LTD4 and TGF-β1 induce the expression of metalloproteinase-1 in chronic rhinosinusitis via a cysteinyl leukotriene receptor 1-related mechanism

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Staphylococcus aureus enterotoxin B regulates prostaglandin E-2 synthesis, growth, and migration in nasal tissue fibroblasts

Background. Superantigens and eicosanoids are important amplifiers and regulators of inflammation in airway diseases. We therefore studied the possible influence of Staphylococcus aureus enterotoxin B ( SEB) on the cyclooxygenase ( COX) pathway and basic functions of airway structural cells. Methods. Fibroblasts were isolated from nasal inferior turbinate tissue and cultured in the presence of different concentrations of SEB. Preincubation with interferon ( IFN)-gamma was performed to induce expression of major histocompatibility complex ( MHC) class II receptors. Prostaglandin E2 ( PGE(2)) production was assayed by enzyme-linked immunosorbent assay, and levels of COX-2 and prostanoid E receptors 1-4 ( EP1-4) were assayed by real-time polymerase chain reaction. Migration and growth tests were performed, and SEB was localized within the cells by confocal microscopy. Results. Stimulation with IFN-gamma and SEB significantly down-regulated PGE2, COX-2, and EP2 expression but not EP1, EP3, or EP4 expression. The enterotoxin blocked cell growth but increased the fibroblast migration rate. SEB was localized within the cell in the presence and absence of MHC-II, suggesting that mechanisms other than conventional binding may allow the enterotoxin to enter the cell. Conclusions. These findings may have major implications for our understanding of the role played by bacterial superantigens in regulating the inflammatory and remodeling mechanisms of upper airway diseases and hence may help elucidate the pathophysiology of these diseases

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement.Methods We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms.Results We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%).Conclusions We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

Corrigendum on: White paper on European patient needs and suggestions on chronic type 2 inflammation of airways and skin by EUFOREA

Background: Type 2 inflammation underlies the chronicity of disease in subgroups of patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and atopic dermatitis (AD), that often co-exist. Although several studies have investigated the unmet needs of asthma, AD and CRSwNP as such, little is known about the similarities and differences in experiences and perspectives of the current management of patients with comorbid Type 2 inflammatory diseases. Aims: To improve insight into the common and organ-specific needs of patients with Type 2 inflammation and comorbidities, allowing the formulation of recommendations to better address these needs in the future. Methodology: This qualitative study was conducted between July 2021 and December 2021 using semi-structured face-to-face or telephone interviews with patients suffering from year-long severe chronic Type 2 inflammation and at least one co-morbid inflammatory condition. Seven participating academic centers in Europe interviewed asthma (Copenhagen and Leuven), CRSwNP (London, Amsterdam and Crete) and/or AD (Oldenburg and Zurich) patients on patient characteristics, disease severity, shortcomings of current care pathways and suggestions for improvement of care. Transcripts were analyzed using an inductive thematic analysis approach. Results: Eighty-one patients with severe Type 2 inflammation and comorbidities were interviewed. Similar needs were recognized by patients with Type 2 inflammation, with both a lack of coordination in care and a lack of a real cure reported as being most frustrating. However, several needs are specific to asthma, CRSwNP and AD. Suggestions for improvement of care were generic across diseases, such as the implementation of a multidisciplinary approach, the improved facilitation of access to better treatments, the increase of general awareness on disease burden, and better educational programs for healthcare providers and patients. Of note, patients with CRSwNP also stated the need for alternatives to sinus surgery, whereas patients with asthma requested better medical care to prevent exacerbations and patients with AD would warmly welcome the reimbursement of emollients. Conclusion: Patients with asthma, CRSwNP and AD have shared unmet needs that need to be addressed by physicians, the academic community and health policy makers. This survey provides unique recommendations made by patients for the implementation of better care

White Paper on European Patient Needs and Suggestions on Chronic Type 2 Inflammation of Airways and Skin by EUFOREA

Background: Type 2 inflammation underlies the chronicity of disease in subgroups of patients with asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and atopic dermatitis (AD), that often co-exist. Although several studies have investigated the unmet needs of asthma, AD and CRSwNP as such, little is known about the similarities and differences in experiences and perspectives of the current management of patients with comorbid Type 2 inflammatory diseases. Aims: To improve insight into the common and organ-specific needs of patients with Type 2 inflammation and comorbidities, allowing the formulation of recommendations to better address these needs in the future. Methodology: This qualitative study was conducted between July 2021 and December 2021 using semi-structured face-to-face or telephone interviews with patients suffering from year-long severe chronic Type 2 inflammation and at least one co-morbid inflammatory condition. Seven participating academic centers in Europe interviewed asthma (Copenhagen and Leuven), CRSwNP (London, Amsterdam and Crete) and/or AD (Oldenburg and Zurich) patients on patient characteristics, disease severity, shortcomings of current care pathways and suggestions for improvement of care. Transcripts were analyzed using an inductive thematic analysis approach. Results: Eighty-one patients with severe Type 2 inflammation and comorbidities were interviewed. Similar needs were recognized by patients with Type 2 inflammation, with both a lack of coordination in care and a lack of a real cure reported as being most frustrating. However, several needs are specific to asthma, CRSwNP and AD. Suggestions for improvement of care were generic across diseases, such as the implementation of a multidisciplinary approach, the improved facilitation of access to better treatments, the increase of general awareness on disease burden, and better educational programs for healthcare providers and patients. Of note, patients with CRSwNP also stated the need for alternatives to sinus surgery, whereas patients with asthma requested better medical care to prevent exacerbations and patients with AD would warmly welcome the reimbursement of emollients. Conclusion: Patients with asthma, CRSwNP and AD have shared unmet needs that need to be addressed by physicians, the academic community and health policy makers. This survey provides unique recommendations made by patients for the implementation of better care

Design and Analysis of Resonant Metamaterials for Acoustic Insulation(Ontwerp en analyse van resonante metamaterialen voor geluidsisolatie)

Increasing customer expectations and more restrictive legal requirements turn the acoustical behaviour of products into an important design criterion in the machine and transportation industry as well as in the construction and consumer goods sector. Ecological trends and the associatedrun for efficiency, however, increased the importance of lightweight design and reduced the applicability of classical (heavy) solutions to improve acoustic behaviour. In view of this challenging and often conflicting task of merging acoustical and lightweight requirements novel acoustic solutions are required. Ideally these novel solutions are easy to design and are characterised by a low mass and compact volume along with a high reliability at an affordable cost.This dissertation investigates the potential of resonant metamaterials with stop band behaviour, i.e. existence of frequency zones with pronounced wave attenuation, to create novel acoustic solutions.Stop band behaviour in metamaterial design is pursued by incorporating resonant elements of sub-wavelength sizes, i.e. features that are actually smaller than the wavelength of the wave to be affected. The decoupling of wavelength and inclusion scale opens up the path towards novel branches of thinner and lighter acoustic solutions.The translation of stop band predictions on unit cell level for infinite periodic structures to vibration reduction in finite structures with possible perturbation of periodicity is investigated through analyses of a set of test cases; predicted stop bands are shown to results in frequency zones of decreased overall vibration and these zones are highly influenced by the amount of damping in the resonant inclusions. The effect of resonance based stop bands on the acoustic radiation efficiency of a structure is analysed; vibrational stop bands have a beneficial effect when designed for frequency ranges above the coincidence frequency but should be designed with care below coincidence.A novel implementation of resonance based stop bands in view of engineering structures is proposed; the addition of resonant structures in the core of a hollow core sandwich structure introduces stop band behaviour. Through design, numerical analyses and experimental validation of a set of demonstrators the potential of resonant metamaterial based stop bands for acoustic insulation in engineering applications is demonstrated. This metamaterial concept can be achieved through a variety of design or production processes, depending on the application, and can offer technological benefits such as possible compact integration in structural parts, usein harsh environments and ease of design of the beneficial frequency ranges without resulting in a high mass penalty.status: publishe