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Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases. This paper reports the first example of targeted anti-biofilm therapy in human disease. We have demonstrated that using low-dose nitric oxide as a non-bactericidal signaling molecule to induce biofilm dispersal may be useful as a novel adjunctive therapy to treat chronic pseudomonal biofilm infection in cystic fibrosis.

Staphylococcus aureus (S. aureus) colonizes the nasal cavities of both healthy individuals and patients with chronic rhinosinusitis (CRS) with (CRSwNP) and without (CRSsNP) nasal polyps. Treatment-resistant S. aureus biofilms and intracellular persistence are common in CRS patients, requiring the expression of specific virulence factor genes to transition into these forms. We hypothesized that S. aureus isolates from non-diseased controls, CRSsNP patients, and CRSwNP patients would exhibit distinct virulence factor patterns contributing to persistence and intracellular survival in CRS patients. Nasal swabs from seventy-seven individuals yielded S. aureus cultures in eight non-diseased controls, eight CRSsNP patients, and five CRSwNP patients. Whole-genome sequencing analyzed stress, antimicrobial resistance, and virulence genes, including plasmids and prophages. Four virulence factor gene patterns emerged: a core set (hlgA, icaC, hlgB, hlgC, hld, and aur) present in all isolates, and accessory sets, including the enterotoxin gene cluster (seo, sem, seu, sei, and sen) and a partial/complete invasive virulence factor set (splE, splA, splB, lukE, and lukD) (p = 0.001). CRSwNP isolates exhibited incomplete carriage of the core set, with frequent loss of scn, icaC, and hlgA (p < 0.05). These findings suggest that S. aureus has clusters of virulence factors that may act in concert to support the survival and persistence of the bacteria, resulting in enhanced pathogenicity. This may manifest clinically with resistant disease and refractoriness to antibiotics.

The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) plays an important role in many chronic respiratory diseases including otitis media, chronic rhinosinusitis, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in NTHi colonisation, persistence of infection and recalcitrance towards antimicrobials. There is therefore a pressing need for the development of novel treatment strategies that are effective against NTHi biofilm-associated diseases. SurgihoneyRO is a honey-based product that has been bioengineered to enable the slow release of H2O2, a reactive oxygen species to which H. influenzae is susceptible. Treatment of established NTHi biofilms with SurgihoneyRO significantly reduced biofilm viability through enhanced H2O2 production and was shown to be more effective than the conventional antibiotic co-amoxiclav.

Abstract Myofibroma is a rare benign myofibroblastic tumour of spindle cell differentiation. Most commonly, myofibromas are observed in the context of a myofibromatosis disorder in children. Rarely, myofibroma can present as a solitary lesion in adults. We report a rare case of solitary myofibroma of the nasal vestibule which presented as a nonhealing ulcer on the anterior nasal septum. This is described in the context of a comprehensive literature review. Punch biopsies were obtained which revealed histological appearances in keeping with myofibroma. Following discussion at the regional head and neck and sarcoma multidisciplinary meetings, surgical excision was performed with staged reconstruction. To our knowledge, this is the first reported case of myofibroma arising from the anterior nasal septum and columella. This case highlights the importance of considering myofibroma as a differential diagnosis for nonhealing ulceration in this anatomical location.

Reports of congenital anomalies of the Eustachian Tube (ET) are scarce, and often associated with chromosomal abnormalities. We report a unique case of a completely bony left Eustachian tube which communicated with the sphenoid sinus. This report details these findings and discusses the potential embryological basis and implications of such an unusual anatomy, in the context of a comprehensive literature review.

Chronic rhinosinusitis (CRS) with or without polyps is a common chronic upper airway condition of multifactorial origin. Fundamental to effective treatment of any infection is the ability to accurately characterize the underlying cause. Many studies have shown that only a small fraction of the total range of bacterial species present in CRS is detected through conventional culture-dependent techniques. Consequently, culture data are often unrepresentative of the true diversity of the microbial community within the sample. These drawbacks, along with the length of time required to complete the analysis, strongly support the development of alternative means of assessing which bacterial species are present. As such, molecular microbiological approaches that assess the content of clinical samples in a culture-independent manner could significantly enhance the range and quality of data obtained routinely from such samples. We aimed to characterize the bacterial diversity present in tissue and mucus samples taken from the CRS setting using molecular nonculture-dependent techniques. Through 16S ribosomal RNA (rRNA) gene clone sequencing and terminal restriction fragment length polymorphism (T-RFLP) analysis, the bacteria present in 70 clinical samples from 43 CRS patients undergoing endoscopic sinus surgery were characterized. Bacterial T-RFLP profiles were generated for 70 of 73 samples and a total of 48 separate bands were detected. Species belonging to 34 genera were identified as present by clone sequence analysis. Of the species detected, those within the genera Pseudomonas, Citrobacter, Haemophilus, Propionibacterium, Staphylococcus, and Streptococcus were found numerically dominant, with Pseudomonas aeruginosa the most frequently detected species. This study has validated the use of the culture-independent technique T-RFLP in sinonasal samples. Preliminary characterization of the microbial diversity in CRS suggests a complex range of common and novel bacterial species within the upper airway in CRS, providing further evidence for the polymicrobial etiology of CRS.

Evidence has been provided of enhanced epithelial transforming growth factor-beta (TGF-beta) immunoreactivity in allergic rhinitis, including correlation with intra-epithelial mast cell numbers, and the co-localisation of TGF-beta receptors to mast cells, suggesting that the epithelial expression of TGF-beta may represent an important biological process involved in either the recruitment or retention of mast cells within the epithelium in naturally occurring allergic rhinitis. In order to extend the above findings, evaluation was undertaken in whole nasal biopsies from subjects with naturally occurring allergic rhinitis, of levels of TGF-beta isotypes and receptors gene expression using real-time quantitative polymerase chain reaction (TaqMan RT-PCR), and the results compared to those for tumour necrosis factor-alpha (TNF-alpha), as a positive control. The study was also extended to evaluate gene expression for connective tissue growth factor (CTGF) and Smad proteins, as downstream markers of TGF-beta bioactivity, in the same populations. There were no significant differences between the rhinitic and non-rhinitic groups in the expression of TGF-beta isoforms or Smad-3, Smad-6 and Smad-7 proteins; however, there was increased gene expression for TGF-betaRI and TGF-betaRII along with CTGF in seasonal allergic rhinitis. TNF-alpha gene expression was also increased in seasonal allergic rhinitis, consistent with a more acute inflammatory response in this form of rhinitis. This study advances our understanding of the role of TGF-beta in the pathogenesis of the inflammatory response in allergic rhinitis.

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age‐related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid‐related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA‐related inflammation (CAA‐ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.