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MicroRNAs are post-transcriptional regulators of gene expression that are differentially regulated during development and in inflammatory diseases. A role for miRNAs in allergic asthma is emerging and further investigation is required to determine whether they may serve as potential therapeutic targets. We profiled miRNA expression in murine lungs from an ovalbumin-induced allergic airways disease model, and compared expression to animals receiving dexamethasone treatment and non-allergic controls. Our analysis identified 29 miRNAs that were significantly altered during allergic inflammation. Target prediction analysis revealed novel genes with altered expression in allergic airways disease and suggests synergistic miRNA regulation of target mRNAs. To assess the impacts of one induced miRNA on pathology, we targeted miR-155-5p using a specific antagomir. Antagomir administration successfully reduced miR-155-5p expression with high specificity, but failed to alter the disease phenotype. Interestingly, further investigation revealed that antagomir delivery has variable efficacy across different immune cell types, effectively targeting myeloid cell populations, but exhibiting poor uptake in lymphocytes. Our findings demonstrate that antagomir-based targeting of miRNA function in the lung is highly specific, but highlights cell-specificity as a key limitation to be considered for antagomir-based strategies as therapeutics.

Background: Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells. Levels of IFN-γ and LPS are often increased in these patients. Cooperative signaling between IFN-γ/LPS induces macrophage-dependent steroid-resistant airway hyperresponsiveness (AHR) in mouse models. MicroRNAs (miRs) are small noncoding RNAs that regulate the function of innate immune cells by controlling mRNA stability and translation. Their role in regulating glucocorticoid responsiveness and AHR remains unexplored., Objective: IFN-γ and LPS synergistically increase the expression of miR-9 in macrophages and lung tissue, suggesting a role in the mechanisms of steroid resistance. Here we demonstrate the role of miR-9 in IFN-γ/LPS-induced inhibition of dexamethasone (DEX) signaling in macrophages and in induction of steroid-resistant AHR., Methods: MiRNA-9 expression was assessed by means of quantitative RT-PCR. Putative miR-9 targets were determined in silico and confirmed in luciferase reporter assays. miR-9 function was inhibited with sequence-specific antagomirs. The efficacy of DEX was assessed by quantifying glucocorticoid receptor (GR) cellular localization, protein phosphatase 2A (PP2A) activity, and AHR., Results: Exposure of pulmonary macrophages to IFN-γ/LPS synergistically induced miR-9 expression; reduced levels of its target transcript, protein phosphatase 2 regulatory subunit B (B56) δ isoform; attenuated PP2A activity; and inhibited DEX-induced GR nuclear translocation. Inhibition of miR-9 increased both PP2A activity and GR nuclear translocation in macrophages and restored steroid sensitivity in multiple models of steroid-resistant AHR. Pharmacologic activation of PP2A restored DEX efficacy and inhibited AHR. MiR-9 expression was increased in sputum of patients with neutrophilic but not those with eosinophilic asthma., Conclusion: MiR-9 regulates GR signaling and steroid-resistant AHR. Targeting miR-9 function might be a novel approach for the treatment of steroid-resistant asthma., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

MicroRNAs are small non-coding RNAs that bind to multiple target mRNAs to control gene expression post-transcriptionally by inhibiting translation. In mammalian cells, microRNAs play important roles in a diverse array of cellular processes (e.g. cell proliferation and differentiation). However, alterations in their levels may compromise cellular function, predisposing to disease. In this review, we discuss microRNAs that have been linked with pathogenesis of asthma and propose functional roles in the regulation of disease. MicroRNAs have the potential to be biomarkers for asthma and provide the platform for the development of new classes of therapeutic compounds.

Respiratory virus infections are often pathogenic, driving severe inflammatory responses. Most research has focused on localized effects of virus infection and inflammation. However, infection can induce broad-reaching, systemic changes that are only beginning to be characterized. In this study, we assessed the impact of acute pneumovirus infection in C57BL/6 mice on bone marrow hematopoiesis. We hypothesized that inflammatory cytokine production in the lung upregulates myeloid cell production in response to infection. We demonstrate a dramatic increase in the percentages of circulating myeloid cells, which is associated with pronounced elevations in inflammatory cytokines in serum (IFN-γ, IL-6, CCL2), bone (TNF-α), and lung tissue (TNF-α, IFN-γ, IL-6, CCL2, CCL3, G-CSF, osteopontin). Increased hematopoietic stem/progenitor cell percentages (Lineage(-)Sca-I(+)c-kit(+)) were also detected in the bone marrow. This increase was accompanied by an increase in the proportions of committed myeloid progenitors, as determined by colony-forming unit assays. However, no functional changes in hematopoietic stem cells occurred, as assessed by competitive bone marrow reconstitution. Systemic administration of neutralizing Abs to either TNF-α or IFN-γ blocked expansion of myeloid progenitors in the bone marrow and also limited virus clearance from the lung. These findings suggest that acute inflammatory cytokines drive production and differentiation of myeloid cells in the bone marrow by inducing differentiation of committed myeloid progenitors. Our findings provide insight into the mechanisms via which innate immune responses regulate myeloid cell progenitor numbers in response to acute respiratory virus infection., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Background: Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-γ (IFN-γ) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-γ and LPS (γ/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function., Methodology/principal Findings: OR expression in airway and pulmonary macrophages in response to IFN-γ, LPS or γ/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that γ/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of γ/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with γ/LPS alone. Supernatants from γ/LPS+octanal exposed macrophages also increased macrophage migration in vitro., Conclusions/significance: Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of γ/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration.

Chronic inflammatory diseases of the lung are leading causes of morbidity and mortality worldwide. Many of these disorders can be attributed to abnormal immune responses to environmental stimuli and infections. As such, understanding the innate host defense pathways and their regulatory systems will be critical to developing new approaches to treatment. In this regard, there is increasing interest in the role of microRNAs (miRNAs) in the regulation of pulmonary innate host defense responses and the inflammatory sequelae in respiratory disease. In this review, we discuss recent findings that indicate an important role for miRNAs in the regulation in mouse models of various respiratory diseases and in host defense against bacterial and viral infection. We also discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies and also as a means to improve pathogen clearance from the lung., (© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

The aim of tympanoplasty graft preparation is to stiffen the fascia or perichondrium and thereby to optimise ease of manipulation. We report 39 cases utilising a novel technique in which the graft is prepared in ear drops containing polyethylene glycol, flumetasone pivalate (0.02 per cent) and clioquinol (1 per cent). This technique is useful in reducing the risk of desiccation if placement is delayed, and may pose less risk of infection and mechanical damage than alternative methods.

The Oral Health Division, Ministry of Health in Malaysia piloted clinical pathways (cpath) in primary care in early 2003. This study investigated the knowledge, perception of cpaths and barriers faced by the clinicians involved in the pilot project. Self-administered questionnaires were sent to the clinicians (n=191). Dentists (67.9%) and dental nurses (70.6%) had good overall knowledge of cpaths. The majority of the clinicians (67.9% to 95.6%) perceived cpath positively in all areas. Only 9.2% of dentists encountered difficulties in using cpath forms compared to 28.4% of dental nurses. A higher proportion of dental nurses (73.5%) compared to dentists (64.8%) were willing to continue using cpath. The majority of dentists (76.7%) and dental nurses (73.1%) were willing to participate in future development of cpaths. Overall, there was evidence of managerial support for the pilot project. A follow-up of the pilot project was somewhat lacking as less than half (43.3%) of the clinicians reported that the state coordinator obtained feedback from them. The findings auger well for the future implementation of cpath should the Oral Health Division decide to adopt cpath routinely in the public oral health care service.

To assess the relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and spontaneous epistaxis in adults over 50 years old, a case control study was carried out by using a record linkage database for the population of Tayside, Scotland, which included 319,465 people. The study group consisted of 326 patients who were hospitalized with epistaxis between May 1989 and December 1992, but who had not previously been hospitalized with this diagnosis. Six community controls and 4 hospital controls, matched for age and sex to each case, were used. Previous exposure to prescribed aspirin and other NSAIDs was investigated. There was a significant association between aspirin exposure and epistaxis when either community or hospital controls were used (p < .001). Patients who had aspirin prescriptions had a relative risk of hospital admission for epistaxis of between 2.17 and 2.75, depending on the control group used. No association between non-aspirin NSAIDs and epistaxis was evident with either control group.

In vitro studies have suggested that beta 2-adrenergic agents increase the ciliary beat frequency in human respiratory epithelium. We carried out a randomized, double-blind placebo-controlled trial to investigate the effects of a topical spray, salmeterol, on nasal mucociliary clearance using the saccharin test. Thirty-three healthy adults were recruited. There was a 21% reduction of nasal mucociliary transport time of saccharin with salmeterol compared to placebo (P = 0.0001). There was no effect of age, sex, order of treatment, interval between spray and saccharin test, or history of seasonal allergic rhinitis on the improvement in clearance times.

The mobility of the malleus and incus was studied in two fresh human temporal bones. Various pressure gradients were applied across the intact tympanic membrane and the movement of the ossicles examined, firstly with the incus in situ and secondly, with the incus removed. The displacement of the long process of the incus was less than 100 microns at the extremes of pressure gradient. However, this mobility increased by over twofold when the posterior incudal ligament was divided. With removal of the incus, the mobility of the umbo with pressure changes was further increased and can be as much as half a millimetre. In all cases the maximal rate of ossicular excursion was noted with pressure gradients of less than 100 daPa (mmH2O) across the tympanic membrane.

A prospective randomized study was carried out to assess the post-tonsillectomy morbidity of the selective diathermy technique as opposed to the ligation technique. One hundred and five patients had one tonsillar fossa haemostasis secured by unipolar diathermy and the opposite side by ligation technique. There was significantly less pharyngeal pain on the diathermy side in the first post-operative day. However, there was no significant difference between the two sides, both in pharyngeal discomfort and otalgia for the rest of the post-operative period. There was no difference in the incidence of haemorrhage between the two techniques.

A case of recurrent epistaxis caused by bone wax in the nasal cavity is reported. This is the first reported case of a nasal complication due to surgical bone wax.

The outcome of initial surgical treatment in children with otitis media with effusion (OME) was analysed in a prospective study involving 225 new patients. The presence or absence of effusion in each ear and type of effusion present were recorded at surgery. The outcome measure studied was resolution or recurrence of middle ear effusions necessitating further surgical intervention. The outcome was significantly more favourable in children with unilateral effusions at surgery as opposed to bilateral effusions (P > 0.03) but was unrelated to the type of effusion (serous or mucoid). Patients with unilateral effusions at surgery appear to have a fluctuating form of OME in which effusions are present in either or both ears at different times.

A prospective study on the dynamics of tympanic membrane atelectasis during the treatment for glue ear was performed in a sample of 115 ears of 83 children aged between one and 11 years. The progression in the degree of pars tensa atelectasis was analysed in relation to six potentially relevant factors. Multivariate analysis showed that the factor with the most predictive value on the progression of the pars tensa retraction was the grade of atelectasis at initial detection (p < 0.0001). The use of grommets did not have any significant influence on the outcome grade of atelectasis. There was an association between previous grommet insertion and localized retractions in the inferior segment of the pars tensa (p < 0.0001). However, localized retractions in the postero-superior quadrant were not associated with previous grommet insertion (p < 0.02). Although the hearing thresholds of atelectatic ears were significantly worse than normal ears especially at 4 kHz (p < 0.006), the difference was less than 5 dB.

Cervical heterotopic salivary tissues are rare and are predominantly found in the anterior triangle of the neck especially at the anterior border of the sternocleidomastoid muscle. We report a case of pleomorphic adenoma arising in the left posterior triangle of the neck.

A prospective hearing survey was performed in a sample of 102 diabetic patients. The hearing data were compared with the hearing thresholds of three control population groups. A significant difference was found in the average hearing thresholds between the diabetic patients and all of the three control populations. Diabetic patients have worse hearing threshold levels especially at low and mid frequencies (P < 0.001). There was also a correlation between the duration of diabetes and hearing loss. No significant correlation was found between the different stages of diabetic retinopathy and the degree of hearing loss.

A prospective randomized study was carried out to assess the post-tonsillectomy morbidity of the electrodissection technique as opposed to the blunt dissection and ligation technique. One hundred and four patients, each serving as his or her own control, were randomized to have either the right or left tonsil removed by electrodissection. There was significantly less pharyngeal pain on the electrodissection side in the first post-operative day in adult patients. This, however, was transient as there was increased pharyngeal discomfort and otalgia, both in severity and duration, on the electrodissection side by the end of first week. There was no difference in the incidence of haemorrhage between the two techniques.

A prospective study of outcome after treatment for glue ear was performed in a sample of 143 children aged between 1 and 11 years. The resolution or recurrence of effusion following initial surgery was analysed in relation to six potentially relevant factors. Multivariate analysis showed that resolution of effusion was statistically more frequent in ears found to have a dry tap at surgery, children with a history of atopy, those who underwent adenoidectomy and it was related to the age of the child at operation. Older children had a better prognosis. Univariate analysis suggested that girls have a significantly better outcome than boys, but this was not confirmed in multivariate analysis. The results suggest that there should be a longer period of observation in atopic individuals and older children. Furthermore, the study showed that ears with dry taps should not be treated with ventilation tubes.

The hearing data from a sample of 73 children undergoing surgical treatment for chronic otitis media with effusion (OME) were analysed using a modification of the Glasgow Benefit Plot. All the patients had bilateral middle ear effusions confirmed at surgery. Using 20 dB average hearing level as the 'cutoff' point between normal and abnormal hearing, 65 (89 per cent) patients had binaural normal hearing, five (7 per cent) had monaural normal hearing and three (4 per cent) had bilateral hearing loss after surgery. However, 70 patients (96 per cent) were found to benefit from surgery. The cases with persistent hearing loss were re-examined to determine the cause of failure.

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology. Nasal sarcoidosis commonly affects the mucosa of the septum and the inferior turbinates. These patients may present with nasal discharge, crusting, obstruction, epistaxis or anosmia. We present an unusual case of nasal sarcoidosis involving the ethmoid sinus causing recurrent eyelid swelling and discuss its management.

A case of cervical glossopharyngeal schwannoma presenting with gagging dysphagia is presented. Treatment was by total excision of the schwannoma following which the patient made a good recovery. To our knowledge, this is the first report of gagging dysphagia associated with a glossopharyngeal schwannoma.

We report two cases of terminal duct carcinoma of the minor salivary glands. The histological features, biological behaviour, treatment and the long-term management are described.