Consensus criteria for chronic rhinosinusitis disease control: an international Delphi Study.

BACKGROUND: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. METHODS: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. RESULTS: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participants’ comments provided insights into caveats of, and disagreements related to, near-consensus items. CONCLUSIONS: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed.

The EUFOREA pocket guide for chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS.

Features of inhalant allergy on nasal endoscopy: a systematic review and meta-analysis.

BACKGROUND: Nasal endoscopy is increasingly accessible to ENT surgeons. The characteristics of the allergic upper airway are not well recognised. METHODOLOGY: MEDLINE (1946-2021), EMBASE (1974-2021), and the Cochrane Library were searched on 16th November 2021 to identify articles that reported endoscopic findings of patients with documented allergy who had undergone nasal endoscopy. The review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. Meta-analysis was performed by pooling sensitivities and specificities using the hierarchical summary receiver operating characteristics model. RESULTS: A total of 4108 articles were identified, of which 15 manuscripts met the inclusion criteria. The included studies involved 4660 patients who had undergone nasal endoscopy. Middle turbinate (diffuse/polypoid) oedema (sensitivity 58.0%, specificity 84.5%), watery secretions (sensitivity 65.7%, specificity 76.5%), inferior turbinate hypertrophy (sensitivity 86.2%, specificity 32.2%), and unspecified turbinate hypertrophy (sensitivity 82.0%, specificity 42.9%) were identified as the features with the highest predictive value of inhalant allergy. CONCLUSIONS: Diffuse or polypoid oedema of the middle turbinate or watery secretions seen on nasal endoscopy can be a useful adjunct in the identification and diagnosis of inhalant allergy. These clinical features should be part of the diagnostic workup for patients that includes a clinical history and surrogate markers of allergic sensitisation from the skin and serum.

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus).

Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta ; a.k.a. ticked), mackerel (Tm ; a.k.a. striped) and blotched (tb ; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby - Abyssinian (Ta ; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine-rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B.

Systemic medication requirement in post-surgical patients with eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (eCRS) is contemporarily managed by surgical creation of a 'neo-sinus' cavity and corticosteroid irrigations. While most patients gain control of their disease with this approach, similar to preventive inhaler therapy in asthma, some patients need systemic therapies. This study aimed to define those patients needing ongoing systemic therapy for eCRS. METHODS: Consecutive adult patients (>18 years) who were seen at a tertiary referral clinic, diagnosed as eCRS and underwent endoscopic sinus surgery were included. Patients were followed up for a minimum of 12 months. All patients had a simple neo- sinus cavity surgically created and used initially a once daily topical corticosteroid irrigation maintenance therapy. Patients who re- quired long term systemic oral corticosteroids and/or biologic therapy were compared to those who remained on topical control. RESULTS: 222 patients with eCRS were assessed (follow-up 2.76 years). Long term systemic therapy was required in 5.4% of pa- tients. Receiver operating curve analysis predicted local treatment failure at an eosinophil count cut-off level 0.455x109/L. Asthma, atopy and aspirin sensitivity also predicted long term systemic therapy. There were no associations with nasal polyposis or revi- sion surgery. Multivariate logistic regression showed elevated blood eosinophil count >0.455 x109/L was 9.27 times more likely to require for systemic medication. CONCLUSION: Pre-operative blood eosinophil count >0.45 x109/L was associated with failure of local therapy following contem- porary management of eCRS. The quantitative value of serum eosinophilia may be a useful predictor of disease progression and those patients in need of systemic therapies, such as biologic agents.

European Position Paper on Rhinosinusitis and Nasal Polyps 2020.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

Characteristics of macrolide responders in persistent post-surgical rhinosinusitis.

INTRODUCTION: The anti-inflammatory effects of long term low dose macrolide therapy have shown benefit in the management of diffuse panbronchiolitis. Dramatic responses to macrolide in the upper airway are seen but our understanding of the patient phenotype predisposing to macrolide response in chronic rhinosinusitis (CRS) is poor. METHODS: A case control study was performed in a tertiary level rhinology practice of consecutive chronic rhinosinusitis patients placed on a 3-month low dose macrolide therapy after failing at least 3 months of corticosteroid irrigation therapy post-endoscopic sinus surgery. Patients were defined as a macrolide responder when having near normal endoscopy after a 3-month period of clarithromycin treatment. Patient characteristics of smoking, asthma, atopy status, revision surgery, symptom severity (SNOT-22) along with biomarkers from serum and tissue histopathology results were compared between groups. RESULTS: Of twenty-eight consecutive macrolide treated patients, 19 responders were compared to 9 non-responders. The groups were similar in age, female gender, non-smoking, asthma, and atopy. Macrolide response was associated with a lack of tissue eosinophilia (more than 10/HPF) and lower serum eosinophilia. Neutrophil expression was similar in tissue and serum. Squamous metaplasia was overexpressed in non-responders. CONCLUSION: Low tissue and serum eosinophilia, and absence of tissue squamous metaplasia may predict a CRS phenotype suitable to a trial of long-term macrolide therapy when surgery and topical therapy has failed.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis.

BACKGROUND: Extra-oral bitter taste receptors have been associated with innate bacterial defence mechanisms. Genetic variation in T2R38 functionality has been shown to be associated with susceptibility to upper respiratory tract infections and chronic rhinosinusitis (CRS). We sought to independently assess the influence of bitter taste receptor genotype on the presence of culturable bacteria in the sinuses. METHODOLOGY: A cross-sectional analysis of patients with CRS undergoing surgery was performed. Middle meatal nasal swabs were sent for microbiological evaluation at the time of the procedure. Mucosal biopsies were taken and sent for bitter taste receptor genotype analysis. Sequencing of 3 polymorphisms in the TAS2R38 gene was performed to identify genotypes as super-tasters (PAV/PAV), non-tasters (AVI/AVI) or heterozygous expression (PAV/AVI). The presence of culturable organisms and common pathogens were compared with bitter taste receptor genotypes. RESULTS: 25 patients (age 52.4 +/- 18.28 years, 51% female) were assessed. Super-tasters comprised 16% of the group, 24% were non-tasters and 48% had heterozygous expression. A cultured pathogen was grown in 48% of patients; 32% gram-positive, 20% gram-negative, 28% grew Staphylococcus aureus and 12% Pseudomonas aeruginosa. A non-taster genotype was predictive of colonised pathogens. Tissue eosinophilia (more than 10 HPF) was seen in 48%. CONCLUSION: Even in a small sample of patients with CRS, non-taster T2R38 genotype appears to predict the presence of culturable bacteria colonising the sinus cavity at the time of surgery for their condition. A genetic link to patients more likely to become infected is likely.

Airflow and symptom outcomes between allergic and non-allergic rhinitis patients from turbinoplasty.

BACKGROUND: Inferior turbinate procedures are applied to relieve medically refractory nasal obstruction. However, the nature of congestion differs between allergic(AR) and non-allergic rhinitis(NAR). This study compares surgical outcomes between AR and NAR patients. METHODOLOGY: A case-control study of patients undergoing turbinate with or without septoplasty surgery for nasal obstruction was performed. Patient reported outcomes were: nasal obstruction, global nasal function(GNF), and sino-nasal outcome test(SNOT-22) with rhinitis, facial symptom, sleep and psychological sub-scores. Nasal peak inspiratory flow(NPIF) assessed nasal airflow. Measurements were obtained preoperatively and 3 months postoperatively. RESULTS: 190 patients were assessed. AR had worse obstruction and worse GNF. All outcomes improved post-surgery; nasal obstruction, GNF, SNOT-22, rhinitis-symptoms, facial-symptoms, sleep-function, psychological-function and NPIF. GNF improvement was greater in AR. NPIF improvement was similar between groups. CONCLUSIONS: Both AR and NAR patients gained benefit from surgery to relieve nasal obstruction. AR patients demonstrate greater improvement in GNF score but allergy management may contribute to this.

Association of gastro-oesophageal reflux and chronic rhinosinusitis: systematic review and meta-analysis.

INTRODUCTION: Gastro-oesophageal reflux disease (GORD) has been implicated in the development of chronic rhinosinusitis (CRS). The association of GORD with CRS is systematically assessed from the medical literature. METHODOLOGY: Embase and MEDLINE were searched using a comprehensive strategy limited to English language and Human subjects. Any study with original data on the experimental, diagnostic, treatment or prognostic association of CRS with GORD was included. Studies without a control group, case reports and review articles were excluded. RESULTS: The search returned 958 records, with an additional 10 found from bibliographic lists; this produced 32 studies. The included studies (n=32) consisted of studies reporting pathogenic factors (n=20), epidemiological association (n=8), prognostic interactions (n=3), and a combination of these outcomes (n=1). Potential pathogenic roles for GORD in CRS were supported; CRS subjects had greater prevalence of intranasal Helicobacter pylori and acid reflux than subjects without CRS. CRS is more prevalent in GORD sufferers than those without GORD. Evidence is conflicting for GORD as a factor in CRS treatment failure. CONCLUSION: The results support a significant association of GORD with CRS. Physicians should be cognizant of the potential for acid and non-acid reflux as a driving factor in CRS.

Periostin as a marker of mucosal remodelling in chronic rhinosinusitis.

BACKGROUND: Although extracellular matrix (ECM) proteins are associated with irreversible lower airway changes, the relationship with upper airway remodelling which occurs during chronic rhinosinusitis (CRS) is poorly understood. This study assessed the expression of ECM proteins periostin, fibulin-1, fibronectin and collagenIV in nasal mucosa of patients with and without histologic features of remodelling. METHODS: A cross-sectional study of sinonasal mucosal biopsies taken from patients, undergoing surgery for CRS was performed, where patients were grouped according to remodelling, defined by basement membrane thickening (BMT over 7.5 micrometer) and subepithelial fibrosis. An overall view and three random fields of immunostained tissue sections that included epithelium, basement membrane and submucosa, were imaged using Zeiss Zen software. The area and intensity of positive staining were scored by two blinded observers, using a 12-point ordinal scale of weak to strong. RESULTS: 65 patients (47.6 +/- 13.4years, 44.6% female) were assessed. Patients were grouped as controls 26.2%, BMT/no fibrosis 38.5% or BMT and fibrosis 33.8%. Stronger grade of periostin expression was associated with remodelling changes and tissue eosinophilia over 10/HPF. Fibulin-1, fibronectin and collagenIV did not differ. CONCLUSION: Periostin expression was associated with the presence of BMT, fibrosis and tissue eosinophilia and may identify patients undergoing remodelling changes.

Group 2 innate lymphoid cells (ILC2s) are increased in chronic rhinosinusitis with nasal polyps or eosinophilia.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease with an uncertain pathogenesis. Group 2 innate lymphoid cells (ILC2s) represent a recently discovered cell population which has been implicated in driving Th2 inflammation in CRS; however, their relationship with clinical disease characteristics has yet to be investigated. OBJECTIVE: The aim of this study was to identify ILC2s in sinus mucosa in patients with CRS and controls and compare ILC2s across characteristics of disease. METHODS: A cross-sectional study of patients with CRS undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies were obtained during surgery and control tissue from patients undergoing pituitary tumour resection through transphenoidal approach. ILC2s were identified as CD45(+) Lin(-) CD127(+) CD4(-) CD8(-) CRTH2(CD294)(+) CD161(+) cells in single cell suspensions through flow cytometry. ILC2 frequencies, measured as a percentage of CD45(+) cells, were compared across CRS phenotype, endotype, inflammatory CRS subtype and other disease characteristics including blood eosinophils, serum IgE, asthma status and nasal symptom score. RESULTS: 35 patients (40% female, age 48 ± 17 years) including 13 with eosinophilic CRS (eCRS), 13 with non-eCRS and 9 controls were recruited. ILC2 frequencies were associated with the presence of nasal polyps (P = 0.002) as well as high tissue eosinophilia (P = 0.004) and eosinophil-dominant CRS (P = 0.001) (Mann-Whitney U). They were also associated with increased blood eosinophilia (P = 0.005). There were no significant associations found between ILC2s and serum total IgE and allergic disease. In the CRS with nasal polyps (CRSwNP) population, ILC2s were increased in patients with co-existing asthma (P = 0.03). ILC2s were also correlated with worsening nasal symptom score in CRS (P = 0.04). CONCLUSION AND CLINICAL RELEVANCE: As ILC2s are elevated in patients with CRSwNP, they may drive nasal polyp formation in CRS. ILC2s are also linked with high tissue and blood eosinophilia and have a potential role in the activation and survival of eosinophils during the Th2 immune response. The association of innate lymphoid cells in CRS provides insights into its pathogenesis.

Simulated postnasal mucus fails to reproduce the symptoms of postnasal drip in rhinitics but only in healthy subjects.

BACKGROUND: Post nasal drip (PND) is a very common symptom associated with upper respiratory tract disorders. While easy to visualize, the concept of PND due to an increased volume of secretions which move from the posterior nasal choanae into the posterior nasopharynx/oropharynx may be overly simplistic. PND could also be associated with altered viscosity of nasal secretions. An alternative hypothesis is that the sensation of PND is due to mucosal inflammation resulting in heightened cough or irritant throat sensory dysfunction. The impact of viscous secretions on the symptoms of PND is assessed. METHODS: Healthy subjects and rhinitis patients were recruited. Patients were asked about PND symptoms with a 9 item PNDSS questionnaire at baseline and after the insertion of two different viscosities of artificial mucus utilizing hydroxypropyl methylcellulose at 1% and 4%. RESULTS: Sixty six patients were recruited. As expected, rhinitics had an increased sense of PND compared to healthy subjects at baseline. However, only healthy subjects could detect the increased viscosity of secretions and where rhinitics failed to respond. Cough was not induced in either group. CONCLUSION: The mechanisms of PND in chronic patients and those with rhinitis are likely to have other aetiologies other than simply increased or more viscous secretions.

Modified Lund Mackay Postoperative Endoscopy Score for defining inflammatory burden in chronic rhinosinusitis.

OBJECTIVE: The Lund Mackay Postoperative Endoscopy Score (LMES) for chronic rhinosinusitis (CRS) is a poor measure of the patient experience. A proposed Modified Lund Mackay Postoperative Endoscopy Score (MLMES) aims to better describe the inflammatory burden in CRS. METHODS: A prospective study on CRS patients having endoscopic sinus surgery (ESS) was conducted. Endoscopy was recorded at the 6th and the 12th week post-op. The MLMES recorded changes in mucosa, mucus and purulence for each of the maxillary, ethmoid, sphenoid, frontal sinuses and olfactory fossa in post-ESS cavities. The correlation between MLMES and visual analogue scale of total rhinosinusitis symptoms, global anchor score of nasal function, Sino-Nasal Outcome Test 22 (SNOT-22) and nasal symptom score was analyzed. The inter-observer reliability, intra-observer reliability and correlation between the change in MLMES and in subjective measures were also investigated. RESULTS: Thirty patients were assessed. The MLMES significantly correlated with visual analogue scale, SNOT-22, global anchor and nasal symptom score. The change in MLMES correlated with the change in SNOT-22 and nasal symptom score. The inter-observer and intra-observer reliability were excellent. CONCLUSION: Objectives measurements for post-ESS patients can be reconsidered to represent the cumulative inflammatory burden of all sinuses. The proposed MLMES represents total sinus inflammatory burden and correlates well with patient reported outcome measures.

Identification of congenital muscular dystonia 2 associated with an inherited GlyT2 defect in Belgian Blue cattle from the United Kingdom.

Two newborn Belgian Blue calves from a farm in the United Kingdom exhibited lateral recumbency, low head carriage and transient muscle spasms following tactile or auditory stimulation. DNA sequence analysis indicated that both calves were homozygous for the recessive congenital muscular dystonia type 2 (CMD2) mutation (c.809T>C, p.Leu270Pro) in SLC6A5, encoding the neuronal glycine transporter GlyT2. Further testing of animals from the index farm and a sample of Belgian Blue sires revealed an unexpectedly high frequency of CMD2 carriers. This implies that linked quantitative trait loci may be influencing the prevalence of CMD2 in the estimated 55,000 Belgian Blue cattle in the United Kingdom. We have therefore developed new inexpensive tests for the CMD2 allele that can be used to confirm diagnosis, identify carriers and guide future breeding strategy, thus avoiding animal distress/premature death and minimizing the future economic impact of this disorder.

Osteitic bone: a surrogate marker of eosinophilia in chronic rhinosinusitis.

BACKGROUND: Causes of osteitis in chronic rhinosinusitis (CRS) other than previous surgery are poorly defined. Patients with eosinophilic CRS (ECRS) have more severe disease and poorer outcomes despite repeated surgery. Associations between osteitis and markers of ECRS are not well described. METHODS: A cross-sectional study of CRS patients undergoing sinus surgery was conducted. Osteitis was scored radiologically using previously published measures. Associations between osteitis and histopathology, symptoms, endoscopy, CT mucosal score and seromarkers were analyzed. RESULTS: Eighty-eight patients were assessed of whom forty-five had osteitis. Patients undergoing revision surgery recorded higher osteitis scores. Patients with mucosal eosinophilia had higher osteitis score than those without. Patients with osteitis had higher serum eosinophil. Similar relationships were also found in primary surgery. Osteitis was associated with endoscopic and radiologic, but not symptomatic disease severity. CONCLUSIONS: Osteitis is associated with tissue and serum eosinophilia in both patients with and without prior surgery. Patients with these features may benefit from post-operative corticosteroid therapy to prevent osteitis.

Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial.

BACKGROUND: In persistent chronic rhinosinusitis (CRS), conventional treatment is often insufficient. Long-term, low-dose administration of macrolides has been suggested as a treatment option. The MACS (Macrolides in chronic rhinosinusitis) study is a randomized placebo-controlled trial evaluating the efficacy of azithromycin (AZM) in CRS. METHODS: We describe a group of patients with recalcitrant CRS with and without nasal polyps unresponsive to optimal medical and (in 92% also) surgical treatment. Patients were treated with AZM or placebo. AZM was given for 3 days at 500 mg during the first week, followed by 500 mg per week for the next 11 weeks. Patients were monitored until 3 months post-therapy. The assessments included Sino-Nasal Outcome Test-22 (SNOT-22), a Patient Response Rating Scale, Visual Analogue Scale (VAS), Short Form-36 (SF-36), rigid nasal endoscopy, peak nasal inspiratory flow (PNIF), Sniffin' Sticks smell tests and endoscopically guided middle meatus cultures. RESULTS: Sixty patients with a median age of 49 years were included. Fifty per cent had asthma and 58% had undergone revision sinus surgery. In the SNOT-22, Patient Response Rating Scale, VAS scores and SF-36, no significant difference between the AZM and the placebo groups was demonstrated. Nasal endoscopic findings, PNIF results, smell tests and microbiology showed no relevant significant differences between the groups either. CONCLUSION: At the investigated dose of AZM over 3 months, no significant benefit was found over placebo. Possible reasons could be disease severity in the investigated group, under-dosage of AZM and under-powering of the study. Therefore, more research is urgently required.

[Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: a new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia]. / Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3: Ein neuer molekularer Mechanismus der Atmungskontrolle zur Kompensation opioidinduzierter Atemdepression ohne Verlust der Analgesie.

To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor α3. The specific activation of serotonin receptor type 1A (5-HTR(1A)), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type α3 (GlyRα3). This 5-HTR(1A)-GlyRα3 signal pathway is independent of the µ-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyRα3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR(1A)-GlyRα3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.

Plasticity of synaptic inhibition in mouse spinal cord lamina II neurons during early postnatal development and after inactivation of the glycine receptor alpha3 subunit gene.

Synaptic inhibition mediated by GABA(A) receptors and glycine receptors (GlyRs) in the outer laminae of the spinal cord dorsal horn efficiently filters ascending nociceptive messages, controlling pathological pain symptoms. However, although many studies have utilized transgenic models to study spinal nociceptive processing, very little is known about the development of functional inhibitory synapses onto these interneurons in mice. Here we report that most interneurons in lamina II are placed under phasic control by both GABAergic and glycinergic synapses, a number of which exhibit dual GABA/glycine co-release. A developmental switch is also apparent: a subpopulation of lamina II interneurons controlled exclusively by either GABAergic or glycinergic synapses becomes detectable only after postnatal days 15 and 21, respectively. Using mice older than postnatal day 21, we also characterized the plastic changes in glycinergic transmission resulting from the inactivation of the GlyR alpha3 subunit gene, a key player in inflammatory pain pathways. This allowed us to demonstrate that synapses containing GlyR alpha3 contribute in large part to synaptic inhibition in lamina II. In Glra3 knockout mice, we found that synaptic currents at the remaining glycinergic synapses, containing GlyR alpha1, showed faster decay kinetics with unchanged amplitudes but increased frequency. These findings explain the absence of any basal nociceptive hypersensitivity in Glra3 knockout mice, as GlyR alpha1 is still available for mediating synaptic inhibition at lamina II synapses, but cannot be modulated by the prostaglandin-E-prostanoid type 2 (EP2) receptor-protein kinase A signalling cascade. Our results clearly demonstrate that presynaptic GABA/glycine release properties are influenced by the nature and complexity of postsynaptic inhibitory receptor subtypes.