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Phosphoproteomic analysis in a mouse model reveals ERK signaling as a key modulator of inflammatory response in nasal mucosa associated with childhood allergic rhinitis.

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.

Animals

Physiologic/clinical comparisons of a sustained-release decongestant combination, its components and placebo in patients with allergic rhinitis.

Fifteen subjects with chronic allergic rhinitis had measurements of nasal airways flow/resistance (Rn) made before, and for 12 hours after, single doses of a sustained release decongestant combination, some of its components given alone or together, and placebo, in a randomized double-blind trial. The magnitude of improvement in Rn was statistically greater for the the four active preparations than for placebo over the first 8 hours; the effects of phenylpropanolamine/chlorpheniramine were still present after 10 hours, while at the end of 12 hours only the full triple-drug capsule had significant activity. Patient-estimates of symptomatic improvement generally mirrored these physiologic changes although statistical differences among the active capsules were not delineated. The data confirm the ability of electronic posterior rhinometry to discriminate between the effects of active medications and placebo at the 95 per cent confidence level or better and suggest that observed decreases in elevated Rn mean reflected helpful clinical activity as well as increased nasal patency.

Airway Resistance

Bacterial allergy in allergic rhinitis and bronchial asthma.

Nineteen patients suffering from allergic rhinitis and bronchial asthma were studied for bacterial allergy with Staphylococcus aureus, Kelbsiella pneumoniae and Diplococcus pneumoniae. Allergy skin tests, provocative tests and the Migratory Inhibition Factor were employed. The correlation indicates to the authors that bacterial allergy is more important than bacterial "infection" as a cause of allergic rhinitis and asthma in many instances. This is often overlooked by practicing allergists.

Antigens, Bacterial

Metabolism of cyclic nucleotides in allergic rhinitis: studies on lymphocytes, granulocytes, and plasma level.

The effect of isoproterenol on the cyclic nucleotide level in peripheral lymphocytes and granulocytes with allergic rhinitis patients and normal subjects has been studied. Responsiveness to 10(-5) M isoproterenol of lymphocytes decreased in the case of allergic rhinitis patients. When asthma was complicated to perennial rhinitis, a more significant depression was noted. In granulocytes the same tendency as with lymphocytes was noted although the difference was not significant. Basal level and responsiveness to 5 X 10(-3) M theophylline of both lymphocytes and granulocytes were similar in allergic rhinitis patients to normal subjects. The ratio of plasma cAMP to cGMP concentration was lower in the allergic rhinitis patients although the difference was not significant.

Adolescent

A trial of ICI 74,917 in seasonal allergic rhinitis.

Twenty-four patients with seasonal allergic rhinitis were treated in a randomized double-blind trial of 6 weeks' duration, using either ICI 74,917 (0.5 mg in each nostril four times a day) or an identical placebo aerosol. Four patients receiving placebo were withdrawn from the trial because of the deteriorationin their rhinitis. The twelve patients using ICI 74,917 were protected as assessed by a combined total symptom score, which was statistically significant (P less than 0.05), from weeks 1 to 4 when the pollen counts were highest.

Adolescent

Flunisolide nasal spray for the treatment of children with seasonal allergic rhinitis.

Forty-eight children with seasonal allergic rhinitis received either 150 microgram/day of flunisolide (a new topical steroid) or placebo. Those receiving flunisolide had a significantly shorter daily duration of sneezing, stuffy nose, runny nose and throat itch. Total or substantial control of their symptoms was reported by 67% of the flunisolide group and 25% of the placebo group.

Administration, Intranasal

Suppression of seasonal allergic rhinitis symptoms with daily hydroxyzine.

The effectiveness of hydroxyzine in the suppression of allergic rhinitis symptoms was evaluated using a double-blind, parallel study design during the 1977 ragweed season. Forty-three subjects with positive ragweed skin tests and a history of an exacerbation of symptoms during August and September of the previous two years were randomly assigned to receive either hydroxyzine or placebo. Subjects scored the severity and duration of symptoms in a daily diary and adverse effects were evaluated from a structured interview at two-week intervals. Although drowsiness and dry mouth were frequent initially among the hydroxyzine-treated patients, these minor side effects rapidly disappeared as the dose was slowly increased, and all but one subject tolerated 150 mg/day. Subsequently, during the period of the highest ragweek pollen counts, the hydroxyzine-treated group spent significantly more days free of symptoms or with only mild sneezing, rhinorrhea, and eye symptoms than subjects who took placebo (p less than 0.05). Thus, hydroxyzine appeared to be well tolerated on a continuous daily basis and was effective in suppressing most of the symptoms of seasonal allergic rhinitis. Comparison of hydroxyzine with antihistamines more traditionally used for allergic rhinitis appears warranted.

Adult

Beclomethasone dipropionate aerosol in treatment of perennial allergic rhinitis in children.

Forty-four children with perennial allergic rhinitis who had failed to respond to conventional therapy, including sodium cromoglycate insufflation and hyposensitization, were treated with beclomethasone aerosol given intranasally. The study was conducted in a double-blind manner, the patients being allocated active drug or placebo for a 3-week period, followed by a 1-week rest period. The treatments were then crossed over for a period of 3 weeks. After this all children were put on active drug and followed-up at monthly intervals for a period of 3 months. Results were graded as either success of failure, and success had to be an unequivocal vote for the active drug by the patient, parent, and doctor. An overall success rate of 77% was obtained and no untoward or toxic effect was noted in any child. Tetracosactrin tests in 5 children remained normal at the end of the study period. We found intranasal beclomethasone dipropionate to be the most effective drug we have used for treating perennial allergic rhinitis in children.

Aerosols

Symptoms of chronic and allergic rhinitis and occurrence of nasal secretion granulocytes in university students, school children and infants.

The prevalence of chronic and allergic rhinitis was studied in an unselected population sample consisting of 315 university students and 319 school children. History was taken by questionnaire, nasal appearance was examined by rhinoscopy, and a nasal smear was studied in all subjects. For comparison, nasal smears were also collected from 60 normal infants. Allergic rhinitis complaints were reported by 28% of the students and by 13% of the school children, with no significant difference in sex distribution. The cytological examination revealed secretion eosinophilia in 20% of the students, 28% of the school children, and 22% of the infants. Secretion eosinophilia correlated significantly with allergic rhinitis history, and with nasal mucosal swelling and nasal secretion seen on rhinoscopy. Nasal secretion neutrophilia, which occurred in 47% of the students, 79% of the school children and 97% of the infants, seemed to have an adverse effect on the reliability of secretion eosinophilia as an indicator of active nasal allergy. Possible reasons for the rising prevalence rates of allergic rhinitis are discussed.

Adult

The Association of Allergic Rhinitis with Chronic Adenotonsillar Diseases and Chronic Rhinosinusitis: A Mendelian Randomization Study.

INTRODUCTION: Allergic rhinitis (AR) has long been considered to be associated with chronic adenotonsillar disease (CATD). However, their causal relationship remains unclear. This study aims to investigate the causal relationship between AR and CATD and to examine the mediating role of chronic rhinosinusitis (CRS) in this association. METHODS: This study employed a two-sample Mendelian randomization (MR) design using genetic instrumental variable analysis. Data for allergic rhinitis (AR) were obtained from the MRC IEU OpenGWAS data infrastructure, data for chronic adenotonsillar disease (CATD) from the FinnGen biobank, and data for chronic rhinosinusitis (CRS) from the GWAS Catalog. Several MR methods were applied. In addition, a two-step MR approach was used to investigate the mediating role of CRS in the relationship between AR and CATD. RESULTS: MR analysis identified a positive correlation between AR and CATD. IVW and weighted median analyses showed significant causal effects (beta = 0.55, 95% CI: 0.26 to 0.84); p <0.001). No causal association was found between CATD and AR. AR and CRS showed a positive correlation (beta = 1.38, 95% CI: 0.78 to 1.98; p = 6.5 &#xd7; 10-6). CRS had a beta value of 0.15 (95% CI: 0.06 to 0.24; p = 0.001) for CATD. CRS mediates 37.6% of the AR to CATD pathway (mediation effect = 0.20, 95% CI: 0.04 to 0.37; p = 0.013). DISCUSSION: These findings indicate that AR may contribute to CATD risk through CRS, highlighting the need for further research to explore underlying biological mechanisms and validate these findings. CONCLUSIONS: This study suggests a positive causal relationship between AR and CATD, with CRS acting as a mediator.

Mendelian Randomization Analysis

Local production of specific IgE antibodies in allergic-rhinitis patients with negative skin tests.

A group of patients with allergic rhinitis had a clinical history strongly suggestive of house-dust-mite (Dermatophagoides pteronyssinus) allergy but negative skin reactions when prick tested with D. pteronyssinus extracts. These patients were proved to be clinically allergic by nasal provocation with this allergen. Although radioallergosorbent tests showed that these patients lacked specific IgE antibodies in their serum, they did have specific antibodies in their nasal secretions. These findings indicate that these patients had allergic rhinitis mediated by the local production of IgE antibodies.

Adolescent

Peroral chromones. A new way to treat allergic rhinitis?

Disodium chromoglycate (DSCG) is well documented in the topical treatment of allergic rhinitis. Its use does not lead to any major side effects. FPL 57579 is a new chromone compound which is well absorbed after oral administration. In a clinical trial, patients with allergic rhinitis underwent a nasal challenge before and after ingestion of FPL 57579. the effect on nasal airway resistance (NAR) was determined by rhinomanometry. In all cases there was a smaller increase in NAR after the intake of FPL 57579.

Administration, Oral

Decoding the genetic landscape of allergic rhinitis: a comprehensive network analysis revealing key genes and potential therapeutic targets.

BACKGROUND: Allergic Rhinitis (AR), an inflammatory affliction impacting the upper respiratory tract, has been registering a substantial surge in incidence across the globe. METHODS: We embarked on examination of differentially expressed genes (DEGs) and the Weighted Gene Co-Expression Network Analysis (WGCNA). With this armory of genes identified, we engaged the tools of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Our study continued with the establishment of a protein-protein interaction (PPI) network and the application of LASSO regression. Finally, we leveraged a docking model to elucidate potential drug-gene interactions involving these key genes. RESULTS: Through WGCNA and different express genes screening, PPI network was performed, identifying top 20&#x2009;key genes, including CD44, CD69, CD274. LASSO regression identified three independent factors, STARD5, CST1, and CHAC1, that were significantly associated with AR. A predictive model was developed with an AUC value over 0.75. Also, 105 potential therapeutic agents were discovered, including Fluorouracil, Cyclophosphamide, Doxorubicin, and Hydrocortisone, offering promising therapeutic strategies for AR. CONCLUSION: By fuzing DEGs with key genes derived from WGCNA, this study has illuminated a comprehensive network of gene interactions involved in the pathogenesis of AR, paving the way for future biomarker and therapeutic target discovery in AR.

Humans