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Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes. Conclusion: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway. [ABSTRACT FROM AUTHOR]

To the editor, Asthma, one of the most common chronic diseases in childhood, is caused by interactions between genes and environmental factors. Since the IL-33/IL1RL1 pathway has been associated with eosinophilic, type 2, inflammation, we hypothesized that I IL1RL1 i SNPs may affect corticosteroid treatment response in asthma patients. No association between I IL1RL1 i and questionnaire-based asthma control was found. [Extracted from the article]

Summary: Background: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome‐wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. Objective: We performed a GWA study to develop insights in asthma remission. Methods: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long‐term follow‐up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. Results: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow‐up of 15.5 (range 3.3‐47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta‐analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta‐analysis of the replication cohorts. The top‐hit, rs6581895, almost reached genome‐wide significance (P‐value 4.68 × 10−7) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis‐eQTL in lung tissue for IL1RL1 and IL18R1 and a trans‐eQTL for IL13. Conclusions and Clinical Relevance: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2,CCT,IL1RL1, IL18R1 and IL13. [ABSTRACT FROM AUTHOR]

Wheezing is common in childhood. However, current prediction models of pediatric asthma have only modest accuracy. Novel biomarkers and definition of subphenotypes may improve asthma prediction. Interleukin-1-receptor-like-1 ( IL1RL1 or ST2) is a well-replicated asthma gene and associates with eosinophilia. We investigated whether serum sST2 predicts asthma and asthma with elevated exhaled NO (Fe NO), compared to the commonly used Asthma Prediction Index ( API). Using logistic regression modeling, we found that serum sST2 levels in 2-3 years-old wheezers do not predict doctors' diagnosed asthma at age 6 years. Instead, sST2 predicts a subphenotype of asthma characterized by increased levels of Fe NO, a marker for eosinophilic airway inflammation. Herein, sST2 improved the predictive value of the API ( AUC=0.70, 95% CI 0.56-0.84), but had also significant predictive value on its own ( AUC=0.65, 95% CI 0.52-0.79). Our study indicates that sST2 in preschool wheezers has predictive value for the development of eosinophilic airway inflammation in asthmatic children at school age. [ABSTRACT FROM AUTHOR]

O01 Serum IL-1RL1-A levels predict an eosinophilic subtype of asthma in preschool wheezing ch... M. E. Ketelaar 1, K. Van De Kant 2, F. N. Dijk 1, E. M. M. Klaassen 3, N. Grotenboer 4,... 1 University Medical Center Groningen, Beatrix Children's Hospital, Groningen Research Instit... B Correspondence b : Maria Elizabeth Ketelaar - m.e.ketelaar@student.rug.nl I Clinical and Translational Allergy i 2017, B 7(Suppl 2) b :O01 B Introduction b : Respiratory symptoms are common in preschool children. The children were divided into four groups - 10 children with scoliosis without asthma (Sc),10 children with scoliosis and asthma (AS), 10 children with moderate asthma (BA), 10 children with severe asthma (SA) and 10 healthy children (HC). B Keywords b : Preschool Wheezing, Respiratory Viruses, Asthma Exacerbation, Severity P09 Tele-monitoring decreases unscheduled outpatient visits in pediatric patients with severe... Mihai Craiu, Iustina Violeta Stan INSMC Alessandrescu-Rusescu, Bucharest, Romania B Correspondence b : Mihai Craiu - mcraiu@yahoo.com I Clinical and Translational Allergy i 2017, B 7(Suppl 2) b :P09 B Introduction b : Pediatric asthma patients originating from poor-resource areas experience a significant increase of unscheduled and emergency department visits and most of medical care for them is delivered in such a facility. [Extracted from the article]

Background Animal data have suggested that the transient receptor potential ankyrin-1 ( TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. Methods We analysed associations between 31 TRPA1 single nucleotide polymorphisms ( SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children ( ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy ( PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. Results In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 ( OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 ( OR 1.30 (1.09-1.55), p = 0.003), rs920829 ( OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 ( OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. Conclusion This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words) [ABSTRACT FROM AUTHOR]

A single‐sideband opto‐RF oscillator based on a monolithic InGaAsP chip containing two distributed feedback (DFB) lasers is demonstrated. The heterodyne signal is stabilised by a hybrid method, combining optical and electronic feedback. It leads to a locking of the beating frequency onto a filtered version of itself. The table‐top setup provides a phase noise level down to −75 dBc/Hz at 1 kHz offset from a 10 GHz carrier. Potential phase noise improvement and integration scheme in a single component are discussed. [ABSTRACT FROM AUTHOR]

Aberrant expression of human leukocyte antigens (HLA) class I has prognostic importance in various cancers. Here, we evaluated the prognostic value of classical (A/B/C) and nonclassical (G/E) HLA expression in 169 high grade epithelial ovarian cancer samples and linked that to clinicopathological characteristics and survival. Expression of HLA-A, -B/C, or -E was not correlated with survival. Survival was prolonged when tumours expressed HLA-G (P = 0.008) and HLA-G was an independent predictor for better survival (P = 0.011). In addition, HLA-G expression was associated with longer progression-free survival (P = 0.036) and response to chemotherapy {P = 0.014). Accordingly, high expression of HLA-G mRNA was associated with prolonged disease-free survival (P = 0.037) in 65 corresponding samples. Elevated serum-soluble HLA-G levels as measured by enzyme-linked immunosorbent assay in 50 matched patients were not correlated to HLA-G protein expression or gene expression nor with survival. During treatment, sHLA-G levels declined {P = 0.038). In conclusion, expression of HLA-G is an independent prognostic factor for improved survival in high grade epithelial ovarian cancer and a predictor for platinum sensitivity. [ABSTRACT FROM AUTHOR]

Patients with head and neck squamous cell carcinoma (HNSCC) have a poor prognosis due to the development of locoregional recurrences, distant metastases, and second primary tumors. There is an urgent need for biomarkers that enable detection and monitoring of the disease to provide adequate therapeutic strategies. In this study, we have investigated markers in peripheral blood cells (PBC) of 28 HNSCC patients who underwent surgery by means of expression profiling. Our hypothesis is that nucleated blood cells circulate continuously, also pass the tumor, and change their expression profile in response to tumor cell factors. For comparison, we enrolled a control group of 11 patients who underwent surgery in the head and neck region for non-HNSCC reasons. A set of 2949 genes was found to be statistically different between the groups (P < 0.05, false discovery rate-corrected) and the most prominently different pathways were ELF2, ELF4, and mTOR signaling. These preliminary results are promising and warrant further studies on the definitive role of PBC gene expression as a biomarker for HNSCC detection and monitoring. [ABSTRACT FROM AUTHOR]

Objectives: Fatigue and other symptoms in cancer patients often interfere with social and occupational activities. Only a few studies, however, have examined relationship between fatigue and work-related outcomes. The aim of this study was to investigate which disease-related factors (treatment, diagnosis, cognitive dysfunction, depression, pain, and sleep disturbance) and work-related factors (work-load, work pressure, relationship to supervisor and colleagues, size of the company, and workplace accommodations) were related to fatigue in employed cancer survivors. Methods: Data was collected by questionnaire at 6 months (baseline) and 18 months (end of the follow-up) after cancer diagnosis from 135 people with different types of cancer who had returned to work at follow-up. Fatigue was measured with a four-item sub-scale of MFI. Scores ranged from 4 to 20, with higher scores indicating more fatigue. Results: The mean rate of general fatigue was 11.9 at baseline decreasing to 10.4 at the end of the follow-up ( p<0.0001). At 6 months, higher work pressure ( p = 0.02), physical workload ( p<0.05) and less workplace accommodations ( p = 0.03) were related to higher levels of fatigue. From disease-related factors, depression was associated with fatigue ( p<0.0001) at baseline. Lack of workplace accommodations was the only factor affecting higher levels of fatigue at 18 months ( p<0.001) and was also related to higher levels of depression at 6 months ( p = 0.02) and at 18 months ( p<0.001). Conclusions: Lack of workplace accommodations was significantly related to fatigue at the end of the follow-up, which suggests that accommodations for illness can help to reduce fatigue and depression. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Celiac disease is a multifactorial disorder caused by an unknown number of genetic factors interacting with an environmental factor. Hence, most patients are singletons and large families segregating with celiac disease are rare. We report on a three-generation family with six patients in which the inheritance pattern is consistent with an autosomal dominant model. To date, 27 loci explain up to 40% of the heritable disease risk. We hypothesized that part of the missing heritability is because of low frequency or rare variants. Such causal variants could be more prominent in multigeneration families where private mutations might co-segregate with the disease. They can be identified by linkage analysis combined with whole exome sequencing. We found three linkage regions on 4q32.3-4q33, 8q24.13-8q24.21 and 10q23.1-10q23.32 that segregate with celiac disease in this family. We performed exome sequencing on two affected individuals to investigate the positional candidate regions and the remaining exome for causal nonsense variants. We identified 12 nonsense mutations with a low frequency (minor allele frequency <10%) present in both individuals, but none mapped to the linkage regions. Two variants in the CSAG1 and KRT37 genes were present in all six affected individuals. Two nonsense variants in the MADD and GBGT1 genes were also present in 5 of 6 and 4 of 6 individuals, respectively; future studies should determine if any of these nonsense variants is causally related to celiac disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Börjeson-Forssman-Lehmann syndrome (BFLs) is an X-linked inherited disorder characterised by unusual facial features, abnormal fat distribution and intellectual disability. As many genetically determined disorders are characterised not only by physical features but also by specific behaviour, we studied whether a specific behavioural phenotype exists in BFLs. METHODS: We studied in detail the behaviour of four molecularly proven BFLs patients, and reviewed available literature on BFLs specifically for behavioural characteristics. RESULTS: Behaviour in persons with BFLs is in general friendly, but can be challenging with externalising and thrill-seeking features. Social skills are good. However, variation among patients is wide. Three patients from a single family showed expressed hypersexual behaviour. This was not present in other patients. CONCLUSION: In BFLs a specific behavioural phenotype exists and in behaviour general is challenging besides a friendly habit. Within single families more problematic behaviour may occur. Further behavioural and molecular analysis of a larger group of patients is warranted to determine whether a genotype-behavioural phenotype correlation exists. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to examine whether a sentinel surveillance project comprising motivated and guided occupational physicians would offer higher quality information than a national registry for a policy to avoid occupational diseases. Researchers reported that the median number of notifications per occupational physician during the project was 13.0 in the sentinel group. Additionally, the overall reported occupational disease incidence was 7 times higher. They found that a sentinel surveillance group comprising motivated and guided occupational physicians reported a higher occupational disease incidence.

To establish which personal and contextual factors are predictive of successful outcomes in postgraduate medical education. We performed a follow-up study of 118 doctors on a postgraduate occupational health training programme on the management of mental health problems. The following personal and contextual variables were measured as potential predictors of outcome: gender; age; years of experience as a doctor; university of graduation; learning style (Kolb); present employer (occupational health service), and educational format (problem-based or lecture-based). The main outcome measures were: scores on knowledge tests consisting of true/false and open answer questions, and performance in practice based on self-report and performance indicators. To determine the effect of potential predictive factors univariate analyses of variance and repeated measurement analysis of variance was applied. The mean scores of knowledge ( P < 0.001) and performance ( P = 0.001) of the participants increased after the educational programme. After multivariate analysis female gender was positively related to accruements in both knowledge and performance (both P < 0.05), independently of the influence of other factors. Accommodator learning style showed a relation with knowledge increase ( P = 0.05), but had no influence on performance ( P = 0.79). The problem-based educational format yielded a better performance outcome ( P = 0.05), but had no influence on knowledge tests ( P = 0.31). Gender and learning style were found to be related to an increase in knowledge. Gender was also found to be related to improvement in performance after a postgraduate medical education programme. We found no interactions with course design (i.e. problem-based or non problem-based learning formats), but further research could reveal other cues, suggesting practical consequences of student characteristics for course design in postgraduate training. [ABSTRACT FROM AUTHOR]

Endothelial cell integrity (coverage and quality) of large donor vessels is important because these vessels are used for vascular reconstructions in solid-organ transplantation. Disruption of the endothelial cell monolayer will initiate blood coagulation and may lead to thrombosis of large vessels, often resulting in the loss of the transplanted organ. Iliac arteries and veins, removed from 10 heart-beating multi-organ donors at the end of the donor procedure, were analyzed using scanning electron microscopy at three different time points of preservation. Endothelial cell coverage and quality were determined immediately after removal from the donor, after 10 h (time of transplantation) and 7 d storage in ‘University of Wisconsin’ cold preservation solution (UW). Endothelial cell coverage decreased during the preservation of arteries, but was maintained in veins. Storage of the veins for 7 d in plastic bags showed a decreased endothelial cell coverage compared to storage in glass vials. Early removal of the blood vessels and proper storage, free floating and in clean UW, may improve maintenance of the endothelial cell integrity. These findings may be important in order to reduce the risk of thrombosis and, consequently, organ failure after transplantation. Furthermore, vessels with maintained endothelial cell integrity after 7 d may be used for in vitro research. [ABSTRACT FROM AUTHOR]

A photonic oscillator, locked to a master RF synthesiser, was built by using a monolithic dual-wavelength DFB semiconductor laser submitted to a frequency-shifted optical feedback. A [3; 10] GHz tuning range is reported, with a phase noise level lower than -70 dBrad2/Hz at a 10 Hz offset from the carrier. [ABSTRACT FROM AUTHOR]

A photonic oscillator, locked to a master RF synthesiser, was built by using a monolithic dual‐wavelength DFB semiconductor laser submitted to a frequency‐shifted optical feedback. A [3; 10] GHz tuning range is reported, with a phase noise level lower than −70 dBrad2/Hz at a 10 Hz offset from the carrier. [ABSTRACT FROM AUTHOR]

Dermatosparaxis Ehlers Danlos syndrome (dEDS) is a very rare monogenic EDS that occurs due to biallelic pathogenic variants in ADAMTS2. Fifteen individuals with dEDS have been reported in the literature, with the oldest being 19 years at follow-up. Given the lack of information regarding adults with dEDS, our aim was to describe adults with dEDS to inform management recommendations in adulthood. We report five individuals (2:3 male:female) with an age range of 22-42 years. Complications include extreme skin fragility resulting in iatrogenic injury, redundant skin folds often requiring surgical resection, severe complications following a gastric volvulus secondary to a diaphragmatic hernia, and multiple fractures. Discussion of management considerations includes thorough investigations of acute pain, careful consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone mineral density after low-impact fracture and/or post-menopause., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5-10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., (© 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.)

Background: In order to support occupational health practitioners, researchers, and experts (clinical librarians, guideline developers) who search the scientific literature in PubMed (Medline), we developed and evaluated an easy-to-use and effective search strategy., Methods: We tested different combinations of search terms, in answering four case vignettes calculating sensitivity and precision in retrieving literature from a gold standard. The use of the Clinical Queries filter from PubMed was evaluated. Based on the outcomes, we developed guidelines for a professional search strategy, using a flow chart., Results: For the occupational health practitioner, we found a sensitivity of at least 65% with a precision of 20%, when terms for occupation and type of industry were combined with terms for disease. For the occupational health expert, a high sensitivity of more than 90% was found adding terms for risk factors to the strategy. Combining the search terms with the sensitive Clinical Queries etiology filter in PubMed, enhanced the precision. Using the specific Clinical Queries etiology filter in PubMed results in a substantial loss of relevant articles., Conclusions: To search for studies on the occupational origin of diseases in Medline, we propose to start with the proper name for the occupational disease. If this does not exist, use a specific term for the occupation and type of industry in combination with terms for disease. To improve the sensitivity of the search, a search term for the specific risk factor should be added. If there is no relevant occupational title available, it is worth trying the general search terms occupational diseases or occupational risk., (Copyright (c) 2005 Wiley-Liss, Inc.)

The retinal rod bipolar cell type is involved in the sign-inverting depolarizing ON-type response to light. This response is mediated by the metabotropic glutamate receptor type 6 (mGluR6) expressed on the rod bipolar dendrites. In a previous immunocytochemical study, an unexpected colocalization was reported [W. Kamphuis et al. (2003) J. Comp. Neurol., 455, 172-186] of mGluR6 with the ionotropic AMPA-type glutamate receptor subunit GluR2 in rod bipolar cells of rat retina. The aim of the present study was to investigate whether expression of both genes could be found at the single-cell level. Two approaches were followed. (i). Retinal cells were isolated by enzymatic and mechanical treatment. Single cells with a bipolar morphology were harvested, subjected to multiplex PCR with protein kinase C (PKC)-, mGluR6- and GluR1-4-specific primers, followed by a real-time quantitative PCR assay. Of 23 studied cells, 74% expressed PKC and 87% expressed mGluR6. Using the presence of both transcripts as the criterion for a rod bipolar cell signature (n = 15), 73% of these cells expressed GluR2, with a minor contribution of GluR1 (20%), GluR3 (7%), and GluR4 (20%). Quantification of the transcript levels demonstrated that mGluR6 and GluR2 genes are expressed at similar levels in rod ON-type bipolar cells. (ii). Rod bipolar cells were identified in retinal sections by immunolabelling with a protein kinase C antibody and isolated using laser pressure catapulting (LPC). Quantitative PCR was employed to assess gene expression levels of reference genes, PKCalpha, mGluR6 and the GluR subunits. However, in samples from PKCalpha-immunopositive somata no significant enrichment of PKCalpha transcript levels was observed when compared with control samples from immunonegative somata. We conclude that this approach lacks sufficient spatial specificity. In conclusion, the results show coexpression of mGluR6 and GluR2 in rod bipolar cells; this is in good agreement with the results of previous immunocytochemical studies. The functional implications of AMPA-type glutamate receptors for ON-type rod bipolar-mediated signal transduction remains to be elucidated.