RESUMEN
Pelvic floor dysfunction in women includes urinary incontinence and pelvic organ prolapse. In midlife, genitourinary atrophy is commonly associated with these conditions and can practically be considered part of the overall condition. The pelvic floor tissues share a common hormone responsiveness and as such respond collectively to midlife estrogen loss. This review article summarizes the expected consequences of menopause and aging on pelvic floor function and discusses how estrogen deprivation might lead to structural and/or functional failure. A framework for the initial evaluation of pelvic function in midlife women is presented, highlighting the importance of assessing the impact of incontinence, prolapse, and genitourinary atrophy on quality of life.
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Menopausia , Trastornos del Suelo Pélvico/fisiopatología , Femenino , Humanos , Persona de Mediana Edad , Prolapso de Órgano Pélvico/fisiopatología , Incontinencia Urinaria/fisiopatologíaRESUMEN
Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti-infectives and both microbe- and host-based immunomodulators and their feasibility for use in asthma.
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Antiasmáticos/uso terapéutico , Antiinfecciosos/uso terapéutico , Asma/tratamiento farmacológico , Asma/patología , Factores Inmunológicos/uso terapéutico , Factores de Edad , Antiasmáticos/administración & dosificación , Antiinfecciosos/administración & dosificación , Asma/etiología , Progresión de la Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Inmunomodulación/efectos de los fármacos , Masculino , Embarazo , Complicaciones del Embarazo , Probióticos/administración & dosificación , Resultado del Tratamiento , Vacunas/administración & dosificación , Vacunas/inmunologíaRESUMEN
BACKGROUND: Interferons play an important role in innate immunity. Previous studies report deficiency in virus induction of interferon (IFN)-α, IFN-ß and IFN-λ in bronchial epithelial and bronchial lavage cells in atopic asthmatics. It is now recognized that asthma is a heterogeneous disease comprising different inflammatory phenotypes, some of which may involve innate immune activation in the absence of overt infection. OBJECTIVE: The aim of this study was to investigate whether the severity of asthma or a specific cellular sputum pattern may be linked to evidence of innate immune activation. METHODS: Here we investigate the expression of IFN-ß, IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) such as myxovirus resistance 1 (Mx1), oligoadenylate synthetase (OAS) and viperin in unstimulated sputum cells in 57 asthmatics (including 16 mild, 19 moderate and 22 severe asthma patients) and compared them with 19 healthy subjects. RESULTS: We observed increased expression of IFN-ß, IFN-λ1/IL-29, OAS and viperin in asthmatics compared with healthy subjects, while IL-28 was not expressed in any group. The overexpression was restricted to neutrophilic asthmatics (sputum neutrophils ≥ 76%), while eosinophilic asthmatics (sputum eosinophils ≥ 3%) did not differ from healthy subjects or even showed a lower expression of Mx1. No difference in interferon or ISG expression was observed according to clinical asthma severity. CONCLUSION AND CLINICAL RELEVANCE: Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-ß, IFN-λ1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation.
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Asma/etiología , Asma/metabolismo , Regulación de la Expresión Génica , Factores Reguladores del Interferón/genética , Interferón beta/metabolismo , Interferones/metabolismo , Corticoesteroides/uso terapéutico , Adulto , Anciano , Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad Innata , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fenotipo , Pruebas de Función Respiratoria , Factores de Riesgo , Índice de Severidad de la Enfermedad , Esputo/inmunología , Esputo/metabolismo , Esputo/virologíaRESUMEN
BACKGROUND: Human rhinoviruses (HRVs) are one of the main causes of virus-induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. OBJECTIVE: To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce the activation of in vitro-cultured human peripheral blood mononuclear cells. METHODS: Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using 3 H-thymidine or CFSE labeling and ICAM-1 blocking. We used bead-based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside the B lymphocytes was detected by a combination of in situ hybridization (ISH), immunofluorescence, and PCR for positive-strand and negative-strand viral RNA. Cell images were acquired with imaging flow cytometry. RESULTS: By means of imaging flow cytometry, we demonstrate a strong and quick binding of HRV types 16 and 1B to monocytes, and slower interaction of these HRVs with CD4+ T cells, CD8+ T cells, and CD19+ B cells. Importantly, we show that HRVs induce the proliferation of B cells, while the addition of anti-ICAM-1 antibody partially reduces this proliferation for HRV16. We prove with ISH that HRVs can enter B cells, form their viral replication centers, and the newly formed virions are able to infect HeLa cells. In addition, we demonstrate that similar to epithelial cells, HRVs induce the production of pro-inflammatory cytokines in PBMCs. CONCLUSION: Our results demonstrate for the first time that HRVs enter and form viral replication centers in B lymphocytes and induce the proliferation of B cells. Newly formed virions have the capacity to infect other cells (HeLa). These findings indicate that the regulation of human rhinovirus-induced B-cell responses could be a novel approach to develop therapeutics to treat the virus-induced exacerbation of asthma.
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Linfocitos B/inmunología , Linfocitos B/virología , Activación de Linfocitos/inmunología , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/virología , Rhinovirus/fisiología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/virología , Infecciones por Picornaviridae/metabolismo , Rhinovirus/clasificación , Serogrupo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/virología , Acoplamiento Viral , Internalización del Virus , Replicación ViralRESUMEN
UNLABELLED: Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms. METHODS: This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h' duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2-4 (TSS2-4). RESULTS: Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean ± SE for TSS2-4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2-4 excluding a patient with aberrantly high symptom scores [TSS2-4, ex 1pt]; mean of TSS over Days 1-4 [TSS1-4]; change in TSS1-4 relative to baseline [TSS1-4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates. CONCLUSIONS: The primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C's activity against rhinovirus/enterovirus. TRIAL REGISTRATION: NCT01944631 (clinicaltrials.gov).
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Antivirales/administración & dosificación , Carragenina/administración & dosificación , Resfriado Común/tratamiento farmacológico , Administración Intranasal , Adolescente , Aerosoles , Antivirales/efectos adversos , Carragenina/efectos adversos , Resfriado Común/diagnóstico , Resfriado Común/virología , Método Doble Ciego , Esquema de Medicación , Enterovirus/efectos de los fármacos , Enterovirus/patogenicidad , Femenino , Humanos , Masculino , Rhinovirus/efectos de los fármacos , Rhinovirus/patogenicidad , Autoadministración , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Carga Viral , Gales , Adulto JovenRESUMEN
BACKGROUND: Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown. METHODS: We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-ß and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed. RESULTS: Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3. CONCLUSIONS: IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
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Citocinas/metabolismo , Inmunidad Innata/inmunología , Rhinovirus/inmunología , Receptor Toll-Like 3/metabolismo , Asma/inmunología , Asma/metabolismo , Bronquios/citología , Células Cultivadas , Citocinas/inmunología , Susceptibilidad a Enfermedades , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Receptor Toll-Like 3/inmunologíaRESUMEN
Primary immunodeficiency is seen in an estimated one in 1200 people, and secondary immunodeficiency is increasingly common, particularly with the use of immunosuppresion, cancer therapies and the newer biological therapies such as rituximab. Delays in the diagnosis of immunodeficiency predictably lead to preventable organ damage. Examples of abnormal pathology tests that suggest immunodeficiency from all laboratory specialities are given, where vigilant interpretation of abnormal results may prompt earlier diagnosis. If immunodeficiency is suspected, suggested directed testing could include measuring immunoglobulins, a lymphocyte count and T-cell and B-cell subsets.
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Síndromes de Inmunodeficiencia/diagnóstico , Diagnóstico Precoz , HumanosRESUMEN
One hundred sixty-two 21-d-old ducks were randomly allotted to 6 treatments with 3 levels of mycotoxin-contaminated corn (0, 50, and 100% M) and 2 levels of Calibrin-A (CA, a clay mycotoxin adsorbent, 0 and 0.1%) to evaluate the effects of increasing levels of mycotoxin-contaminated corn on nutrient utilization in ducks fed diets with or without CA. Endogenous losses were obtained from another 27 ducks. Excreta samples were collected to determine DM, OM, CP, amino acids, and gross energy. Gross energy was analyzed for computation of AME and TME. The apparent digestibility (AD) and true digestibility (TD) of the nutrients in all treatments with and without CA had common (P > 0.05) intercepts and slopes except Pro (P < 0.05). The AME, TME, AD, and TD of DM, OM, Phe, and Gly were linearly (P < 0.05) decreased as the concentration of contaminated corn in the diet increased. Ducks fed the 100% M diet supplemented with 0.1% CA increased AD and TD of Gly compared with the 100% M diet, and ducks fed 50 and 100% M diet supplemented with 0.1% CA increased AD and TD of Pro compared with 50% M and 100% M diet, respectively. In the present study, ducks fed mycotoxin-contaminated corn decreased nutrient digestibility in dose-dependent manner, and 0.1% CA supplementation improved AD and TD of Gly and Pro.
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Aflatoxina B1/toxicidad , Silicatos de Aluminio/farmacología , Dieta/veterinaria , Digestión/efectos de los fármacos , Patos/metabolismo , Metabolismo Energético/efectos de los fármacos , Microbiología de Alimentos , Adsorción , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión/veterinaria , Arcilla , Patos/crecimiento & desarrollo , Ensayo de Inmunoadsorción Enzimática/veterinaria , Heces/química , Femenino , Fluorometría/veterinaria , Masculino , Zea mays/microbiologíaRESUMEN
RATIONALE: Rhinoviruses (RVs) are the major triggers of asthma exacerbations. We have shown previously that lower respiratory tract symptoms, airflow obstruction, and neutrophilic airway inflammation were increased in experimental RV-induced asthma exacerbations. OBJECTIVES: We hypothesized that neutrophil-related CXC chemokines and antimicrobial peptides are increased and related to clinical, virologic, and pathologic outcomes in RV-induced exacerbations of asthma. METHODS: Protein levels of antimicrobial peptides (SLPI, HNP 1-3, elafin, and LL-37) and neutrophil chemokines (CXCL1/GRO-α, CXCL2/GRO-ß, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2, and CXCL8/IL-8) were determined in bronchoalveolar lavage (BAL) fluid of 10 asthmatics and 15 normal controls taken before, at day four during and 6 weeks post-experimental infection. RESULTS: BAL HNP 1-3 and Elafin were higher, CXCL7/NAP-2 was lower in asthmatics compared with controls at day 4 (P = 0.035, P = 0.048, and P = 0.025, respectively). BAL HNP 1-3 and CXCL8/IL-8 were increased during infection (P = 0.003 and P = 0.011, respectively). There was a trend to increased BAL neutrophils at day 4 compared with baseline (P = 0.076). BAL HNP 1-3 was positively correlated with BAL neutrophil numbers at day 4. There were no correlations between clinical parameters and HNP1-3 or IL-8 levels. CONCLUSIONS: We propose that RV infection in asthma leads to increased release of CXCL8/IL-8, attracting neutrophils into the airways where they release HNP 1-3, which further enhances airway neutrophilia. Strategies to inhibit CXCL8/IL-8 may be useful in treatment of virus-induced asthma exacerbations.
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Péptidos Catiónicos Antimicrobianos/metabolismo , Asma/etiología , Asma/metabolismo , Quimiocinas CXC/metabolismo , Infecciones por Picornaviridae/complicaciones , Rhinovirus/inmunología , Adolescente , Adulto , Asma/diagnóstico , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/virología , Estudios de Casos y Controles , Quimiotaxis de Leucocito/inmunología , Progresión de la Enfermedad , Elafina/metabolismo , Femenino , Humanos , Masculino , Neutrófilos/inmunología , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.
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Interferón Tipo I/metabolismo , Interleucina-15/metabolismo , Células Asesinas Naturales/inmunología , Infecciones por Picornaviridae/inmunología , Rhinovirus/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Regulación hacia ArribaRESUMEN
BACKGROUND: Rhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral infection-induced exacerbations. METHODS: Allergic mice were challenged with OVA followed by three daily intranasal challenges with dsRNA or saline. Bronchoalveolar lavage fluid (BALF) was analysed for total protein, lactate dehydrogenase (LDH), CXCL1/KC, CCL2/MCP-1 and differential cell counts. Lung tissue histology, neutrophils and TSLP, TNF-α, IFN-ß and IFN-λ mRNA were examined. Alternatively, allergen-challenged mice received intranasal rhinovirus-(RV)-1B followed by lung TSLP immunostaining. RESULTS: In mice with allergic airway inflammation, dsRNA challenges caused a significant exacerbation increasing lung tissue inflammation score and tissue neutrophilia. Bronchoalveolar lavage fluid neutrophils, total protein, LDH, CXCL1/KC and CCL2/MCP-1 were also increased (P < 0.01), and so were lung tissue expressions of TNF-α, IFN-λ and TSLP (P < 0.01), but IFN-ß was not increased. TSLP, IFN-λ and LDH were not increased by allergen or dsRNA challenges alone, but increased exclusively at exacerbations. RV1B infection-induced exacerbation also increased lung tissue TSLP (P < 0.05). CONCLUSIONS: dsRNA-induced exacerbation in mice with experimental asthma involved general inflammation, cytokines and interferons, in agreement with previous observations in exacerbating human asthma. Additionally, both dsRNA and RV1B infection increased lung TSLP exclusively at exacerbations. Our data suggest that dsRNA challenges superimposed on allergic inflammation are suited for pharmacological studies of asthma exacerbations including the regulation of lung tissue TSLP, TNF-α, IFN-ß and IFN-λ.
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Asma/genética , Asma/inmunología , Citocinas/genética , Pulmón/inmunología , Pulmón/metabolismo , Neutrófilos/inmunología , ARN Bicatenario/inmunología , Rhinovirus/inmunología , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Expresión Génica , Interferón gamma/genética , Pulmón/patología , Ratones , Ovalbúmina/inmunología , ARN Bicatenario/administración & dosificación , Factor de Necrosis Tumoral alfa/genética , Linfopoyetina del Estroma TímicoRESUMEN
The effects of increasing aflatoxin B1 concentration (0, 0.75, 1.5 mg/kg) on broilers with or without necrotic enteritis or virginiamycin were determined. In the 23-d study, 22 male Cobb 500 chicks per pen were allotted to 12 treatments (3 × 2 × 2 factorial arrangement) with 8 replications. Intestines of 5 birds per pen were examined for lesions on d 21. Birds were allowed to consume feed and water ad libitum. Aflatoxin was included in the diets from d 0. All birds received a 10× dose of coccidiosis vaccine on d 10. Pens of birds where necrotic enteritis was being induced were on Clostridium perfringens pathogen (CPP) contaminated litter from d 0. Aflatoxin decreased gain and feed intake and resulted in poorer feed:gain, increased mortality, and higher lesion scores. Inducing necrotic enteritis increased lesion scores and decreased feed intake and gain. Adding virginiamycin to the diets improved gain, feed intake, feed conversion, and decreased mortality. There was a 3-way interaction (aflatoxin × virginiamycin × CPP) on gain; increasing aflatoxin decreased gain and the effects of CPP and virginiamycin were dependent on aflatoxin concentration. In the absence of aflatoxin virginiamycin increased gain but was unable to prevent the growth suppression caused by CPP. At 0.75 mg/kg of aflatoxin virginiamycin no longer increased growth in non-CPP challenged birds but was able to increase growth in CPP-challenged birds. At the 1.5 mg/kg of aflatoxin concentration, virginiamycin increased gain in non-CPP-challenged birds but challenging birds with CPP had no effect on gain. Virginiamycin improved overall feed conversion with the greatest improvement at 1.5 mg/kg (aflatoxin × virginiamycin, P < 0.05). Aflatoxin increased lesion scores in unchallenged birds but not in challenged birds (aflatoxin × CPP, P < 0.001). Aflatoxin and necrotic enteritis decrease broiler performance and interact to decrease weight gain, virginiamycin helps improve gain in challenged birds at 0.75 mg/kg of aflatoxin, but not at 1.5 mg/kg of aflatoxin.
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Aflatoxina B1/toxicidad , Pollos , Enteritis/veterinaria , Enfermedades de las Aves de Corral/tratamiento farmacológico , Virginiamicina/farmacología , Envejecimiento , Alimentación Animal/análisis , Animales , Ingestión de Alimentos , Enteritis/mortalidad , Enteritis/patología , Masculino , Enfermedades de las Aves de Corral/mortalidad , Enfermedades de las Aves de Corral/patologíaRESUMEN
A total of 1,280 1-d-old ducks were used in a study to investigate the effects of increasing aflatoxin B1 (AFB1) concentrations from naturally contaminated corn on young ducklings, and the effectiveness of a clay adsorbent (CA) to protect against those effects. Ducks were randomly allotted to 8 treatments (TRT) in a 4 × 2 factorial arrangement with 4 levels of AFB1 (0, 25, 50, and 100 µg/kg) and 2 levels of CA (0 and 0.1%) with 8 pens per TRT and 20 ducks per pen. All ducks were allowed ad libitum access to feed and water during the 21-d experiment. The ADG, ADFI, feed conversion rate, mortality, bill color, and CV of BW of each replicate were measured at the end of the study. Blood and tissue samples from 8 ducks per TRT were obtained on d 21 of the experiment to determine the serum immunoglobulin and protein concentrations, relative organ weights, and intestinal morphology. Average daily gain and relative weights of the liver, spleen, thymus, and bursa of Fabricius decreased linearly (P < 0.05) as dietary AFB1 increased. Serum proteins and intestinal villi heights and villus/crypt ratio followed the same pattern. Bill decolorization ratio, CV of BW, and mortality increased linearly (P < 0.05) as dietary AFB1 increased. Adding 0.1% CA to the diet improved (P < 0.05) the relative weights of the small intestine, spleen, and thymus, and the villus height and villus/crypt ratio of the duodenum and jejunum, as well as the serum IgG and IgM concentrations. Adding CA also reduced (P < 0.05) bill decolorization ratio, CV of BW, mortality, and serum IgA concentration. Therefore, duck performance was negatively affected by increasing AFB1 concentrations in diets. But the addition of 0.1% CA can protect against the detrimental effects caused by AFB1-contaminated corn in diets for ducks.
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Aflatoxina B1/toxicidad , Silicatos de Aluminio/administración & dosificación , Alimentación Animal/microbiología , Patos/metabolismo , Microbiología de Alimentos , Venenos/toxicidad , Adsorción , Animales , Análisis Químico de la Sangre/veterinaria , Cromatografía Líquida de Alta Presión/veterinaria , Arcilla , Dieta/veterinaria , Suplementos Dietéticos , Patos/crecimiento & desarrollo , Ensayo de Inmunoadsorción Enzimática/veterinaria , Femenino , Fluorometría/veterinaria , Intestinos/microbiología , Intestinos/patología , Masculino , Zea mays/microbiologíaRESUMEN
Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.
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Asma/inmunología , Infecciones por Picornaviridae/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Rhinovirus , Células Th2/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Asma/etiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Progresión de la Enfermedad , Humanos , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Infecciones por Picornaviridae/complicaciones , Células Th2/efectos de los fármacosRESUMEN
Deficient type I interferon-ß and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-ß and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.
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Asma/genética , Asma/inmunología , Hipersensibilidad Inmediata/genética , Hipersensibilidad Inmediata/inmunología , Inmunidad Innata/genética , Interferones/genética , Adolescente , Asma/metabolismo , Niño , Preescolar , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Hipersensibilidad Inmediata/metabolismo , Inmunoglobulina E/inmunología , Helicasa Inducida por Interferón IFIH1 , Interferón beta/genética , Interferón gamma/genética , Interleucina-8/biosíntesis , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/virología , Masculino , Infecciones por Picornaviridae/genética , Infecciones por Picornaviridae/inmunología , Poli I-C/administración & dosificación , Poli I-C/inmunología , ARN Mensajero/genética , Receptores Inmunológicos , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Rhinovirus/inmunología , Factores de Tiempo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismoRESUMEN
Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.
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Asma/diagnóstico , Asma/terapia , Animales , Asma/prevención & control , Progresión de la Enfermedad , Humanos , Guías de Práctica Clínica como Asunto , Índice de Severidad de la EnfermedadRESUMEN
Respiratory virus infections play an important role in cystic fibrosis (CF) exacerbations, but underlying pathophysiological mechanisms are poorly understood. We aimed to assess whether an exaggerated inflammatory response of the airway epithelium on virus infection could explain the increased susceptibility of CF patients towards respiratory viruses. We used primary bronchial and nasal epithelial cells obtained from 24 healthy control subjects and 18 CF patients. IL-6, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, RANTES/CCL5 and GRO-α/CXCL1 levels in supernatants and mRNA expression in cell lysates were measured before and after infection with rhinoviruses (RV-16 and RV-1B) and RSV. Cytotoxicity was assessed by lactate dehydrogenate assay and flow cytometry. All viruses induced strong cytokine release in both control and CF cells. The inflammatory response on virus infection was heterogeneous and depended on cell type and virus used, but was not increased in CF compared with control cells. On the contrary, there was a marked trend towards lower cytokine production associated with increased cell death in CF cells. An exaggerated inflammatory response to virus infection in bronchial epithelial cells does not explain the increased respiratory morbidity after virus infection in CF patients.
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Fibrosis Quística , Mucosa Nasal , Infecciones por Picornaviridae , Mucosa Respiratoria , Rhinovirus/inmunología , Bronquios/inmunología , Bronquios/patología , Bronquios/virología , Línea Celular , Fibrosis Quística/inmunología , Fibrosis Quística/patología , Fibrosis Quística/virología , Citocinas/genética , Citocinas/inmunología , Expresión Génica/inmunología , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/virología , Mucosa Nasal/inmunología , Mucosa Nasal/patología , Mucosa Nasal/virología , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/patología , Infecciones por Picornaviridae/virología , Cultivo Primario de Células , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Mucosa Respiratoria/virología , Rhinovirus/crecimiento & desarrolloRESUMEN
The cytokine interleukin (IL)-15, major histocompatibility complex (MHC) class I molecules and MHC class I chain-related proteins (MIC) A and B are involved in cellular immune responses to virus infections but their role in respiratory syncytial virus (RSV) infection has not been studied. We aimed to determine how RSV infection modulates IL-15 production, MHC class I and MICA expression in respiratory epithelial cells, the molecular pathways implicated in virus-induced IL-15 production and how interferon (IFN)-γ alters RSV-induced IL-15 production and MHC class I and MICA expression. We infected respiratory epithelial cell lines (A549 and BEAS-2B cells) and primary bronchial epithelial cells with RSV and measured production of IL-15, expression of MHC I and MICA and the role of the transcription factor nuclear factor (NF)-κB. We report here that RSV increases IL-15 in respiratory epithelial cells via virus replication and NF-κB-dependent mechanisms. Furthermore, RSV infection of epithelial cells upregulated cell surface expression of MICA and levels of soluble MICA. IFN-γ upregulated RSV induction of soluble IL-15 but inhibited induction of MICA. Upregulation of IL-15, MHC I and MICA are likely to be important mechanisms in activating immune responses to RSV by epithelial cells.
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Antígenos de Histocompatibilidad Clase I/biosíntesis , Antígenos de Histocompatibilidad Clase I/inmunología , Interleucina-15/biosíntesis , Mucosa Respiratoria/metabolismo , Infecciones por Virus Sincitial Respiratorio/inmunología , Células Cultivadas , Humanos , Interferón gamma/inmunología , Interferón gamma/farmacología , Interleucina-15/inmunología , FN-kappa B/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/virología , Regulación hacia ArribaRESUMEN
Severe viral respiratory illnesses and atopy are risk factors for childhood wheezing and asthma. The aim of this study was to explore associations between severe respiratory infections and atopy in early childhood with wheeze and asthma persisting into later childhood. 147 children at high atopic risk were followed from birth to age 10 yrs. Data on all respiratory infections occurring in infancy were collected prospectively and viral aetiology ascertained. Atopy was measured by skin prick tests at 6 months, and 2 and 5 yrs. History of wheeze and doctor-diagnosed eczema and asthma was collected regularly until 10 yrs of age. At 10 yrs, 60% of the cohort was atopic, 25.9% had current eczema, 18.4% current asthma and 20.4% persistent wheeze. 35.8% experienced at least one lower respiratory infection (LRI) associated with fever and/or wheeze in first year of life. Children who had wheezy or, in particular, febrile LRI in infancy and were atopic by 2 yrs, were significantly more likely to have persistent wheeze (RR 3.51, 95% CI 1.83-6.70; p<0.001) and current asthma (RR 4.92, 95% CI 2.59-9.36; p<0.001) at 10 yrs. Severe viral respiratory infections in infancy and early atopy are risk factors for persistent wheeze and asthma. The strongest marker of the asthmatogenic potential of early life infections was concurrent fever. The occurrence of fever during respiratory illnesses is an important marker of risk for wheeze and asthma later in childhood, suggesting it should be measured in prospective studies of asthma aetiology.
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Asma/epidemiología , Fiebre/epidemiología , Hipersensibilidad Inmediata/epidemiología , Neumonía/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Niño , Preescolar , Conjuntivitis Alérgica/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Valor Predictivo de las Pruebas , Prevalencia , Ruidos Respiratorios/etiología , Rinitis Alérgica Perenne/epidemiología , Rinitis Alérgica Estacional/epidemiología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Virosis/epidemiologíaRESUMEN
The objectives of this study were to investigate the toxicity of zearalenone (ZEA) on hepatonephric organs, serum metabolites and oxidative stress of piglets and to evaluate the efficacy of Calibrin-Z (CAZ) in preventing ZEA-induced adverse effects. The experiment was conducted for 22 days using 36 piglets weaned at 21 days of age (Landrace × Yorkshire × Duroc, 18 females and 18 males; 8.84 ± 0.21 kg average body weight). Piglets of each gender were randomly allocated to the following six dietary treatments: (i) Control (basal diet only); (ii) Control + 1 g/kg CAZ; (iii) Control + 1 mg/kg ZEA; (iv) Control + 1 mg/kg ZEA + 1 g/kg CAZ; (v) Control + 1 mg/kg ZEA + 2 g/kg CAZ; (vi) Control + 1 mg/kg ZEA + 4 g/kg CAZ. Piglets were housed and fed individually for the entire experimental period. Blood samples were taken, and piglets were killed at the end of the experiment to obtain organs for physiological assessment. Results showed that piglets fed the ZEA-contaminated diet had increased (p < 0.05) activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase (GGT), creatine kinase and cholinesterase, concentrations of urea, and creatinine in serum, and malondialdehyde (MDA) in serum and liver. Pigs fed the ZEA-only diet also showed reductions in serum (p < 0.05) globulin, triglycerides and high-density lipoproteins (HDL), and reductions in total superoxide dismutase (TSOD) and glutathione peroxidase (GSHPx) activity in both serum and liver. Supplementation of CAZ at the dosages of 1-4 g/kg to the diet containing 1.05 mg/kg ZEA linearly increased (p < 0.05) concentrations of triglycerides and HDL in serum, activity of TSOD and GSHPx in serum and liver, but linearly reduced (p < 0.05) all tested serum enzymes and lowered (p < 0.05) the elevated concentrations of urea, and creatinine in serum, and MDA in serum and liver caused by dietary ZEA. Piglets fed the ZEA-contaminated diet showed increased (p < 0.05) relative weight of liver and kidney compared with the control, whereas only numerical improvement on relative weight of liver and kidney was observed with simultaneous addition of CAZ at 4 g/kg diet and ZEA. However, feeding the diet with CAZ alone at 1 g/kg had no impact on any of the measured parameters when compared to the control. It is suggested that feeding ZEA at 1.05 mg/kg exerted a deleterious effect on piglets, which was totally or partly ameliorated by dietary supplementation of CAZ at concentrations between 1 and 4 g/kg diet.