Dissemination and implementation of the ARIA guidelines for allergic rhinitis in general practice.

BACKGROUND: Allergic rhinitis (AR) is a prevalent problem in general practice. The first evidence-based guidelines for AR, the ARIA guidelines, were published and have been updated repeatedly since 2001 in order to improve the care of AR patients. Very limited information, however, is available on the impact of these guidelines on everyday clinical practice. The aim of this study was to evaluate the dissemination and implementation of the ARIA guidelines in general practice. METHODS: Three hundred and fifty Flemish general practitioners (GPs) were recruited to complete a questionnaire covering their demographic and professional characteristics, awareness, perception and implementation of the ARIA guidelines. To assess compliance with the ARIA treatment recommendations, 4 fictitious case scenarios of AR were presented, in which the respondents were asked to select the treatment of choice. RESULTS: Of the 350 GPs included, only 31% were aware of the ARIA guidelines and 10% stated that they implement them. For the diagnosis of AR, 71% of the GPs ask specific IgE tests or perform skin prick tests, whereas only 29% perform an anterior rhinoscopy. ARIA users are more likely to screen for concomitant asthma. In the clinical-case section, there was a large variability in proposed therapeutic strategies. Adherence to the evidence-based ARIA treatment guidelines was low, but recent graduation was a significant predictor of compliance with these recommendations. CONCLUSIONS: The ARIA guidelines remain relatively unknown among Flemish GPs and even those who are aware of them still tend to treat AR independently of the guideline recommendations.

Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.

BACKGROUND: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. OBJECTIVE: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. METHODS: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. RESULTS: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. CONCLUSION: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.

Syk-kinase inhibition prevents mast cell activation in nasal polyps.

BACKGROUND: Mast cells are crucial effector cells in the allergic cascade. The cross-linking of the high affinity IgE receptor (FcεRI) activates mast cells and basophils. Spleen tyrosine kinase (Syk) is positioned upstream of the IgE receptor signal transducing pathway and may represent an important target for the treatment of nasal inflammatory diseases. OBJECTIVE: We measured effects of a specific Syk inhibitor in the release of mast cell mediators in human cord blood-derived mast cells (CBDMCs) (in-vitro) and in human nasal tissue (ex-vivo). METHODS: Surgical samples were collected from patients with nasal polyposis who underwent sinus surgery. Tissue cubes of +- 0.9 mm3 were primed with myeloma IgE (1 microg/ml), preincubated with Syk inhibitor NVP-QAB205 in different concentrations and then stimulated with tissue culture medium, anti-IgE 10 microg/ml and anti-IgE 30 microg/ml. Supernatants were analysed for concentrations of histamine, LTC4/LTD4/LTE4 and PGD2. CBDMCs were likewise pre-incubated with compound, prior to stimulation with anti-IgE at 10 microg/ml. RESULTS: In CBDMCs, the Syk inhibitor prevented degranulation assessed by measurement of histamine release and the production of LTC4/LTD4/LTE4 and PGD2. Furthermore, the Syk inhibitor was similarly able to significantly inhibit the release of these granules and newly synthesized mediators by nasal polyp mast cells in a dose dependent manner. CONCLUSION: Although the critical role of Syk in the IgE receptor signal transduction pathway has been well documented in vitro, this study supports the importance of Syk in IgE receptor-mediated degranulation of mast cells ex-vivo within nasal tissue. Thus, inhibition of Syk may represent an important therapeutic strategy for the treatment of upper airway disease with mast cell involvement, such as allergic rhinitis.

Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.

BACKGROUND: Nasal polyps often are associated with asthma. The phenotype of these patients is unknown. OBJECTIVE: To identify the mucosal factors associated with asthma comorbidity, we analyzed the inflammatory patterns of nasal polyps. METHODS: Nasal polyps from 70 Belgian patients, 34% with asthma, were analyzed for type of inflammation, T-cell cytokines, and IgE antibodies to Staphylococcus aureus enterotoxins. The same investigations were repeated in 93 Chinese patients with polyps, a group with a low asthma comorbidity rate (8%). RESULTS: In Belgian patients with polyps, 54% of samples showed eosinophilic inflammation. A classification tree evaluation identified IL-5 as the main positive determinant. Enterotoxin IgE in tissue (37%) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. Expression of enterotoxin IgE, total IgE at greater than 1,442 kU/L, and eosinophil cationic protein at greater than 17,109 µg/L in samples with a total IgE concentration of greater than 246 kU/L significantly predicted asthma (odds ratio, 5.8-13). Only 7.5% of the samples from Chinese patients with polyps showed eosinophilic inflammation. IL-5 was confirmed as a positive determinant of eosinophilic inflammation, and enterotoxin IgE in tissue (17% of patients) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. The expression of IL-5 or total IgE at greater than 790 kU/L in samples with an IL-5 concentration of greater than 194 pg/mL significantly predicted comorbid asthma (odds ratio, 17.2-96). CONCLUSION: Mucosal inflammation in nasal polyps orchestrated by T(H)2 cytokines and amplified by S aureus enterotoxins is characterized by an increased eosinophilic inflammation and formation of IgE antibodies. This phenotype is associated with comorbid asthma in white and Asian patients with nasal polyps.

Oral steroids and doxycycline: two different approaches to treat nasal polyps.

BACKGROUND: There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps. OBJECTIVE: We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps. METHODS: In a double-blind, placebo-controlled, multicenter trial, we randomly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses (32-8 mg once daily), doxycycline (200 mg on the first day, followed by 100 mg once daily), or placebo for 20 days. Participants were followed for 12 weeks. Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy. Markers of inflammation such as eosinophilic cationic protein (ECP), IL-5, myeloperoxidase, matrix metalloproteinase 9, and IgE were measured in nasal secretions. Concentrations of eosinophils, ECP, and soluble IL-5 receptor alpha were measured in peripheral blood samples. RESULTS: Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo. The effect of methylprednisolone was maximal at week 3 and lasted until week 8, whereas the effect of doxycycline was moderate but present for 12 weeks. Methylprednisolone significantly reduced levels of ECP, IL-5, and IgE in nasal secretions, whereas doxycycline significantly reduced levels of myeloperoxidase, ECP, and matrix metalloproteinase 9 in nasal secretions. CONCLUSION: This is the first double-blind, placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps, nasal symptoms, and mucosal and systemic markers of inflammation.

Efficacy of desloratadine in persistent allergic rhinitis - a GA²LEN study.

BACKGROUND: The ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines proposed a classification for allergic rhinitis based on the duration of symptoms (intermittent or persistent) rather than on the time of allergen exposure (seasonal or perennial). There had been no placebo-controlled, randomized, clinical trial of desloratadine (DL) in patients with persistent allergic rhinitis to date. OBJECTIVES: To assess the efficacy and safety of DL in patients with persistent allergic rhinitis based on the ARIA classification. METHODS: Patients 12 years of age and older with persistent allergic rhinitis were assessed over 85 days of treatment with DL 5 mg once daily (n = 360) or placebo (n = 356). The primary endpoint was the AM/PM reflective total 5-symptom score (T5SS) averaged over days 1-29. Secondary endpoints included AM/PM instantaneous T5SS and individual symptoms, therapeutic response, symptom severity assessed by a visual analogue scale and quality of life. RESULTS: The mean reduction in AM/PM reflective T5SS was significantly greater with DL than placebo over days 1-29 (-3.76 vs. -2.87, p < 0.001) and on each individual day (p < 0.05). The mean AM instantaneous T5SS was significantly reduced with DL compared with placebo as early as day 2 (-1.90 vs. -1.46; p < 0.001). The therapeutic response and improvement in quality of life were significantly greater with DL than placebo (p < 0.001 for each). The frequency of treatment-related adverse events was low and similar between DL (10.0%) and placebo (8.4%). CONCLUSIONS: This study showed DL to be effective and safe in the treatment of persistent allergic rhinitis.

TGF-beta signaling and collagen deposition in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. OBJECTIVE: The objective was to analyze the presence of TGF-beta isoforms, receptors, intracellular signaling, and collagen deposition in chronic rhinosinusitis. METHODS: Sinonasal mucosal samples obtained from chronic rhinosinusitis with nasal polyps (CRSwNP; n = 13), chronic rhinosinusitis without nasal polyps (CRSsNP; n = 13), and controls (n = 10) were analyzed for TGF-beta isoforms 1 and 2 by means of ELISA and IHC, and for TGF-beta R1, 2, and 3 by RT-PCR and IHC. As downstream proteins, phospho-Smad 2 (pSmad 2) and collagen were analyzed by performing immunostaining and picrosirius red staining, respectively. RESULTS: TGF-beta 1 and 2 protein concentrations, TGF-beta receptor (R) I and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly higher in CRSsNP versus controls. In CRSwNP, TGF-beta 1 protein concentration, TGF-beta RII and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly lower versus controls. Only TGF-beta 2 protein was found higher in CRSwNP versus controls. CONCLUSION: A high TGF-beta 1 protein expression, increased TGF-beta RI expression, and a high number of pSmad 2-positive cells all indicate an enhanced TGF-beta signaling in CRSsNP, whereas a low TGF-beta 1 protein concentration, a decreased expression of TGF-beta RII, and a low number of pSmad 2-positive cells in CRSwNP indicate a low level of TGF-beta signaling in CRSwNP. These findings are compatible with the remodeling patterns observed, reflected by a lack of collagen in CRSwNP, and excessive collagen production with thickening of the collagen fibers in the extracellular matrix in CRSsNP.

THP-1 monocytes but not macrophages as a potential alternative for CD34+ dendritic cells to identify chemical skin sensitizers.

Early detection of the sensitizing potential of chemicals is an emerging issue for chemical, pharmaceutical and cosmetic industries. In our institute, an in vitro classification model for prediction of chemical-induced skin sensitization based on gene expression signatures in human CD34+ progenitor-derived dendritic cells (DC) has been developed. This primary cell model is able to closely mimic the induction phase of sensitization by Langerhans cells in the skin, but it has drawbacks, such as the availability of cord blood. The aim of this study was to investigate whether human in vitro cultured THP-1 monocytes or macrophages display a similar expression profile for 13 predictive gene markers previously identified in DC and whether they also possess a discriminating capacity towards skin sensitizers and non-sensitizers based on these marker genes. To this end, the cell models were exposed to 5 skin sensitizers (ammonium hexachloroplatinate IV, 1-chloro-2,4-dinitrobenzene, eugenol, para-phenylenediamine, and tetramethylthiuram disulfide) and 5 non-sensitizers (l-glutamic acid, methyl salicylate, sodium dodecyl sulfate, tributyltin chloride, and zinc sulfate) for 6, 10, and 24 h, and mRNA expression of the 13 genes was analyzed using real-time RT-PCR. The transcriptional response of 7 out of 13 genes in THP-1 monocytes was significantly correlated with DC, whereas only 2 out of 13 genes in THP-1 macrophages. After a cross-validation of a discriminant analysis of the gene expression profiles in the THP-1 monocytes, this cell model demonstrated to also have a capacity to distinguish skin sensitizers from non-sensitizers. However, the DC model was superior to the monocyte model for discrimination of (non-)sensitizing chemicals.

Anti-IgE for the treatment of allergic rhinitis--and eventually nasal polyps?

In allergic rhinitis, cross-linking of IgE molecules upon allergen contact induces degranulation of mast cells and basophils within the mucosal tissue and results in the release of typical mediators, which consecutively induce the well-known symptoms. Omalizumab counteracts these interactions by reducing serum levels of free IgE. Therapy targeted at IgE also interferes with its binding to the low-affinity receptors inhibiting the amplification of the Th(2)-type response. Treatment of allergic rhinitis with anti-IgE has been shown to be safe and to reduce specific symptoms. Furthermore, the combination of omalizumab with specific immunotherapy may not only increase efficacy but also safety in selected patients. Therefore, we reviewed previously published studies on omalizumab therapy in allergic rhinitis, either as monotherapy or in combination with immunotherapy. In patients with nasal polyps, a local multiclonal IgE response has recently been described, initiated by Staphylococcus aureus-derived enterotoxins, which at least modifies the inflammatory reaction within the tissue. Evidence accumulates that these enterotoxins act as superantigens resulting in a multiclonal T- and B-cell activation with massive IgE formation within the airways. Because of the multiclonality, a range of allergens could possibly maintain a constant degranulation of mast cells present in the polyp tissue, which may contribute to disease severity. We here discuss a proof-of-concept treatment trial with omalizumab in nasal polyposis, which--in case of a positive therapeutic response--would also pave the way for anti-IgE treatment approaches for severe non-atopic lower airway disease.

Gene profiles of a human bronchial epithelial cell line after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis.

Respiratory sensitization is a concern for occupational and environmental health in consumer product development. Despite international regulatory requirements there is no established protocol for the identification of chemical respiratory sensitizers. New tests should be based on mechanistic understanding and should be preferentially restricted to in vitro assays. The major goal of this study was to investigate the alterations in gene expression of human bronchial epithelial (BEAS-2B) cells after exposure to respiratory sensitizers and respiratory non-sensitizing chemicals, and to identify genes that are able to discriminate between both groups of chemicals. BEAS-2B cells were exposed during 6, 10, and 24h to the respiratory sensitizers ammonium hexachloroplatinate IV, hexamethylene diisocyanate, and trimellitic anhydride, the irritants acrolein and methyl salicylate, and the skin sensitizer 1-chloro-2,4-dinitrobenzene. Overall changes in gene expression were evaluated using Agilent Whole Human Genome 4x 44K oligonucleotide arrays. Fisher Linear Discriminant Analysis was used to obtain a ranking of genes that reflects their potential to discriminate between respiratory sensitizing and respiratory non-sensitizing chemicals. The 10 most discriminative genes were BC042064, A_24_P229834, DOCK11, THC2544911, DLGAP4, NINJ1, PFKM, FLJ10986, IL28RA, and CASP9. Based on the differentially expressed genes, pathway analysis was used to identify possible underlying mechanisms of respiratory sensitization. We demonstrated that in bronchial epithelial cells the canonical PTEN signaling pathway is probably the most specific pathway in the context of respiratory sensitization. Results are indicative that the BEAS-2B cell line can be used as an alternative cell model to screen chemical compounds for their respiratory sensitizing potential.

Chronic rhinosinusitis with and without nasal polyps: what is the difference?

Chronic rhinosinusitis is a heterogeneous group of chronic sinus diseases that may consist of clearly different disease entities. Further investigation of the pathomechanisms of chronic rhinosinusitis and the introduction of appropriate disease markers have recently facilitated disease classification. Evaluation of inflammatory cell profiles, the differentiation of T-effector cells, characterization of remodeling processes such as fibrosis or edema formation, and innate or adaptive immunity products such as Toll-like receptors and immunoglobulins all provide tools to identify distinct disease entities within the group of chronic sinus diseases. This disease differentiation will not only increase our knowledge of the pathophysiology of sinusitis but may lead to new diagnostic and therapeutic strategies specifically targeted and adapted to the diagnosed disease entity.

Gene profiles of a human alveolar epithelial cell line after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis.

There are currently no accepted biological prediction models for assessing the potential of a substance to cause respiratory sensitization. New tests should be based on mechanistic understanding and should be preferentially restricted to in vitro assays. The major goal of this study was to investigate the alterations in gene expression of human alveolar epithelial (A549) cells after exposure to respiratory sensitizing and non-respiratory sensitizing chemicals, and to identify genes that are able to discriminate between both groups of chemicals. A549 cells were exposed during 6, 10, and 24 h to the respiratory sensitizers ammonium hexachloroplatinate IV, hexamethylene diisocyanate, and trimellitic anhydride, the irritants acrolein and methyl salicylate, and the skin sensitizer 1-chloro-2,4-dinitrobenzene. Overall changes in gene expression were evaluated using Agilent Whole Human Genome 4x44K oligonucleotide arrays. A Fisher linear discriminant analysis was used to obtain a ranking of genes that reflects their potential to discriminate between respiratory sensitizing and respiratory non-sensitizing chemicals. Among the 20 most discriminating genes, which were categorized into molecular and biological gene ontology (GO) terms, CTLA4 could be associated with asthma and/or respiratory sensitization. When categorizing the top-1000 genes into biological GO terms, 22 genes were associated with immune function. Using a pathway analysis tool to identify possible underlying mechanisms of respiratory sensitization, no known canonical signaling pathway was observed to be activated in the A549 cell line.

Acoustic measurement of overall voice quality: a meta-analysis.

Over the past several decades, many acoustic markers have been proposed to be sensitive to and measure overall voice quality. This meta-analysis presents a retrospective appraisal of scientific reports, which evaluated the relation between perceived overall voice quality and several acoustic-phonetic correlates. Twenty-five studies met the inclusion criteria and were evaluated using meta-analytic techniques. Correlation coefficients between perceptual judgments and acoustic measures were computed. Where more than one correlation coefficient for a specific acoustic marker was available, a weighted average correlation coefficient was calculated. This was the case in 36 acoustic measures on sustained vowels and in 3 measures on continuous speech. Acoustic measures were ranked according to the strength of the correlation with perceptual voice quality ratings. Acoustic markers with more than one correlation value available in literature and yielding a homogeneous weighted r of 0.60 or above were considered to be superior. The meta-analysis identified four measures that met these criteria in sustained vowels and three measures in continuous speech. Although acoustic measures are routinely utilized in clinical voice examinations, the results of this meta-analysis suggest that caution is warranted regarding the concurrent validity and thus the clinical utility of many of these measures.

Staphylococcus aureus enterotoxin B, protein A, and lipoteichoic acid stimulations in nasal polyps.

BACKGROUND: Increasing evidence points toward a modifying role of Staphylococcus aureus and its products in the pathogenesis of nasal polyposis. OBJECTIVE: The aim of this study was to investigate cytokine and mediator production after stimulation with S aureus-derived proteins enterotoxin B, protein A, and lipoteichoic acid in nasal polyp and control inferior turbinate tissue. METHODS: Tissue fragments were stimulated with RPMI (negative control), enterotoxin B, protein A, and lipoteichoic acid for 30 minutes and 24 hours. Supernatants were measured by multiplex for proinflammatory cytokines (IL-1beta, TNF-alpha) and T-cell and subset-related cytokines (IFN-gamma, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13). Histamine, TGF-beta1, cysteinyl leukotrienes, and prostaglandin D(2) were analyzed by ELISA. RESULTS: Thirty minutes of protein A stimulation resulted in a significant increase of histamine, leukotrienes, and prostaglandin D(2). Enterotoxin B stimulation over a period of 24 hours induced a significant increase of IL-1beta, TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-10, and IL-13 in both groups, with this increase significantly higher in nasal polyps compared with controls. CONCLUSION: We here show that S aureus products have various effects on mucosal tissues: surface protein A induces mast cell degranulation, whereas enterotoxins induce the release of cytokines, with a T(H)2-skewed pattern in nasal polyps, supporting the stimulatory role of superantigens in the development of this inflammatory disease.

Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian (south Chinese), patients with polyps. OBJECTIVE: We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. METHODS: Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. RESULTS: Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio = 0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor alpha and significant downregulation of Foxp3 expression and TGF-beta1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in T(H)2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a T(H)1/T(H)17 cell pattern versus control tissue. CONCLUSION: Nasal polyps (CRSwNP) from white and Asian patients are both characterized by T-cell activation and impaired regulatory T-cell function; however, T-effector cells in the samples from white patients were T(H)2-biased, whereas samples from their Asian counterparts demonstrated a T(H)1/T(H)17 polarization.

T-cell regulation in chronic paranasal sinus disease.

BACKGROUND: Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a T(H)2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant T(H)1 milieu. OBJECTIVE: We aimed to study the direct tissue expression of transcription factors for T-cell subpopulations, including T regulatory cells, in relation to the cytokine expression patterns in the different disease subgroups. METHODS: The expression of forkhead box P3 (FOXP3), T-box transcription factor (T-bet), GATA-3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-beta1 and IL-10, and T(H)1/ T(H)2/ T(H)17 cytokines (IFN-gamma, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP, and 10 control samples. Additional protein measurements were performed for TGF-beta1 and IFN-gamma. RESULTS: In CRSwNP, we observed a significantly lower FOXP3 mRNA and TGF-beta1 protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with controls, whereas RORc was not significantly different compared with controls. In CRSsNP, FOXP3, T-bet, GATA-3, and RORc expression was not significantly different from controls, whereas TGF-beta1 mRNA, IFN-gamma mRNA, and protein were significantly higher in CRSsNP compared with controls. For IL-17, no significant differences were noted among all groups. CONCLUSION: We demonstrate for the first time a decreased FOXP3 expression accompanied by an upregulation of T-bet and GATA-3 and a downregulation of TGF-beta1 in CRSwNP versus controls and CRSsNP.

The current burden of allergic rhinitis amongst primary care practitioners and its impact on patient management.

AIMS: To investigate the burden of allergic rhinitis (AR) amongst primary care practitioners (PCPs), the impact of AR on PCPs' professional lives, and the effect on their management of AR patients of PCPs' personal experience of AR. METHODS: An online questionnaire was completed by 1201 PCPs (50% AR sufferers) from eight countries. RESULTS: 21% of PCPs reported very well controlled symptoms and 66% quite good control. Six hours work per week, on average, was missed by PCPs whose AR symptoms resulted in absence. AR symptoms affected concentration, stress level, mood, time spent with patients, physical contact with patients, and patient throughput. PCPs with AR reported a significantly higher proportion of AR patients in their practice and gave a significantly higher ranking to specific treatment requests and emotional well-being, and gave a significantly lower ranking to preventing comorbidity development and providing a treatment most likely to result in high patient compliance. DISCUSSION: This is the first study demonstrating the impact of AR on PCPs showing association with lost productivity, absenteeism and reduction in professional performance. Personal experience of AR significantly influences PCPs' management of AR and may improve their AR diagnostic ability.

Perturbation measures of voice: a comparative study between Multi-Dimensional Voice Program and Praat.

BACKGROUND/AIMS: Frequency and amplitude perturbations are inherent in voice acoustic signals. The assessment of voice perturbation is influenced by several factors, including the type of recording equipment used and the measurement extraction algorithm applied. In the present study, perturbation measures provided by two computer systems (a purpose-built professional voice analysis apparatus and a personal computer-based system for acoustic voice assessment) and two computer programs (Multi-Dimensional Voice Program and Praat) were compared. METHODS: Correlations and inferential statistics for seven perturbation measures (absolute jitter, percent jitter, relative average perturbation, pitch perturbation quotient, shimmer in decibels, percent shimmer, and amplitude perturbation quotient) in 50 subjects with various voice disorders are presented. RESULTS: Results indicate statistically significant differences between the two systems and programs, with the Multi-Dimensional Voice Program yielding consistently higher measures than Praat. Furthermore, correlation analyses show weak to moderate proportional relationships between the two systems and weak to strong proportional relationships between the two programs. CONCLUSION: Based on the literature and the proportional relationships and differences between the two systems and programs under consideration in this study, one can state that one can hardly compare frequency perturbation outcomes across systems and programs and amplitude perturbation outcomes across systems.

Pilot study using doxycycline-releasing stents to ameliorate postoperative healing quality after sinus surgery.

Poor postoperative healing after sinus surgery is associated with high concentrations of matrix metalloproteinase-9 (MMP-9). The frontal recess is especially vulnerable to restenosis, and frontal sinus stents have been used to overcome this problem. However, the long-term success rate is still controversial and may be poor. In this perspective, we developed doxycycline (DC)-releasing stents, delivering the MMP-9 synthesis-suppressing agent locally to the frontal recess area. We evaluated postoperative MMP-9 levels, bacterial colonization, healing quality, and symptom scores in patients suffering from chronic rhinosinusitis with (CRSwNP) and without nasal polyposis (CRSsNP) (n=10) who underwent functional endoscopic sinus surgery during which the DC-releasing and placebo stents were placed. We found that MMP-9 concentrations were significantly lower at the side of the DC-releasing stent (3,414+/-582 ng/mL) compared with the contralateral placebo stent (9,172+/-2,564 ng/mL) (p<0.05) at month 3 postsurgery. DC stents adequately suppressed bacterial growth compared with placebo stents. Furthermore, the visual analog scale (VAS) for the frontal region was significantly better (mean value 75.1 vs. 52.8, p<0.001) compared with its placebo counterpart. We conclude that compared with placebo stents, DC-releasing stents significantly lowered MMP-9 concentrations and bacterial colonization locally, and improved postoperative healing quality after functional endoscopic sinus surgery, as demonstrated by visual analog scale and ostial closure.

Histamine and leukotriene receptor antagonism in the treatment of allergic rhinitis: an update.

Allergic rhinitis represents a global health burden. The disease can seriously affect quality of life and is associated with multiple co-morbidities. Histamine and leukotrienes are important pro-inflammatory mediators in nasal allergic inflammation. Their actions on target cells are mediated through specific receptors and, consequently, molecules that block the binding of histamine and leukotrienes to their receptors have been important areas of pharmacological research. The published literature of the pathophysiology of histamine and leukotrienes, and the effects of histamine H(1)-receptor antagonists (H(1) antihistamines) and leukotriene antagonists in monotherapy or in combination therapy in the treatment of allergic rhinitis was reviewed. The presented results are based on the best available evidence. The efficacy of H(1) antihistamines and leukotriene antagonists (montelukast in particular) in allergic rhinitis has been established in numerous randomised placebo-controlled trials. Results from meta-analyses indicate that H(1) antihistamines and leukotriene antagonists are equally effective in improving symptoms of allergic rhinitis and quality of life, but that both drugs are less effective than intranasal corticosteroids. Data on the combination of H(1) antihistamines and leukotriene antagonists in allergic rhinitis are limited. The available evidence shows that a combined mediator inhibition has additional benefits over the use of each agent alone, but is still inferior to intranasal corticosteroids. More well designed studies are needed to fully understand the benefits of a concomitant use of these agents.