aged
- Prognosis
- Retrospective Studies
- Risk Factors
- Survival Rate/trends
- arrhythmia
- atrial fibrillation
- electrocardiogram
- pulmonary hypertension
|
10.5603/CJ.a2016.0044 |
Cardiol J |
PH |
JLU, Thorax |
TLRC, UGMLC |
Original |
2016 |
