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Background: Health-related quality of life (HRQoL) is impaired in patients with pulmonary hypertension (PH). The EmPHasis-10 and CAMPHOR questionnaires are developed to evaluate HRQoL specifically in patients with PH. Data on the longitudinal use of both questionnaires are still limited. We evaluated the longitudinal value of both questionnaires and established minimal clinically important differences (MCID)., Methods: Sixty-one treatment naïve pulmonary arterial hypertension or chronic thromboembolic patients were prospectively included. Patients were treated according to the current ESC/ERS guidelines. We compared EmPHasis-10 and CAMPHOR scores between baseline, 6 and 12 months of follow-up and evaluated the correlation between these scores and a 5-scale symptom severity score, 5-scale overall health score, NYHA-classification, 6 min walk test distance (6MWD), NT-proBNP and echocardiographic parameters., Results: After one year of treatment a significant reduction in EmPHasis-10 score and CAMPHOR QoL and symptoms domain score was observed. Moderate to good correlations were observed between the questionnaires and the overall-health and symptom severity score and 6MWD. No relevant correlations were seen between the questionnaires and NT-pro-BNP and echocardiographic parameters. EmPHasis-10 scores showed strong correlations with all CAMPHOR domains. The MCID for the EmPHasis-10 questionnaire was -8. The MCIDs for the CAMPHOR domains were: activity -3, symptoms -4, QoL -3., Conclusion: The EmPHasis-10 and CAMPHOR questionnaires are valid tools for the longitudinal measurement of HRQoL in patients with PH. The much shorter EmPHasis-10 correlates well with the CAMPHOR domain scores and with the clinical endpoints and it may be easier to use in daily practice., (Copyright © 2021. Published by Elsevier Ltd.)

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of pulmonary function and exercise capacity, leading to loss of quality of life and often social isolation. A new walking aid, the walk-bike, showed an improvement in exercise performance in COPD patients. Aims of this pilot study were to evaluate feasibility of a homebased walk-bike intervention study in IPF patients and to explore the effect of the walk-bike on quality of life (QoL) and exercise capacity. Twenty-three patients with IPF were included in a randomized multicenter crossover study with 8 weeks of standard care and 8 weeks of walk-bike use at home. Ten patients completed both study phases. Study barriers included reluctance to participate and external factors (e.g. weather and road conditions) that hampered adherence. Patients' satisfaction and experience with the walk-bike varied greatly. After training with the walk-bike, health-related QoL (St. George's Respiratory and King's Brief Interstitial Lung Disease questionnaires) demonstrated a tendency towards improvement, exercise capacity did not. A clinically important difference was found between 6-minute walk test with the walk-bike and the standard test; median (range) respectively 602 m (358-684) and 486 m (382-510). Conclusions: Due to practical barriers a larger study with the walk-bike in patients with IPF seems not feasible. Individual patients may benefit from the use of a walk-bike as it improved action radius and showed a tendency towards improvement in QoL. No effect on exercise capacity was observed. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 192-202) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Purpose: Pulmonary arterial hypertension (PAH) is characterized by right ventricular failure, leading to exertional dyspnea, skeletal muscle weakness, and poor quality of life (QOL). Apart from treatment with PAH-specific drugs, guidelines recommend pulmonary rehabilitation (PR). Clinical PR programs have shown improvement in functional capacity and QOL. However, little is known about the effectiveness of an outpatient PR program. The aim of our study was to assess effectiveness of a multidisciplinary outpatient PR program., Methods: Patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH), who were in a stable condition on optimized drug therapy, followed a 10-wk outpatient program in a rehabilitation center. The PR program was designed to improve exercise capacity and health status by means of low load cycling, walking, and muscle training twice a week combined with psychological counseling. QOL was measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire., Results: Twenty-one patients (13 women) with PAH (n = 16) or CTEPH (n = 5) completed the study. All patients were in New York Heart Association (NYHA) functional class III, and their mean age was 45 ± 16 yr. After PR, the mean cycling endurance time increased by 4.4 min (P < .001), 6-min walk distance by 12.2 m (P < .05), and maximum inspiratory pressure by 5.8 cm H2O (P = .01). Skeletal muscle function increased significantly. The CAMPHOR questionnaire demonstrated significant decrease in symptoms and improvement in QOL. Soluble biomarkers did not show any change before and after PR., Conclusions: Outpatient PR could be an effective instrument to improve exercise capacity and health status in patients with PAH or CTEPH.

Background: Prednisone is used as first-line therapy for pulmonary sarcoidosis. What dosing strategy has the best balance between effect and side-effects is largely unknown. We analyzed change in forced vital capacity (FVC) and weight during different prednisone doses used in daily practice for treatment naïve pulmonary sarcoidosis patients., Methods: Multilevel models were used to describe FVC and weight change over time. Correlations were calculated using linear regression models., Results: Fifty-four patients were included. FVC changed over time (p < 0.001), with an average increase of 9.6% predicted (95% CI: 7.2 to 12.1) at 12 months. Weight changed significantly over time (p < 0.001), with an average increase of 4.3 kg (95% CI: 3.0 to 5.6) at 12 months. Although FVC and weight changed significantly over time, there was little correlation between prednisone dose and FVC change, while weight increase correlated significantly with cumulative prednisone dose at 24 months. In patients treated with a high cumulative prednisone dose, baseline FVC was on average lower (p = 0.001) compared to low dose treated patients, while no significant differences were observed in need for second/third-line therapy or number of exacerbations. A strategy leading to a low cumulative dose at 12 months was defined by rapid dose tapering to 10 mg/day within 3.5 months., Conclusions: These results suggest that prednisone therapy aimed at improving or preserving FVC in newly- treated pulmonary sarcoidosis can often be reduced in dose, using a treatment regimen that is characterized by early dose tapering., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

No disease-specific instruments exist in Dutch, French, Italian, and Swedish to measure health status in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). The King's Brief Interstitial Lung Disease (K-BILD) is a 15-item validated questionnaire assessing health status in patients with ILD. The aim of this study was to translate and validate the K-BILD to French, Italian, Swedish, and Dutch versions. The K-BILD was translated following a forward-backward multistep procedure and tested in structured patient interviews. Subsequently, 195 outpatients with ILD were asked to complete K-BILD, St. George's Respiratory Questionnaire (SGRQ), and Euroqol EQ-5D-5L (EQ5D), twice, 2 weeks apart. Internal consistency, concurrent validity, and repeatability were determined. No major difficulties occurred in the translation processes. The K-BILD was considered comprehensible and relevant by patients. One hundred seventy-six patients (108 IPF and 68 other ILDs) completed the translated K-BILD. Internal consistency was good for all K-BILD modules (Cronbach's α 0.70-0.93). Concurrent validity of K-BILD was strong compared with SGRQ ( r = -0.86) and EQ5D ( r = 0.68), low with transfer capacity of the lung for carbon monoxide corrected for hemoglobin ( r = 0.33) and with forced vital capacity ( r = 0.35). The K-BILD and its domains were repeatable over 2 weeks; intraclass correlation coefficients were 0.86-0.93 ( n = 159). Known groups validity showed K-BILD was able to discriminate between patients based on severity of disease. K-BILD's validity and reliability for patients with IPF was similar to that of other ILDs. The French, Italian, Swedish, and Dutch translated K-BILD questionnaires were well-received by patients and demonstrated excellent validity comparable to the original English K-BILD.

Background: Health status and quality of life are impaired in patients with interstitial lung disease (ILD). To assess these parameters in ILD patients no valid and reliable questionnaire exists in German language so far. The K-BILD questionnaire is a brief and valid tool to evaluate health status in ILD patients, with no validated German version. Method: The linguistic validation of K-BILD was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by ILD patients ensured that the translated questionnaire reflected the intention of the original K-BILD. Results: A German version of K-BILD with 15 questions concerning the health status was composed. The questions cover the three domains breathlessness and activities, psychological aspects and chest symptoms. Problems in understanding or difficulties in replying to the questions were not stated by the ILD patients. Conclusion: The German version of the K-BILD questionnaire allows the clinical and scientific use to measure reliable health quality in ILD patients., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health status using five modules (General Health Status, Lung, Eyes, Skin, Medication) in patients with sarcoidosis. The KSQ was only validated in one English sarcoidosis cohort., Objective: The aim of this study was to validate the KSQ in a Dutch sarcoidosis population., Methods: The KSQ was translated according to international guidelines and tested in interviews with patients. Consecutive outpatients completed multiple questionnaires twice, two weeks apart. Construct validity, internal consistency and repeatability were determined., Results: Of the 98 patients included 85 had lung, 22 skin and 24 eye disease. There was good construct validity of the KSQ General Health Status module against the World Health Organization Quality of Life-BREF questionnaire. The Medication module correlated weak to moderate with most questionnaires. The correlations with organ-specific questionnaires varied from strong for Eyes (r=0.75), Skin (r=-0.62) to moderate for Lung (r=-0.45 with MRC breathlessness scale). Internal consistency was good for all KSQ modules (Cronbach's α 0.72-0.93). Intraclass correlation coefficients (0.70-0.90) and Bland-Altman plots showed good repeatability of the KSQ., Conclusion: The Dutch KSQ is the first translation of the English KSQ, validated in a Dutch sarcoidosis population.

The identification of genes primarily responsible for complex genetic disorders is a daunting task. Despite the assignment of many susceptibility loci, there has only been limited success in identifying disease genes based solely on positional information from genome-wide screens. The incorporation of several complementary strategies in a single integrated approach should facilitate and further enhance the efficacy of this search for genes. To permit the integration of linkage, association and expression data, together with functional annotations, we have developed a Java-based software tool: TEAM (tool for the integration of expression, and linkage and association maps). TEAM includes a genome viewer, capable of overlaying karyobands, genes, markers, linkage graphs, association data, gene expression levels and functional annotations in one composite view. Data management, analysis and filtering functionality was implemented and extended with links to the Ensembl, Unigene and Gene Ontology databases to facilitate gene annotation. Filtering functionality can help prevent the exclusion of poorly annotated, but differentially expressed, genes that reside in candidate regions that show linkage or association. Here we demonstrate the program's functionality in our study on coeliac disease (OMIM 212750), a multifactorial gluten-sensitive enteropathy. We performed a combined data analysis of a genome-wide linkage screen in 82 Dutch families with affected siblings and the microarray expression profiles of 18,110 cDNAs in 22 intestinal biopsies.

The human X chromosome is known to contain several disease genes yet to be cloned. In the course of a project aimed at the construction of a transcription map of the Xp22 region, we fully characterized a novel cDNA, Cxorf5 (HGMW-approved symbol, alias 71-7A), previously mapped to this region but for which no sequence information was available. We isolated and sequenced the full-length transcript, which encodes a predicted protein of unknown function containing a large number of coiled-coild domains, typically presented in a variety of different molecules, from fibrous proteins to transcription factors. We showed that the Cxorf5 cDNA is ubiquitously expressed, undergoes alternative splicing, and escapes X inactivation. Furthermore, we precisely mapped two additional Cxorf5-related loci on the Y chromosome and on chromosome 5. By virtue of its mapping assignment to the Xp22 region, Cxorf5 represents a candidate gene for at least four human diseases, namely spondyloepiphiseal dysplasia late, oral-facial-digital syndrome type 1, craniofrontonasal syndrome, and a nonsyndromic sensorineural deafness.

We have applied a yeast artificial chromosome (YAC)-based cosmid isolation and binning strategy to convert a YAC contig in Xp22 into 1.6 Mb of overlapping cosmids. This strategy is based on the screening of a high-density arrayed X chromosome-specific cosmid library with large YAC-derived restriction fragments and entire YAC probes. Cosmids selected in this way were gridded on dot blots and further mapped into bins defined by the overlap intervals of the YACs and YAC fragments. This rapid binning of cosmids simplified the subsequent assembly of cosmid contigs by restriction fingerprint hybridization. In total, we identified 139 cosmids spanning the entire 1.6 Mb region with a minimal overlap set of 53 clones. These cosmids were assigned to 17 bins and 9 contigs. One of the contigs is 665 kb in length and is one of the largest uninterrupted cosmid contigs in humans reported to date. The gaps between the contigs are minor and, together, they represent less than 7% of the region covered. Two previously identified genes are contained in these cosmids, the gene for amelogenin (AMG) and the recently isolated putative chloride channel gene CICN4. In addition, two disease loci have been mapped to this region: X-linked ocular albinism type 1 (OA1) and the microphthalmia with linear skin defects (MLS) syndrome. The assembly of the cosmid maps allowed us to determine the size of the deletion intervals for these two loci, which were estimated to be 110 kb for OA1 and 570 kb for MLS.(ABSTRACT TRUNCATED AT 250 WORDS)

In the framework of constructing a comprehensive transcript map of the human Xp22.3 region, we identified an evolutionary conserved CpG island and cloned the corresponding gene. The predicted 760 amino acid protein encoded by this gene contains 12 hydrophobic domains and shares significant sequence and structural similarities with all the previously isolated members of a recently identified family of voltage-gated chloride channels (the 'CIC family'). This gene, termed CICN4 (Chloride Channel 4), contains at least 10 exons spanning 60 to 80 kb on the X chromosome. In contrast to most genes isolated from the human Xp22.3 region, the CICN4 gene does not share homology with the Y chromosome and it is conserved in mouse and hamster. Expression studies revealed the presence of a 7.5 kb transcript which is particularly abundant in skeletal muscle and is also detectable in brain and heart. These data suggest that we have identified a new voltage-gated chloride channel which is encoded by a gene located in the distal short arm of the X chromosome.

New findings on the pseudoautosomal area of X and Y chromosomes potentiate the importance of this part of the human genome for direct and indirect DNA diagnosis. The submitted paper is focused on the characteristic features of the given area with special emphasis on loci used in the Institute of Haematology and Blood Transfusion during DNA monitoring of patients after allogeneic transplantation of bone marrow and which thus provide important information with a major clinical impact. The authors indicate trends of future research focused on investigation of the polymorphism of the receptor of the haematopoietic factor GM CSF in relation to its function and the influence on the pathogenesis of AML.

We have used cell lines from patients with deletions and translocations involving the Xp22 region to map the genes for two X-linked disorders, ocular albinism type 1 (OA1) and microphthalmia with linear skin defects (MLS). Using existing and newly isolated DNA markers, the map position within Xp22 of key patient breakpoints, defining the boundaries of the genomic regions involved in these disorders (the critical regions), has been precisely determined. A 2.6 Mb yeast artificial chromosome (YAC) contig, spanning the critical regions for these two disorders, was assembled. Detailed long-range restriction analysis of the contig established the sizes of the critical regions to be 200 kb for OA1 and 800 - 925 kb for MLS. Ten potential CpG-islands, representing candidate sites for genes, have been mapped within the 2.6 Mb region. Our data should greatly facilitate efforts aimed at cloning the genes for these developmental defects.