Mometasone and desloratadine additive effect on eosinophil survival and cytokine secretion from epithelial cells

Although antihistamines and topical corticosteroids are used in combination to treat allergic rhinitis, their additive effect has not been yet demonstrated. The aim was investigate the antiinflammatory additive effect of mometasone and desloratadine on cytokine and sICAM-1 secretion by epithelial cells, and on eosinophil survival stimulated by human epithelial cells secretions from nasal mucosa and polyps. Methods Epithelial cells obtained from nasal mucosa or polyps were stimulated with 10% fetal bovine serum in presence of mometasone (10-11M-10-5M) with/without desloratadine (10-5M). Cytokine and sICAM-1 concentrations in supernatants were measured by ELISA. Peripheral blood eosinophils were incubated during 4 days with epithelial cell secretions with (10-11M-10-5M) and/or desloratadine (10-5M) and survival assessed by Trypan blue. Results are expressed as percentage (mean ± SEM) compared to control. Results Fetal bovine serum stimulated IL-6, IL-8, GM-CSF and sICAM-1 secretion. In mucosa and polyp epithelial cells, mometasone inhibited this induced secretion while desloratadine inhibited IL-6 and IL-8. The combination of 10-5M desloratadine and 10-9M mometasone reduced IL-6 secretion (48 ± 11%, p < 0.05) greater extent than mometasone alone (68 ± 10%) compared to control (100%). Epithelial cell secretions induced eosinophil survival from day 1 to 4, this effect being inhibited by mometasone. At day 4, the combination of mometasone (10-11M) and desloratadine (10-5M) provoked an increased inhibition of eosinophil survival induced by cell secretions (27 ± 5%, p < 0.01) than mometasone (44 ± 7%) or desloratadine (46 ± 7%) alone. Conclusions These results suggest that the combination of desloratadine and mometasone furoate have a greater antinflammatory effect in an in vitro model of eosinophil inflammation than those drugs administered alone.

Direct to consumer advertising : the case for greater consumer control

A nyone traveling to the United States from countries other than New Zealand will be surprised by the prevalence of health-related advertisements on television, including ads for drugs. Typically, these TV ads follow a pattern: an ad for a burger at only 99 cents, followed by one for a proton-pump inhibitor, then an ad on healthy home-cooked food delivered directly to your home and an ad for a home-based abdominal workout DVD, followed by an ad for a lipid-lowering drug. There are, however, nuances. After 8 pm, the visitor might encounter an ad for the "little blue pill." This sequence sometimes includes an ad featuring antihistamines for allergic rhinitis in spring and one promoting antidepressants in the winter. Such direct-to-consumer advertising (DTCA) of prescription drugs is usual business in the United States and New Zealand but is prohibited in the rest of the world. Why? Because DTCA for prescribing drugs has pros and cons (discussed elsewhere,1-3 including in JGIM4) that are balanced differently in different countries. Constitutional factors-such as the First Amendment protections on speech, including commercial speech, in the United States5 -as well as patient and population safety considerations, which all differ across countries, modulate reactions to DTCA. Additionally, lack of robust data on the impact of DTCA on prescription drug use adds to the confusion. Evidence, though limited, suggests that DTCA increases drug sales. However, whether the increase in sales corrects existing underuse or encourages over/misuse is not clear.

Humoral and cellular immune responses to Blomia tropicalis and concanavalin A-binding fractions in atopic patients

Blomia tropicalis, Dermatophagoides pteronyssinus and D. farinae are prevalent house dust mites. Concanavalin A-binding components derived from B. tropicalis (Bt-ConA extract) are highly immunogenic in allergic diseases. The aim of the present study was to evaluate the humoral and cellular immune responses to B. tropicalis in mite-sensitized patients. A total of 137 patients with allergic rhinitis with/without asthma and 109 non-atopic subjects were selected and analyzed by the skin prick test, and for total serum IgE and specific IgE levels to both Bt-total and Bt-ConA extracts, their proliferative response and cytokine (IFN-γ and IL-5) production by peripheral blood mononuclear cells (PBMC) stimulated with both extracts. Skin prick test showed that 70% of the patients were sensitized to Bt (Bt+) and similar levels of specific IgE to Bt-total and Bt-ConA extracts were demonstrable in Bt+ patients. Significant PBMC proliferation was observed in response to Bt-total extract in Bt+, but not in Bt- patients and non-atopic subjects (P < 0.001). Bt-ConA extract induced increased proliferative responses in all patient groups compared to medium alone (P < 0.05), but these responses were significantly decreased in the presence of the mannopyranoside ConA inhibitor (P < 0.05). Significant IFN-γ production was observed after Bt-ConA stimulation of Bt+ patients (P < 0.05), while Bt-total extract had no effect. IL-5 production was consistently detected in Bt+ patients after allergen-specific stimulation or with no stimulus, indicating that PBMC from allergic patients are prone to produce Th2 profile cytokines, spontaneously or inductively by allergen restimulation. These data showed that ConA-binding components isolated from B. tropicalis may contain relevant antigens that are involved in both humoral and cellular immune responses. However, without an additional purification procedure to eliminate the residual contamination with ConA, its use in immunotherapeutic procedures cannot be recommended.

IgE cross-reactivity between Lolium multiflorum and commercial grass pollen allergen extracts in Brazilian patients with pollinosis

Lolium multiflorum (Lm) grass pollen is the major cause of pollinosis in Southern Brazil. The objectives of this study were to investigate immunodominant components of Lm pollen allergens and the cross-reactivity of IgE with commercial grass pollen allergen extracts. Thirty-eight serum samples from patients with seasonal allergic rhinitis (SAR), 35 serum samples from patients with perennial allergic rhinitis (PAR) and 30 serum samples from non-atopic subjects were analyzed. Allergen sensitization was evaluated using skin prick test and serum IgE levels against Lm pollen extract were determined by ELISA. Inhibition ELISA and immunoblot were used to evaluate the cross-reactivity of IgE between allergens from Lm and commercial grass pollen extracts, including L. perenne (Lp), grass mix I (GI) and II (GII) extracts. IgE antibodies against Lm were detected in 100% of SAR patients and 8.6% of PAR patients. Inhibition ELISA demonstrated IgE cross-reactivity between homologous (Lm) and heterologous (Lp or GII) grass pollen extracts, but not for the GI extract. Fifteen IgE-binding Lm components were detected and immunoblot bands of 26, 28-30, and 32-35 kDa showed >90% recognition. Lm, Lp and GII extracts significantly inhibited IgE binding to the most immunodominant Lm components, particularly the 55 kDa band. The 26 kDa and 90-114 kDa bands presented the lowest amount of heterologous inhibition. We demonstrated that Lm extract contains both Lm-specific and cross-reactive IgE-binding components and therefore it is suitable for measuring quantitative IgE levels for diagnostic and therapeutic purposes in patients with pollinosis sensitized to Lm grass pollen rather than other phylogenetically related grass pollen extracts.

Asociación entre los valores de RANTES y la clínica en pacientes con rinitis alérgica

Objetivo: El siguiente estudio tiene como objetivo determinar, los valores de RANTES, posterior a la exposición a ácaros, para evaluar su asociación con la escala ARIA, en el grupo de pacientes seleccionado. Diseño: Estudio descriptivo correlacional, Materiales y Métodos: Se incluyeron 17 pacientes que consultaron por Rinitis Alérgica al Hospital de la Samaritana entre el 01 Julio del 2010 y el 01 Julio del 2011, y que cumplieron los criterios de selección, de los cuales se obtuvieron 34 muestras de lavados nasales posterior a provocación intranasal con ácaros. Resultados: Los pacientes mostraron mayor tendencia a pertenecer al grupo de síntomas de mayor severidad y frecuencia según la escala ARIA. Los valores de RANTES encontrados en lavados nasales tuvieron un promedio de 8,1 pg/ml (+/- 19DS). Conclusión: Se encontró una positividad en los valores de la citoquina CCL5 en los lavados nasales del 20% de los pacientes. El coeficiente de correlación obtenido, muestra una asociación débil.

Prevalence of asthma and risk factors associated: population based study in Sao Paulo, Southeastern Brazil, 2008-2009

OBJECTIVE: To assess the prevalence of asthma and risk factors associated in children and adolescents. METHODS: Population-based cross-sectional study with 1,185 female and male children and adolescents carried out in the city of Sao Paulo, Southeastern Brazil, from 2008 to 2009. Data were collected through home interviews. Respondents were selected from two-stage (census tract, household) cluster random sampling stratified by gender and age. Multiple Poisson regression was used in the adjusted analysis between the outcome and socioeconomic, demographic, lifestyle and health condition variables. RESULTS: Of all respondents, 9.1% (95%CI 7.0; 11.7) reported asthma. After adjustment, the following variables were found independently associated with asthma: age (0 to 4 years vs. 15 to 19) (PR 3.18, 95%CI 1.20;8.42); age (5 to 9 years vs. 15 to 19) (PR 6.37, 95%CI 2.64;15.39); age (10 to 14 years vs. 15 to 19) (PR 4.51,95%CI 1.95;10.40); allergy (yes vs. no) (PR 2.22, 95%CI 1.24;4.00); rhinitis (yes vs. no) (PR 2.13, 95%CI 1.22;3.73); health conditions in the 15 days preceding the interview (yes vs. no) (PR 1.96, 95%CI 1.23;3.11); number of rooms in the household (1 to 3 vs. 4 and more) (PR 1.67, 95%CI 1.05;2.66); and skin color (black and mixed vs. white) (PR 2.00, 95%CI 1.14;3.49). CONCLUSIONS: This study showed the importance of factors associated with asthma including rhinitis and allergy; age between 5 to 9 years old; black and mixed skin color; and household with few rooms. Frequent health problems are seen as a common consequence of asthma.

Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

Purpose: We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC). Methods: A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay. Results: Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p = 0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p < 0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173,55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9-3.1; p = 0.122). Conclusions: Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Respiratory diseases and associated factors: population-based study in Sao Paulo, Brazil, 2008-2009

OBJECTIVE: To assess the prevalence of acute bronchitis, rhinitis, and sinusitis among children and adolescents and identify associated factors. METHODS: This is a population-based, cross-sectional study. A household survey was conducted with 1,185 children and adolescents from the city of Sao Paulo (Southeastern Brazil), from 2008 to 2009. The participants were selected by means of probability sampling, stratified by sex and age, and by two-stage cluster sampling. For the adjusted analysis, multiple Poisson regression was used. RESULTS: Of the respondents, 7.3% reported acute bronchitis, 22.6% rhinitis and 15.3% sinusitis. After the adjusted analysis, the following characteristics were associated with self;reported acute bronchitis: age 0 to 4 years (PR=17.86; 95%Cl: 3.65;90.91), 5 to 9 years (PR=37.04; 95%CI: 8.13;166.67), 10 to 14 years (PR.=20,83; 95%Cl: 4.93;90.91), allergy (PR=3.12; 95%Cl: 1.70;5.73), black and mixed-ethnicity (black and white) skin color (PR=2.29; 95%Cl: 1.21;4.35), and living in a household with 1 to 3 rooms (PR=1.85; 95%Cl: 1.17;2.94). As to self-reported rhinitis, the following characteristics were associated: age 10 to 14 years (PR=2.77; 95%Cl: 1.60;4.78), 15 to 19 years (P.R=2.58; 95%Cl: 1.52;4.39), allergy (PR=4.32; 95%Cl: 2.79;6.70), asthma (PR=2.30; 95%CI: 1.30;4.10) and living in flats (PR=1.70; 95%Cl: 1.06;2.73). Concerning self-reported sinusitis, the following characteristics were associated: age 5 to 9 years (PR=2.44; 95%Cl: 1.09;5.43), 10 to 14 years (PR=2.99; 95%CI: 1.36;6.58), 15 to 19 years (PR=3.62; 95%Cl: 1.68;7.81), allergy (PR=2.23 (95%CI: 1.41;3.52) and obesity (PR=4.42; 95%Cl: 1.56;12.50). CONCLUSIONS: Respiratory diseases were more prevalent in population groups with defined characteristics, such as age group, self-reported diseases, type of household and obesity.

Why do we not find polyps in the lungs? Bronchial mucosa as a model in the treatment of polyposis

The link between lower and upper airways has been reported since the beginning of 1800s. They share the same pseudostratified ciliated columnar epithelium lining and the concept of one airway, one disease is quite well widespread. Nasal polyposis and asthma share basically the same inflammatory process: predominant infiltration of eosinophils, mucus cell hyperplasia, edema, thickened basal membrane, polarization for Th2 cell immune response, similar pro-inflammatory mediators are increased, for example cysteinyl leukotrienes. If the lower and upper airways share a lot of common epithelial structural features so why is the edema in the nasal mucosa able to increase so much the size of the mucosa to the point of developing polyps? The article tries to underline some differences between the nasal and the bronchial mucosa that could be implicated in this aberrant change from normal mucosa to polyps. This paper creates the concept that there are no polyps with the features of nasal polyposis disease in the lower airway and through it is developed the hypothesis of the nasal polyps origin could partially lie on the difference between the upper and lower airway histology. (C) 2012 Elsevier Ltd. All rights reserved.

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists

The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also propose definitions for 'difficult to treat' rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between the upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists.

Influence of treatment with intranasal corticosteroids on the nasal mucosa, weight, and corticosteroid concentration in rats

Background: The effect of intranasal corticosteroids on the nasal epithelium mucosa is an important parameter of treatment safety. This study was designed to examine whether treatment with topical corticosteroids in patients with allergic rhinitis causes atrophic nasal mucosal changes, when compared with systemic corticosteroids, in rats. Methods: Male Wistar rats were treated daily during 7 weeks with topical administration with 10 microliters of normal saline (control group), 10 microliters of mometasone furoate group, 10 microliters of triamcinolone acetonide (T group), and 8 mg/kg of daily subcutaneous injections of methylprednisolone sodium succinate (MP group). Body weight was evaluated weekly. At the end of the treatment, rats were killed by decapitation to collect blood for determination of corticosterone levels and nasal cavities were prepared for histological descriptive analyses. Results: Treatment with T and MP decreased body weight. Plasma corticosterone concentration was significantly reduced by MP treatment and presented a clear tendency to decrease after T treatment. Histological changes observed in group T included ripples, cell vacuolization, increase in the number of nuclei, and decrease in the number of cilia in the epithelial cells. Conclusion: Growth and corticosterone concentration were impaired by T and MP at the same proportion, suggesting a role of this hormone in body gain. With the exception of T, intranasal or systemic treatment with the corticosteroids evaluated in this study did not affect nasal mucosa. (Am J Rhinol Allergy 26, e46-e49, 2012; doi: 10.2500/ajra.2012.26.3702)

Isolierung und Charakterisierung allergener Proteine aus der Amerikanischen Schabe (Periplaneta americana)

Allergie gegen Schaben ist eine der Hauptursachen für das Auftreten von allergischem Asthma und allergischer Rhinitis. Verursacht werden diese Krankheiten durch die Schabenallergene. Obwohl bisher zahlreiche Allergene identifiziert wurden, ist bisher nicht bekannt, was ein Protein tatsächlich zu einem Allergen macht. Um die intrinsischen Eigenschaften von Allergenen besser verstehen zu können, wurden in dieser Arbeit Reinigungsprotokolle für die zwei Allergenklassen Per a 3 und Per a 9 aus der Amerikanischen Schabe entwickelt und die Allergene biochemisch und immunologisch charakterisiert. Die Besonderheit der Per a 3-Allergene liegt zum einen darin, dass bisher keine kreuzreagierenden Allergene bekannt sind und zum anderen, dass es sich um -hinsichtlich Temperatur, Harnstoff und Hydrolyse- sehr stabile hexamere Proteine handelt. Zudem sind sie in ihrer nativen hexameren Oligomerisierung stärkere Allergene und in dissoziierter Form könnten sie geeignete Kandidaten für eine Immuntherapie sein. Proteinbiochemisch sind die Per a 3-Allergene als Hexamerine einzustufen. Bei Per a 9 handelt es sich um eine monomere Arginin-Kinase mit allergenem Potential. Aufgrund der weiten Verbreitung der Arginin-Kinasen, den hohen Sequenzidentitäten zu weiteren Invertebraten-Arginin-Kinasen und den bisher bekannten Kreuzreaktionen sind diese Proteine aus Invertebraten wahrscheinlich als Pan-Allergene einzustufen.

Strategie formulative per la veicolazione nasale di farmaci

Microparticelle a base di complessi polielettrolitici di Chitosano/Pectina per il rilascio nasale di Tacrina cloridrato. Lo scopo di questo studio è stata la ricerca di nuove formulazioni solide per la somministrazione nasale di Tacrina cloridrato allo scopo di ridurre l’eccessivo effetto di primo passaggio epatico ed aumentarne la biodisponibilità a livello del Sistema Nervoso Centrale. La Tacrina è stata incapsulata in microparticelle mucoadesive a base di complessi elettrolitici di chitosano e pectina. Le microparticelle sono state preparate mediante due diversi approcci tecnologici (spray-drying e spray-drying/liofilizzazione) e analizzate in termini di caratteristiche dimensionali, morfologiche e chimico-fisiche. Nanoparticelle di Chitosano reticolate con Sodio Cromoglicato per il trattamento della rinite allergica. Il Sodio Cromoglicato è uno dei farmaci utilizzati per il trattamento della rinite allergica. Come noto, la clearance mucociliare provoca una rapida rimozione dei farmaci in soluzione dalla cavità nasale, aumentando così il numero di somministrazioni giornaliere e, di conseguenza, riducendo la compliance del paziente. Per ovviare a tale problema, si è pensato di includere il sodio cromoglicato in nanoparticelle di chitosano, un polimero capace di aderire alla mucosa nasale, prolungare il contatto della formulazione con il sito di applicazione e ridurre il numero di somministrazioni giornaliere. Le nanoparticelle ottenute sono state caratterizzate in termini di dimensioni, resa, efficienza di incapsulazione e caricamento del farmaco, potenziale zeta e caratteristiche mucoadesive. Analisi quantitativa di Budesonide amorfa tramite calorimetria a scansione differenziale. È stato sviluppato un nuovo metodo quantitativo allo stato solido basato sulla Calorimetria a Scansione Differenziale (DSC) in grado di quantificare in modo selettivo e accurato la quantità di Budesonide amorfa presente in una miscela solida. Durante lo sviluppo del metodo sono stati affrontati problemi relativi alla convalida di metodi analitici su campioni solidi quali la miscelazione di polveri solide per la preparazione di miscele standard e il calcolo della precisione.

Meta-analysis of mould and dampness exposure on asthma and allergy in eight European birth cohorts: an ENRIECO initiative

Background:  Several cross-sectional studies during the past 10 years have observed an increased risk of allergic outcomes for children living in damp or mouldy environments. Objective:  The objective of this study was to investigate whether reported mould or dampness exposure in early life is associated with the development of allergic disorders in children from eight European birth cohorts. Methods:  We analysed data from 31 742 children from eight ongoing European birth cohorts. Exposure to mould and allergic health outcomes were assessed by parental questionnaires at different time points. Meta-analyses with fixed- and random-effect models were applied. The number of the studies included in each analysis varied based on the outcome data available for each cohort. Results:  Exposure to visible mould and/or dampness during first 2 years of life was associated with an increased risk of developing asthma: there was a significant association with early asthma symptoms in meta-analyses of four cohorts [0–2 years: adjusted odds ratios (aOR), 1.39 (95%CI, 1.05–1.84)] and with asthma later in childhood in six cohorts [6–8 years: aOR, 1.09(95%CI, 0.90–1.32) and 3–10 years: aOR, 1.10 (95%CI, 0.90–1.34)]. A statistically significant association was observed in six cohorts with symptoms of allergic rhinitis at school age [6–8 years: aOR, 1.12 (1.02–1.23)] and at any time point between 3 and 10 years [aOR, 1.18 (1.09–1.28)]. Conclusion:  These findings suggest that a mouldy home environment in early life is associated with an increased risk of asthma particularly in young children and allergic rhinitis symptoms in school-age children.

Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts

Objective To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6–10 years. Design Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s. Exposure definition Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life. Outcome definition Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 6–10 years of age. Data synthesis Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models. Results We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with “no pets” (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with “no pets” (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to “no pets” resulted in an odds ratio of 1.04 (0.59 to 1.84) (I2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens. Conclusions Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given.