Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis

Background Epidemiological and experimental data suggest that bacteria] lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th 1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. Objective We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. Results Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1 -affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. Conclusion Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.

Functional interferences in host inflammatory immune response by airway allergic inflammation restrain experimental periodontitis development in mice

Aims Periodontal disease (PD) and airway allergic inflammation (AL) present opposing inflammatory immunological features and clinically present an inverse correlation. However, the putative mechanisms underlying such opposite association are unknown. Material and Methods Balb/C mice were submitted to the co-induction of experimental PD (induced by Actinobacillus actinomycetemcomitans oral inoculation) and AL [induced by sensitization with ovalbumin (OVA) and the subsequent OVA challenges], and evaluated regarding PD and AL severity, immune response [cytokine production at periodontal tissues, and T-helper transcription factors in submandibular lymph nodes (LNs)] and infection parameters. Results PD/AL co-induction decreased PD alveolar bone loss and periodontal inflammation while experimental AL parameters were unaltered. An active functional interference was verified, because independent OVA sensitization and challenge not modulate PD outcome. PD+AL group presented decreased tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, -gamma, IL-17A, receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand and matrix metalloproteinase (MMP)-13 levels in periodontal tissues, while IL-4 and IL-10 levels were unaltered by AL co-induction. AL co-induction also resulted in upregulated T-bet and related orphan receptor gamma and downregulated GATA3 levels expression in submandibular LNs when compared with PD group. Conclusion Our results demonstrate that the interaction between experimental periodontitis and allergy involves functional immunological interferences, which restrains experimental periodontitis development by means of a skewed immune response.

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Clinical and experimental evidences show that formaldehyde (FA) exposure has an irritant effect on the upper airways. As being an indoor and outdoor pollutant, FA is known to be a causal factor of occupational asthma. This study aimed to investigate the repercussion of FA exposure on the course of a lung allergic process triggered by an antigen unrelated to FA. For this purpose, male Wistar rats were subjected to FA inhalation for 3 consecutive days (1%, 90-min daily), subsequently sensitized with ovalbumin (OVA)-alum via the intraperitoneal route, and 2 weeks later challenged with aerosolized OVA. The OVA challenge in rats after FA inhalation (FA/OVA group) evoked a low-intensity lung inflammation as indicated by the reduced enumerated number of inflammatory cells in bronchoalveolar lavage as compared to FA-untreated allergic rats (OVA/OVA group). Treatment with FA also reduced the number of bone marrow cells and blood leukocytes in sensitized animals challenged with OVA, which suggests that the effects of FA had not been only localized to the airways. As indicated by passive cutaneous anaphylactic reaction, FA treatment did not impair the anti-OVA IgE synthesis, but reduced the magnitude of OVA challenge-induced mast cell degranulation. Moreover, FA treatment was associated to a diminished lung expression of PECAM-1 (platelet-endothelial cell adhesion molecule 1) in lung endothelial cells after OVA challenge and an exacerbated release of nitrites by BAL-cultured cells. Keeping in mind that rats subjected solely to either FA or OVA challenge were able to significantly increase the cell influx into lung, our study shows that FA inhalation triggers long-lasting effects that affect multiple mediator systems associated to OVA-induced allergic lung such as the reduction of mast cells activation, PECAM-1 expression and exacerbation of NO generation, thereby contributing to the decrease of cell recruitment after the OVA challenge. In conclusion, repeated expositions to air-borne FA may impair the lung cell recruitment after an allergic stimulus, thereby leading to a non-responsive condition against inflammatory stimuli likely those where mast cells are involved. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Preventive and curative glycoside kaempferol treatments attenuate the TH2-driven allergic airway disease

Asthma is a chronic respiratory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). One strategy to treat allergic diseases is the development of new drugs. Flavonoids are compounds derived from plants and are known to have antiallergic, anti-inflammatory, and antioxidant properties. To investigate whether the flavonoid kaempferol glycoside 3-O-[beta-D-glycopiranosil-(1 -> 6)-alpha-L-ramnopiranosil]-7-O-alpha-L-ramnopiranosil-kaempferol (GRRK) would be capable of modulating allergic airway disease (AAD) either as a preventive (GRRK P) or curative (GRRK C) treatment in an experimental model of asthma. At weekly intervals, BALB/c mice were subcutaneously (sc) sensitized twice with ovalbumin (OVA)/alum and challenged twice with OVA administered intranasally. To evaluate any preventive effects GRRK was administered 1 h (hour) before each OVA-sensitization and challenge, while to analyze the curative effects mice were first sensitized with OVA, followed by GRRK given at day 18 through 21. The onset: of AAD was evaluated 24 h after the last OVA challenge. Both treatments resulted in a dose-dependent reduction in total leukocyte and eosinophil counts in the bronchoalveolar lavage fluid (BAL). GRRK also decreased CD4(+), B220(+), MHC class II and CD40 molecule expressions in BAL cells. Histology and lung mechanic showed that GRRK suppressed mucus production and ameliorated the AHR induced by OVA challenge. Furthermore, GRRK impaired Th2 cytokine production (IL-5 and IL-13) and did not induce a Th1 pattern of inflammation. These findings demonstrate that GRRK treatment before or after established allergic lung disease down-regulates key asthmatic features. Therefore. GRRK has a potential clinical use for the treatment of allergic asthma. (C) 2009 Elsevier B.V. All rights reserved.

Asthma Polymorphic Loci genotyping in Madeira population: identification of potential genetic markers of disease susceptibility, severity and clinical relevance

Asthma is a complex disease, influenced by both environmental and genetic factors. In this study, the analysis of multiple environmental factos assessed by questionnaire and the genotyping of SNPs IL131c.144 G/A, IL41590 C/T, IL41RP2 253183, ADRB21c.16 A/G, ADAM331V4 C/G, ADAM331S1 c.710 G/A, GSDML1236 C/T and STAT6121 C/T were performed in a sample of Madeiran asthmatic patients and their families, and their association to asthma susceptibility and severity was assessed. Family, environmental, social and individual factos such as the presence of rhinitis in one of the parents,the habitation conditions, the family smoking habits, individual food habits and allergen sensitivity, were found to account for asthma severity. IL41590*T and IL41RP2*183$ alleles as well as the combined genotypes IL41590*CT/IL41590*TT and IL41 RP2*253183/IL41RP2*253183 were associated to both asthma susceptibility and severity.GSDML1236*TT was found associated only to asthma severity.Allele ADAM331 V4*C was significantly overM transmitted to asthmatic offspring being linked with the disease by TDT. These findings suggest that in addition to environmental influences, IL41 590 C/T, IL41RP2 253183, ADAM331V4 C/G and GSDML1236 C/T SNPs may constitute important genetic factos contributing to asthmasusceptibility and/or severity in Madeira population.

Profiling allergic asthma volatile metabolic patterns using a headspace-solid phase microextraction/gas chromatography based methodology

Allergicasthmarepresentsanimportantpublichealthissuewithsignificantgrowthovertheyears,especially in the paediatric population. Exhaled breath is a non-invasive, easily performed and rapid method forobtainingsamplesfromthelowerrespiratorytract.Inthepresentmanuscript,themetabolicvolatile profiles of allergic asthma and control children were evaluated by headspace solid-phase microextraction combined with gas chromatography–quadrupole mass spectrometry (HS-SPME/GC–qMS). The lack ofstudiesinbreathofallergicasthmaticchildrenbyHS-SPMEledtothedevelopmentofanexperimental design to optimize SPME parameters. To fulfil this objective, three important HS-SPME experimental parameters that influence the extraction efficiency, namely fibre coating, temperature and time extractions were considered. The selected conditions that promoted higher extraction efficiency corresponding to the higher GC peak areas and number of compounds were: DVB/CAR/PDMS coating fibre, 22◦C and 60min as the extraction temperature and time, respectively. The suitability of two containers, 1L Tedlar® bags and BIOVOC®, for breath collection and intra-individual variability were also investigated. The developed methodology was then applied to the analysis of children exhaled breath with allergicasthma(35),fromwhich13hadalsoallergicrhinitis,andhealthycontrolchildren(15),allowing to identify 44 volatiles distributed over the chemical families of alkanes (linear and ramified) ketones, aromatic hydrocarbons, aldehydes, acids, among others. Multivariate studies were performed by Partial LeastSquares–DiscriminantAnalysis(PLS–DA)usingasetof28selectedmetabolitesanddiscrimination between allergic asthma and control children was attained with a classification rate of 88%. The allergic asthma paediatric population was characterized mainly by the compounds linked to oxidative stress, such as alkanes and aldehydes. Furthermore, more detailed information was achieved combining the volatile metabolic data, suggested by PLS–DA model, and clinical data.

Prevalence of dementia in Latin America: a collaborative study of population-based cohorts

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Alterações orofaciais em doenças alérgicas de vias aéreas

OBJETIVO: Apontar as possíveis alterações orofaciais decorrentes do sintoma obstrução nasal em pacientes portadores de doenças alérgicas de vias aéreas superiores, por meio de revisão de literatura. FONTES DE DADOS: Levantamento bibliográfico utilizando bancos de dados eletrônicos, como Medline, Ovid, SciELO e Lilacs, com as palavras-chave asthma, rhinitis e mouth breathing, abrangendo os 30 últimos anos. Foram incluídos artigos de revisão, estudos observacionais e ensaios clínicos. SÍNTESE DOS DADOS: A obstrução nasal é encontrada freqüentemente em doenças alérgicas de vias aéreas, como rinite e asma. A respiração bucal decorrente da obstrução nasal pode interferir de maneira direta no desenvolvimento infantil, com alterações no crescimento do crânio e orofacial, na fala, na alimentação, na postura corporal, na qualidade do sono e no desempenho escolar. CONCLUSÕES: Devido à variedade de alterações orofaciais encontradas na criança respiradora bucal decorrente de obstrução nasal por doenças alérgicas de vias aéreas, é necessário realizar diagnóstico e tratamento precoces por uma equipe multidisciplinar, composta por médico, ortodontista e fonoaudiólogo, contemplando a visão de uma via respiratória única, que traz conseqüências ao crescimento e desenvolvimento do sistema motor oral.

Clinical and histopathological aspects of the insect bite hypersensitivity in horses

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry

OBJECTIVES. The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome.PATIENTS and METHODS. A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient's 18th birthday.RESULTS. As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-beta(2)-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.CONCLUSIONS. Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups. Pediatrics 2008; 122: e1100-e1107

High incidences of DNA ploidy abnormalities in tongue squamous cell carcinoma of young patients: an international collaborative study

Aims: This multi-centre analysis assessed the DNA content of TSCC in 37 young patients (<40 years) and 28 old patients (>50 years) and determined the correlation of DNA ploidy findings with clinicopathological data.Methods and results: Image cytometry was carried out using an automated cellular imaging system on Feulgen-stained histological sections to obtain high-fidelity DNA histograms. Among young patients, 37.8% were females compared to 18.7% in the older group (P = 0.002). In total, 48.6% patients were non-smokers and 40.5% were non-drinkers compared to 10.7% non-smokers and non-drinkers in the older group (P < 0.0001). TNM, clinical stage of disease and histological grade of differentiation did not differ between groups. Tumour aneuploidy was detected in 86.5% and tetraploidy in 24.3% young patients; this was significantly greater than in the older group where 64.3% were aneuploid (P < 0.0001) and 7.2% tetraploid (P < 0.0001). The mean values of DNA index (DI) and DNA heterogeneity index as well as the percentage of cells with DI exceeding 5N were higher in young patients (P < 0.0001).Conclusions: Young patients with TSCC represent a distinct clinical entity. The high incidence of DNA ploidy abnormalities suggest that they may have increased genomic instability and indicates underlying genetic differences between TSCC in young and older patients.

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Alergia látex-fruta

O látex está sendo considerado o alergênico do ano 2000, tendo em vista que inúmeros indivíduos, principalmente profissionais da área de saúde e pacientes submetidos a várias intervenções diagnósticas e terapêuticas, estão freqüentemente expostos aos alérgenos do látex, presentes em produtos de borracha natural. As manifestações clínicas conseqüentes às reações alérgicas de hipersensibilidade imediata vão desde rinite, urticária, conjuntivite, angioedema, asma, até anafilaxia. Estudos recentes estão demonstrando que pacientes alérgicos ao látex desenvolvem concomitantemente sensibilização a certos alimentos de origem vegetal, especialmente frutas como papaia, figo, banana, abacate, kiwi, pêssego, abacaxi, melão e castanha, acreditando-se numa provável ocorrência de reações cruzadas entre os alérgenos do látex e destas frutas. Faz-se, então, uma revisão sobre a alergia ao látex, em particular sobre os grupos de risco, incluindo a presença de reatividade cruzada entre o látex e as frutas.

The Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders: recruitment, assessment instruments, methods for the development of multicenter collaborative studies and preliminary results

OBJETIVO: Descrever o recrutamento de pacientes, instrumentos de avaliação, métodos para o desenvolvimento de estudos colaborativos multicêntricos e os resultados preliminares do Consórcio Brasileiro de Pesquisa em Transtornos do Espectro Obsessivo-Compulsivo, que inclui sete centros universitários. MÉTODO: Este estudo transversal incluiu entrevistas semi-estruturadas (dados sociodemográficos, histórico médico e psiquiátrico, curso da doença e diagnósticos psiquiátricos comórbidos) e instrumentos que avaliam os sintomas do transtorno obsessivo-compulsivo (Escala para Sintomas Obsessivo-Compulsivos de Yale-Brown e Escala Dimensional para Sintomas Obsessivo-Compulsivos de Yale-Brown), sintomas depressivos (Inventário de Depressão de Beck), sintomas ansiosos (Inventário de Ansiedade de Beck), fenômenos sensoriais (Escala de Fenômenos Sensoriais da Universidade de São Paulo), juízo crítico (Escala de Avaliação de Crenças de Brown), tiques (Escala de Gravidade Global de Tiques de Yale) e qualidade de vida (questionário genérico de avaliação de qualidade de vida, Medical Outcome Quality of Life Scale Short-form-36 e Escala de Avaliação Social). O treinamento dos avaliadores consistiu em assistir cinco entrevistas filmadas e entrevistar cinco pacientes junto com um pesquisador mais experiente, antes de entrevistar pacientes sozinhos. A confiabilidade entre todos os líderes de grupo para os instrumentos mais importantes (Structured Clinical Interview for DSM-IV, Dimensional Yale-Brown Obsessive-Compulsive Scale, Universidade de São Paulo Sensory Phenomena Scale ) foi medida após seis entrevistas completas. RESULTADOS: A confiabilidade entre avaliadores foi de 96%. Até março de 2008, 630 pacientes com transtorno obsessivo-compulsivo tinham sido sistematicamente avaliados. A média de idade (±SE) foi de 34,7 (±0,51), 56,3% eram do sexo feminino e 84,6% caucasianos. Os sintomas obsessivo-compulsivos mais prevalentes foram os de simetria e os de contaminação. As comorbidades psiquiátricas mais comuns foram depressão maior, ansiedade generalizada e transtorno de ansiedade social. O transtorno de controle de impulsos mais comum foi escoriação neurótica. CONCLUSÃO: Este consórcio de pesquisa, pioneiro no Brasil, permitiu delinear o perfil sociodemográfico, clínico e terapêutico do paciente com transtorno obsessivo-compulsivo em uma grande amostra clínica de pacientes. O Consórcio Brasileiro de Pesquisa em Transtornos do Espectro Obsessivo-Compulsivo estabeleceu uma importante rede de colaboração de investigação clínica padronizada sobre o transtorno obsessivo-compulsivo e pode abrir o caminho para projetos semelhantes destinados a integrar outros grupos de pesquisa no Brasil e em todo o mundo.