RESUMEN
AIM: The objective of this study is to examine the relationship between self-reported birth weight and the adult occurrence of type 2 diabetes mellitus in a large multi-ethnic population of women. METHODS: Baseline data from the Women's Health Initiative Observational Study [n=75,993] was used to examine the association between participant birth weight category and prevalent type 2 diabetes mellitus. Models were adjusted for age, ethnicity, body mass index and other pertinent risk factors. Sub-analyses were performed stratifying by ethnicity. RESULTS: There was a strong inverse association between birth weight and type 2 diabetes mellitus with a birth weight of <6 pounds (lbs) (OR: 1.16, 95% CI: 1.01, 1.33) significantly associated with an increased risk of type 2 diabetes mellitus and a birth weight of ≥10 lbs (OR: 0.72, 95% CI: 0.57, 0.92) associated with a decreased risk of type 2 diabetes mellitus compared to women who reported their birth weight between 7 and 8 lbs 15 ounces (oz). Stratifying by ethnicity, the inverse association between birth weight and type 2 diabetes mellitus was only apparent in White women, but not Black, Hispanic or Asian women. CONCLUSION: Lower birth weight was associated with increased T2D risk in American White and Black post-menopausal women.
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Asiático/estadística & datos numéricos , Peso al Nacer , Negro o Afroamericano/estadística & datos numéricos , Diabetes Mellitus Tipo 2/epidemiología , Hispánicos o Latinos/estadística & datos numéricos , Posmenopausia , Población Blanca/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Estudios Transversales , Femenino , Desarrollo Fetal , Humanos , Persona de Mediana Edad , Prevalencia , Modelos de Riesgos Proporcionales , Factores de Riesgo , Estados Unidos/epidemiología , Salud de la MujerRESUMEN
Three hundred forty-nine patients with asthma previously treated with medium doses of inhaled corticosteroids during a 2-wk, single-blind, run-in period were randomized to treatment with salmeterol 50 microg combined with fluticasone propionate (FP) 250 microg, salmeterol 50 microg, FP 250 microg, or placebo, each given twice daily through a Diskus device for 12 wk. Mean change in FEV(1) at endpoint was significantly (p = 0.001) greater with the salmeterol/FP combination product (0.48 L) than with placebo (-0.11 L), salmeterol (0.05 L), or FP (0.25 L). The combination product significantly increased the area under the 12-h serial FEV(1) curve relative to baseline over that with placebo, salmeterol, or FP at Day 1, Week 1, and Week 12 (p = 0.025). Patients in the combination-product group had a significantly greater probability of remaining in the study without being withdrawn because of worsening asthma than did patients in the placebo, salmeterol, or FP groups (p = 0.002). The combination product significantly increased (p < 0. 001) morning PEF at endpoint (53.5 L/min) as compared with placebo (-14 L/min), salmeterol (-11.6 L/min), or FP (15.2 L/min). The combination product significantly (p = 0.011) reduced asthma symptom scores and supplemental albuterol use, and significantly increased the percentage of nights with no awakenings as compared with placebo, salmeterol, and FP (p = 0.016). Combination treatment with salmeterol 50 microg and FP 250 microg given twice daily from the Diskus device provided better asthma control and greater improvement in pulmonary function than did the individual agents, and may simplify the management of asthma in patients who need both classes of drugs for optimal control of their disease.
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Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Adolescente , Adulto , Anciano , Albuterol/administración & dosificación , Albuterol/efectos adversos , Androstadienos/efectos adversos , Antiasmáticos/efectos adversos , Asma/diagnóstico , Broncodilatadores/efectos adversos , Niño , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Diseño de Equipo , Femenino , Fluticasona , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Polvos , Xinafoato de Salmeterol , Método Simple CiegoRESUMEN
BACKGROUND: The published literature is lacking in data on the frequency and severity of medication side effects in the general asthma population. METHODS: Questionnaires regarding asthma severity, treatment, and medication side effects were answered by 1230 and 604 pediatric and adult asthmatics, respectively, 70% to 75% of whom were consulting a specialist. RESULTS: Most respondents (58%-79%) reported unwanted side effects from their bronchodilators, most of which had been racemic albuterol prescribed in either generic or name brand form. Side effects were most common in nebulizer users of all ages and in pediatric patients using oral medications. The most common troublesome side effects were jitteriness (58%), restlessness (57%), tachycardia (56%) and cough (56%) in the pediatric patients and tachycardia (64%), jitteriness (60%), shaky hands (43%), and restlessness (42%) in the adult respondents. Most patients had spoken to their physicians about their side effects, and the most common response was to change brands within the same class of medication, adjust the dose, or advise the patients to tolerate the side effects because the medications were necessary and side effects were to be expected. Fewer than 4% of all respondents viewed their physicians as "caring/sympathetic/willing to listen/discuss their bronchodilator side effects." Twenty-five to thirty percent of patients had reduced their bronchodilator dose on their own, and 14% to 24% had skipped doses to avoid unwanted side effects. Hospitalizations were infrequent and were most commonly seen in the nebulizer users, who were also rated by their physicians as more likely to have severe asthma. Other markers of asthma control (such as emergency room visits, unscheduled doctor visits, and being sent home from school/work for asthma symptoms) were not only common in the nebulizer user group but also in children who used oral medications. This group was more likely to have been classified by their physicians as having mild asthma, suggesting perhaps a need for more intensive asthma education in this group. CONCLUSION: Medication side effects are common in individuals with asthma and are most often ascribed by the patients to their bronchodilators. There is a need for new, rapid-acting bronchodilators with fewer side effects.
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Agonistas Adrenérgicos beta/efectos adversos , Asma/tratamiento farmacológico , Broncodilatadores/efectos adversos , Encuestas y Cuestionarios , Administración por Inhalación , Administración Oral , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/uso terapéutico , Adulto , Albuterol/administración & dosificación , Albuterol/efectos adversos , Albuterol/uso terapéutico , Asma/fisiopatología , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Niño , Servicios Médicos de Urgencia , Hospitalización , Humanos , Nebulizadores y Vaporizadores , Satisfacción del Paciente , Calidad de Vida , Estaciones del AñoRESUMEN
OBJECTIVE: This study evaluated the efficacy and safety of four dosing regimens of budesonide inhalation suspension in children ages 6 months to 8 years with moderate persistent asthma. METHODS: This 12-week, randomized, double-blind, placebo-controlled, parallel-group study involved 481 children at 38 centers throughout the United States. Active treatment groups were budesonide inhalation suspension .25 mg once daily (QD), .25-mg two times daily (BID), .5-mg BID, or 1-mg QD. Efficacy was assessed by recording nighttime and daytime asthma symptoms, use of rescue medication, and discontinuation from the study because of worsening asthma and/or a requirement for systemic steroids. Objective measures of pulmonary function were assessed in children who were capable of consistently performing pulmonary function tests; peak expiratory flow (PEF) measurements were recorded twice daily on diary cards, and spirometry was recorded at clinic visits. RESULTS: Baseline patient demographics, nighttime and daytime symptom scores, and pulmonary function data were similar across placebo and budesonide treatment groups. The majority of patients were male (64%) with a mean age of 55.0 +/- 26.3 months. The mean duration of asthma was 34.2 +/- 22.9 months, and mean baseline forced expiratory volume in 1 second (FEV1) was 79.8% of predicted, with 29.1% reversibility. Significant improvements in nighttime and daytime asthma symptoms scores were observed in budesonide treatment groups, compared with placebo. The mean change from baseline to week 0-12 for nighttime and daytime asthma symptom scores was significantly greater for the .25-mg BID, .5-mg BID, and 1-mg QD budesonide treatment groups, compared with placebo; significant clinical improvement was observed by the second week of treatment. The lowest budesonide dose used (.25 mg QD) resulted in numerical improvements in symptom scores that were not statistically significant when compared to placebo. Significant improvements in morning PEF were observed in all budesonide treatment groups, except for the .25-mg QD group, compared with placebo. All treatment groups showed numerical improvement in FEV1, but only the .5-mg BID dose was significantly different from placebo. CONCLUSIONS: The results of this study demonstrate that budesonide inhalation suspension is effective and well tolerated for infants and young children with moderate persistent asthma. Budesonide inhalation suspension is an important therapeutic option for young children who are not able to use other available delivery devices.
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Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Budesonida/administración & dosificación , Administración por Inhalación , Análisis de Varianza , Niño , Preescolar , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Lactante , Masculino , Nebulizadores y Vaporizadores , Pruebas de Función Respiratoria , Estados UnidosRESUMEN
Sinusitis affects up to 14% of Americans. Traditionally, most patients with sinusitis are evaluated and treated by either primary care physicians or otolaryngologists. In order to gain information regarding the characteristics at presentation and the outcome of treatment of sinusitis by an allergist, the records of 200 consecutive patients seen at the Institute for Asthma and Allergy at the Washington Hospital Center for chronic sinusitis were reviewed. The most common presenting symptoms were nasal congestion, postnasal drip, purulent rhinorrhea, headache, cough, facial pressure, anosmia or hyposmia, hypogeusia, and throat clearing. Initial abnormal physical exam findings included abnormal transillumination, purulent secretions, nasal mucosal swelling, nasal polyps, and nasal crusting. Treatment included 4 weeks of oral antibiotics, nasal corticosteroids, nasal lavage, and topical decongestants. All of the presenting symptoms (23-75% of the patients) and signs (50-84% of patients) improved with medical management. Patients have been followed for 1 to 27 months, with a mean of 6 months, and 6% have required surgery, with one complication of cerebrospinal fluid leak. These findings indicate that medical management of chronic sinusitis in an allergist's office is effective.
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Sinusitis/diagnóstico , Sinusitis/inmunología , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Contaminantes Atmosféricos/efectos adversos , Animales , Antibacterianos/uso terapéutico , Niño , Preescolar , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Anamnesis , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Estudios Retrospectivos , Sinusitis/terapia , Resultado del TratamientoRESUMEN
OBJECTIVE: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid. METHODS: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 microg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 microg) bid; group 2, 4 inhalations (1000 microg) qd in the morning; group 3, 4 inhalations (1000 microg) qd in the evening; or group 4, 2 inhalations (500 microg) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV1, and methacholine PC20. In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization. RESULTS: Outcome measures in the four groups were not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 microg daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 microg qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC20 or 24-hour urinary cortisol levels in any group. CONCLUSIONS: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 microg) bid, switching to 4 inhalations (1000 microg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 microg) qd in the morning, however, leads to a deterioration in asthma control.
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Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Fluocinolona Acetonida/análogos & derivados , Administración por Inhalación , Adolescente , Adulto , Albuterol/uso terapéutico , Pruebas de Provocación Bronquial , Broncodilatadores/uso terapéutico , Niño , Método Doble Ciego , Femenino , Fluocinolona Acetonida/administración & dosificación , Fluocinolona Acetonida/uso terapéutico , Volumen Espiratorio Forzado , Humanos , Hidrocortisona/análisis , Hidrocortisona/orina , Masculino , Cloruro de Metacolina/farmacología , Persona de Mediana Edad , Ápice del Flujo EspiratorioRESUMEN
Muscarinic receptors play a double role in airway disorders, mediating an increase in mucus secretion, as well as constriction of smooth muscle. Cholinergic activity of the lung is more pronounced in large than in peripheral airways; in the nose parasympathetic stimulation leads to hypersecretion and vasodilation. This article reviews the differences in muscarinic subreceptors in the upper and lower airways and discusses the effectiveness of anticholinergic agents in blocking parasympathetic stimulation at these sites.
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Receptores Muscarínicos/fisiología , Fenómenos Fisiológicos Respiratorios , Asma/tratamiento farmacológico , Asma/fisiopatología , Antagonistas Colinérgicos/farmacología , Humanos , Receptores Muscarínicos/efectos de los fármacos , Sistema Respiratorio/efectos de los fármacos , Rinitis/tratamiento farmacológico , Rinitis/fisiopatologíaRESUMEN
BACKGROUND: The role of inflammatory cells at the local site of allergic inflammation in the nose is unclear. METHODS: Nasal biopsy specimens were obtained from 10 patients with symptomatic seasonal allergic rhinitis and 10 normal subjects. Freeze-dried paraffin-embedded sections were stained for mononuclear cells and eosinophils. Tissues in Carnoy's fixative were stained for mast cells. RESULTS: T cells were much more plentiful than B cells or macrophages, and no significant differences were found between the two groups in the number of T cells, T-cell subsets, B cells, and macrophages. However, the number of CD25+ cells (lymphocyte activation markers) and the number of eosinophils were significantly higher in the allergic group than in the control group. There were no significant differences between the two groups in the total mast cell number. However, mucosal type mast cells were slightly increased, and a higher ratio of mast cells were costained for IgE in the allergic group. IgE+ cells mostly constained for mast cell tryptase and did not costain for J chain. CONCLUSIONS: These data suggest that unlike granulocytes, in some mononuclear cells qualitative, not quantitative, changes may be important in allergic rhinitis and that IgE may not be locally produced in the nasal mucosa.
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Eosinófilos/inmunología , Leucocitos Mononucleares/inmunología , Mastocitos/inmunología , Mucosa Nasal/inmunología , Mucosa Nasal/patología , Rinitis Alérgica Estacional/inmunología , Adulto , Recuento de Células , Eosinófilos/patología , Femenino , Humanos , Inmunoglobulina E/análisis , Inmunohistoquímica , Inflamación/patología , Leucocitos Mononucleares/patología , Masculino , Mastocitos/patología , Persona de Mediana Edad , Receptores de Interleucina-2/análisis , Rinitis Alérgica Estacional/fisiopatologíaRESUMEN
BACKGROUND: A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. METHODS: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. RESULTS: Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. CONCLUSION: The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.
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Aspirina/efectos adversos , Asma/metabolismo , Mastocitos/fisiología , Mucosa Nasal/efectos de los fármacos , Ribonucleasas , Adulto , Proteínas Sanguíneas/análisis , Quimasas , Estudios Cruzados , Método Doble Ciego , Proteínas en los Gránulos del Eosinófilo , Femenino , Histamina/análisis , Humanos , Hidroxiurea/análogos & derivados , Hidroxiurea/farmacología , Leucotrienos/análisis , Masculino , Persona de Mediana Edad , Serina Endopeptidasas/metabolismo , TriptasasRESUMEN
BACKGROUND: To determine the underlying mechanisms for rhinovirus-induced nasal secretions, nasal lavage fluids were analyzed during experimental rhinovirus infections. METHODS: Twenty patients with allergic rhinitis and 18 nonallergic control subjects were inoculated with rhinovirus type 39. Nasal lavage was performed before and on days 2 through 7 after viral inoculation, and the lavage fluids were assayed for proteins and mast cell mediators. RESULTS: The secretion of total protein and both plasma proteins (albumin and IgG) and glandular proteins (lactoferrin, lysozyme, and secretory IgA) increased after rhinovirus inoculation. Analysis of the specific protein constituents revealed that nasal secretions during the initial response to the rhinovirus infection were predominantly due to increased vascular permeability. Allergic subjects tended to have fewer symptoms and more vascular permeability than control subjects, and increased histamine secretion after rhinovirus inoculation was more frequently seen in the allergy group. CONCLUSION: Nasal secretions found early in the course of a viral upper respiratory infection are due to increased vascular permeability, whereas glandular secretions predominate later in the infection.
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Resfriado Común/metabolismo , Mucosa Nasal/metabolismo , Infecciones del Sistema Respiratorio/metabolismo , Rhinovirus , Adolescente , Adulto , Femenino , Histamina/análisis , Humanos , Inmunoglobulina A Secretora/análisis , Inmunoglobulina G/análisis , Lactoferrina/análisis , Masculino , Moco/química , Muramidasa/análisis , Albúmina Sérica/análisisRESUMEN
BACKGROUND: The luminal surface of respiratory mucous membranes is lined with an epithelial lining fluid (ELF) layer. Previous attempts to determine ELF volumes in airways have used dyes or freely diffusible molecules such as urea, yet have not led to a universally accepted method. The nasal mucous membrane provides an accessible area to examine whether urea is an appropriate marker of respiratory ELF volume. METHODS AND RESULTS: Collection of undiluted nasal secretions after either glandular stimulation or induction of vascular permeability confirmed that plasma urea and nasal urea concentrations are equivalent. Baseline ELF volume was calculated as 800 microliters/nostril. The calculated molar concentrations of urea in ELF did not vary with either methacholine or histamine challenge. CONCLUSIONS: These data indicate the plasma, interstitial, glandular, and ELF urea concentrations are equivalent and, therefore, that urea is a useful marker of ELF volume in the nasal mucosa.
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Líquidos Corporales/metabolismo , Mucosa Nasal/metabolismo , Urea/metabolismo , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Epitelio/metabolismo , Femenino , Humanos , Masculino , Proteínas/metabolismo , Irrigación Terapéutica , Urea/sangreRESUMEN
BACKGROUND: Atopic individuals have previously been shown to have an autonomic imbalance consisting of heightened cholinergic responsiveness in the lung, skin, and eyes, and beta-adrenergic hyporesponsiveness in the lungs, eyes, and vasculature. This array of abnormalities is often accompanied by nonspecific bronchial hyperresponsiveness, as well as alpha-adrenergic hyperresponsiveness in individuals with asthma. METHODS: To determine whether atopic individuals have intrinsic nasal airway hyperresponsiveness to methacholine, 21 nonatopic subjects and 37 subjects with allergic rhinitis were studied. All subjects were studied out of their allergy seasons, and all allergy-related medications were discontinued before the study began. Subjects underwent nasal challenge with methacholine (1 to 25 mg), and lavaged nasal secretions were analyzed for total protein, the plasma marker albumin, and the glandular marker lactoferrin. RESULTS: Atopic subjects demonstrated increased glandular responsiveness to methacholine as evidenced by an increase in the secretion of lactoferrin in response to individual doses of methacholine. Although the maximal lactoferrin secretion did not increase, glandular sensitivity to methacholine was heightened because the dose of methacholine required to induce lactoferrin secretion achievable by 60% of the study population was significantly lower in the atopic group. The volume of lavaged secretions recovered and congestion scores were also higher in the atopic group as compared with the normal control group. CONCLUSIONS: These data strongly suggest that atopic individuals have intrinsic nasal glandular hyperresponsiveness to cholinergic stimulation.
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Hipersensibilidad/fisiopatología , Cloruro de Metacolina/farmacología , Cavidad Nasal/efectos de los fármacos , Estaciones del Año , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactoferrina/metabolismo , Masculino , Persona de Mediana Edad , Cavidad Nasal/fisiopatología , Mucosa Nasal/metabolismo , Pruebas de Provocación Nasal , Proteínas/metabolismo , Albúmina Sérica/metabolismoRESUMEN
BACKGROUND: There is suggestive evidence that neuropeptides participate in allergic reactions. Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by sensory nerves, whereas vasoactive intestinal peptide (VIP) is released mainly by parasympathetic nerves. Both sets of nerves are thought to be stimulated by allergic inflammation. The aim of this study was to assess nasal secretions to determine whether SP, CGRP, and VIP were increased after allergen challenge. METHODS: Eight patients with allergic rhinitis were challenged nasally with 1 mg histamine or increasing doses of allergen. Nasal lavages were collected into a cocktail of protease inhibitors in order to restrict neuropeptide degradation. Radioimmunoassay for SP, CGRP, and VIP were performed on each sample. RESULTS: All patients had immediate clinical reactions to both histamine and allergen challenges, and seven patients experienced a later allergic reaction. After histamine challenge, SP and CGRP did not increase significantly above baseline in the nasal lavages, whereas VIP did (p < 0.02). In contrast, SP, CGRP, and VIP all significantly increased immediately after allergen challenge and returned to baseline within 2 hours. At the clinical peak of the late allergic reaction, SP, but not CGRP or VIP, was increased slightly but significantly (p < 0.01). CONCLUSIONS: Thus SP, CGRP, and VIP are found in nasal secretions after allergen challenge, which confirms that neuropeptides are released in human beings during allergic reactions. The selective stimulation of VIP secretion by histamine challenge suggests that histamine-induced cholinergic reflexes induce the release of VIP. These data support the suggestion that neuropeptides may be partly responsible for some of the nasal symptoms of allergy.
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Alérgenos , Péptido Relacionado con Gen de Calcitonina/análisis , Mucosa Nasal/metabolismo , Rinitis Alérgica Estacional/fisiopatología , Sustancia P/análisis , Péptido Intestinal Vasoactivo/análisis , Adulto , Cromatografía Líquida de Alta Presión/métodos , Cromatografía en Capa Delgada/métodos , Relación Dosis-Respuesta Inmunológica , Femenino , Histamina , Humanos , Masculino , Pruebas de Provocación Nasal/métodos , Radioinmunoensayo/métodos , Rinitis Alérgica Estacional/etiología , Irrigación Terapéutica , Factores de TiempoRESUMEN
BACKGROUND: To define the normal resident inflammatory cell population in the nasal mucosa, surgical specimens of human nasal turbinates were immunohistologically stained for various cell markers. METHODS: Freeze-dried paraffin-embedded sections were stained for lymphocyte cell-surface markers, and Carnoy's fixed sections were stained for mast cells and immunoglobulins. The numbers of stained cells were microscopically counted. RESULTS: T cells (CD3+ cells) were abundant in the lamina propria, and the number of CD4+ cells and CD8+ cells accounted for two thirds and one third of CD3+ cell number, respectively. Cells that stained for the alpha-chain of the interleukin-2 receptor (activated cells, CD25+) were limited and accounted for only 0.6% of CD3+ cell number. B cells (CD22+ cells) and monocytes and macrophages (CD14+ cells) were observed less frequently than T cells. Many immunoglobulin-producing cells were found in close proximity to the submucosal glands, and those cells were predominantly IgA+. Mast cells were widely distributed in the nasal mucosa, and about one third of these cells were stained for IgE molecules. Nonmast cells bearing IgE were rarely observed. CONCLUSION: Thus the dominant cell in the nasal mucosa is a CD3+, CD4+, CD25-lymphocyte.
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Linfocitos/inmunología , Mucosa Nasal/citología , Animales , Antígenos CD/análisis , Recuento de Células , Quimasas , Humanos , Inmunoglobulinas/análisis , Inmunohistoquímica , Macrófagos/inmunología , Mastocitos/enzimología , Ratones , Monocitos/inmunología , Mucosa Nasal/inmunología , Conejos , Serina Endopeptidasas/análisisRESUMEN
Endothelin (ET), a potent vasoconstrictor and bronchoconstrictor peptide synthesized by endothelial and epithelial cells, was examined for its potential functions in human inferior turbinate nasal mucosal tissue by four techniques: (1) immunoreactive ET was localized in the mucosa by immunohistochemistry; (2) receptors for ET were identified by autoradiography employing [125I]ET; (3) ET-1 mRNA was localized by in situ hybridization; and (4) the secretory functions of ET were examined by the release of mucous and serous cell products after the addition of ET to human nasal turbinates in short-term cultures. Specific ET-1-immunoreactive material was found most extensively in small muscular arteries and in serous cells in submucosal glands. ET-1 was also found to a lower extent in the walls of venous sinusoids. [125I]ET-1 binding sites were localized by autoradiography to submucosal glands and to venous sinusoids and small muscular arterioles. mRNA for ET-1 was found most extensively in the venous sinusoids and to a lesser extent in small muscular arteries. In mucosal explant cultures, ET-1 and ET-2 stimulated lactoferrin and mucous glycoprotein release from serous and mucous cells, but ET-3 was inactive. The observations indicate that in the human nasal mucosa, ET is present in the vascular endothelium and the serous cells in submucosal glands and acts on glandular ET receptors to induce both serous and mucous cell secretion. It is also likely that ET plays a role in the regulation of vasomotor tone.
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Endotelinas/metabolismo , Mucosa Nasal/metabolismo , Sitios de Unión , Técnicas de Cultivo , Endotelinas/genética , Humanos , Inmunohistoquímica , Hibridación in Situ , Cinética , ARN Mensajero/metabolismoRESUMEN
Mast cells can release arachidonic acid (AA) metabolites as well as preformed mediators with IgE mediated stimulation, and these mediators are considered to play an important role in allergic reactions. The coincident release of preformed mediators and AA metabolites suggests that AA metabolism is related to mast cell degranulation. To clarify the relationship between mast cell degranulation and AA metabolism, the effects of various A cascade inhibitors on rat basophilic leukemia cell (RBL) mediator release induced by either anti-IgE or A23187 were examined. 5,8,11,14-eicosatetraynoic acid (ETYA) inhibited both PGD2 and LTC4/D4 generation, and partially inhibited serotonin release. Nordihydroguaiaretic acid (NDGA) caused complete inhibition of LTC4/D4 generation, and partial inhibition of PGD2 generation and serotonin release. The cyclooxygenase inhibitor, indomethacin, and the specific 5-lipoxygenase inhibitor, L-651,392 completely inhibited PGD2 and LTC4/D4 generation, respectively, without affecting release of other mediators. Both PGD2 and LTC4/D4 generation were abolished by the combination of indomethacin and L-651,392, however, serotonin release remained intact. HPLC analysis showed that no shift to other AA metabolites occurred after the treatment with these inhibitors. Mepacrine, a phospholipase A2 inhibitor, completely inhibited PGD2 and LTC4/D4 generation, as well as AA release itself, without affecting serotonin release. Therefore, neither AA metabolism nor AA release is necessary for RBL degranulation.
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Ácido Araquidónico/metabolismo , Mastocitos/efectos de los fármacos , Serotonina/metabolismo , Ácido 5,8,11,14-Eicosatetrainoico/farmacología , Animales , Cromatografía Líquida de Alta Presión , Inhibidores de la Ciclooxigenasa/farmacología , Indometacina/farmacología , Leucemia Basofílica Aguda , Inhibidores de la Lipooxigenasa/farmacología , Masoprocol/farmacología , Mastocitos/metabolismo , Fenotiazinas/farmacología , Prostaglandina D2/metabolismo , Ratas , SRS-A/metabolismo , Células Tumorales CultivadasRESUMEN
Secretory leukoprotease inhibitor (SLPI) is a secreted glandular protein thought to regulate elastase activity and, more recently, to inhibit both mast cell chymase activity and histamine release from mast cells. To begin to examine the possible role of SLPI in humans, we determined the distribution of SLPI in the human nasal mucosa and quantitated the functional activity of SLPI in nasal lavage fluid. Immunochemical staining of the nasal mucosa revealed intense, selective immunoreactivity in the serous cells of the submucosal glands. The level of SLPI in nasal secretions was measured by enzyme immunoassay. In control subjects (n = 8), the level of SLPI in nasal lavage fluid (NLF) after saline challenge (baseline level) was 2.5 +/- 0.5 micrograms/ml, accounting for 3.3 +/- 0.6% of total protein in nasal secretions. After methacholine (MCh) and histamine (HIST) challenge, the level of SLPI increased to 7.0 +/- 1.4 and 6.1 +/- 1.6 micrograms/ml, respectively (both p < 0.05). In atopic patients (n = 8), the level of SLPI after MCh and HIST challenge increased from a baseline level of 7.6 +/- 2.0 micrograms/ml to 22.1 +/- 6.4 and 25.2 +/- 10.5 micrograms/ml, respectively. After allergen challenge, the concentration of SLPI increased significantly in atopic patients, whereas there was no increase in the level of SLPI in control subjects. Western blot analysis of MCh-induced nasal secretions revealed a single band with a molecular weight of 12 kD, the same as recombinant SLPI.(ABSTRACT TRUNCATED AT 250 WORDS)
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Leucocitos/metabolismo , Mucosa Nasal/metabolismo , Proteínas , Inhibidores de Serina Proteinasa/metabolismo , Adolescente , Adulto , Western Blotting/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Inmunohistoquímica , Leucocitos/química , Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Mucosa Nasal/efectos de los fármacos , Pruebas de Provocación Nasal/métodos , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Elastasa Pancreática/antagonistas & inhibidores , Elastasa Pancreática/efectos de los fármacos , Proteínas Inhibidoras de Proteinasas Secretoras , Inhibidor Secretorio de Peptidasas Leucocitarias , Inhibidores de Serina Proteinasa/análisis , Inhibidores de Serina Proteinasa/farmacologíaRESUMEN
BACKGROUND: Acetylsalicylic acid (ASA) induces rhinorrhea in a subset of patients with asthma or chronic rhinosinusitis or both and nasal polyps. The underlying mechanism of the reaction is obscure. METHODS: To assess the nasal response to ASA challenge, four groups of patients were challenged orally with ASA: group A (10 ASA-sensitive patients); group B (nine patients with nasal polyps and histories of tolerance to ASA); group C (nine ASA-tolerant patients with chronic allergic rhinitis); and group D (eight healthy nonatopic subjects). RESULTS: Nasal lavages obtained before and after ASA challenge were assayed for proteins (total protein, lactoferrin, lysozyme, albumin) and inflammatory mediators (histamine, prostaglandin D2, and leukotriene C4). ASA challenges induced severe rhinorrhea and congestion and significant increases in mean concentrations of all measured nasal proteins in group A. Histamine and prostaglandin D2 rose, but not significantly. In the two control groups with chronic rhinitis, ASA induced increases in the concentration of proteins and histamine. Leukotriene C4 concentrations were significantly elevated in nasal lavages after ASA challenge in groups A and C only. In group D no symptoms or changes in nasal proteins were observed after aspirin challenge. CONCLUSIONS: These observations suggest that production of lipoxygenase products of arachidonate may induce glandular secretions that may participate in the clinical changes associated with ASA sensitivity.
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Aspirina/inmunología , Asma/metabolismo , Hipersensibilidad a las Drogas/metabolismo , Mucosa Nasal/metabolismo , Rinitis/metabolismo , Sinusitis/metabolismo , Adulto , Anciano , Femenino , Humanos , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Pólipos Nasales/metabolismo , Proteínas/metabolismo , Irrigación TerapéuticaRESUMEN
Interleukin (IL)-4 causes the dose limiting sensation of nasal congestion when administered systematically at doses of 3 micrograms/kg or higher thrice daily to humans. This side effect was observed in a group of patients treated as part of an immunotherapy protocol for cancer management. To determine the source of this congestion, nasal secretions were collected prospectively in a group of patients at baseline and after provocation with normal saline, methacholine (which stimulates glandular secretion), and histamine (which causes increased vascular permeability). Nasal lavages obtained at baseline and after provocation were analyzed for the presence of these glandular and vascular proteins and inflammatory mediators. Washings and provocations were performed before IL-4 administration, after 24 hours of IL-4 treatment, and after 3 days of treatment, at a time when nasal congestion was maximal. Compared with histamine challenge before IL-4 treatment, the secretion of the plasma proteins albumin and IgG were significantly decreased after 3 days of IL-4 treatment. IL-4 treatment had no apparent effect on methacholine-induced responses. Thus systemically administered IL-4 causes the subjective sensation of nasal congestion, increased histamine in nasal lavages, and the development of vascular unresponsiveness to histamine, without affecting parasympathetic responses to histamine. The relationships among increases in nasal lavage histamine, vascular unresponsiveness to histamine, and the sensation of nasal congestion are unclear.