Paraneoplastic Autoimmunity in Thymus Tumors

Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4 +AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal Tcell selection by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas

CLN3 loss disturbs membrane microdomain properties and protein transport in brain endothelial cells

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal childhood-onset neurodegenerative disorder caused by mutations in ceroid lipofuscinosis neuronal-3 (CLN3), a hydrophobic transmembrane protein of unresolved function. Previous studies indicate blood–brain barrier (BBB) defects in JNCL, and our earlier report showed prominent Cln3 expression in mouse brain endothelium. Here we find that CLN3 is necessary for normal trafficking of the microdomain-associated proteins caveolin-1, syntaxin-6, and multidrug resistance protein 1 (MDR1) in brain endothelial cells. Correspondingly, CLN3-null cells have reduced caveolae, and impaired caveolae- and MDR1-related functions including endocytosis, drug efflux, and cell volume regulation. We also detected an abnormal blood–brain barrier response to osmotic stress in vivo. Evaluation of the plasma membrane with fluorescent sphingolipid probes suggests

Impact of pulmonary rehabilitation on patients’ health care needs and asthma control:a quasi-experimental study

Background!#!Pulmonary rehabilitation offers potential benefits to people with asthma. It is however unknown if rehabilitation favourably affects patients' health care needs. We therefore examined if rehabilitation reduced needs and, in addition, if it improved asthma control.!##!Methods!#!One hundred fifty patients with asthma were surveyed in three rehabilitation clinics at admission and at discharge. Additionally, we surveyed 78 participants with asthma twice 4 weeks apart. The latter sample (i.e. the control group) was recruited through other pathways than rehabilitation clinics. The Patient Needs in Asthma Treatment (NEAT) questionnaire and the Asthma Control Test (ACT) were completed at baseline and follow-up. Differences between baseline and follow-up and between rehabilitation and control group were examined by t-tests and chi-squared-tests. Univariate ANCOVAS were used to examine if NEAT and ACT follow-up scores differed significantly between groups. Within the rehabilitation group, linear regressions were used to examine if self-reported utilization of more interventions that addressed needs were associated with NEAT scores at follow-up.!##!Results!#!At baseline, there were no differences between the rehabilitation and the control group regarding needs and asthma control. At follow-up, the rehabilitation group showed reduced needs (t(149) = 10.33, p <  0.01) and increased asthma control (t(130) = -6.67, p <  0.01), whereas members of the control group exhibited no changes. Univariate ANCOVAS showed that unmet follow-up needs (F(1, 212) = 36.46, p <  0.001) and follow-up asthma control (F(1, 195) = 6.97, p = 0.009) differed significantly between groups. In the rehabilitation group, self-reported utilization of more interventions was associated with reduced needs (β = 0.21; p = 0.03).!##!Conclusions!#!This study provides preliminary evidence suggestion that pulmonary rehabilitation in adults with asthma may reduce asthma-related needs and confirms previous findings that rehabilitation may improve asthma control

Structural genomics of human proteins – target selection and generation of a public catalogue of expression clones

BACKGROUND: The availability of suitable recombinant protein is still a major bottleneck in protein structure analysis. The Protein Structure Factory, part of the international structural genomics initiative, targets human proteins for structure determination. It has implemented high throughput procedures for all steps from cloning to structure calculation. This article describes the selection of human target proteins for structure analysis, our high throughput cloning strategy, and the expression of human proteins in Escherichia coli host cells. RESULTS AND CONCLUSION: Protein expression and sequence data of 1414 E. coli expression clones representing 537 different proteins are presented. 139 human proteins (18%) could be expressed and purified in soluble form and with the expected size. All E. coli expression clones are publicly available to facilitate further functional characterisation of this set of human proteins

Preferences of patients with asthma or COPD for treatments in pulmonary rehabilitation

Introduction: Pulmonary rehabilitation (PR) aims to improve disease control in patients with chronic obstructive pulmonary disease (COPD) and asthma. However, the success of PR-programs depends on the patients’ participation and willingness to cooperate. Taking the patients’ preferences into consideration might improve both of these factors. Accordingly, our study aims to analyze patients’ preferences regarding current rehabilitation approaches in order to deduce and discuss possibilities to further optimize pulmonary rehabilitation. Methods and analysis: At the end of a 3 weeks in-house PR, patients’ preferences concerning the proposed therapies were assessed during two different time slots (summer 2015 and winter 2015/2016) in three clinics using a choice-based conjoint analysis (CA). Relevant therapy attributes and their levels were identified through literature search and expert interviews. Inclusion criteria were as follows: PR-inpatient with asthma and/or COPD, confirmed diagnosis, age over 18 years, capability to write and read German, written informed consent obtained. The CA analyses comprised a generalized linear mixed-effects model and a latent class mixed logit model. Results: A total of 542 persons participated in the survey. The most important attribute was sport and exercise therapy. Rehabilitation preferences hardly differed between asthma and COPD patients. Health-related quality of life (HRQoL) as well as time since diagnosis were found to have a significant influence on patients’ rehabilitation preferences. Conclusions: Patients in pulmonary rehabilitation have preferences regarding specific program components. To increase the adherence to, and thus, the effectiveness of rehabilitation programs, these results must be considered when developing or optimizing PR-programs.Introduction: Pulmonary rehabilitation (PR) aims to improve disease control in patients with chronic obstructive pulmonary disease (COPD) and asthma. However, the success of PR-programs depends on the patients’ participation and willingness to cooperate. Taking the patients’ preferences into consideration might improve both of these factors. Accordingly, our study aims to analyze patients’ preferences regarding current rehabilitation approaches in order to deduce and discuss possibilities to further optimize pulmonary rehabilitation. Methods and analysis: At the end of a 3 weeks in-house PR, patients’ preferences concerning the proposed therapies were assessed during two different time slots (summer 2015 and winter 2015/2016) in three clinics using a choice-based conjoint analysis (CA). Relevant therapy attributes and their levels were identified through literature search and expert interviews. Inclusion criteria were as follows: PR-inpatient with asthma and/or COPD, confirmed diagnosis, age over 18 years, capability to write and read German, written informed consent obtained. The CA analyses comprised a generalized linear mixed-effects model and a latent class mixed logit model. Results: A total of 542 persons participated in the survey. The most important attribute was sport and exercise therapy. Rehabilitation preferences hardly differed between asthma and COPD patients. Health-related quality of life (HRQoL) as well as time since diagnosis were found to have a significant influence on patients’ rehabilitation preferences. Conclusions: Patients in pulmonary rehabilitation have preferences regarding specific program components. To increase the adherence to, and thus, the effectiveness of rehabilitation programs, these results must be considered when developing or optimizing PR-programs

Physical Activity and Sedentary Behaviour Patterns in 326 Persons with COPD before Starting a Pulmonary Rehabilitation: A Cluster Analysis

This study applies a cluster analysis to identify typical physical activity (PA) and sedentary behaviour (SB) patterns in people with chronic obstructive pulmonary disease (COPD) before starting pulmonary rehabilitation (PR). We implemented an observational design which assessed baseline data of objectively measured PA and SB from the STAR (Stay Active after Rehabilitation) study. A total of 355 persons wore an accelerometer (Actigraph wGT3X) for seven days before the start of their PR. Sociodemographic and disease-related parameters were assessed at the start of PR. We applied cluster analysis and compared clusters applying univariate variance analyses. Data was available for 326 persons (31.6% women; age ø = 58 years). Cluster analysis revealed four movement clusters with distinct PA and SB patterns: Sedentary non-movers (28.5%), sedentary occasional movers (41.7%), sedentary movers (19.6%), and sedentary exercisers (10.1%). The four clusters displayed varying levels of moderate PA before rehabilitation (Ø daily min: 9; 28; 38; 70). Notably, all four clusters displayed considerably long average sedentary time per day (Ø daily minutes: 644; 561; 490; 446). The clusters differed significantly in disease-related parameters of GOLD severity, FEV1, CAT, and 6-Min-Walk-Test. In addition to PA promotion, PR programs should consider the reduction of sedentary behaviour as a valuable goal

Impact of Disease-Specific Fears on Pulmonary Rehabilitation Trajectories in Patients with COPD

Disease-specific fears predict health status in chronic obstructive pulmonary disease (COPD), but their role in pulmonary rehabilitation (PR) remains poorly understood and especially longer-term evaluations are lacking. We therefore investigated changes in disease-specific fears over the course of PR and six months after PR, and investigated associations with PR outcomes (COPD assessment test (CAT) and St. Georges respiratory questionnaire (SGRQ)) in a subset of patients with COPD (n = 146) undergoing a 3-week inpatient PR program as part of the STAR study (Clinicaltrials.gov, ID: NCT02966561). Disease-specific fears as measured with the COPD anxiety questionnaire improved after PR. For fear of dyspnea, fear of physical activity and fear of disease progression, improvements remained significant at six-month follow-up. Patients with higher disease-specific fears at baseline showed elevated symptom burden (CAT and SGRQ Symptom scores), which persisted after PR and at follow-up. Elevated disease-specific fears also resulted in reduced improvements in Quality of Life (SGRQ activity and impact scales) after PR and at follow-up. Finally, improvement in disease-specific fears was associated with improvement in symptom burden and quality of life. Adjustment for potential confounding variables (sex, smoking status, age, lung function, and depressive symptoms) resulted in comparable effects. These findings show the role of disease-specific fears in patients with COPD during PR and highlight the need to target disease-specific fears to further improve the effects of PR

Thresholds for clinically important deterioration versus improvement in COPD health status:results from a randomised controlled trial in pulmonary rehabilitation and an observational study during routine clinical practice

OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease. Preventing deterioration of health status is therefore an important therapy goal. (Minimal) Clinically Important Differences ((M)CIDs) are used to interpret changes observed. It remains unclear whether (M)CIDs are similar for both deterioration and improvement in health status. This study investigates and compares these clinical thresholds for three widely-used questionnaires. DESIGN AND SETTING: Data were retrospectively analysed from an inhouse 3-week pulmonary rehabilitation (PR) randomised controlled trial in the German Klinik Bad Reichenhall (study 1), and observational research in Dutch primary and secondary routine clinical practice (RCP) (study 2). PARTICIPANTS: Patients with COPD aged ≥18 years (study 1) and aged ≥40 years (study 2) without respiratory comorbidities were included for analysis. PRIMARY OUTCOMES: The COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) were completed at baseline and at 3, 6 and 12 months. A Global Rating of Change scale was added at follow-up. Anchor-based and distribution-based methods were used to determine clinically relevant thresholds. RESULTS: In total, 451 patients were included from PR and 207 from RCP. MCIDs for deterioration ranged from 1.30 to 4.21 (CAT), from 0.19 to 0.66 (CCQ), and from 2.75 to 7.53 (SGRQ). MCIDs for improvement ranged from -3.78 to -1.53 (CAT), from -0.50 to -0.19 (CCQ), and from -9.20 to -2.76 (SGRQ). Thresholds for moderate improvement versus deterioration ranged from -5.02 to -3.29 vs 3.89 to 8.14 (CAT), from -0.90 to -0.72 vs 0.42 to 1.23 (CCQ), and from -15.85 to -13.63 vs 7.46 to 9.30 (SGRQ). CONCLUSIONS: MCID ranges for improvement and deterioration on the CAT, CCQ and SGRQ were somewhat similar. However, estimates for moderate and large change varied and were inconsistent. Thresholds differed between study settings. TRIAL REGISTRATION NUMBER: Routine Inspiratory Muscle Training within COPD Rehabilitation trial: #DRKS00004609; MCID study: #UMCG201500447