PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (66)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
more »
1.  Integrative pathway genomics of lung function and airflow obstruction 
Human Molecular Genetics  2015;24(23):6836-6848.
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
doi:10.1093/hmg/ddv378
PMCID: PMC4643644  PMID: 26395457
2.  Using concept mapping in the development of the EU-PAD framework (EUropean-Physical Activity Determinants across the life course): a DEDIPAC-study 
BMC Public Health  2016;16:1145.
Background
A large proportion of European children, adults and older adults do not engage in sufficient physical activity (PA). Understanding individual and contextual factors associated with PA behaviours is essential for the identification and implementation of effective preventative environments, policies, and programmes that can promote an active lifestyle across life course and can potentially improve health. The current paper intends to provide 1) a multi-disciplinary, Pan-European and life course view of key determinants of PA behaviours and 2) a proposal of how these factors may cluster.
Methods
After gathering a list of 183 potential PA behaviours-associated factors and a consensus meeting to unify/consolidate terminology, a concept mapping software was used to collate European experts’ views of 106 identified factors for youth (<19 years), adults (19–64 years), and older adults (≥65 years). The analysis evaluated common trends in the clustering of factors and the ratings of the distinct factors’ expected modifiability and population-level impact on PA behaviours across the life course. Priority for research was also assessed for each cluster.
Results
The concept mapping resulted in six distinct clusters, broadly merged in two themes: 1) the ‘Person’, which included clusters ‘Intra-Personal Context and Wellbeing’ and ‘Family and Social Economic Status’ (42 % of all factors) and 2) the ‘Society’, which included the remaining four clusters ‘Policy and Provision’, ‘Cultural Context and Media’, ‘Social Support and Modelling’, and ‘Supportive Environment’ (58 % of all factors). Overall, 25 factors were rated as the most impactful on PA behaviours across the life course and being the most modifiable. They were mostly situated in the ‘Intra-Personal Context and Wellbeing’ cluster. Furthermore, 16 of them were rated as top priority for research.
Conclusions
The current framework provides a preliminary overview of factors which may account for PA behaviour across the life course and are most relevant to the European community. These insights could potentially be a foundation for future Pan-European research on how these factors might interact with each other, and assist policy makers to identify appropriate interventions to maximize PA behaviours and thus the health of European citizens.
doi:10.1186/s12889-016-3800-8
PMCID: PMC5101801  PMID: 27825370
Factors; Active lifestyles; Youth; Adults; Older adults; Priority for research
3.  Molecular mechanisms underlying variations in lung function: a systems genetics analysis 
The Lancet. Respiratory medicine  2015;3(10):782-795.
Summary
Background
Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs.
Methods
The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature.
Findings
SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD.
Interpretation
The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico.
Funding
The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
doi:10.1016/S2213-2600(15)00380-X
PMCID: PMC5021067  PMID: 26404118
4.  A qualitative investigation of barriers and facilitators of rehabilitation success from the psychosomatic inpatients’ perspective 
Patient preference and adherence  2016;10:1881-1888.
Objective
Psychosomatic inpatient rehabilitation aims at promoting functioning in patients with mental disorders. Although generally effective, some patients do not benefit from this rehabilitation and suffer from symptoms as well as functional impairment. This study aimed to identify patient-reported factors influencing activity and participation outcomes.
Subject and methods
Five focus groups with N=23 former psychosomatic rehabilitation inpatients were conducted. The discussions focused on facilitators and barriers of treatment outcome. The material was analyzed inductively according to qualitative content analysis. Categories were derived from the material.
Results
Patients reported sociodemographic and clinical characteristics as well as personal factors, preparation before psychotherapy, and aspects of employment and health care as predictors of treatment success.
Conclusion
A wide range of possible factors that influence the course of functioning from the patients’ perspective were determined. These factors can be assigned to the ICF conceptual model. Clinician and researcher perspectives may complement these factors.
doi:10.2147/PPA.S108117
PMCID: PMC5034928  PMID: 27698554
activities of daily living; qualitative study; psychiatric rehabilitation; patient-centered care
5.  Asthma and Rhinitis Are Associated with Less Objectively-Measured Moderate and Vigorous Physical Activity, but Similar Sport Participation, in Adolescent German Boys: GINIplus and LISAplus Cohorts 
PLoS ONE  2016;11(8):e0161461.
Introduction
Physical activity (PA) protects against most noncommunicable diseases and has been associated with decreased risk of allergic phenotype, which is increasing worldwide. However, the association is not always present; furthermore it is not clear whether it is strongest for asthma, rhinitis, symptoms of these, or atopic sensitization; which sex is most affected; or whether it can be explained by either avoidance of sport or exacerbation of symptoms by exercise. Interventions are thus difficult to target.
Methods
PA was measured by one-week accelerometry in 1137 Germans (mean age 15.6 years, 47% boys) from the GINIplus and LISAplus birth cohorts, and modeled as a correlate of allergic symptoms, sensitization, or reported doctor-diagnosed asthma or rhinitis.
Results
8.3% of children had asthma, of the remainder 7.9% had rhinitis, and of the remainder 32% were sensitized to aero-allergens (atopic). 52% were lung-healthy controls. Lung-healthy boys and girls averaged 46.4 min and 37.8 min moderate-to-vigorous PA per day, of which 14.6 and 11.4 min was vigorous. PA in allergic girls was not altered, but boys with asthma got 13% less moderate and 29% less vigorous PA, and those with rhinitis with 13% less moderate PA, than lung-healthy boys. Both sexes participated comparably in sport (70 to 84%). Adolescents with wheezing (up to 68%, in asthma) and/or nose/eye symptoms (up to 88%, in rhinitis) were no less active.
Conclusions
We found that asthma and rhinitis, but not atopy, were independently associated with low PA in boys, but not in girls. These results indicate that allergic boys remain a high-risk group for physical inactivity even if they participate comparably in sport. Research into the link between PA and allergy should consider population-specific and sex-specific effects, and clinicians, parents, and designers of PA interventions should specifically address PA in allergic boys to ensure full participation.
doi:10.1371/journal.pone.0161461
PMCID: PMC4999273  PMID: 27560942
6.  What is the impact of different spirometric criteria on the prevalence of spirometrically defined COPD and its comorbidities? Results from the population-based KORA study 
Background
There is an ongoing debate about the appropriate spirometric criterion for airway obstruction to detect COPD. Furthermore, the association of different criteria with comorbidity prevalence and inflammatory biomarkers in advanced age is unclear.
Materials and methods
Spirometry was performed in a population-based study (n=2,256) covering an age range of 41–90 years. COPD was spirometrically determined either by a fixed ratio (FR) of <0.7 for forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or by FEV1/FVC below the lower limit of normal (LLN). Comorbidity prevalences and circulating biomarker levels (C-reactive protein [CRP], interleukin [IL]-6) were compared between subjects with or without COPD by the two criteria using logistic and multiple regression models, adjusting for sex and age.
Results
The prevalence of spirometrically defined COPD by FR increased with age from 10% in subjects aged <65 years to 26% in subjects aged ≥75 years. For LLN-defined COPD, it remained below 10% for all age groups. Overall, COPD diagnosis was not associated with specific comorbidities, except for a lower prevalence of obesity in both FR- and LLN-defined cases. Both CRP and IL-6 tended to be higher in cases by both criteria.
Conclusion
In a population-based cohort of adults up to the age of 90 years, the prevalence of spirometrically defined COPD was higher for the FR criterion than for the LLN criterion. This difference increased with age. Neither prevalences of common comorbidities nor levels of the biomarkers, CRP or IL-6, were conclusively associated with the selection of the COPD criterion. Results have to be considered in light of the predominantly mild cases of airway obstruction in the examined study population.
doi:10.2147/COPD.S104529
PMCID: PMC4993254  PMID: 27574413
chronic obstructive pulmonary disease; spirometry; prevalence; comorbidity; biomarkers
7.  Age Dependency of GLI Reference Values Compared with Paediatric Lung Function Data in Two German Studies (GINIplus and LUNOKID) 
PLoS ONE  2016;11(7):e0159678.
A hallmark of the newly published GLI (Global Lungs Initiative) spirometric reference values is their "all-age" (3-95yr) predictive power, accomplished by incorporating non-linear age dependencies into modelling parameters. This modelling strategy is especially promising for the age range of puberty; however, the performance of GLI-values for adolescents is currently unknown. We calculated GLI-based z-scores for children/adolescents without apparent respiratory diseases from two different German studies, LUNOKID (N = 1943, 4–19 years) and GINIplus (N = 1042, 15 years) and determined the goodness of fit for specific age groups. We defined fit sufficient if the absolute mean of z-scores was <0.5. For children (<10yr) the mean GLI-based z-scores for FEV1 and FVC reached a good fit with mean z-scores for FEV1 between -0.11 and 0.01 and mean z-scores for FVC between 0.01 and 0.16, but larger deviations were observed in adolescents, especially boys (mean z-score -0.58 for FEV1 and -0.57 for FVC in GINIplus). The fit for FEV1/FVC was sufficient. GLI reference values provided reasonable estimates for the individuals enrolled in our studies, which span the age range of lung growth and development. However, we found that GLI-predictions overestimated lung volumes, especially those for German adolescent boys, which may, left unrecognised, lead to erroneous diagnosis of lung disease. Caution should be taken when applying these reference values to epidemiologic studies.
doi:10.1371/journal.pone.0159678
PMCID: PMC4954644  PMID: 27438002
8.  Relative impact of COPD and comorbidities on generic health-related quality of life: a pooled analysis of the COSYCONET patient cohort and control subjects from the KORA and SHIP studies 
Respiratory Research  2016;17:81.
Background
Health-related quality of life (HRQL) is an important patient-reported outcome measure used to describe the burden of chronic obstructive pulmonary disease (COPD) which is often accompanied by comorbid conditions.
Methods
Data from 2275 participants in the COPD cohort COSYCONET and from 4505 lung-healthy control subjects from the population-based KORA and SHIP studies were pooled. Main outcomes were the five dimensions of the generic EQ-5D-3 L questionnaire and two EQ-5D index scores using a tariff based on valuations from the general population and an experience-based tariff.
The association of COPD in GOLD grades 1–4 and of several comorbid conditions with the EQ-5D index scores was quantified by multiple linear regression models while adjusting for age, sex, education, body mass index (BMI), and smoking status.
Results
For all dimensions of the EQ-5D, the proportion of participants reporting problems was higher in the COPD group than in control subjects. COPD was associated with significant reductions in the EQ-5D index scores (-0.05 points for COPD grades 1/2, -0.09 for COPD grade 3, -0.18 for COPD grade 4 according to the preference-based utility tariff, all p < 0.0001). Adjusted mean index scores were 0.89 in control subjects and 0.85, 0.84, 0.81, and 0.72 in COPD grades 1-4 according to the preference-based utility tariff and 0.76, 0.71, 0.68, 0.64, and 0.58 for control subjects and COPD grades 1-4 for the experience-based tariff respectively. Comorbidities had additive negative effects on the index scores; the effect sizes for comorbidities were comparable to or smaller than the effects of COPD grade 3. No statistically significant interactions between COPD and comorbidities were observed. Score differences between COPD patients and control subjects were most pronounced in younger age groups.
Conclusions
Compared with control subjects, the considerable reduction of HRQL in patients with COPD was mainly due to respiratory limitations, but observed comorbidities added linearly to this effect. Younger COPD patients showed a greater loss of HRQL and may therefore be in specific need of comprehensive disease management.
Trial registration
NCT01245933
doi:10.1186/s12931-016-0401-0
PMCID: PMC4943009  PMID: 27405652
COPD; Health-related quality of life; Utilities; Cohort study; Comorbidities
9.  Assessing health-related quality of life in COPD: comparing generic and disease-specific instruments with focus on comorbidities 
Background
Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient’s health-related quality of life (HRQL). While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health. This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George’s Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments.
Methods
Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions. Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences.
Results
In 2,291 subjects in COPD GOLD grades 1–4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease. Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions. The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions. For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL.
Conclusion
All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities. Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0238-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12890-016-0238-9
PMCID: PMC4862227  PMID: 27160582
Chronic obstructive pulmonary disease; Health-related quality of life; Utility; Comorbidity; Cohort study; Questionnaires
10.  Physical Activity Levels and Domains Assessed by Accelerometry in German Adolescents from GINIplus and LISAplus 
PLoS ONE  2016;11(3):e0152217.
Background
Physical activity (PA) is a well-known and underused protective factor for numerous health outcomes, and interventions are hampered by lack of objective data. We combined accelerometers with diaries to estimate the contributions to total activity from different domains throughout the day and week in adolescents.
Methods
Accelerometric and diary data from 1403 adolescents (45% male, mean age 15.6 ± 0.5 years) were combined to evaluate daily levels and domains of sedentary, light, and moderate-to-vigorous activity (MVPA) during a typical week. Freedson’s cutoff points were applied to determine levels of activity. Total activity was broken down into school physical education (PE), school outside PE, transportation to school, sport, and other time.
Results
About 2/3 of adolescents’ time was spent sedentary, 1/3 in light activity, and about 5% in MVPA. Boys and girls averaged 46 (SD 22) and 38 (23) minutes MVPA per day. Adolescents were most active during leisure sport, spending about 30% of it in MVPA, followed by PE (about 20%) transport to school (14%) and either school class time or other time (3%). PE provided 5% of total MVPA, while leisure sport provided 16% and transportation to school 8%. School was the most sedentary part of the day with over 75% of time outside PE spent sedentary.
Conclusions
These German adolescents were typical of Europeans in showing low levels of physical activity, with significant contributions from leisure sport, transportation and school PE. Leisure sport was the most active part of the day, and participation did not vary significantly by sex, study center (region of Germany) or BMI. Transportation to school was frequent and thus accounted for a significant fraction of total MVPA. This indicates that even in a population with good access to dedicated sporting activities, frequent active transportation can add significantly to total MVPA.
doi:10.1371/journal.pone.0152217
PMCID: PMC4806867  PMID: 27010227
11.  Analysis of mammalian gene function through broad based phenotypic screens across a consortium of mouse clinics 
de Angelis, Martin Hrabě | Nicholson, George | Selloum, Mohammed | White, Jacqui | Morgan, Hugh | Ramirez-Solis, Ramiro | Sorg, Tania | Wells, Sara | Fuchs, Helmut | Fray, Martin | Adams, David J | Adams, Niels C | Adler, Thure | Aguilar-Pimentel, Antonio | Ali-Hadji, Dalila | Amann, Gregory | André, Philippe | Atkins, Sarah | Auburtin, Aurelie | Ayadi, Abdel | Becker, Julien | Becker, Lore | Bedu, Elodie | Bekeredjian, Raffi | Birling, Marie-Christine | Blake, Andrew | Bottomley, Joanna | Bowl, Mike | Brault, Véronique | Busch, Dirk H | Bussell, James N | Calzada-Wack, Julia | Cater, Heather | Champy, Marie-France | Charles, Philippe | Chevalier, Claire | Chiani, Francesco | Codner, Gemma F | Combe, Roy | Cox, Roger | Dalloneau, Emilie | Dierich, André | Di Fenza, Armida | Doe, Brendan | Duchon, Arnaud | Eickelberg, Oliver | Esapa, Chris T | El Fertak, Lahcen | Feigel, Tanja | Emelyanova, Irina | Estabel, Jeanne | Favor, Jack | Flenniken, Ann | Gambadoro, Alessia | Garrett, Lilian | Gates, Hilary | Gerdin, Anna-Karin | Gkoutos, George | Greenaway, Simon | Glasl, Lisa | Goetz, Patrice | Da Cruz, Isabelle Goncalves | Götz, Alexander | Graw, Jochen | Guimond, Alain | Hans, Wolfgang | Hicks, Geoff | Hölter, Sabine M | Höfler, Heinz | Hancock, John M | Hoehndorf, Robert | Hough, Tertius | Houghton, Richard | Hurt, Anja | Ivandic, Boris | Jacobs, Hughes | Jacquot, Sylvie | Jones, Nora | Karp, Natasha A | Katus, Hugo A | Kitchen, Sharon | Klein-Rodewald, Tanja | Klingenspor, Martin | Klopstock, Thomas | Lalanne, Valerie | Leblanc, Sophie | Lengger, Christoph | le Marchand, Elise | Ludwig, Tonia | Lux, Aline | McKerlie, Colin | Maier, Holger | Mandel, Jean-Louis | Marschall, Susan | Mark, Manuel | Melvin, David G | Meziane, Hamid | Micklich, Kateryna | Mittelhauser, Christophe | Monassier, Laurent | Moulaert, David | Muller, Stéphanie | Naton, Beatrix | Neff, Frauke | Nolan, Patrick M | Nutter, Lauryl MJ | Ollert, Markus | Pavlovic, Guillaume | Pellegata, Natalia S | Peter, Emilie | Petit-Demoulière, Benoit | Pickard, Amanda | Podrini, Christine | Potter, Paul | Pouilly, Laurent | Puk, Oliver | Richardson, David | Rousseau, Stephane | Quintanilla-Fend, Leticia | Quwailid, Mohamed M | Racz, Ildiko | Rathkolb, Birgit | Riet, Fabrice | Rossant, Janet | Roux, Michel | Rozman, Jan | Ryder, Ed | Salisbury, Jennifer | Santos, Luis | Schäble, Karl-Heinz | Schiller, Evelyn | Schrewe, Anja | Schulz, Holger | Steinkamp, Ralf | Simon, Michelle | Stewart, Michelle | Stöger, Claudia | Stöger, Tobias | Sun, Minxuan | Sunter, David | Teboul, Lydia | Tilly, Isabelle | Tocchini-Valentini, Glauco P | Tost, Monica | Treise, Irina | Vasseur, Laurent | Velot, Emilie | Vogt-Weisenhorn, Daniela | Wagner, Christelle | Walling, Alison | Weber, Bruno | Wendling, Olivia | Westerberg, Henrik | Willershäuser, Monja | Wolf, Eckhard | Wolter, Anne | Wood, Joe | Wurst, Wolfgang | Yildirim, Ali Önder | Zeh, Ramona | Zimmer, Andreas | Zimprich, Annemarie | Holmes, Chris | Steel, Karen P | Herault, Yann | Gailus-Durner, Valérie | Mallon, Ann-Marie | Brown, Steve DM
Nature genetics  2015;47(9):969-978.
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse ES cell knockout resource provides a basis for characterisation of relationships between gene and phenotype. The EUMODIC consortium developed and validated robust methodologies for broad-based phenotyping of knockouts through a pipeline comprising 20 disease-orientated platforms. We developed novel statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no prior functional annotation. We captured data from over 27,000 mice finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. Novel phenotypes were uncovered for many genes with unknown function providing a powerful basis for hypothesis generation and further investigation in diverse systems.
doi:10.1038/ng.3360
PMCID: PMC4564951  PMID: 26214591
12.  Metabolomics profiling reveals novel markers for leukocyte telomere length 
Aging (Albany NY)  2016;8(1):77-86.
Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers to investigate potential underlying pathways. Five metabolites were associated with LTL: Two lysolipids, 1-stearoylglycerophosphoinositol (P=1.6×10−5) and 1-palmitoylglycerophosphoinositol (P=1.6×10−5), were found to be negatively associated with LTL and positively associated with phospholipase A2 expression levels suggesting an involvement of fatty acid metabolism and particularly membrane composition in biological aging. Moreover, two gamma-glutamyl amino acids, gamma-glutamyltyrosine (P=2.5×10−6) and gamma-glutamylphenylalanine (P=1.7×10−5), were negatively correlated with LTL. Both are products of the glutathione cycle and markers for increased oxidative stress. Metabolites were also correlated with functional measures of aging, i.e. higher blood pressure and HDL cholesterol levels and poorer lung, liver and kidney function. Our results suggest an involvement of altered fatty acid metabolism and increased oxidative stress in human biological aging, reflected by LTL and age-related phenotypes of vital organ systems.
PMCID: PMC4761715  PMID: 26797767
telomere length; biological aging; metabolomics; glutathione; oxidative stress
13.  Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation 
Artigas, María Soler | Wain, Louise V. | Miller, Suzanne | Kheirallah, Abdul Kader | Huffman, Jennifer E. | Ntalla, Ioanna | Shrine, Nick | Obeidat, Ma'en | Trochet, Holly | McArdle, Wendy L. | Alves, Alexessander Couto | Hui, Jennie | Zhao, Jing Hua | Joshi, Peter K. | Teumer, Alexander | Albrecht, Eva | Imboden, Medea | Rawal, Rajesh | Lopez, Lorna M. | Marten, Jonathan | Enroth, Stefan | Surakka, Ida | Polasek, Ozren | Lyytikäinen, Leo-Pekka | Granell, Raquel | Hysi, Pirro G. | Flexeder, Claudia | Mahajan, Anubha | Beilby, John | Bossé, Yohan | Brandsma, Corry-Anke | Campbell, Harry | Gieger, Christian | Gläser, Sven | González, Juan R. | Grallert, Harald | Hammond, Chris J. | Harris, Sarah E. | Hartikainen, Anna-Liisa | Heliövaara, Markku | Henderson, John | Hocking, Lynne | Horikoshi, Momoko | Hutri-Kähönen, Nina | Ingelsson, Erik | Johansson, Åsa | Kemp, John P. | Kolcic, Ivana | Kumar, Ashish | Lind, Lars | Melén, Erik | Musk, Arthur W. | Navarro, Pau | Nickle, David C. | Padmanabhan, Sandosh | Raitakari, Olli T. | Ried, Janina S. | Ripatti, Samuli | Schulz, Holger | Scott, Robert A. | Sin, Don D. | Starr, John M. | Viñuela, Ana | Völzke, Henry | Wild, Sarah H. | Wright, Alan F. | Zemunik, Tatijana | Jarvis, Deborah L. | Spector, Tim D. | Evans, David M. | Lehtimäki, Terho | Vitart, Veronique | Kähönen, Mika | Gyllensten, Ulf | Rudan, Igor | Deary, Ian J. | Karrasch, Stefan | Probst-Hensch, Nicole M. | Heinrich, Joachim | Stubbe, Beate | Wilson, James F. | Wareham, Nicholas J. | James, Alan L. | Morris, Andrew P. | Jarvelin, Marjo-Riitta | Hayward, Caroline | Sayers, Ian | Strachan, David P. | Hall, Ian P. | Tobin, Martin D.
Nature Communications  2015;6:8658.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
doi:10.1038/ncomms9658
PMCID: PMC4686825  PMID: 26635082
14.  Development and Psychometric Evaluation of an Instrument to Assess Cross-Cultural Competence of Healthcare Professionals (CCCHP) 
PLoS ONE  2015;10(12):e0144049.
Background
Cultural competence of healthcare professionals (HCPs) is recognized as a strategy to reduce cultural disparities in healthcare. However, standardised, valid and reliable instruments to assess HCPs’ cultural competence are notably lacking. The present study aims to 1) identify the core components of cultural competence from a healthcare perspective, 2) to develop a self-report instrument to assess cultural competence of HCPs and 3) to evaluate the psychometric properties of the new instrument.
Methods
The conceptual model and initial item pool, which were applied to the cross-cultural competence instrument for the healthcare profession (CCCHP), were derived from an expert survey (n = 23), interviews with HCPs (n = 12), and a broad narrative review on assessment instruments and conceptual models of cultural competence. The item pool was reduced systematically, which resulted in a 59-item instrument. A sample of 336 psychologists, in advanced psychotherapeutic training, and 409 medical students participated, in order to evaluate the construct validity and reliability of the CCCHP.
Results
Construct validity was supported by principal component analysis, which led to a 32-item six-component solution with 50% of the total variance explained. The different dimensions of HCPs’ cultural competence are: Cross-Cultural Motivation/Curiosity, Cross-Cultural Attitudes, Cross-Cultural Skills, Cross-Cultural Knowledge/Awareness and Cross-Cultural Emotions/Empathy. For the total instrument, the internal consistency reliability was .87 and the dimension’s Cronbach’s α ranged from .54 to .84. The discriminating power of the CCCHP was indicated by statistically significant mean differences in CCCHP subscale scores between predefined groups.
Conclusions
The 32-item CCCHP exhibits acceptable psychometric properties, particularly content and construct validity to examine HCPs’ cultural competence. The CCCHP with its five dimensions offers a comprehensive assessment of HCPs’ cultural competence, and has the ability to distinguish between groups that are expected to differ in cultural competence. This instrument can foster professional development through systematic self-assessment and thus contributes to improve the quality of patient care.
doi:10.1371/journal.pone.0144049
PMCID: PMC4671537  PMID: 26641876
15.  Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice 
Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14–P28) as compared with C3H/HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1(−/−) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (Lm) compared with Spp1(+/+) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, wingless-related mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1(−/−) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased Lm). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1(−/−) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.
doi:10.1165/rcmb.2013-0471OC
PMCID: PMC4224082  PMID: 24816281
osteopontin; chronic obstructive pulmonary disease; asthma; emphysema; pulmonary fibrosis
16.  Evaluating a collaborative smoking cessation intervention in primary care (ENTER): study protocol for a cluster-randomized controlled trial 
Trials  2015;16:447.
Background
Tobacco consumption is a preventable risk factor for chronic disease and complicates the treatment of medical conditions. Therefore, the German health insurance company AOK NORDWEST has developed a collaborative smoking cessation intervention for individuals with cardiovascular disease, chronic obstructive pulmonary disease and heavy smokers, with the aim of reducing tobacco consumption. The objective of the study ENTER is to evaluate the effectiveness of the collaborative smoking cessation intervention and determine its cost-effectiveness.
Methods/Design
This study is a cluster-randomized controlled trial conducted with 40 medical practices that are being selected from different geographic regions in Germany. Participating medical practices will be randomly allocated to either the intervention or control group. Within the medical practices, a total of 800 patients will be recruited for participation in the study and blinded to group assignment. Patients are included in the study if they are 18 years or older, insured by AOK, heavy smokers (smoke at least 20 cigarettes per day) and/or suffer from chronic obstructive pulmonary disease or cardiovascular disease. Exclusion criteria are patients who are nonsmokers, who have cognitive impairments or who are illiterate. Physicians from medical practices in the intervention group will motivate patients to participate in a smoking cessation program offered by the health insurance, refer them to the program and ask about their program participation. Physicians from medical practices in the control group will provide usual care. Data collection will take place on the date of study inclusion and after 6 and 12 months. The primary outcome is the amount of cigarettes consumed during the past 30 days, 12 months after the initial medical consultation. Secondary outcomes are abstinence from smoking, health-related quality of life and respiratory complaints. Moreover, a process evaluation and health economic analysis will be performed.
Discussion
The results of this study will help to determine whether the collaborative smoking cessation intervention is an effective and feasible way to promote smoking cessation in the primary care setting and provide evidence regarding its cost-effectiveness.
Trial registration
German Clinical Trials Register DRKS00006079. Registered 4 June 2014.
doi:10.1186/s13063-015-0977-6
PMCID: PMC4600205  PMID: 26452466
Cardiovascular disease; Chronic obstructive pulmonary disease; Health services research; Primary medical care; Smoking cessation
17.  Sport Engagement by Accelerometry under Field Conditions in German Adolescents: Results from GINIPlus 
PLoS ONE  2015;10(8):e0135630.
Introduction
Sporting activities differ in their ability to promote moderate-to-vigorous physical activity (MVPA). To assess adolescents’ engagement in sport under field conditions we used accelerometers to measure their MVPA levels during sport. We pay special attention to differences between team and individual sport and between common sports.
Methods
Diary data and 7-day accelerometry from 1054 Germans ages 15–17 were combined to measure physical activity. 1373 diaried episodes of more than 40 common sports were identified from 626 participants and grouped into team and individual sport. We modeled the effect of team and individual sport, and described levels of MVPA and episodes of no MVPA for all recorded sports.
Results
German boys and girls averaged 43 (SD 21) and 37 (SD 24) minutes MVPA per day. Boys got 2.2 times as much MVPA per minute during team compared to individual sport (p<0.0001) but there was no significant difference for girls. Percent of time spent in MVPA during sport ranged from 6% for weight training to 74% for jogging, with individual sports averaging 10–30% and team sports 30–50%. 11% of sport episodes had no MVPA: half of episodes of cycling, 5% of jogging, and none for tennis or badminton. An episode of individual sport was 17 times more likely to have no MVPA than an episode of team sport (p<0.0001).
Conclusion
Under field condition, adolescents were active for only a fraction of diaried sporting time. As measured by accelerometry, individual sport often produced no MVPA. Characteristics of the sport, such as team vs. individual, were more predictive of MVPA than were characteristics of the participant, such as background activity levels.
doi:10.1371/journal.pone.0135630
PMCID: PMC4546233  PMID: 26291984
18.  The association between physical activity and healthcare costs in children – results from the GINIplus and LISAplus cohort studies 
BMC Public Health  2015;15:437.
Background
Physical inactivity in children is an important risk factor for the development of various morbidities and mortality in adulthood, physical activity already has preventive effects during childhood. The objective of this study is to estimate the association between physical activity, healthcare utilization and costs in children.
Methods
Cross-sectional data of 3356 children aged 9 to 12 years were taken from the 10-year follow-up of the birth cohort studies GINIplus and LISAplus, including information on healthcare utilization and physical activity given by parents via self-administered questionnaires. Using a bottom-up approach, direct costs due to healthcare utilization and indirect costs resulting from parental work absence were estimated for the base year 2007. A two-step regression model compared effects on healthcare utilization and costs for a higher (≥7 h/week) versus a lower (<7 h/week) level of moderate-to-vigorous physical activity (MVPA) adjusted for age, gender, BMI, education and income of parents, single parenthood and study region. Recycled predictions estimated adjusted mean costs per child and activity group.
Results
The analyses for the association between physical activity, healthcare utilization and costs showed no statistically significant results. Different directions of estimates were noticeable throughout cost components in the first step as well as the second step of the regression model. For higher MVPA (≥7 h/week) compared with lower MVPA (<7 h/week) total direct costs accounted for 392 EUR (95% CI: 342–449 EUR) versus 398 EUR (95% CI: 309–480 EUR) and indirect costs accounted for 138 EUR (95% CI: 124–153 EUR) versus 127 EUR (95% CI: 111–146 EUR).
Conclusions
The results indicate that childhood might be too early in life, to detect significant preventive effects of physical activity on healthcare utilization and costs, as diseases attributable to lacking physical activity might first occur later in life. This underpins the importance of clarifying the long-term effects of physical activity as it may strengthen the promotion of physical activity in children from a health economic perspective.
doi:10.1186/s12889-015-1721-6
PMCID: PMC4423115  PMID: 25925399
Physical activity; Healthcare utilization; Healthcare costs; Direct costs; Indirect costs; Children; Cross-sectional study
19.  Effectiveness of case management-based aftercare coordination by phone for patients with depressive and anxiety disorders: study protocol for a randomized controlled trial 
BMC Psychiatry  2015;15:90.
Background
Depressive and anxiety disorders are highly prevalent, but only a small percentage (approximately 50%) of patients receive appropriate treatment. Relevant barriers include communication and coordination gaps between different providers that result from the lack of integration between different care-giving systems. Aftercare following inpatient treatment represents one of these gaps because systematic follow-up care does not exist. Case management-based aftercare coordination by phone might be a promising approach to overcoming this gap and improving long-term treatment outcomes. Case management is a patient-centered and situation-based approach comprising systematic tracking and support of patients by a case manager.
The aim of this study is to evaluate the effectiveness of aftercare coordination by phone for patients with depressive and anxiety disorders.
Methods/design
The effectiveness of aftercare coordination will be investigated in a prospective randomized controlled trial in four psychotherapeutic inpatient routine care units (St. Franziska-Stift Bad Kreuznach, MediClin Seepark Klinik Bad Bodenteich, Segeberger Kliniken Gruppe Bad Segeberg and Luisenklinik Bad Dürrheim). The patients receiving aftercare coordination (intervention group; IG) will be compared with those who receive treatment as usual (TAU control group; CG). Eligible patients will be required to have a diagnosis of an anxiety and/or depressive disorder and a recommendation for follow-up outpatient psychotherapy.
The aftercare coordination consists of six phone contacts at intervals of two weeks that are performed by therapists in the inpatient units. The patients will complete questionnaires at discharge (t1), 3 months after discharge (i.e., at the end of the intervention (t2)) and 9 months after discharge (t3). The primary outcome will be change in symptom severity from t1 to t3, the secondary outcomes will be health-related quality of life and the proportion of patients who manage to begin outpatient psychotherapy by t3.
Discussion
This study will determine whether case management-based aftercare coordination by phone is an adequate approach for overcoming treatment barriers in the clinical pathways of patients with depressive and anxiety disorders. If proven effective, an accessible supplementary treatment approach that will help to maintain and even improve long-term treatment outcomes will be made available for patients following inpatient treatment.
Trial registration
ClinicalTrials.gov: (NCT02044913).
doi:10.1186/s12888-015-0469-y
PMCID: PMC4422041  PMID: 25897757
Randomized controlled trial; Aftercare; Case management; Phone-based; Depression; Anxiety; Evaluation; Effectiveness
20.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
21.  Associations between Multiple Accelerometry-Assessed Physical Activity Parameters and Selected Health Outcomes in Elderly People – Results from the KORA-Age Study 
PLoS ONE  2014;9(11):e111206.
Introduction
Accelerometry is an important method for extending our knowledge about intensity, duration, frequency and patterns of physical activity needed to promote health. This study has used accelerometry to detect associations between intensity levels and related activity patterns with multimorbidity and disability. Moreover, the proportion of people meeting the physical activity recommendations for older people was assessed.
Methods
Physical activity was measured in 168 subjects (78 males; 65–89 years of age), using triaxial GT3X accelerometers for ten consecutive days. The associations between physical activity parameters and multimorbidity or disability was examined using multiple logistic regression models, which were adjusted for gender, age, education, smoking, alcohol consumption, lung function, nutrition and multimorbidity or disability.
Results
35.7% of the participants met the physical activity recommendations of at least 150 minutes of moderate to vigorous activity per week. Only 11.9% reached these 150 minutes, when only bouts of at least 10 minutes were counted. Differences in moderate to vigorous activity between people with and without multimorbidity or disability were more obvious when shorter bouts instead of only longer bouts were included. Univariate analyses showed an inverse relationship between physical activity and multimorbidity or disability for light and moderate to vigorous physical activity. A higher proportion of long activity bouts spent sedentarily was associated with higher risk for multimorbidity, whereas a high proportion of long bouts in light activity seemed to prevent disability. After adjustment for covariates, there were no significant associations, anymore.
Conclusions
The accumulated time in moderate to vigorous physical activity seems to have a stronger relationship with health and functioning when shorter activity bouts and not only longer bouts were counted. We could not detect an association of the intensity levels or activity patterns with multimorbidity or disability in elderly people after adjustment for covariates.
doi:10.1371/journal.pone.0111206
PMCID: PMC4220984  PMID: 25372399
22.  Ultrafine carbon particle mediated cardiovascular impairment of aged spontaneously hypertensive rats 
Background
Studies provide compelling evidences for particulate matter (PM) associated cardiovascular health effects. Elderly individuals, particularly those with preexisting conditions like hypertension are regarded to be vulnerable. Experimental data are warranted to reveal the molecular pathomechanism of PM related cardiovascular impairments among aged/predisposed individuals. Thus we investigated the cardiovascular effects of ultrafine carbon particles (UfCP) on aged (12–13 months) spontaneously hypertensive rats (SHRs) and compared the findings with our pervious study on adult SHRs (6–7 months) to identify age related predisposition events in cardiovascular compromised elderly individuals.
Methods
Aged SHRs were inhalation exposed to UfCP for 24 h (~180 μg/m3) followed by radio-telemetric assessment for blood pressure (BP) and heart rate (HR). Bronchoalveolar lavage (BAL) fluid cell differentials, interleukin 6 (IL-6) and other proinflammatory cytokines; serum C-reactive protein (CRP) and haptoglobin (HPT); and plasma fibrinogen were measured. Transcript levels of hemeoxygenase 1 (HO-1), endothelin 1 (ET1), endothelin receptors A, B (ETA, ETB), tissue factor (TF), and plasminogen activator inhibitor-1 (PAI-1) were measured in the lung and heart to assess oxidative stress, endothelial dysfunction and coagulation cascade.
Result
UfCP exposed aged SHRs exhibited increased BP (4.4%) and HR (6.3%) on 1st recovery day paralleled by a 58% increase of neutrophils and 25% increase of IL-6 in the BAL fluid. Simultaneously higher CRP, HPT and fibrinogen levels in exposed SHRs indicate systemic inflammation. HO-1, ET1, ET-A, ET-B, TF and PAI-1 were induced by 1.5-2.0 folds in lungs of aged SHRs on 1st recovery day. However, in UfCP exposed adult SHRs these markers were up-regulated (2.5-6 fold) on 3rd recovery day in lung without detectable pulmonary/systemic inflammation.
Conclusions
The UfCP induced pulmonary and systemic inflammation in aged SHRs is associated with oxidative stress, endothelial dysfunction and disturbed coagulatory hemostasis. UfCP exposure increased BP and HR in aged SHRs rats which was associated with lung inflammation, and increased expression of inflammatory, vasoconstriction and coagulation markers as well as systemic changes in biomarkers of thrombosis in aged SHRs. Our study provides further evidence for potential molecular mechanisms explaining the increased risk of particle mediated cardiac health effects in cardiovascular compromised elderly individuals.
doi:10.1186/s12989-014-0036-6
PMCID: PMC4410795  PMID: 25442699
Inflammation; Lung; Heart; Dust; Particle exposure; Cardiovascular risk individuals
23.  Effects of ultrafine particles on the allergic inflammation in the lung of asthmatics: results of a double-blinded randomized cross-over clinical pilot study 
Background
Epidemiological and experimental studies suggest that exposure to ultrafine particles (UFP) might aggravate the allergic inflammation of the lung in asthmatics.
Methods
We exposed 12 allergic asthmatics in two subgroups in a double-blinded randomized cross-over design, first to freshly generated ultrafine carbon particles (64 μg/m3; 6.1 ± 0.4 × 105 particles/cm3 for 2 h) and then to filtered air or vice versa with a 28-day recovery period in-between. Eighteen hours after each exposure, grass pollen was instilled into a lung lobe via bronchoscopy. Another 24 hours later, inflammatory cells were collected by means of bronchoalveolar lavage (BAL). (Trial registration: NCT00527462)
Results
For the entire study group, inhalation of UFP by itself had no significant effect on the allergen induced inflammatory response measured with total cell count as compared to exposure with filtered air (p = 0.188). However, the subgroup of subjects, which inhaled UFP during the first exposure, exhibited a significant increase in total BAL cells (p = 0.021), eosinophils (p = 0.031) and monocytes (p = 0.013) after filtered air exposure and subsequent allergen challenge 28 days later. Additionally, the potential of BAL cells to generate oxidant radicals was significantly elevated at that time point. The subgroup that was exposed first to filtered air and 28 days later to UFP did not reveal differences between sessions.
Conclusions
Our data demonstrate that pre-allergen exposure to UFP had no acute effect on the allergic inflammation. However, the subgroup analysis lead to the speculation that inhaled UFP particles might have a long-term effect on the inflammatory course in asthmatic patients. This should be reconfirmed in further studies with an appropriate study design and sufficient number of subjects.
doi:10.1186/s12989-014-0039-3
PMCID: PMC4354282  PMID: 25204642
Ultrafine particles; Asthma; Pulmonary inflammation; Aerosol exposure; Aeroallergen
24.  Effectiveness and cost-effectiveness of a guideline-based stepped care model for patients with depression: study protocol of a cluster-randomized controlled trial in routine care 
BMC Psychiatry  2014;14:230.
Background
Depression is a widespread and serious disease often accompanied by a high degree of suffering and burden of disease. The lack of integration between different care providers impedes guideline-based treatment. This constitutes substantial challenges for the health care system and also causes considerable direct and indirect costs. To face these challenges, the aim of this project is the implementation and evaluation of a guideline-based stepped care model for depressed patients with six treatment options of varying intensity and setting, including low-intensity treatments using innovative technologies.
Methods/design
The study is a randomized controlled intervention trial of a consecutive sample of depressive patients from primary care assessed with a prospective survey at four time-standardized measurement points within one year. A cluster randomization at the level of participating primary care units divides the general practitioners into two groups. In the intervention group patients (n = 660) are treated within the stepped care approach in a multiprofessional network consisting of general practitioners, psychotherapists, psychiatrists and inpatient care facilities, whereas patients in the control condition (n = 200) receive routine care. The main research question concerns the effectiveness of the stepped-care model from baseline to t3 (12 months). Primary outcome is the change in depressive symptoms measured by the PHQ-9; secondary outcomes include response, remission and relapse, functional quality of life (SF-12 and EQ-5D-3 L), other clinical and psychosocial variables, direct and indirect costs, and the incremental cost-effectiveness ratio. Furthermore feasibility and acceptance of the overall model as well as of the separate treatment components are assessed.
Discussion
This stepped care model integrates all primary and secondary health care providers involved in the treatment of depression; it elaborates innovative and evidence-based treatment elements, follows a stratified approach and is implemented in routine care as opposed to standardized conditions. In case of positive results, its sustainable implementation as a collaborative care model may significantly improve the health care situation of depressive patients as well as the interaction and care delivery of different care providers on various levels.
Trial registration
This study is registered with ClinicalTrials.gov, number NCT01731717 (date of registration: 24 June 2013).
doi:10.1186/s12888-014-0230-y
PMCID: PMC4243822  PMID: 25182269
Depression; Stepped care; Collaborative care; Complex intervention; Primary care; Secondary care; Low intensity treatments; e-Mental health
25.  Health-related quality of life and chronic obstructive pulmonary disease in early stages – longitudinal results from the population-based KORA cohort in a working age population 
BMC Pulmonary Medicine  2014;14:134.
Background
It is widely recognized that health-related quality of life (HRQL) is impaired in patients with Chronic Obstructive Pulmonary Disease (COPD), but there is a lack of research on longitudinal associations of COPD and HRQL. This study examined the effects of COPD in early stages of disease on HRQL over ten years in a working-age general population setting in Southern Germany while considering the influence of common comorbidities.
Methods
In the population-based KORA F4 study (2006–08) 1,321 participants aged 41–61 years performed spirometry and reported information on HRQL (measured by the generic SF-12) and comorbidities. For the same participants, HRQL information was available seven years before and three years after the lung function test from the previous S4 (1999–2001) and the F4L follow-up study (2010). Using linear mixed models, the physical and mental component summary scores (PCS-12 / MCS-12) of the SF-12 were compared over time between COPD groups.
Results
7.8% of participants were classified as having COPD (according to the LLN definition and the Global Lungs Initiative), 59.4% of them in grade 1. Regression models showed a negative cross-sectional association of COPD grade 2+ with PCS-12 which persisted when comorbidities were considered. Adjusted mean PCS-12 scores for the COPD grade 2+ group were reduced (−3.5 (p = 0.008) in F4, −3.3 (p = 0.014) in S4 and −4.7 (p = 0.003) in F4L) compared to the group without airflow limitation. The size of the COPD effect in grade 2+ was similar to the effect of myocardial infarction and cancer. Over ten years, a small decline in PCS-12 was observed in all groups. This decline was larger in participants with COPD grade 2+, but insignificant. Regarding MCS-12, no significant cross-sectional or longitudinal associations with COPD were found.
Conclusion
Despite small HRQL differences between COPD patients in early disease stages and controls and small changes over ten years, our results indicate that it is important to prevent subjects with airflow limitation from progression to higher grades. Awareness of HRQL impairments in early stages is important for offering early interventions in order to maintain high HRQL in COPD patients.
doi:10.1186/1471-2466-14-134
PMCID: PMC4130122  PMID: 25107380
COPD; Health-related quality of life; SF-12; Comorbidities; General population study; Longitudinal

Results 1-25 (66)