Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-ß from the brain and retina with age and Alzheimer's disease: Opportunities for therapy.

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 ß (Aß) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

Staphylococcus aureus internalization in mast cells in nasal polyps: Characterization of interactions and potential mechanisms.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps is a common chronic condition. The exact cause of nasal polyps remains unknown. Recently, we made the novel observation of intracellular localization of Staphylococcus aureus within mast cells in nasal polyps. OBJECTIVE: This follow-up study aimed to further characterize interactions between S aureus and mast cells in this setting and elucidate potential internalization mechanisms with particular emphasis on the role of staphylococcal enterotoxin B (SEB). METHODS: A prospective study was performed using an explant tissue model with ex vivo inferior turbinate mucosa obtained from patients with chronic rhinosinusitis with nasal polyps (n = 7) and patients without CRS (n = 5). Immunohistochemistry was used to characterize S aureus uptake into mast cells and investigate the effects of SEB on this process. An in vitro cell-culture model was used to investigate mast cell-S aureus interactions by using a combination of fluorescent in situ hybridization, confocal laser scanning microscopy, scanning electron microscopy, transmission electron microscopy, and proliferation assays. RESULTS: S aureus was captured by extracellular traps and entered mast cells through phagocytosis. Proliferating intracellular S aureus led to the expansion and eventual rupture of mast cells, resulting in release of viable S aureus into the extracellular space. The presence of SEB appeared to promote internalization of S aureus into mast cells. CONCLUSION: This study provides new insights into the interactions between S aureus and mast cells, including the internalization process, and demonstrates a prominent role for SEB in promoting uptake of the bacteria into these cells.

Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.

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.

Cephalosporin-NO-donor prodrug PYRRO-C3D shows ß-lactam-mediated activity against Streptococcus pneumoniae biofilms.

Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3'-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with ß-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following ß-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (ß-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks ß-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of ß-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the ß-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.

Eustachian tube communicating with sphenoid sinus: report of a novel anatomical variant.

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.

Low Concentrations of Nitric Oxide Modulate Streptococcus pneumoniae Biofilm Metabolism and Antibiotic Tolerance.

Streptococcus pneumoniaeis one of the key pathogens responsible for otitis media (OM), the most common infection in children and the largest cause of childhood antibiotic prescription. Novel therapeutic strategies that reduce the overall antibiotic consumption due to OM are required because, although widespread pneumococcal conjugate immunization has controlled invasive pneumococcal disease, overall OM incidence has not decreased. Biofilm formation represents an important phenotype contributing to the antibiotic tolerance and persistence ofS. pneumoniaein chronic or recurrent OM. We investigated the treatment of pneumococcal biofilms with nitric oxide (NO), an endogenous signaling molecule and therapeutic agent that has been demonstrated to trigger biofilm dispersal in other bacterial species. We hypothesized that addition of low concentrations of NO to pneumococcal biofilms would improve antibiotic efficacy and that higher concentrations exert direct antibacterial effects. Unlike in many other bacterial species, low concentrations of NO did not result inS. pneumoniaebiofilm dispersal. Instead, treatment of bothin vitrobiofilms andex vivoadenoid tissue samples (a reservoir forS. pneumoniaebiofilms) with low concentrations of NO enhanced pneumococcal killing when combined with amoxicillin-clavulanic acid, an antibiotic commonly used to treat chronic OM. Quantitative proteomic analysis using iTRAQ (isobaric tag for relative and absolute quantitation) identified 13 proteins that were differentially expressed following low-concentration NO treatment, 85% of which function in metabolism or translation. Treatment with low-concentration NO, therefore, appears to modulate pneumococcal metabolism and may represent a novel therapeutic approach to reduce antibiotic tolerance in pneumococcal biofilms.

Common airborne fungi induce species-specific effects on upper airway inflammatory and remodelling responses.

OBJECTIVE: Whilst the exact cause of chronic rhinosinusitis (CRS) remains elusive, it is clear that both inflammation and remodelling are key disease processes. Environmental fungi have been linked to airway inflammation in CRS; however, their role in the pathogenesis of this condition remains controversial. The current consensus suggests that whilst fungi may not be directly causative, it is likely that CRS patients have deficits in their innate and potentially acquired immunity, which in turn may modify their ability to react to fungi. This study used a nasal polyp explant tissue stimulation model to study the inflammatory and remodelling responses related to challenge with common airborne fungal species. METHODS: Ex vivo nasal polyp tissue from six well phenotyped CRSwNP patients undergoing functional endoscopic sinus surgery was stimulated with 1, 10 and 100 µg/ml of Alternaria alternata, Aspergillus niger, Cladosporium sphaerospermum and Penicillium notatum and compared with unchallenged polyp tissue as control. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of pro-inflammatory cytokines interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF) and tumour necrosis factor-α (TNF-α); and pro-remodelling cytokines transforming growth factor-b1 (TGF-b1), and basic fibroblast growth factor (bFGF) in the polyp supernatant. RESULTS: Aspergillus niger stimulation increased pro-inflammatory cytokines TNF-α, GM-CSF and IL-6 whilst having little effect on the remodelling cytokines bFGF and TGF-b1. In contrast, stimulation with Cladosporium sphaerospermum, Alternaria alternata and Penicillium notatum reduced pro-inflammatory cytokines TNF-α and IL-6, but induced a dose-dependent increase in remodelling cytokines TGF-b1 and bFGF. CONCLUSIONS: This study shows that common airborne fungi induce species-specific effects on the upper airway inflammatory and remodelling responses. These findings provide further immunological evidence of a disease-modifying role for fungi in CRS.

Reducing Aerosolized Particles and Droplet Spread in Endoscopic Sinus Surgery during COVID-19.

OBJECTIVES: The presence of high SARS-Cov-2 viral loads in the upper airway, including the potential for aerosolized transmission of viral particles, has generated significant concern amongst otolaryngologists worldwide, particularly those performing endoscopic sinus surgery (ESS). We evaluated a simple negative-pressure mask technique to reduce viral exposure. METHODS: Two models simulating respiratory droplets >5-10 µm and fine respiratory nuclei <5 µm using fluorescein dye and wood smoke, respectively, were utilized in a fixed cadaveric study in a controlled environment. Using ultraviolet light, fluorescein droplet spread was assessed during simulated ESS with powered microdebrider and powered drilling. Wood smoke ejection was used to evaluate fine particulate escape from a negative-pressure mask using digital subtraction image processing. RESULTS: The use of a negative-pressure mask technique resulted in 98% reduction in the fine particulate aerosol simulation and eliminated larger respiratory droplet spread during simulated ESS, including during external drill activation. CONCLUSIONS: As global ear, nose & throat (ENT) services resume routine elective operating, we demonstrate the potential use of a simple negative-pressure mask technique to reduce the risk of viral exposure for the operator and theatre staff during ESS. LEVEL OF EVIDENCE: 5 Laryngoscope, 131:956-960, 2021.

A rare presentation of a paediatric sinonasal inverted papilloma.

Sinonasal inverted papilloma (IP) is a benign tumour with an extremely low incidence in children. We report the case of an 11-year-old Caucasian male presenting with recurrent right-sided epistaxis, nasal obstruction and a mass in the right nasal cavity. An initial diagnosis of a nasopharyngeal angiofibroma was considered; however, on detailed histological examination, the mass was found to be an inverted papilloma. This report aims to increase awareness of IP in the paediatric age group, as well as reinforcing the role of endoscopic surgery in the management of this condition.

Antimicrobial activity of a novel bioengineered honey against non-typeable Haemophilus influenzae biofilms: an in vitro study.

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.

Hot topics in reactive oxygen therapy: Antimicrobial and immunological mechanisms, safety and clinical applications.

Reactive oxygen species (ROS), when combined with various delivery mechanisms, has the potential to become a powerful novel therapeutic agent against difficult-to-treat infections, especially those involving biofilm. It is important in the context of the global antibiotic resistance crisis. ROS is rapidly active in vitro against all Gram-positive and Gram-negative bacteria tested. ROS also has antifungal and antiviral properties. ROS prevents the formation of biofilms caused by a range of bacterial species in wounds and respiratory epithelium. ROS has been successfully used in infection prevention, eradication of multiresistant organisms, prevention of surgical site infection, and intravascular line care. This antimicrobial mechanism has great potential for the control of bioburden and biofilm at many sites, thus providing an alternative to systemic antibiotics on epithelial/mucosal surfaces, for wound and cavity infection, chronic respiratory infections and possibly recurrent urinary infections as well as local delivery to deeper structures and prosthetic devices. Its simplicity and stability lend itself to use in developing economies as well.

The acceptability and tolerability of nasal douching in children with allergic rhinitis: A systematic review.

BACKGROUND: Allergic rhinitis (AR) is a significant issue in children. Treatment options include allergen avoidance, pharmacotherapy and immunotherapy. The use of nasal saline douching (NSD) in children has recently gained acceptability. However, there is limited data regarding the acceptability and tolerability of NSD in children with AR. METHODS: A search was conducted using Medline and Embase databases from January 1946 until June 2015 on the use of NSD in children aged 4-12 years with AR. All publications identified that assessed the beneficial effects, acceptability and tolerability were included. RESULTS: 40 studies were analyzed. Data varied considerably in terms of saline solutions used, modality of application, participant numbers, study design, follow up and outcomes. Factors that appear to influence the acceptability and tolerability of NSD include parental and health professionals' preconceptions, and characteristics of the solution. CONCLUSIONS: Nasal saline douching appears to be effective, being accepted and tolerated in the majority of children (78-100%). NSD has a significant positive impact on the quality of life in children with allergic rhinitis. When used as an adjunctive treatment having mainly a cleansing property, NSD potentiates the effects and may reduce the dose required of AR medications. Among the principal factors that influence the acceptability and tolerability of NSD are the child's age, delivery system and method, and tonicity. Nasal saline douching provides an accessible, low cost, low morbidity, easy to use treatment in children with allergic rhinitis.

Reactive oxygen: A novel antimicrobial mechanism for targeting biofilm-associated infection.

Reactive oxygen species (ROS) is a novel therapeutic strategy for topical or local application to wounds, mucosa or internal structures where there may be heavy bacterial bioburden with biofilm and chronic inflammation. Bacterial biofilms are a significant problem in clinical settings owing to their increased tolerance towards conventionally prescribed antibiotics and their propensity for selection of further antibacterial resistance. There is therefore a pressing need for the development of alternative therapeutic strategies that can improve antibiotic efficacy towards biofilms. ROS has been successful in treating chronic wounds and in clearing multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and carbapenemase-producing isolates from wounds and vascular line sites. There is significant antifungal activity of ROS against planktonic and biofilm forms. Nebulised ROS has been evaluated in limited subjects to assess reductions in bioburden in chronically colonised respiratory tracts. The antibiofilm activity of ROS could have great implications for the treatment of a variety of persistent respiratory conditions. Use of ROS on internal prosthetic devices shows promise. A variety of novel delivery mechanisms are being developed to apply ROS activity to different anatomical sites.

A novel insight into the immunologic basis of chronic granulomatous invasive fungal rhinosinusitis.

BACKGROUND: Chronic granulomatous invasive fungal rhinosinusitis (CGIFRS) is a rare disease. The underlying immune responses that drive the development of CGIFRS, as opposed to successful pathogen clearance and controlled inflammation, are not currently known. OBJECTIVE: To characterize the immune responses associated with CGIFRS. METHODS: In addition to a battery of basic investigations, more in-depth immunologic testing involves ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with interleukin (IL) 12, was undertaken to investigate cell-mediated immune responses associated with CGIFRS. RESULTS: Ex vivo whole-blood stimulation with the polyclonal T-cell mitogen phytohemagglutinin and fungal antigens with IL-12 identified reduced interferon gamma and increased IL-17A levels within the supernatant, which indicated increased in vivo T-helper (Th)17 responses and impaired Th1 responses compared with healthy controls. CONCLUSION: These findings suggest that the development of CGIFRS may be associated with an abnormally exaggerated host Th17 response, which caused failure to clear the fungal pathogen with refractory fungal infection of mucosal membranes, resulting in chronic tissue inflammation.

Safety and tolerability profiles of intranasal antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis.

Intranasal corticosteroids and intranasal antihistamines are efficacious topical therapies in the treatment of allergic rhinitis. This review addresses their relative roles in the management of this disease, focusing on their safety and tolerability profiles. The intranasal route of administration delivers drug directly to the target organ, thereby minimising the potential for the systemic adverse effects that may be evident with oral therapy. Furthermore, the topical route of delivery enables the use of lower doses of medication. Such therapies, predominantly available as aqueous formulations following the ban of chlorofluorocarbon propellants, have minimal local adverse effects. Intranasal application of therapy can induce sneezing in the hyper-reactive nose, and transient local irritation has been described with certain formulations. Intranasal administration of corticosteroids is associated with minor nose bleeding in a small proportion of recipients. This effect has been attributed to the vasoconstrictor activity of the corticosteroid molecules, and is considered to account for the very rare occurrence of nasal septal perforation. Nasal biopsy studies do not show any detrimental structural effects within the nasal mucosa with long-term administration of intranasal corticosteroids. Much attention has focused on the systemic safety of intranasal application. When administered at standard recommended therapeutic dosage, the intranasal antihistamines do not cause significant sedation or impairment of psychomotor function, effects that would be evident when these agents are administered orally at a therapeutically relevant dosage. The systemic bioavailability of intranasal corticosteroids varies from <1% to up to 40-50% and influences the risk of systemic adverse effects. Because the dose delivered topically is small, this is not a major consideration, and extensive studies have not identified significant effects on the hypothalamic-pituitary-adrenal axis with continued treatment. A small effect on growth has been reported in one study in children receiving a standard dosage over 1 year, however. This has not been found in prospective studies with the intranasal corticosteroids that have low systemic bioavailability and therefore the judicious choice of intranasal formulation, particularly if there is concurrent corticosteroid inhalation for asthma, is prudent. There is no evidence that such considerations are relevant to shorter-term use, such as in intermittent or seasonal disease. Intranasal therapy, which represents a major mode of drug delivery in allergic rhinitis, thus has a very favourable benefit/risk ratio and is the preferred route of administration for corticosteroids in the treatment of this disease, as well as an important option for antihistaminic therapy, particularly if rapid symptom relief is required.

De novo papillary squamous carcinoma of the lacrimal sac.

We report a rare case of a papillary squamous carcinoma of the lacrimal sac diagnosed at first presentation. The initial presentation of the patient discussed here mimicked that of a lacrimal sac mucocele. This report highlights the clinicopathological characteristics of this tumour, as well as the multidisciplinary approach required in its management.

Traumatic fracture of the stapes suprastructure following minor head injury.

Traumatic fracture of the stapes occurs rarely following head injury. Ossicular dislocation is more commonly encountered. When present, stapes fractures are usually associated with an underlying temporal bone fracture. A higher incidence has been reported in childhood, possibly because of the greater flexibility of the skull in this age group. This report highlights the fact that these fractures can be associated with a relatively minor head injury. This possibility should be kept in mind when evaluating patients, especially children, who have a persistent conductive deafness of more than 30 dB with an intact tympanic membrane following any form of head injury. An exploratory tympanotomy with appropriate ossicular reconstruction, as described in this case, can yield excellent results.