RESUMEN
A patient-reported history of penicillin allergy is a common label with a prevalence of about 10%. However, as many as 95% of patients reporting a penicillin allergy do not have a true immunoglobin-E (IgE)-mediated allergic reaction. Unfortunately, penicillin allergy mislabeling is problematic, leading to inappropriate antibiotic use and negative consequences, such as adverse drug events, suboptimal outcomes, and increased costs. As physicians who treat patients of all ages for common sinonasal pathology in the clinic and operating room in addition to frequently providing testing and management of allergic diseases, rhinologists are well positioned to aid in delabeling patients with inaccurate penicillin allergies. This viewpoint highlights the consequences of inaccurate penicillin allergy designation in the clinic and perioperative period and explores misconceptions regarding cross-reactivity between penicillins and cephalosporins. Opportunities are explored for shared decision-making with colleagues in other specialties, such as anesthesiology, and practical recommendations are provided to aid rhinologists when faced with a patient who holds a questionable history of penicillin allergy. Rhinologists can play an active role in delabeling patients with inaccurate penicillin allergies with the goal of ensuring appropriate antibiotic use for future medical encounters.
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Hipersensibilidad a las Drogas , Hipersensibilidad , Humanos , Penicilinas/efectos adversos , Antibacterianos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/terapia , Cefalosporinas/efectos adversosRESUMEN
Cleaners have an elevated risk for the development or exacerbation of asthma and other respiratory conditions, possibly due to exposure to cleaning products containing volatile organic compounds (VOCs) leading to inflammation and oxidative stress. This pilot study aimed to quantify total personal exposure to VOCs and to assess biomarkers of inflammation and pulmonary oxidative stress in 15 predominantly Hispanic women working as domestic cleaners in San Antonio, Texas, between November 2019 and July 2020. In partnership with a community organization, Domésticas Unidas, recruited women were invited to attend a training session where they were provided 3M 3500 passive organic vapor monitors (badges) and began a 72-hr sampling period during which they were instructed to wear one badge during the entire period ("AT," for All the Time), a second badge only while they were inside their home ("INS," for INSide), and a third badge only when they were outside their home ("OUT," for OUTside). At the end of the sampling period, women returned the badges and provided blood and exhaled breath condensate (EBC) samples. From the badges, 30 individual VOCs were measured and summed to inform total VOC (TVOC) concentrations, as well as concentrations of the following VOC groups: aromatic hydrocarbons, alkanes, halogenated hydrocarbons, and terpenes. From the blood and EBC samples, concentrations of serum C-reactive protein (CRP) and EBC 8-isoprostane (8-ISP) and pH were quantified. Data analyses included descriptive statistics. The 72-hr average of personal exposure to TVOC was 34.4 ppb and ranged from 9.2 to 219.5 ppb. The most prevalent class of VOC exposures for most women (66.7%) was terpenes, specifically d-limonene. Overall, most women also experienced higher TVOC concentrations while outside their home (86.7%) as compared to inside their home. Serum CRP concentrations ranged from 0.3 to 20.3 mg/dL; 8-ISP concentrations ranged from 9.5 to 44.1 pg/mL; and EBC pH ranged from 7.1 to 8.6. Overall, this pilot study demonstrated personal VOC exposure among Hispanic domestic cleaners, particularly to d-limonene, which may result from the use of scented cleaning products.
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Compuestos Orgánicos Volátiles , Femenino , Hispánicos o Latinos , Humanos , Inflamación , Limoneno , Proyectos PilotoRESUMEN
2'3'-cGAMP is known as a nonclassical second messenger and small immune modulator that possesses potent antitumor and antiviral activities via inducing the stimulator of IFN genes-mediated (STING-mediated) signaling pathway. However, its function in regulating type 2 immune responses remains unknown. Therefore, we sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperreactivity induced by IL-33 and a fungal allergen, Aspergillus flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING/IFN regulatory factor 3/type I IFN signaling axis to induce the production of inhibitory factors containing IFN-α, which blocked the IL-33-mediated activation of group 2 innate lymphoid (ILC2) cells in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 cells in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.
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Asma/inmunología , Interleucina-33/metabolismo , Linfocitos/inmunología , Macrófagos Alveolares/inmunología , Proteínas de la Membrana/metabolismo , Alérgenos/administración & dosificación , Animales , Aspergillus flavus/inmunología , Asma/metabolismo , Asma/patología , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/metabolismo , Eosinofilia/patología , Femenino , Nucleótidos de Guanina/administración & dosificación , Nucleótidos de Guanina/inmunología , Nucleótidos de Guanina/metabolismo , Humanos , Inmunidad Innata , Técnicas In Vitro , Interleucina-33/administración & dosificación , Interleucina-33/genética , Linfocitos/patología , Macrófagos Alveolares/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Transducción de SeñalRESUMEN
The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists. We used the R-CEPIAer endoplasmic reticulum calcium reporter to functionally assay for Gq-coupled receptor signaling, and investigated the bis-quinolinium cyclophanes as antagonists of M3 mACHR activation in transfected CHO cells. Given mACHR roles in airway smooth muscle (ASM) contractility, we also tested the ability of UCL 1684 to relax ASM. We find that these compounds antagonized M3 mACHRs with an IC50 of 0.27 µM for dequalinium chloride, 1.5 µM for UCL 1684 and 1.0 µM for UCL 1848. UCL 1684 also antagonized M1 (IC50 0.12 µM) and M5 (IC50 0.52 µM) mACHR responses. UCL 1684 was determined to be a competitive antagonist at M3 receptors as it increased the EC50 for carbachol without a reduction in the maximum response. The Ki for UCL1684 determined from competition binding experiments was 909 nM. UCL 1684 reduced carbachol-evoked ASM contractions (>90%, IC50 0.43 µM), and calcium mobilization in rodent and human lung ASM cells. We conclude that dequalinium and bis-quinolinium cyclophanes antagonized M3 mACHR activation at sub- to low micromolar concentrations, with UCL 1684 acting as an ASM relaxant. Caution should be taken when using these compounds to block SK potassium channels, as inhibition of mACHRs may be a side-effect if excessive concentrations are used.
RESUMEN
Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.
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Trampas Extracelulares/inmunología , Inmunidad Innata/inmunología , Linfocitos/inmunología , Neumonía/inmunología , ARN/inmunología , Hipersensibilidad Respiratoria/inmunología , Inmunidad Adaptativa , Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Adaptadoras del Transporte Vesicular/fisiología , Alérgenos/inmunología , Alérgenos/metabolismo , Animales , Citocinas/metabolismo , Trampas Extracelulares/metabolismo , Interleucina-33/inmunología , Interleucina-33/metabolismo , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/metabolismo , Neumonía/patología , ARN/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Transducción de Señal , Células Th2/inmunología , Células Th2/metabolismo , Receptor Toll-Like 3/fisiologíaRESUMEN
The innate immune sensing of allergens or allergen-associated components regulate the development of type 2 inflammatory responses. However, the underlying molecular basis by which allergens or allergen-associated components are detected by innate immune receptors remains elusive. In this study, we report that the most common aeroallergen, house dust mite (HDM), harbors a dsRNA species (HDM-dsRNA) that can activate TLR3-mediated IFN responses and counteract the development of an uncontrolled type 2 immune response. We demonstrate that the mouse strains defective in the dsRNA-sensing pathways show aggravated type 2 inflammation defined by severe eosinophilia, elevated level of type 2 cytokines, and mucus overproduction in a model of allergic lung inflammation. The inability to sense HDM-dsRNA resulted in significant increases in airway hyperreactivity. We further show that the administration of the purified HDM-dsRNA at a low dose is sufficient to induce an immune response to prevent the onset of a severe type 2 lung inflammation. Collectively, these results unveil a new role for the HDM-dsRNA/TLR3-signaling axis in the modulation of a type 2 lung inflammation in mice.
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Alérgenos/inmunología , Interferones/biosíntesis , Neumonía/etiología , Pyroglyphidae/inmunología , ARN Bicatenario/inmunología , Animales , Humanos , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Hipersensibilidad Respiratoria/etiología , Transducción de Señal/fisiología , Receptor Toll-Like 3/fisiologíaRESUMEN
OBJECTIVES: While pembrolizumab improves overall survival (OS) in a subset of advanced nonsmall cell lung cancer (aNSCLC) patients (pts) in clinical trials, individuals with poor Eastern Cooperative Oncology Group performance status (ECOG PS) were excluded. Furthermore, some studies have identified a potential link between improved pt outcomes and development of immune related adverse events (irAE.) In a large provincial cohort, we studied the efficacy and safety of pembrolizumab for poor ECOG PS pts and whether irAE correlate with improved OS. MATERIALS AND METHODS: aNSCLC pts treated with pembrolizumab between 06/2015 and 08/2018 at BC Cancer were retrospectively identified. Kaplan-Meier curves of OS from initiation of pembrolizumab were plotted. 3-, 6-, and 9- month landmark Kaplan-Meier analysis was performed and log-rank tests used to determine an association of irAE subtypes with OS. Multivariable logistic regression identified variables associated with grade ≥3 irAE within 3 months of pembrolizumab initiation. RESULTS: Of 190 pts, 74.2% were treatment naïve and 92.6% had PD-L1 expression ≥ 50%. Median OS in the 1st line and ≥2nd line settings were 24.3 months (95% CI, 9.7-not reached, NR) and 13.4 months (95% CI, 8.1-NR), respectively. Pts with ECOG PS 2/3 had lower median OS than if ECOG PS 0/1 (5.8 months vs. 16.7 months, p < 0.0001). In multivariable analysis, the odds of grade ≥ 3 irAE within 3 months was 6.3 fold higher if ECOG PS 2/3 versus 0/1 (p = 0.05). Development of pneumonitis at the 9 month landmark weakly correlated with decreased OS (p = 0.09). CONCLUSION: In the studied cohort, ECOG PS 2/3 pts had a significantly lower OS and greater odds of experiencing high-grade irAE than if ECOG PS 0/1. Development of irAE did not result in improved OS. Randomized trials to determine benefit of pembrolizumab for poor ECOG PS pts are needed.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Neoplasias Pulmonares/tratamiento farmacológico , Neumonía/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Cohortes , Femenino , Humanos , Estado de Ejecución de Karnofsky , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neumonía/etiología , Población Rural , Análisis de SupervivenciaRESUMEN
Eosinophilic esophagitis is an atopic disease defined clinically by esophageal symptoms in combination with a dense esophageal eosinophilia. EoE is triggered and maintained by exposure to certain foods and it is known that dietary modification controls symptoms and achieves disease remission. Recently, aeroallergens have been implicated in the pathogenesis of EoE. To examine the role of aeroallergens in EoE, we reviewed the published literature. Sensitization and production of IgE antibodies to foods and aeroallergens in subjects with EoE has been demonstrated. However, the evidence suggests only a minor role for IgE-mediated immune reactions in EoE. There is some evidence to support an association of EoE diagnosis and flares with environmental allergen exposure, and animal studies support the notion that EoE may be induced by exposure to inhalant allergens. Some studies show that newly diagnosed cases of EoE follow a seasonal pollen distribution (summer and spring), but the weight of evidence does not support the seasonal occurrence of diagnosis or worsening of symptoms. Overall, we conclude that the current evidence does not support causality in inhalant allergen exposure and the genesis nor exacerbations of EoE in humans, although there is a possibility that inhalant allergen sensitization could play a modifying role in EoE in the context of cross-reacting food allergens.
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Eosinofilia/inmunología , Esofagitis Eosinofílica/inmunología , Esófago/inmunología , Contaminantes Atmosféricos/inmunología , Alérgenos/inmunología , Animales , Antígenos de Plantas/inmunología , Reacciones Cruzadas , Dietoterapia , Exposición a Riesgos Ambientales/efectos adversos , Alimentos , Humanos , Polen/inmunología , Estaciones del AñoRESUMEN
Mycoplasma pneumoniae infection has been linked to poor asthma outcomes. M. pneumoniae produces an ADP-ribosylating and vacuolating toxin called community-acquired respiratory distress syndrome (CARDS) toxin that has a major role in inflammation and airway dysfunction. The objective was to evaluate the immunopathological effects in primates exposed to M. pneumoniae or CARDS toxin. A total of 13 baboons were exposed to M. pneumoniae or CARDS toxin. At Days 7 and 14, BAL fluid was collected and analyzed for cell count, percent of each type of cell, CARDS toxin by PCR, CARDS toxin by antigen capture, eosinophilic cationic protein, and cytokine profiles. Serum IgM, IgG, and IgE responses to CARDS toxin were measured. All animals had a necropsy for analysis of the histopathological changes on lungs. No animal developed signs of infection. The serological responses to CARDS toxin were variable. At Day 14, four of seven animals exposed to M. pneumoniae and all four animals exposed to CARDS toxin developed histological "asthma-like" changes. T cell intracellular cytokine analysis revealed an increasing ratio of IL-4/IFN-γ over time. Both M. pneumoniae and CARDS toxin exposure resulted in similar histopathological pulmonary changes, suggesting that CARDS toxin plays a major role in the inflammatory response.
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Asma/inmunología , Asma/patología , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/inmunología , Pulmón/inmunología , Pulmón/patología , Mycoplasma pneumoniae/patogenicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Interleucina-13/inmunología , Interleucina-4/inmunología , Pulmón/microbiología , Ratones , Mycoplasma pneumoniae/inmunología , PapioRESUMEN
OBJECTIVE: The immunosuppressive efficacy of inhaled nanoparticle tacrolimus was compared with systemic tacrolimus in a rodent allogeneic lung transplant model. METHODS: Sixteen rats underwent allogeneic left orthotopic lung transplantation and were divided into 3 treatment groups: (1) inhaled nanoparticle tacrolimus: 6.4 mg tacrolimus/6.4 mg lactose twice per day; (2) intramuscular tacrolimus: 1 mg/kg tacrolimus once per day; and (3) inhaled lactose: 6.4 mg of lactose twice per day. Five days after transplant, the rats were necropsied and underwent histologic rejection grading and cytokine analysis. Trough levels of tacrolimus were measured in allograft, blood, and kidney. RESULTS: Both intramuscular (n = 6) and nanoparticle tacrolimus (n = 6) rats displayed lower histologic grades of rejection (mean scores 3.4 ± 0.6 and 4.6 ± 0.9, respectively) when compared with lactose rats (n = 4) (mean score 11.38 ± 0.5, P = .07). Systemic tacrolimus trough levels (median) were lower in nanoparticle tacrolimus-treated rats versus intramuscular-treated rats (29.2 vs 118.6 ng/g; P < .001 in kidney, and 1.5 vs 4.8 ng/mL; P = .01 in blood). CONCLUSIONS: Inhaled nanoparticle tacrolimus provided similar efficacy in preventing acute rejection when compared with systemic tacrolimus while maintaining lower systemic levels.
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Inhibidores de la Calcineurina/administración & dosificación , Rechazo de Injerto/prevención & control , Inmunosupresores/administración & dosificación , Trasplante de Pulmón/efectos adversos , Nanopartículas , Tacrolimus/administración & dosificación , Administración por Inhalación , Aloinjertos , Animales , Inhibidores de la Calcineurina/sangre , Inhibidores de la Calcineurina/química , Inhibidores de la Calcineurina/farmacocinética , Citocinas/sangre , Modelos Animales de Enfermedad , Composición de Medicamentos , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Inmunosupresores/sangre , Inmunosupresores/química , Inmunosupresores/farmacocinética , Inyecciones Intramusculares , Lactosa/química , Masculino , Ratas Endogámicas BN , Ratas Endogámicas Lew , Tacrolimus/sangre , Tacrolimus/química , Tacrolimus/farmacocinéticaRESUMEN
BACKGROUND: Acute infections with Mycoplasma pneumoniae (Mp) have been associated with worsening asthma in children. Mp can be present in the respiratory tract for extended periods; it is unknown whether the long-term persistence of Mp in the respiratory tract affects long-term asthma control. OBJECTIVE: To determine the effect of Mp on asthma control. METHODS: We enrolled 31 pediatric subjects 3 to 10 years of age with persistent asthma who completed up to 8 visits over a 24-month period. We detected Mp by antigen capture and polymerase chain reaction. Primary outcome measurements included symptom scores, quality of life, medication scores, oral corticosteroid use, health care usage, school absences, and exhaled breath condensate pH. RESULTS: Low levels of Mp community-acquired respiratory distress syndrome toxin were detected in 20 subjects (64.5%) at enrollment. Subjects with Mp positivity at a given visit had a .579 probability of remaining Mp positive at the subsequent visit, whereas those with Mp negativity had a .348 probability of becoming Mp positive at the following visit. The incidence of Mp overall was higher in the spring and summer months. Overall, we found no significant relation between the detection of Mp and worse outcome measurements at the same visit or at subsequent visits. CONCLUSION: The long-term persistence of Mp in the respiratory tract is common in children with asthma. However, the detection of Mp was not associated significantly with worse asthma symptoms, quality of life, health care usage, school absences, or exhaled breath condensate pH in this pediatric asthma cohort.
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Asma/inmunología , Asma/microbiología , Estado de Salud , Mycoplasma pneumoniae/aislamiento & purificación , Calidad de Vida , Sistema Respiratorio/microbiología , Niño , Preescolar , Femenino , Humanos , Masculino , Mycoplasma pneumoniae/inmunología , Neumonía por Mycoplasma/inmunología , Neumonía por Mycoplasma/microbiología , Estudios Prospectivos , Estaciones del AñoRESUMEN
Mycoplasma pneumoniae is strongly associated with new onset asthma and asthma exacerbations. Until recently, the molecular mechanisms utilized by M. pneumoniae to influence asthma symptoms were unknown. However, we recently reported that an ADP-ribosylating and vacuolating toxin called the Community Acquired Respiratory Distress Syndrome toxin, CARDS toxin, produced by M. pneumoniae was sufficient to promote allergic inflammation and asthma-like disease in mice. A mouse model of CARDS toxin exposure was used to evaluate total and CARDS-toxin specific serum IgE responses. Mast cell sensitization, challenge, and degranulation studies determined functionality of the CARDS toxin-specific IgE. In the current study, we report that a single mucosal exposure to CARDS toxin was sufficient to increase total serum IgE and CARDS toxin-specific IgE in mice. Mice given a second mucosal challenge of CARDS toxin responded with significant increases in total and CARDS toxin-specific IgE. CARDS toxin-specific IgE bound to an N-terminal peptide of CARDS toxin but not the C-terminal peptide. Likewise, full-length CARDS toxin and the N-terminal peptide induced mast cell degranulation. Altogether, these data demonstrate that exposure to CARDS toxin is sufficient to generate functional IgE in mice. M. pneumoniae and CARDS toxin are strongly associated with asthma exacerbations raising the possibility that the CARDS toxin-specific IgE-mast cell axis contributes to disease pathogenesis.
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Proteínas Bacterianas/inmunología , Toxinas Bacterianas/inmunología , Inmunoglobulina E/sangre , Mycoplasma pneumoniae/metabolismo , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Epítopos/inmunología , Hexosaminidasas , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/aislamiento & purificación , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismoRESUMEN
Environmental pollutant exposures are major risk factors for adverse health outcomes, with increased morbidity and mortality in humans. Diesel exhaust (DE) is one of the major harmful components of traffic-related air pollution. Exposure to DE affects several physiological systems, including the airways, and pulmonary diseases are increased in highly populated urban areas. Hence, there are urgent needs to (1) create newer and lesser polluting fuels, (2) improve exhaust aftertreatments and reduce emissions, and (3) understand mechanisms of actions for toxic effects of both conventional and cleaner diesel fuels on the lungs. These steps could aid the development of diagnostics and interventions to prevent the negative impact of traffic-related air pollution on the pulmonary system. Exhaust from conventional, and to a lesser extent, clean fuels, contains particulate matter (PM) and more than 400 additional chemical constituents. The major toxic constituents are nitrogen oxides (NOx) and polycyclic aromatic hydrocarbons (PAHs). PM and PAHs could potentially act via transient receptor potential (TRP) channels. In this review, we will first discuss the associations between DE from conventional as well as clean fuel technologies and acute and chronic airway inflammation. We will then review possible activation and/or potentiation of TRP vanilloid type 1 (TRPV1) and ankyrin 1 (TRPA1) channels by PM and PAHs. Finally, we will discuss and summarize recent findings on the mechanisms whereby TRPs could control the link between DE and airway inflammation, which is a primary determinant leading to pulmonary disease.
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Exposición a Riesgos Ambientales/efectos adversos , Contaminación Ambiental/efectos adversos , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/metabolismo , Canales de Potencial de Receptor Transitorio/genética , Canales de Potencial de Receptor Transitorio/metabolismo , Emisiones de Vehículos/toxicidad , Contaminación del Aire/efectos adversos , Animales , Calcio/metabolismo , Expresión Génica , Humanos , Enfermedades Pulmonares/epidemiología , Material Particulado/efectos adversos , Especies Reactivas de OxígenoRESUMEN
RATIONALE: The primary purpose of this study was to evaluate the feasibility of obtaining acceptable and reproducible spirometry data in preschool aged children (3-5 years) by technicians without prior experience with spirometry. METHODS: Two technicians were trained to perform spirometry testing (ndd Easy on-PC) and to administer standardized questionnaires. Preschool aged children were enrolled from two Head Start centers and a local primary care clinic. Subjects were trained in proper spirometry technique and tested until at least two acceptable efforts were obtained or the subject no longer produced acceptable efforts. RESULTS: 200 subjects were enrolled: mean age 4.0 years (± 0.7 SD); age distribution: 51 (25.5%) 3 years old, 103 (51.5%) 4 years old, and 46 (23%) 5 years old. Fifty-six percent male and 75% Hispanic. One hundred thirty (65%) subjects produced at least one acceptable effort on their first visit: 23 (45%) for 3 years old, 67 (65%) for 4 years old, and 40 (87%) for 5 years old. The number of acceptable efforts correlated with age (r = 0.29, P < 0.001) but not gender. The mean number of acceptable efforts on the first visit was 2.66 (± 2.54 SD; range 0-10). One hundred twenty subjects (60%) had two acceptable efforts; 102 had FEV0.5 within 10% or 0.1 L and 104 had FVC within 10% or 0.1 L of best effort. The Asthma Health Screening Survey (AHSS) was 78% sensitive when compared to a specialist exam and 86% compared to a self-reported prior diagnosis of asthma. CONCLUSIONS: Technicians without prior experience were able to obtain acceptable and reproducible spirometry results from the preschool aged children; the number of acceptable efforts correlated significantly with age.
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Asma/diagnóstico , Espirometría/métodos , Preescolar , Estudios de Factibilidad , Femenino , Hispánicos o Latinos , Humanos , Masculino , Tamizaje MasivoRESUMEN
The impact of treatment delays on outcomes in Hodgkin lymphoma (HL) is currently unknown. Time from definitive histologic diagnosis to first ABVD treatment (TDT) was calculated in 810 adults with HL: 365 (45%) TDT ≤4 weeks, 369 (46%) TDT 5-8 weeks, 76 (9%) TDT >8 weeks. The 5-year overall survival (OS) was 92% TDT ≤4 weeks, 92% TDT 5-8 weeks, and 83% TDT >8 weeks (p = 0.007). The 5-year disease-specific survival (DSS) was 93% TDT ≤4 weeks, 95% TDT 5-8 weeks, and 87% TDT >8 weeks (p = 0.094). The 5-year progression-free survival (PFS) was similar between groups (p = 0.139). In the multivariate analysis, TDT >8 weeks was not associated with worse OS, DSS, or PFS. Despite the univariate association between initiation of ABVD >8 weeks and worse OS, these data do not support such cut-off to improve outcomes. Nevertheless, clinicians should make every effort possible to initiate curative-intent chemotherapy as soon as a diagnosis of HL is established.
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Enfermedad de Hodgkin/epidemiología , Tiempo de Tratamiento , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Colombia Británica , Causas de Muerte , Terapia Combinada , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Sistema de Registros , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body's response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction.
RESUMEN
Mycoplasma pneumoniae causes a range of airway and extrapulmonary pathologies in humans. Clinically, M. pneumoniae is associated with acute exacerbations of human asthma and a worsening of experimentally induced asthma in mice. Recently, we demonstrated that Community Acquired Respiratory Distress Syndrome (CARDS) toxin, an ADP-ribosylating and vacuolating toxin synthesized by M. pneumoniae, is sufficient to induce an asthma-like disease in BALB/cJ mice. To test the potential of CARDS toxin to exacerbate preexisting asthma, we examined inflammatory responses to recombinant CARDS toxin in an ovalbumin (OVA) murine model of asthma. Differences in pulmonary inflammatory responses between treatment groups were analyzed by histology, cell differentials and changes in cytokine and chemokine concentrations. Additionally, assessments of airway hyperreactivity were evaluated through direct pulmonary function measurements. Analysis of histology revealed exaggerated cellular inflammation with a strong eosinophilic component in the CARDS toxin-treated group. Heightened T-helper type-2 inflammatory responses were evidenced by increased expression of IL-4, IL-13, CCL17 and CCL22 corresponding with increased airway hyperreactivity in the CARDS toxin-treated mice. These data demonstrate that CARDS toxin can be a causal factor in the worsening of experimental allergic asthma, highlighting the potential importance of CARDS toxin in the etiology and exacerbation of human asthma.
Asunto(s)
Asma/patología , Proteínas Bacterianas/toxicidad , Toxinas Bacterianas/toxicidad , Hiperreactividad Bronquial/patología , Sistema Respiratorio/efectos de los fármacos , Animales , Asma/inducido químicamente , Asma/inmunología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Quimiocina CCL17/biosíntesis , Quimiocina CCL17/inmunología , Quimiocina CCL22/biosíntesis , Quimiocina CCL22/inmunología , Eosinófilos/inmunología , Eosinófilos/patología , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Interleucina-13/biosíntesis , Interleucina-13/inmunología , Interleucina-4/biosíntesis , Interleucina-4/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , Proteínas Recombinantes/toxicidad , Sistema Respiratorio/inmunología , Sistema Respiratorio/patología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
Increases in asthma worldwide have been associated epidemiologically with expanding urban air pollution. The mechanistic relationship between airway hyper-responsiveness, inflammation, and ambient airborne triggers remains ambiguous. Acrolein, a ubiquitous aldehyde pollutant, is a product of incomplete combustion reactions. Acrolein is abundant in cigarette smoke, effluent from industrial smokestacks, diesel exhaust, and even hot oil cooking vapors. Acrolein is a potent airway irritant and can induce airway hyper-responsiveness and inflammation in the lungs of animal models. In the present study, we utilized the mast cell analog, RBL-2H3, to interrogate the responses of cells relevant to airway inflammation and allergic responses as a model for the induction of asthma-like conditions upon exposure to acrolein. We hypothesized that acrolein would induce oxidative stress and degranulation in airway mast cells. Our results indicate that acrolein at 1 ppm initiated degranulation and promoted the generation of reactive oxygen species (ROS). Introduction of antioxidants to the system significantly reduced both ROS generation and degranulation. At higher levels of exposure (above 100 ppm), RBL-2H3 cells displayed signs of severe toxicity. This experimental data indicates acrolein can induce an allergic inflammation in mast cell lines, and the initiation of degranulation was moderated by the application of antioxidants.
Asunto(s)
Acroleína/toxicidad , Contaminantes Atmosféricos/toxicidad , Degranulación de la Célula/efectos de los fármacos , Mastocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Línea Celular , Línea Celular Tumoral , Citocinas/metabolismo , Mastocitos/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar (Juniperus ashei) season as the predominate model. OBJECTIVE: To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. METHODS: The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. RESULTS: Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. CONCLUSION: Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis.