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.
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.
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.
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.
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.
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.
osteopontin; chronic obstructive pulmonary disease; asthma; emphysema; pulmonary fibrosis
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.
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.
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.
German Clinical Trials Register DRKS00006079. Registered 4 June 2014.
Cardiovascular disease; Chronic obstructive pulmonary disease; Health services research; Primary medical care; Smoking cessation
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.
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.
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).
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.
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.
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.
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).
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.
Physical activity; Healthcare utilization; Healthcare costs; Direct costs; Indirect costs; Children; Cross-sectional study
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.
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.
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.
Randomized controlled trial; Aftercare; Case management; Phone-based; Depression; Anxiety; Evaluation; Effectiveness
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.
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.
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.
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.
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.
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.
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.
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.
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.
Inflammation; Lung; Heart; Dust; Particle exposure; Cardiovascular risk individuals
Epidemiological and experimental studies suggest that exposure to ultrafine particles (UFP) might aggravate the allergic inflammation of the lung in asthmatics.
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)
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.
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.
Ultrafine particles; Asthma; Pulmonary inflammation; Aerosol exposure; Aeroallergen
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.
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.
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.
This study is registered with ClinicalTrials.gov, number NCT01731717 (date of registration: 24 June 2013).
Depression; Stepped care; Collaborative care; Complex intervention; Primary care; Secondary care; Low intensity treatments; e-Mental health
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.
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.
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.
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.
COPD; Health-related quality of life; SF-12; Comorbidities; General population study; Longitudinal
Type I Bartter syndrome is a recessive human nephropathy caused by loss-of-function mutations in the SLC12A1 gene coding for the Na+-K+-2Cl− cotransporter NKCC2. We recently established the mutant mouse line Slc12a1I299F exhibiting kidney defects highly similar to the late-onset manifestation of this hereditary human disease. Besides the kidney defects, low blood pressure and osteopenia were revealed in the homozygous mutant mice which were also described in humans. Beside its strong expression in the kidney, NKCC2 has been also shown to be expressed in other tissues in rodents i.e. the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye.
To examine if, besides kidney defects, further organ systems and/or metabolic pathways are affected by the Slc12a1I299F mutation as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the mutant mouse line Slc12a1I299F in the German Mouse Clinic. Slc12a1I299F homozygous mutant mice and Slc12a1I299F heterozygous mutant littermates as controls were tested at the age of 4–6 months. Beside the already published changes in blood pressure and bone metabolism, a significantly lower body weight and fat content were found as new phenotypes for Slc12a1I299F homozygous mutant mice. Small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. For other functions, such as immunology, lung function and neurology, no distinct alterations were observed.
In this systemic analysis no clear primary effects of the Slc12a1I299F mutation appeared for the organs other than the kidneys where Slc12a1 expression has been described. On the other hand, long-term effects additional and/or secondary to the kidney lesions might also appear in humans harboring SLC12A1 mutations.
Animal model; NKCC2; Systematic phenotype analysis
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations.
Chloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation.
Cftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte-colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15-hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice.
Despite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution.
Aerosol; Biokinetics; Cystic fibrosis; Energy filtering transmission electron microscopy; Inflammation; Inhalation; Iridium; Lung function; Nanoparticles; Titanium dioxide; Ultrafine particles
Elderly people obtain significant health benefits from physical activity (PA), but the role of activity patterns has scarcely been researched. The present study aims to describe the patterns of PA among different intensities of activity in elderly people. We assess how patterns differ between more and less active groups (‘rare’, ‘average’, and ‘frequent’), and explore whether and how various PA parameters are associated with functional exercise capacity (FEC).
PA was measured in 168 subjects (78 males; 65–89 years of age), using a triaxial GT3X accelerometer for ten consecutive days. Subjects were divided into three groups by activity and the groups were compared. A multiple linear regression model was used to predict FEC.
Participants greater than or equal to 80 years are most prone to being sedentary for long periods, while women and the obese are the groups most likely to spend insufficient time in moderate to vigorous PA (MVPA). Rarely active elderly people had a decreased proportion of long bouts of MVPA and light PA and of short bouts in sedentary behavior than frequently active subjects did (p < 0.001). As predictors of FEC, younger age, lower BMI, male sex, better lung function, absence of multimorbidity, longer times and longer bouts of MVPA emerged as significant parameters (r2 = 0.54). Patterns of MVPA explained most of the variance.
PA patterns provide information beyond reports of activity alone. MVPA in elderly people may be increased by increasing the proportion of long bouts, in order to increase FEC as well as average PA. However, health conditions may limit PA. In rarely active people (often with reduced FEC, worse lung function, and diagnosis of multimorbidity or disability), longer periods of time in light PA may be sufficient to increase the overall level of activity.
Elderly; Aged; Older; Physical activity; Exercise; Pattern; Intensity; Movement; Ambulation
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.
Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines UmodA227T and UmodC93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects.
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.
We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.
Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.
Low levels of alpha1-antitrypsin (AAT) in the blood are a well-established risk factor for accelerated loss in lung function and chronic obstructive pulmonary disease. While a few infrequent genetic polymorphisms are known to influence the serum levels of this enzyme, the role of common genetic variants has not been examined so far. The present genome-wide scan for associated variants in approximately 1400 Swiss inhabitants revealed a chromosomal locus containing the functionally established variants of AAT deficiency and variants previously associated with lung function and emphysema. We used dense genotyping of this genetic region in more than 5500 individuals and subsequent conditional analyses to unravel which of these associated variants contribute independently to the phenotype's variability. All associations of common variants could be attributed to the rarer functionally established variants, a result which was then replicated in an independent population-based Danish cohort. Hence, this locus represents a textbook example of how a large part of a trait's heritability can be hidden in infrequent genetic polymorphisms. The attempt to transfer these results to lung function furthermore suggests that effects of common variants in this genetic region in ever-smokers may also be explained by rarer variants, but only in individuals with hampered pulmonary health.
Background Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age.
Methods Metabolomic profiling on fasting blood was carried out in 6055 individuals from the UK. Stepwise regression was performed to identify a panel of independent metabolites which could be used as a surrogate for age. We also investigated the association with birthweight overall and within identical discordant twins and with genome-wide methylation levels.
Results We identified a panel of 22 metabolites which combined are strongly correlated with age (R2 = 59%) and with age-related clinical traits independently of age. One particular metabolite, C-glycosyl tryptophan (C-glyTrp), correlated strongly with age (beta = 0.03, SE = 0.001, P = 7.0 × 10−157) and lung function (FEV1 beta = −0.04, SE = 0.008, P = 1.8 × 10−8 adjusted for age and confounders) and was replicated in an independent population (n = 887). C-glyTrp was also associated with bone mineral density (beta = −0.01, SE = 0.002, P = 1.9 × 10−6) and birthweight (beta = −0.06, SE = 0.01, P = 2.5 × 10−9). The difference in C-glyTrp levels explained 9.4% of the variance in the difference in birthweight between monozygotic twins. An epigenome-wide association study in 172 individuals identified three CpG-sites, associated with levels of C-glyTrp (P < 2 × 10−6). We replicated one CpG site in the promoter of the WDR85 gene in an independent sample of 350 individuals (beta = −0.20, SE = 0.04, P = 2.9 × 10−8). WDR85 is a regulator of translation elongation factor 2, essential for protein synthesis in eukaryotes.
Conclusions Our data illustrate how metabolomic profiling linked with epigenetic studies can identify some key molecular mechanisms potentially determined in early development that produce long-term physiological changes influencing human health and ageing.
Ageing; metabolomics; epigenetics; twin studies; developmental origins of health and disease; birthweight
Surveillance of physical activity (PA) is increasingly based on accelerometry. However, data management guidelines are lacking. We propose an approach for combining accelerometry and diary based PA information for assessment of PA in adolescents and provide an example of this approach using data from German adolescents.
The 15-year-old participants comprised a subsample the GINIplus birth cohort (n = 328, 42.4% male). Data on PA was obtained from hip-worn accelerometers (ActiGraph GT3X) for seven consecutive days, combined with a prospective activity diary. Major aspects of data management were validity of wear time, handling of non-wear time and diary comments. After data cleaning, PA and percentage of adolescents meeting the recommendations for moderate-to-vigorous activity (MVPA) per day were determined.
From the 2224 recorded days 493 days (25%) were invalid, mainly due to uncertainties relating to non-wear time (322 days). Ultimately, 269 of 328 subjects (82%) with valid data for at least three weekdays and one weekend day were included in the analysis. Mean MVPA per day was 39.1 minutes (SD ±25.0), with boys being more active than girls (41.8±21.5 minutes vs. 37.1±27.8 minutes, p<0.001). Accordingly, 24.7% of boys and 17.2% of girls (p<0.01) met the WHO recommendations for PA. School sport accounted for only 6% of weekly MVPA. In fact, most MVPA was performed during leisure time, with the majority of adolescents engaging in ball sports (25.4%) and endurance sports (19.7%). Girls also frequently reported dancing and gymnastics (23%).
For assessment of PA in adolescents, collecting both accelerometry and diary-based information is recommended. The diary is vital for the identification of invalid data and non-compliant participants. Preliminary results suggest that four out of five German adolescents do not meet WHO recommendations for PA and that school sport contributes only little to MVPA.
Impulse oscillometry (IOS) is a non-demanding lung function test. Its diagnostic use may be particularly useful in patients of advanced age with physical or mental limitations unable to perform spirometry. Only few reference equations are available for Caucasians, none of them covering the old age. Here, we provide reference equations up to advanced age and compare them with currently available equations.
IOS was performed in a population-based sample of 1990 subjects, aged 45–91 years, from KORA cohorts (Augsburg, Germany). From those, 397 never-smoking, lung healthy subjects with normal spirometry were identified and sex-specific quantile regression models with age, height and body weight as predictors for respiratory system impedance, resistance, reactance, and other parameters of IOS applied.
Women (n = 243) showed higher resistance values than men (n = 154), while reactance at low frequencies (up to 20 Hz) was lower (p<0.05). A significant age dependency was observed for the difference between resistance values at 5 Hz and 20 Hz (R5–R20), the integrated area of low-frequency reactance (AX), and resonant frequency (Fres) in both sexes whereas reactance at 5 Hz (X5) was age dependent only in females. In the healthy subjects (n = 397), mean differences between observed values and predictions for resistance (5 Hz and 20 Hz) and reactance (5 Hz) ranged between −1% and 5% when using the present model. In contrast, differences based on the currently applied equations (Vogel & Smidt 1994) ranged between −34% and 76%. Regarding our equations the indices were beyond the limits of normal in 8.1% to 18.6% of the entire KORA cohort (n = 1990), and in 0.7% to 9.4% with the currently applied equations.
Our study provides up-to-date reference equations for IOS in Caucasians aged 45 to 85 years. We suggest the use of the present equations particularly in advanced age in order to detect airway dysfunction.
Physical inactivity among children is an increasing problem that adversely affects children’s health. A better understanding of factors which affect physical activity (PA) will help create effective interventions aimed at raising the activity levels of children. This cross-sectional study examined the associations of PA with individual (biological, social, behavioral, psychological) and environmental (East vs. West Germany, rural vs. urban regions) characteristics in children.
Information on PA and potential correlates was collected from 1843 girls and 1997 boys using questionnaires during the 10-year follow-up of two prospective birth cohort studies (GINIplus and LISAplus). Study regions represent urban and rural sites as well as East and West of Germany. Logistic regression modeling was applied to examine cross-sectional associations between individual as well as environmental factors and PA levels.
Five of fourteen variables were significantly associated with PA. Among children aged 10, girls tended to be less active than boys, especially with respect to vigorous PA (OR = 0.72 for summer). Children who were not a member of a sports club showed a substantially reduced amount of PA in winter (OR = 0.15). Rural environments promote moderate PA, particularly in winter (OR = 1.88), whereas an increased time outdoors primarily promotes moderate PA in summer (OR = 12.41). Children with abnormal emotional symptoms exhibited reduced physical activity, particularly in winter (OR = 0.60). BMI, puberty, parental BMI, parental education, household income, siblings, TV/PC consumption, and method of arriving school, were not associated with PA.
When considering correlates of PA from several domains simultaneously, only few factors (sex, sports club membership, physical environment, time outdoors, and emotional symptoms) appear to be relevant. Although the causality needs to be ascertained in longitudinal studies, variables which cannot be modified should be used to identify risk groups while modifiable variables, such as sports club activities, may be addressed in intervention programs.
Activity; Children; Correlates; Exercise; Inactivity; Determinants; Associations; Behavior; Environment; Social