Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin‐1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)‐induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c‐deficient (Fbln1c^–/–) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild‐type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c^–/– mice with AAD also had reduced numbers of α‐smooth muscle actin‐positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)‐5, IL‐13, IL‐33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL‐5, IL‐33 and TNF levels in lung‐draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3‐positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL‐5 and IL‐13 from co‐cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium‐treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Quantitative Ultrashort Echo Time Magnetic Resonance Imaging Evaluation of Postoperative Menisci: a Pilot Study

BackgroundMagnetic resonance imaging (MRI) visualization of meniscal signal is particularly challenging as the highly organized ultrastructure of meniscal fibrocartilage yields very short T2 values (∼6 ms) and a paucity of signal intensity during conventional image acquisition.Question/PurposeThe purpose of this study was to evaluate the feasibility of imaging postoperative menisci using an experimental, quantitative ultrashort echo time (UTE) MRI pulse sequence. This sequence acquires short echo images (echo time (TE) ∼0.3 ms) to produce multi-echo images for quantitative T2* calculations that provide an objective measure of collagen organization.ResultsA wide range of mean T2* values for both postsurgical groups was measured, and these values changed for each patient between the 6- and 12-month intervals. In many instances, the UTE sequence demonstrated quantitative differences between the two time intervals that were not detected with conventional sequences.ConclusionsThis pilot study presents preliminary, observational data to be used as a baseline for future studies. Although the T2* values did not reveal a trend in either group or correlate with expected signal changes on conventional MRI, we speculate that the UTE sequence may detect ultrastructural alterations in meniscal composition that are otherwise not perceived with routine fast spin echo (FSE) sequences.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-014-9420-x) contains supplementary material, which is available to authorized users.     

Rasch analysis of the Pediatric Evaluation of Disability Inventory–computer adaptive test (PEDI‐CAT) item bank for children and young adults with spinal muscular atrophy

Introduction: In this study we evaluated the suitability of a caregiver‐reported functional measure, the Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI‐CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI‐CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI‐CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI‐CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54 : 1097–1107, 2016     

Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome.

Three distinct gene products, the alpha and beta chains of glycoprotein (GP) Ib and GP IX, constitute the platelet membrane GP Ib-IX complex, a receptor for von Willebrand factor and thrombin involved in platelet adhesion and aggregation. Defective function of the GP Ib-IX complex is the hallmark of a rare congenital bleeding disorder of still undefined pathogenesis, the Bernard-Soulier syndrome. We have analyzed the molecular basis of this disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ib alpha but presence of a smaller immunoreactive species. The truncated polypeptide was also present, along with normal protein, in platelets from the patient's mother and two of his four children. Genetic characterization identified a nucleotide transition changing the Trp-343 codon (TGG) to a nonsense codon (TGA). Such a mutation explains the origin of the smaller GP Ib alpha, which by lacking half of the sequence on the carboxyl-terminal side, including the trans-membrane domain, cannot be properly inserted in the platelet membrane. Both normal and mutant codons were found in the patient, suggesting that he is a compound heterozygote with a still unidentified defect in the other GP Ib alpha allele. Nonsense mutation and truncated GP Ib alpha polypeptide were found to cosegregate in four individuals through three generations and were associated with either Bernard-Soulier syndrome or carrier state phenotype. The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GP Ib alpha alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome.     

Pulmonary oxygen toxicity: increased microvascular permeability to protein in unanesthetized lambs

To study transvascular filtration of fluid and microvascular permeability to protein in the lung during prolonged hyperoxia, we measured lung lymph flow, protein transport, and simultaneous pulmonary vascular pressures of six lambs breathing 100 percent O2 for five days. Lymph flow doubled, protein flow increased by 131 percent, and radioactive tracer studies demonstrated a clearcut increase in pulmonary microvascular permeability to protein after five days of continuous O2 breathing.     

Prolapse of the antero-superior leaflet of the tricuspid valve secondary to congenital anomalies of the valvar and sub-valvar apparatus: a rare cause of severe tricuspid regurgitation

Congenital anomalies of the tricuspid valve, and/or its supporting apparatus, leading to severe tricuspid regurgitation are rare. Although well tolerated in early childhood, long-standing and progressive volume loading of the right heart leads to symptoms of decreased exercise tolerance, and may predispose to arrhythmias in the long term. We report three cases of severe tricuspid regurgitation related to anomalies of the cords supporting the antero-superior leaflet of the tricuspid valve. Shortened cords leading to tethering of the leaflet were seen in two cases, and hypoplasia of the leaflet in the other. In all cases, the regurgitant jet was directed posteriorly towards the coronary sinus and atrial septum. Surgical repair was possible in one case, while it proved necessary to replace the valve in a second. The third child is asymptomatic and under regular review.     

Position paper for the organization of ECMO programs for cardiac failure in adults

Extracorporeal membrane oxygenation (ECMO) has been used increasingly for both respiratory and cardiac failure in adult patients. Indications for ECMO use in cardiac failure include severe refractory cardiogenic shock, refractory ventricular arrhythmia, active cardiopulmonary resuscitation for cardiac arrest, and acute or decompensated right heart failure. Evidence is emerging to guide the use of this therapy for some of these indications, but there remains a need for additional evidence to guide best practices. As a result, the use of ECMO may vary widely across centers. The purpose of this document is to highlight key aspects of care delivery, with the goal of codifying the current use of this rapidly growing technology. A major challenge in this field is the need to emergently deploy ECMO for cardiac failure, often with limited time to assess the appropriateness of patients for the intervention. For this reason, we advocate for a multidisciplinary team of experts to guide institutional use of this therapy and the care of patients receiving it. Rigorous patient selection and careful attention to potential complications are key factors in optimizing patient outcomes. Seamless patient transport and clearly defined pathways for transition of care to centers capable of providing heart replacement therapies (e.g., durable ventricular assist device or heart transplantation) are essential to providing the highest level of care for those patients stabilized by ECMO but unable to be weaned from the device. Ultimately, concentration of the most complex care at high-volume centers with advanced cardiac capabilities may be a way to significantly improve the care of this patient population.