Rhinophototherapy in chronic rhinosinusitis: a double blind randomized placebo-controlled trial.

BACKGROUND: This study evaluated the efficacy of rhinophototherapy in patients with chronic rhinosinusitis (CRS) without nasal polyps. METHOD: In this randomized double-blind, placebo-controlled trial, CRS patients (n=50) received either mixed visible and ultraviolet (UVA and UVB) light source application (mUV/VIS) or visible light alone that served as placebo. Both groups were treated for 3 weeks. RESULTS: Results in the rhinophototherapy and placebo group were not significantly different and failed to reduce patient-reported outcomes measures (Rhinosinusits Disability Index, Visual Analogic Scale of symptom severity) and objective scores (rhinomanometry, olfactory thresholds, nasal Nitic Oxide concentrations), immediately and one month after treatment. CONCLUSIONS: The present data suggest that rhinophototherapy is not an efficient treatment for chronic rhinosinusitis without nasal polyps.

Cx26 regulates proliferation of repairing basal airway epithelial cells.

The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

Spatio-temporal dynamics of olfactory processing in the human brain: an event-related source imaging study.

Although brain structures involved in central nervous olfactory processing in humans have been well identified with functional neuroimaging, little is known about the temporal sequence of their activation. We recorded olfactory event-related potentials (ERP) to H(2)S stimuli presented to the left and right nostril in 12 healthy subjects. Topographic and source analysis identified four distinct processing steps between 200 and 1000 ms. Activation started ipsilateral to the stimulated nostril in the mesial and lateral temporal cortex (amygdala, parahippocampal gyrus, superior temporal gyrus, insula). Subsequently, the corresponding structures on the contralateral side became involved, followed by frontal structures at the end of the activation period. Thus, based on EEG-related data, current results suggest that olfactory information in humans is processed first ipsilaterally to the stimulated nostril and then activates the major relays in olfactory information processing in both hemispheres. Most importantly, the currently described techniques allow the investigation of the spatial processing of olfactory information at a high temporal resolution.

Taste disorders.

Taste disorders are rare compared to olfactory problems, and so the workup and understanding of taste disorders is limited. In this article, we try to update knowledge about human taste disorders with a special focus on taste disorders occurring after ENT surgery.

Future perspectives in smell and taste disorders.

Large sections of the medical community have, in the past, thought of human olfaction as a minor sense that was destined to disappear soon. This view has changed completely in the last two decades. This article will attempt to highlight the most important recent advances in our understanding of the human olfactory function and focus in particular on questions for the future and developments required in this field.

Neurogenic inflammation of the upper airway mucosa.

Chronic inflammation of the upper airway mucosa is most likely caused by multiple factors, but is frequently associated with local neurogenic inflammation. This phenomenon can be induced by the inhalation of exogenous particles and chemicals present in our environment, as well as irritants produced endogenously. These irritants, i.e. histamine, H+ or bradykinin, can stimulate the abundant afferent sensory nerves endings, epithelial and neuroendocrine cells present in the upper airways mucosa. These structures can interact with our immune and neural cells by producing pro-inflammatory neuropeptides, cytokines, chemokines and neurotrophins. This short review summarizes some of our current knowledge with regard to the role of airborne chemical stimuli and their possible implications in the development of chronic inflammation of the upper airways mucosa.

Neuroendocrine cells of nasal mucosa are a cellular source of brain-derived neurotrophic factor.

There is growing evidence for extensive interaction between sensory neurons, immune and mucosal epithelial cells during airway inflammation and hyperreactivity. This neuro-immune cross-talk (neurogenic inflammation) involves different groups of mediators, which include the neurotrophin family (nerve growth factor, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 and -4). Neurotrophins modulate airway inflammation by enhancing sensory nerve excitability and production of neuropeptides, and by interaction with different immune cell types. In the present study, it was questioned whether airway epithelial cells express BDNF, and if proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-1beta and interferon-gamma) and a glucocorticoid (budesonide) affect this expression. Primary cultures of nasal epithelial cells were used. It was found that BDNF was stored in chromogranin A-containing secretory granules of specialised epithelial cells, i.e. neuroendocrine cells, and was secreted in a polarised manner. Apical secretion appears to be constitutive, whereas basolateral secretion is markedly enhanced upon stimulation with cytokines. This enhanced basolateral secretion was not due to enhanced synthesis and was not affected by inhibitors of the processing enzymes, such as furin and the metalloproteinases involved in the maturation of BDNF, but was considerably diminished by budesonide. Therefore, airway mucosa might contribute to neurogenic inflammation through increased secretion of brain-derived neurotrophic factor by neuroendocrine cells under inflammatory conditions.

Nasal lavage with sodium hypochlorite solution in Staphylococcus aureus persistent rhinosinusitis.

OBJECTIVE: To determine a selected concentration of sodium hypochlorite (NaOCl) in saline solution for nasal lavage and evaluate its clinical efficiency in the treatment of symptomatic patients with persistent, Staphylococcus aureus (SA) associated rhinosinusitis (RS). MATERIAL AND METHODS: In vitro tests for cilia and epithelial cell viability were done on reconstituted primary epithelial cells in vitro. Cells were exposed for 5 and 15 minutes twice daily for 5 consecutive days to one of the following conditions, (1) saline, (2) 0.5% NaOCl in saline, and (3) 0.05% NaOCl in saline. In order to evaluate tolerance, immunostaining was done for ezrin and F-actin network and observed with confocal microscopy. The patients (n=20) were all persistent SA symptomatic carriers, with unique patient-specific SA clonotypes, and multiple infection recurrence despite effective systemic antibiotic therapy. Each patient applied first saline alone for 3 months followed by saline + 0.05% NaOCl solution, as nasal lavage twice daily on both nostrils for 3 months. Symptom intensity and endoscopic findings were recorded with visual analogue scale (VAS). Nasal airway resistance (NAR) and nasal Nitric Oxide (NO) levels were measured before and after the saline lavage regimen, and after the saline + NaOCl treatment. RESULTS: F-actin network loss and decreased expression of ezrin were significant in cells exposed to 0.5%, but not in those exposed to 0.05% NaOCl. These changes were more obvious when exposed for 15 min. than 5 min. daily. The nasal lavage with 0.05% NaOCl in saline was well tolerated and a significant improvement in nasal obstruction (p = 0.001), posterior nasal discharge (p = 0.018), olfaction (p = 0.007) and headache (p = 0.009) was demonstrated. Significant improvement was also recorded in nasal endoscopic grading of oedema (p = 0.001), erythema (p = 0.001), purulent discharge (p = 0.002), nasal crusts (p = 0.001), and NAR (p = 0.05) as measured by rhinomanometry. There was no significant improvement in nasal NO production or subjective anterior nasal discharge. Bacteriological cultures of middle meatus secretions collected one month after the end of the treatment revealed the persistence of SA. CONCLUSION: Nasal lavage with 0.05% NaOCl solution in saline is suitable for long-term use and seems to be a good alternative to lavage with saline alone in the management of symptomatic RS associated with recurrent SA infections due to patient-specific SA clonotypes.

Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.

BACKGROUND: Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. OBJECTIVE: To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. METHODS: DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. RESULTS AND CONCLUSIONS: DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor.

Olfactory function and nasal nitric oxide.

OBJECTIVE: To determine the relationship between nasal nitric oxide (nNO) concentration and its influence on olfactory function. SETTING: Tertiary otolaryngology care centre. PARTICIPANTS: Sixty-four patients suffering from chronic rhinosinusitis and 20 healthy subjects participated. STUDY DESIGN: Prospective study. OUTCOME MEASURES: The nNO concentration was measured by chemiluminescence and olfactory thresholds were measured with the phenyl ethanol threshold of the Sniffin' Sticks. In chronic rhinosinusitis patients this measure was done preoperatively and 3 months after endoscopic sinus surgery. RESULTS: Healthy subjects had significantly higher nNO concentrations and better olfactory thresholds compared to the chronic rhinosinusitis patients, both before and after those had undergone sinus surgery. Olfactory thresholds and nNO concentrations remained unchanged after surgery in the chronic rhinosinusitis group. In the chronic rhinosinusitis group, nNO concentrations correlated positively with the olfactory threshold preoperatively (P < 0.0001) and 3 months after surgery (P < 0.05). In the control group, nNO production did not correlate with the olfactory thresholds (P > 0.05). CONCLUSION: Olfactory function and nNO concentration correlate in chronic rhinosinusitis patients but not in healthy subjects. This suggests that both parameters do rather not directly influence each other but it might be the inflammatory processes found in chronic rhinosinusitis that affects olfaction and nNO. Nasal nitric oxide produced by the paranasal sinuses seems not to directly influence olfactory function.

BDNF and DPP-IV in polyps and middle turbinates epithelial cells.

HYPOTHESIS: Neuropeptides released from sensory nerves may contribute to airway inflammation, particularly if their metabolism is impaired through defective inactivation and/or increased production. In the airways, neuropeptides are subjected to degradation by enzymes such as dipeptidyl peptidase (DPP-IV), and are upregulated by neurotrophins such as brain derived neurotrophic factor (BDNF). We therefore assessed in primary human nasal epithelial cells the expression of DPP-IV and BDNF under basal and inflammatory conditions. METHODS: Human epithelial cells were isolated from nasal polyps and middle turbinates, and grown on collagen-coated polycarbonate filters with an air liquid-interface. After three weeks of culture, constitutive cellular expression of DPP-IV and BDNF was assessed by measuring its activity and by ELISA, respectively. To mimick in vivo inflammatory conditions, cells were exposed apically and basolaterally to 50 ng/ml of TNFalpha, IL-1beta, and IFN-gamma for two days. DPP-IV activity and BDNF protein expression were measured in cell lysates and in the apical and basolateral media. RESULTS: Constitutive DPP-IV activity was similar in polyps and turbinates cells. In contrast, polyps epithelial cells expressed higher amounts of BDNF compared to turbinates derived cells. On the other hand, TNFalpha, IL-1beta, and IFN-gamma did not affect DPP-IV activity but significantly increased the cellular expression and the basolateral secretion of BDNF. CONCLUSIONS: Our data show for the first time that primary human airway epithelial cells produced DPP-IV and BDNF under basal conditions. Furthermore, the production and secretion of BDNF were markedly increased in response to pro-inflammatory cytokines, confirming the involvement of BDNF in airway inflammation.

Transient hemiageusia in cerebrovascular lateral pontine lesions.

Knowledge of human central taste pathways is largely based on textbook (anatomical dissections) and animal (electrophysiology in vivo) data. It is only recently that further functional insight into human central gustatory pathways has been achieved. Magnetic resonance imaging studies, especially selective imaging of vascular, tumoral, or inflammatory lesions in humans has made this possible. However, some questions remain, particularly regarding the exact crossing site of human gustatory afferences. We present a patient with a pontine stroke after a vertebral artery thrombosis. The patient had infarctions in areas supplied by the anterior inferior cerebellar artery and showed vertical diplopia, right sided deafness, right facial palsy, and transient hemiageusia. A review of the sparse literature of central taste disorders and food preference changes after strokes with a focus on hemiageusia cases is provided. This case offers new evidence suggesting that the central gustatory pathway in humans runs ipsilaterally within the pons and crosses at a higher, probably midbrain level. In patients with central lesions, little attention has been given to taste disorders. They may often go unnoticed by the physician and/or the patient. Central lesions involving taste pathways seem to generate perceptions of quantitative taste disorders (hemiageusia or hypogeusia), in contrast to peripheral gustatory lesions that are hardly recognised as quantitative but sometimes as qualitative (dysgeusia) taste disorders by patients.

Intracellular residency is frequently associated with recurrent Staphylococcus aureus rhinosinusitis.

AIM: The prevalence of intracellular Staphylococcus aureus organisms in the nasal mucosa of patients with recurrent infectious rhinosinusitis episodes was studied. METHOD: Twenty-seven consecutive adult patients who failed medical management of chronic rhinosinusitis (CRS) of multiple origins, associated or not with nasal polyposis, were consecutively enrolled for endonasal sinus surgery (including partial middle turbinectomy, middle antrostomy, ethmoidectomy, sphenoidotomy) and followed for a 12-month post-operative period. RESULTS: Seventeen of these patients showed the presence of intracellular S. aureus as detected by confocal laser scan immunofluorescence microscopy in epithelial cells of surgical intranasal biopsy specimens. Nine of the patients with and two without intracellular bacteria yielded S. aureus in endoscopically guided cultures of middle meatus secretions, despite the recent administration of prophylactic antibiotics. Eleven of the 17 patients with intracellular S. aureus relapsed for rhinosinusitis within the 12-month follow-up period. Molecular typing of sequential S. aureus isolates demonstrated the persistence of unique patient-specific S. aureus clonotypes in nine of the patients with intracellular bacteria during the 12-month follow-up. CONCLUSION: The presence of intracellular S. aureus in epithelial cells of the nasal mucosa is a significant risk factor for recurrent episodes of rhinosinusitis due to persistent bacterial clonotypes, which appear refractory to antimicrobial and surgical therapy.

Basic and clinical aspects of olfaction.

Disturbances of olfaction are a common occurrence in many neurological and neurosurgical patients and their correct diagnosis might be helpful in management and enhancement of quality of life. However, olfaction is seldom checked in most neurosurgical units and the "smell bottles" are often either absent or out of date. This chapter reviews systematically recent advances in our understanding of the anatomy, physiology (olfactory coding) and measurement of olfactory function in the human. The causes and symptoms of smell disorders, risk of damage to the olfactory system by various surgical procedures and, finally, the natural history of recovery and treatment of smell disorders, for example after trauma, are discussed.

[Neurogenic inflammation and chronic rhinosinusitis]. / Hlyperréactivité non spécifique et rhinosinusite chronique.

The nasal mucosa is one of the anatomical region which have the highest density of sensory innervation. The function of this sensory innervation is probably linked to the protection of the lower airways against inhalation of airborne particles and potentially harmful substances. Chronic rhinosinusitis (CRS) is associated with nasal obstruction, rhinorrhea, loss of sense of smell and facial pain or headaches. When allergy or specific hyperreactivity, infection, systemic or genetic deseases have been excluded, the diagnosis of non specific hyperreactivity or neurogenic inflammation is proposed. Sensory neuropeptides released by sensory nerves endings have powerful proinflammatory effects. The best treatment yet available include nasal lavages and the local application of topical corticosteroid spray.

Clinical presentation of qualitative olfactory dysfunction.

Many patients with olfactory dysfunction not only experience quantitative reduction of olfactory function, but also suffer from distorted olfactory sensations. This qualitative dysfunction is referred to as parosmia (also called "troposmia") or phantosmia, with the major difference that distorted olfactory sensations are experienced in the presence or absence of an odor, respectively. Our clinical observations corroborate the literature in terms of a general underestimation of the incidence of olfactory distortions. Based on selected cases we try to show that olfactory distortions exhibit a large variance in their clinical appearance. Further, emphasis is placed on the fact that only a detailed and directed history of the patient can provide cues to the correct diagnosis.

Chronic rhinosinusitis and neuropeptides.

The nose is an air conditioner and is involved in the protection of the lower airways against inhalation of exogenous particles and airborne irritants. The nasal mucosa is therefore densely innervated by sensory nerves containing several neuropeptides. In the airways, activation of sensory C and A? fibres leads to the release of multiple neuropeptides. In addition to their involvement in vasodilatation, plasma protein exudation and mucus secretion, sensory neuropeptides also participate in inflammatory cell recruitment. This neurogenic inflammation contributes to the intensity of nasal obstruction, rhinorrhea and headaches, the most common symptoms in chronic rhinosinusitis. The concentration of sensory neuropeptides is increased in the nasal mucosa of patients suffering from chronic rhinosinusitis. In contrast, the activity of the enzymes involved in the degradation of these sensory neuropeptides is markedly reduced. These observations should contribute to a better understanding of the pathophysiological mechanisms of one of the most frequently occurring chronic inflammatory diseases.

Ratings of overall olfactory function.

The aim of this study was to investigate the accuracy of self-reported ratings of olfactory function in 83 healthy subjects. Such ratings were compared with quantitative measures of olfactory function, as well as with ratings of nasal patency. In experiment 1 subjects rated olfactory function and nasal patency before olfactory testing, whereas in experiment 2 the reverse was the case. No feedback regarding test results were provided until after completion of the testing. The principal findings were: (i) when ratings preceded measurements of olfactory function, there was no significant correlation between the two parameters. However, ratings of olfactory function correlated significantly with ratings of nasal airway patency. (ii) In contrast, when measurements of olfactory function preceded the ratings, this constellation switched. Now ratings of olfactory function correlated significantly with measured olfactory function, whereas there was no significant correlation between ratings of nasal airway patency and ratings of olfactory function. In conclusion, these data suggest that ratings of olfactory function are unreliable in healthy, untrained subjects. The ratings seem to reflect changes of nasal airway patency to a larger degree than measurable olfactory function. The results further indicate that this is mainly due to the limited attention the sense of smell receives in daily life.

Comparison of once- versus twice-daily use of beclomethasone dipropionate aqueous nasal spray in the treatment of allergic and non-allergic chronic rhinosinusitis.

The aim of the study was to assess the efficacy and safety of nasal aqueous beclomethasone dipropionate (BDP), 400 micro g/day, given via a metered pump in a once-daily or twice-daily regimen following a double-blind, parallel group design over a 12-week period. Adult patients (n=112) with allergic or non-allergic chronic rhinosinusitis recorded their nasal and ocular symptoms for the 7-day run-in period and for the first 4 weeks of treatment. At baseline and after 4 weeks the airways' resistance via active anterior rhinomanometry and the volume and area section via acoustic rhinometry were measured. Morning serum cortisol was measured at baseline and at week 12. Adverse events were to be reported at each visit. Of the 112 randomised patients, three did not enter the ITT analysis and another 13 in total discontinued the treatment. Significant improvements over the baseline were reported in both groups for the primary variable sum of nasal scores (-53.7% in the once-daily group and -59.7 in the twice-daily group), as well as for each nasal and ocular symptoms, without differences between the groups. Because of a wider variability than expected, the 95% confidence interval (C.I.) for the difference between the least square means exceeded the pre-defined limit of +/-10% of the reference mean. Similar improvements in both groups were also reported for the nasal airway patency's parameters. The total number of drug-related adverse events was 26 in the once-daily group and 32 in the twice-daily group, with most of the events consisting of local effects at the site of application. No signs of adrenal suppression were observed, and serum morning cortisol values did not significantly change. The once-daily BDP dosing (400 micro g/day) therefore has a similar efficacy and safety profile as the same daily dose given in a twice-daily regimen.