Airway cell involvement in intermittent hypoxia-induced airway inflammation.

PURPOSE: Respiratory inflammation has been described in patients with obstructive sleep apnea syndrome, but it is unknown whether the increased neutrophil and interleukin (IL)-8 levels observed in induced sputum reflect systemic or local airway inflammation. We assessed the potential role of resident cells in intermittent hypoxia-induced airway inflammation. METHODS: Airway epithelial cells (AEC) and bronchial smooth muscle cells (BSMC) were exposed to intermittent hypoxia (IH) in vitro. Cell supernatants were assessed for matrix metalloproteinase, growth factor, and cytokine expression. The role of IH on neutrophil and BSMC migration capacities was evaluated, and the effect of supernatants from IH-exposed or control AEC was tested. RESULTS: Compared to normoxic conditions, 24 h of exposure to IH induced a significant increase of MMP-9 and MMP-2 expression and pro-MMP-9 activation (p < 0.05), and IL-8 (p < 0.05), platelet-derived growth factor (PDGF)-AA (p < 0.05), and vascular endothelial growth factor (VEGF) (p < 0.05) expression by AEC and VEGF expression (p = 0.04) by BSMC. Neutrophil chemotaxis and BSMC migration were enhanced by IH and supernatants of IH-exposed AEC (112.00 ± 4.80 versus 0.69 ± 0.43 %, p = 0.0053 and 247 ± 76 versus 21 ± 23, p = 0.009 respectively). This enhanced BSMC migration was totally abolished in the presence of an antibody blocking PDGF-AA. CONCLUSIONS: These data suggest a specific inflammatory response of airway cells to IH, independently of systemic events.

Surgery for chronic rhinosinusitis with nasal polyps: An update.

This update aimed to evaluate surgical indications in the management of chronic rhinosinusitis with nasal polyps (CRSwNP). It was conducted and reported according to the criteria stipulated by the Synthesis Without Meta-analysis (SwiM) guidelines. From the PubMed-National Library of Medicine database, 1098 articles were identified for the period 2006-2021 using the key words "nasal polyps" and "surgery". After screening and analysis, 39 publications were selected. The efficacy of surgery on functional improvement in CRSwNP, measured by the specific quality-of-life score SNOT-22, is established, and improvement in olfactory function is expected in 50% of patients. The rate of surgical revision is at least 10-15% at 4 years, but the disease can be controlled for several years, with the interval between primary surgery and symptomatic recurrence exceeding 10 years in some cases. The criteria for surgery are not clearly defined in the literature. However, several authors consider failure of ≥ 8 weeks' well-conducted local medical treatment and use of more than 2 courses of systemic corticosteroids as a reliable indication. No studies or meta-analyses are currently available to determine the superiority of one surgical technique over another.

French health insurance data for chronic rhinosinusitis with nasal polyps between 2011 and 2018: A STROBE-compliant analysis.

AIMS: The main aim of the present study was to report the annual volume of surgeries performed for chronic rhinosinusitis with nasal polyps (CRSwNP) in France, based on health insurance data. The secondary objectives were to describe the different characteristics of the surgeries and their complications, and to estimate the number of patients eligible for biotherapy. MATERIAL AND METHODS: This was a descriptive observational retrospective study using data from French national health insurance databases for the period 2011-2018. Inclusion criteria comprised all hospital stays with procedures related to CRSwNP according to the French Common Classification of Medical Acts and consistent with French practices. RESULTS: Ninety-two thousand one hundred and fourty one patients (92,141) for 92,884 admissions for CRSwNP surgery were analyzed, providing an accurate representation of CRSwNP surgery in France between 2011 and 2018. The revision surgery rate for patients operated on in 2011 was 13.0% (1,457/11,212), corresponding to an average annual rate of 1.86% over 7 years. In the 11,750 sinus surgery admissions in 2018, the complications rate was only 0.65% (77/11,750). CONCLUSION: Sinus surgery is safe (0.65% complications) and reliable (estimated revision rate, 5.5%: 5,078/92,884). This study provides the first evaluation of the target population for biotherapy in France.

Oxidative stress induces unfolding protein response and inflammation in nasal polyposis.

BACKGROUND: Nasal polyposis, a chronic inflammatory disease affecting the upper airways, is a valuable and accessible model to investigate the mechanisms underlying chronic inflammation. The main objective of this study was to investigate a potential involvement of the unfolded protein response (UPR) in the context of oxidative stress and inflammation in nasal epithelial cells from nasal polyps (NP). METHODS: Epithelial cells from NP (n = 20) and normal mucosa (Controls, n = 15) in primary culture were analyzed by global proteomic approach and cell biology techniques for the glucose-regulated protein 78 (GRP78), the spliced X-box-binding protein 1 (sXBP-1), the glucose-regulated protein 94 (GRP94), and the calreticulin (immunoblot, mass spectrometry, immunocytochemistry). RESULTS: Proteomics analysis of human nasal epithelial cells in culture revealed the activation of the unfolded protein response in NP. Systematic cell biology and biochemical analysis of two markers (GRP78, sXBP-1) in the presence and absence of oxidative stress in NP showed a susceptibility of the unfolded protein response to oxidative stress compared to controls at least partially linked to an abnormal redox state of the protein disulfide-isomerase 4. This unfolded protein response was correlated with mitochondrial depolarization and secretion of interleukin 8 (IL-8) and leukotriene B4 (LTB4) and was prevented by mitochondrial antioxidant. CONCLUSIONS: We show the existence of UPR in nasal epithelial cells that is linked to oxidative stress leading to IL-8 and LTB4 secretions. These mechanisms may participate in chronic inflammation in nasal polyposis.

Sinus fungal balls: characteristics and management in patients with host factors for invasive infection.

BACKGROUND: The characteristics of sinus fungal ball (SFB), classically considered being a non-invasive form of fungal infection, in patients with host factors for invasive fungal infection (IFI) are unknown. OBJECTIVE: To characterize SFB and their management in patients with host factors for IFI. METHODOLOGY: Retrospective single-centre study of the clinical, radiology, histology and mycology records of patients treated for SFB between 1997 and 2007. Patients with and without host factors for IFI were compared. RESULTS: One hundred eighty one patients were classified into two groups: 19 (group 1) with and 162 (group 2) without host fac- tors for IFI. In group 1, SFB were asymptomatic in 26.3% of the cases, ethmoido-sphenoidal sinuses were more frequently involved than in group 2 and fungal culture was positive in 37.5% of the cases. The main species was Aspergillus sp. in both groups. Four cases of complicated SFB were observed, only in patients of group 1. Cure without recurrence was obtained in both groups by endonasal surgery, combined with triazole therapy in complicated forms with osteolysis. CONCLUSION: In patients with host factors for IFI, SFB more frequently involves deep sinuses and can be complicated by clinical signs suggestive of invasion and radiological signs of osteolysis, with no histological evidence of fungal invasion.

Prevalence and Characteristics of Altered Sense of Smell/Taste During Covid-19 first wave: A French Nationwide Cross-sectional Study.

AIM: Altered sense of smell and/or taste is a leading symptom of SARS-CoV-2 infection, but its prevalence at a population-level is unknown. METHODS: From a questionnaire addressed to a representative subset of the French general adult (≥18-year) population over a 6-week period during the first French lockdown (April 7 to May 19 2020), self-reported new cases of altered sense of smell and/or taste were collected. RESULTS: From 29,660 participants, new altered sense of smell and/or taste was 2.18% and 2.11% after direct standardization on the French population representing more than 1,110,000 subjects in France. Moreover, 0.5% of participants reported a positive SARS-CoV-2 test, among which 47.4% reported a newly altered sense of smell and/or taste. Male participants, younger ones together with those presenting with chronic condition had higher odds of reporting a newly altered sense of smell and/or taste. CONCLUSION: This study provides an accurate estimate of new cases of altered sense of smell and/or taste in the general population at a nationwide level during the Covid-19 first wave.

Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations.

BACKGROUND: Leber congenital amaurosis (LCA) is the earliest and most severe inherited retinal degeneration. Isolated forms of LCA frequently result from mutation of the CEP290 gene which is expressed in various ciliated tissues. METHODS: Seven LCA patients with CEP290 mutations were investigated to study otorhinolaryngologic phenotype and respiratory cilia. Nasal biopsies and brushing were performed to study cilia ultrastructure using transmission electron microscopy and ciliary beating using high-speed videomicroscopy, respectively. CEP290 expression in normal nasal epithelium was studied using real-time RT-PCR. RESULTS: When electron microscopy was feasible (5/7), high levels of respiratory cilia defects were detected. The main defects concerned dynein arms, central complex and/or peripheral microtubules. All patients had a rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in the neural retina and nasal epithelial cells compared with other tissues. DISCUSSION: These data provide the first clear demonstration of respiratory cilia ultrastructural defects in LCA patients with CEP290 mutations. The frequency of these findings in LCA patients along with the high expression of CEP290 in nasal epithelium suggest that CEP290 has an important role in the proper development of both the respiratory ciliary structures and the connecting cilia of photoreceptors. The presence of respiratory symptoms in patients could represent additional clinical criteria to direct CEP290 genotyping of patients affected with the genetically heterogeneous cone-rod dystrophy subtype of LCA.

Bug22p, a conserved centrosomal/ciliary protein also present in higher plants, is required for an effective ciliary stroke in Paramecium.

Centrioles, cilia, and flagella are ancestral conserved organelles of eukaryotic cells. Among the proteins identified in the proteomics of ciliary proteins in Paramecium, we focus here on a protein, Bug22p, previously detected by cilia and basal-body high-throughput studies but never analyzed per se. Remarkably, this protein is also present in plants, which lack centrioles and cilia. Bug22p sequence alignments revealed consensus positions that distinguish species with centrioles/cilia from plants. In Paramecium, antibody and green fluorescent protein (GFP) fusion labeling localized Bug22p in basal bodies and cilia, and electron microscopy immunolabeling refined the localization to the terminal plate of the basal bodies, the transition zone, and spots along the axoneme, preferentially between the membrane and the microtubules. RNA interference (RNAi) depletion of Bug22p provoked a strong decrease in swimming speed, followed by cell death after a few days. High-speed video microscopy and morphological analysis of Bug22p-depleted cells showed that the protein plays an important role in the efficiency of ciliary movement by participating in the stroke shape and rigidity of cilia. The defects in cell swimming and growth provoked by RNAi can be complemented by expression of human Bug22p. This is the first reported case of complementation by a human gene in a ciliate.

A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia.

Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results. TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%). TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD). In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin.

Consensus statement. Corticosteroid therapy in ENT in the context of the COVID-19 pandemic.

This consensus statement about the indications and modalities of corticosteroid treatment in the context of the COVID-19 pandemic was jointly written by experts from the French Association of Otology and Oto-Neurology (AFON) and from the French Society of Otorhinolaryngology, Head and Neck Surgery (SFORL). There is currently not enough data in favour of danger or benefit from corticosteroids in COVID-19, so until this matter is resolved it is advisable to limit their indications to the most serious clinical pictures for which it is well established that this type of treatment has a positive impact on the progression of symptoms. In Grade V and VI Bell's palsy according to the House-Brackmann grading system, a week's course of oral corticosteroids is recommended. Corticosteroid therapy is also recommended in cases of sudden hearing loss of more than 60dB, either in the form of intratympanic injections or a week's course of oral medication. In rhinology, there is no indication for systemic corticosteroid therapy in the current situation. However, patients are advised to continue with their local corticosteroid therapy in the form of a nasal spray or by inhalation. Treatments with corticosteroid nasal sprays can still be prescribed if there is no alternative. Finally, systemic or local corticosteroid therapy is not indicated for bacterial ENT infections.

COVID-19 and rhinology, from the consultation room to the operating theatre.

The purpose of this article is to give rhinologists advice on how to adapt their standard practice during the COVID-19 pandemic. The main goal of these recommendations is to protect healthcare workers against COVID-19 while continuing to provide emergency care so as to prevent loss of chance for patients. We reviewed our recommendations concerning consultations, medical prescriptions and surgical activity in rhinology.

French Otorhinolaryngology Society (SFORL) good practice guidelines for dental implant surgery close to the maxillary sinus.

OBJECTIVES: To draw up guidelines for ENT management associated with dental implant surgery with or without sinus lift. MATERIALS AND METHODS: The methodology followed the rules of laid down by the French Health Authority (HAS): "Methodological bases for drawing up professional recommendations by formalized consensus". The chosen method was the RAND/UCLA "RAND appropriateness method" (short version). RESULTS: In the pre-implantation check-up, it is recommended to systematically screen for sinonasal pathology on medical interview and to favor 3D CT or cone-beam imaging. It is recommended that imaging include the entire maxillary sinus when the patient does not have sinonasal history or functional signs on interview. Otherwise, examination of all sinonasal cavities is recommended. This attitude enables simultaneous analysis of maxillary infrastructure for pre-implantation work-up and assessment of sinonasal cavity status. Sinus mucosal incidentalomas are very common in the healthy population and must be assessed with reference to the clinical, endoscopic and radiological context. CONCLUSION: This formalized expert consensus establishes a common base of knowledge, to clarify the issues and clinical situations and to standardize practices.

Unilateral recurrent laryngeal nerve palsy post-thyroidectomy: Looking for hyperventilation syndrome.

AIMS: Unilateral Recurrent Laryngeal Nerve (RLN) palsy is responsible for dysphonia and difficulties in swallowing. The role of unilateral RLN palsy on dyspnea is not fully elucidated. Our hypothesis is that air leak could be responsible for development of hyperventilation syndrome (HVS). OBJECTIVE: The objective of this study was to determine in patients with unilateral RLN palsy if dyspnea could be associated with HVS. MATERIAL AND METHODS: Over a 12-month period, all patients with permanent unilateral RLN palsy after thyroidectomy complaining from the onset of unexplained dyspnea were tested. Measurement of Nijmegen score, an hyperventilation test, an arterial blood gas, lung function and cardiac tests were performed. The diagnosis of HVS was defined if at least two criteria were present among: Nijmegen score>23; reproduction of at least 2 usual symptoms during hyperventilation test; an expirated pressure of CO2 (EpCO2)<30mmHg or<90% of the initial EpCO2 after a 5minutes recovery period following a 3minutes voluntary hyperventilation. RESULTS: Ten out of 366 patients with thyroidectomy for benign disease had permanent unilateral RLN palsy and dyspnea. Among 10 patients included, 8 were diagnosed having HVS on the hyperventilation test without cardiac/lung dysfunction. CONCLUSION: In summary, this study is a proof of concept that HVS might be involved in dyspnea associated with unilateral RLN palsy.

Childhood granular cell tumors: two case reports.

Granular cell tumors (GCT), also known as Abrikossoff tumors, are rare tumors found largely in children, with few reports of laryngo-tracheal involvement. Two childhood cases of laryngo-tracheal GCT are reported here, of which one case had multifocal lesions. The histopathological features and the therapeutic management of GCT are also discussed.

Alkylation of prohibitin by cyclohexylphenyl-chloroethyl urea on an aspartyl residue is associated with cell cycle G(1) arrest in B16 cells.

BACKGROUND AND PURPOSE: Phenyl-chloroethyl ureas (CEUs) are a class of anticancer drugs that mainly react with proteins. Two molecules of this family, cyclohexylphenyl-chloroethyl urea (CCEU) and iodophenyl-chloroethyl urea (ICEU) induced G(1)/S and G(2)/M cell cycle blocks, respectively. We hypothesised that these observations were linked to a differential protein alkylation pattern. EXPERIMENTAL APPROACH: Proteins from B16 cells incubated with [(14)C-urea]-CCEU and [(125)I]-ICEU were compared by 2D-analyses followed by MALDI-TOF identification of modified proteins and characterisation of the CCEU binding. Protein expression was investigated by Western blot analyses and cell cycle data were obtained by flow cytometry. KEY RESULTS: Several proteins (PDIA1, PDIA3, PDIA6, TRX, VDAC2) were alkylated by both ICEU and CCEU but beta-tubulin and prohibitin (PHB) were specifically alkylated by either ICEU or CCEU respectively. Specific alkylation of these two proteins might explain the observed difference in B16 cell cycle arrest in G(2) and G(1) phases respectively. Mass spectrometry studies on the alkylated prohibitin localised the modified peptide and identified Asp-40 as the target for CCEU. This alkylation induced an increased cellular content of PHB that should contribute to the accumulation of cells in G(1) phase. CONCLUSIONS AND IMPLICATIONS: This study reinforces our findings that CEUs alkylate proteins through an ester linkage with an acidic amino acid and shows that PHB alkylation contributes to G(1)/S arrest in CCEU treated B16 cells. Modification of PHB status and/or activity is an open route for new cancer therapeutics.

[Microdebrider polypectomy and local corticosteroids]. / Polypectomie au microdébrideur et corticothérapie locale.

OBJECTIVES: To subjectively evaluate the efficiency and tolerance of polypectomy using the microdebrider followed by local corticosteroids in nasal polyposis (NP) after medical therapy failure. METHODS: Between 2000 and 2003, a polypectomy using the microdebrider was performed in 24 patients with NP. Efficiency was evaluated retrospectively by comparing pre- and postoperative functional and polyp scores. Efficiency was also evaluated regarding extension of NP on preoperative computed tomography (CT). Overall satisfaction was evaluated using a standardized phone questionnaire. RESULTS: Mean follow-up was 23.6+/-12.5 months. The overall and individual functional scores and the anatomical score were very significantly improved after polypectomy using the microdebrider. Extension of NP on preoperative CT was not related to polypectomy efficiency. Among the patients surveyed, 87.5% were globally satisfied, 73% considered the operative conditions as satisfactory, and 83% qualified the postoperative period as simple. CONCLUSION: Polypectomy using the microdebrider followed by local corticosteroids appears to be an efficient and well-tolerated treatment for improving functional symptomatology of patients with NP.

Specific immunotherapy in allergic rhinitis.

Allergic rhinitis is a common condition, with significant impact on quality of life depending on severity and quality of control. Allergen-specific immunotherapy (allergen-SIT) is the only known treatment able to alter the natural course of allergic rhinitis. Although well known to allergologists, it has yet to be fully adopted by the ENT community. This review, based on the most recent meta-analyses and clinical studies, shows that SIT significantly reduces symptoms and medication requirements (nasal corticosteroids, H1-antihistamines) in allergic rhinitis. It can reduce the risk of progression to asthma and, if initiated early enough, of developing new sensitizations. Immunobiological analysis shows an altered inflammatory profile following SIT, with immune tolerance involving T-regulatory lymphocyte induction and IgG production. Sublingual SIT with drops is as effective as subcutaneous SIT and is simpler to use, with less anaphylactic risk. Standardization of trial protocols in terms of treatment response assessment and side effect grading is recommended to improve comparative studies. Sublingual SIT with tablets has recently been introduced, providing a good opportunity for ENT practitioners to adopt the SIT approach in rhinitis triggered by allergy to pollens and, in the near future, to house dust mites.

Matrix metalloproteinase-2 and -9 expression in sinonasal inverted papilloma.

STATEMENT OF PROBLEM: Inverted papilloma (IP) is a proliferative lesion of the epithelium lining the sinonasal tract, characterized by marked propensity for recurrence and association with carcinoma. To determine a putative role of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the establishment of IP, their expression was studied in IP. METHODS: Archived surgical specimens from 15 IPs were studied using immunohistochemistry and compared to 12 nasal polyps (NP), a model of chronic respiratory mucosal inflammation, and to 6 control nasal mucosa (CM) samples obtained from snorers during turbinectomy. Within IP, MMP-2 and -9 expression was compared between tumoral areas with hyperplastic epithelium and non tumoral areas with nonhyperplastic epithelium. RESULTS: In IP, MMP-2 and MMP-9 epithelial expression was not different compared to CM and NP. MMP-9 expression in submucosal inflammatory cells was not different between IP and CM or NP. However, within IP, a significantly increased number of MMP-9 positive inflammatory cells in the lamina propria adjacent to the hyperplastic epithelium was observed compared to the lamina propria adjacent to nonhyperplastic epithelium. CONCLUSION: Our findings suggest that MMP 9 expressing inflammatory cells may be involved in the pathophysiology of IP.