RESUMO
Mycobacterium tuberculosis (Mtb) in sputum originates from lung cavities in tuberculosis (TB) patients. But drug susceptibility testing (DST) of sputum Mtb can not be conducted the same as in the lung because mutagenesis of bacilli may be happening in the lung during treatment and result in the possibility of the presence of heterogeneous drug-resistant subpopulations in the different lung lesions. This could be one of the reasons for low cure rates for multi-drug resistant (MDR)-TB. We studied the resected lungs of nine surgery patients with chronic TB. The isolates isolated from the sputum and different lung lesions of each patient were tested for phenotypic DST and genotyped using restriction fragment length polymorphism (RFLP) typing method. Genetic analysis to resistance to first and second line drugs was also performed. Five of nine patients were MDR-TB and three XDR-TB. DST results for ten anti-TB drugs were in accordance among different lung lesions in eight patients. However, only three of these eight patients showed the concordance of DST with sputum. Even though the isolates were heteroresistant, genotyping them by RFLP showed the clonal population in each individual patient. Six of eight followed-up patients achieved successful cure. In conclusion, the heteroresistance between sputum and lung lesions and a clonal population without mixed infection might provide useful information in establishing treatment regimen and surgery decision for MDR- and XDR-TB.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Polimorfismo de Fragmento de Restrição , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
The purpose of this study was to develop and evaluate a navigation program for patients with thyroid cancer. The navigation program was developed following an analysis of the unmet needs of patients who underwent surgery for thyroid cancer. Ninety-nine patients in the control group received usual care, and 95 in the navigation group were managed with a navigation program during the perioperative period. The effectiveness of the navigation program was assessed by administering a questionnaire to both groups. Overall satisfaction scores were significantly higher in the navigation than in the control group (p = .025), as were satisfaction scores on the continuity of information (p < .001), the continuity of management (p = .002), the continuity of relationships with healthcare providers (p<.001), and patient empowerment (p < .001). The newly developed navigation program for patients with thyroid cancer was effective in raising satisfaction levels and in actively managing the disease during the perioperative period.
Assuntos
Navegação de Pacientes/métodos , Assistência Perioperatória/métodos , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Continuidade da Assistência ao Paciente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação das Necessidades , Satisfação do Paciente , Avaliação de Programas e Projetos de Saúde , Adulto JovemRESUMO
1. The effect of the immunosuppressive agent, FK-506, an allergen-induced airways eosinophilia and bronchial hyperreactivity (BHR) in hyper IgE mice (BP2 selection) was investigated. 2. Administration of FK-506 at 2 mg kg-1 s.c., 1 h before and 5 h after the first four ovalbumin challenges, reduced the recruitment of eosinophils into the bronchoalveolar lavage fluid (BALF) from 1.36 +/- 0.22 x 10(5) to 0.53 +/- 0.24 x 10(5) cells ml-1 (n = 5-6, P < 0.05; 60% inhibition), inhibited by 80% BHR in response to i.v. 5-HT and practically suppressed BHR in response to inhaled methacholine. 3. The antigen-induced interleukin (IL)-5 formation in the BALF and serum was inhibited by FK-506 by 75% in both instances. 4. FK-506 failed to modify the bronchoconstriction in BP2 mice, suggesting that different mechanisms are involved in acute bronchoconstriction and BHR. 5. The increased number of CD4+, CD8+, CD3+ T lymphocytes in the BALF to antigen-challenged mice was unaffected by FK-506. 6. These findings indicate that antigen-induced in vivo IL-5 release and eosinophil, but not T-cell, infiltration into the bronchial lumen of sensitized BP2 mice are targets for the anti-allergic activities of FK-506.
Assuntos
Hiper-Reatividade Brônquica/fisiopatologia , Eosinofilia/fisiopatologia , Imunossupressores/farmacologia , Tacrolimo/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Técnica Indireta de Fluorescência para Anticorpo , Técnicas Imunoenzimáticas , Interleucina-5/biossíntese , Contagem de Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Ovalbumina/imunologia , Testes de Função Respiratória , Linfócitos T/efeitos dos fármacosRESUMO
1. Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent. 2. Methysergide or atropine inhibited OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro. 3. Neostigmine potentiated the OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited. 4. Neostigmine also potentiated the serotonin (5-HT)- and acetylcholine (ACh)-induced bronchoconstriction and this potentiation was significantly reversed by atropine. 5. These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5-HT, which in turn acts via the cholinergic mediator, ACh.
Assuntos
Anafilaxia/induzido quimicamente , Broncoconstrição/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Atropina/farmacologia , Broncoconstrição/imunologia , Broncodilatadores/farmacologia , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Metisergida/farmacologia , Camundongos , Contração Muscular/efeitos dos fármacos , Neostigmina/farmacologia , Ovalbumina/imunologia , Ovalbumina/farmacologia , Serotonina/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Vasoconstritores/farmacologiaRESUMO
To explore the possible role of eosinophils in NO-mediated tissue injury, we studied a murine model of allergic asthma. Male A/J mice were sensitized and challenged intranasally with ovalbumin (OVA). Following challenge, the number of eosinophils in bronchoalveolar lavage fluid (BALF) increased from 0.4% of total cells at baseline (0.02 x 10(4) cells/ml) to 60.2% at 48 h after the challenge (9.34 x 10(4) cells/ml). The rise in eosinophil count was accompanied by a 40.3% increase in total NO(2-) plus NO(3-) (NO(x)) in BALF. This in turn was accompanied by expression of inducible NO synthase (NOS II) in airway epithelial and inflammatory cells, as well as by evidence of staining for 3-nitrotyrosine (3NT) in peribronchial inflammatory cells and at the epithelial surface. Both NO(x) production and 3NT were significantly reduced by pretreatment of the challenged mice with the highly specific NOS II inhibitor N-3-aminomethyl-benzyl-acetamidine-dihydrochloride (1400W), as well as by the nonselective NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). L-NAME and 1400W also reduced the number of BALF eosinophils (37.2% and 61.5%, respectively, as compared with the control value), suggesting that NO production by NOS II contributes to eosinophil recruitment. To further examine the role of eosinophils, we pretreated additional mice with an anti-interleukin (IL)-5 antibody, which reduced BALF eosinophilia following OVA challenge by 90.1%. In concert with the decrease in eosinophils, the anti-IL-5 antibody reduced NO(x) in BALF almost to the baseline value, and decreased the number of 3NT-positive cells in the peribronchial region by 74.4%. Western blot analysis of protein extracted from whole lung confirmed the reduction in tyrosine nitration by anti-IL-5 antibody. These findings indicate that NO and eosinophilic inflammation are closely coupled, and suggest that eosinophils are an important source of tyrosine nitration.
Assuntos
Asma/imunologia , Eosinófilos/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Análise de Variância , Animais , Anticorpos/farmacologia , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Eosinófilos/imunologia , Interleucina-5/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Óxido Nítrico/imunologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/imunologia , Óxido Nítrico Sintase Tipo II , Nitrosação , Ovalbumina/imunologia , Fatores de Tempo , Tirosina/imunologiaRESUMO
BACKGROUND: Infiltration of inflammatory cells in the airways is a constant characteristic of asthma and is considered to result in bronchial hyperreactivity (BHR). We have recently developed a model of BHR using a selection of mice, named BP2, which display eosinophil-dependent BHR following antigen challenges. An anti-IL-5 antibody suppressed antigen-induced eosinophil recruitment to the airways and BHR in BP2 mice. OBJECTIVE: To investigate the implication of infiltrated inflammatory cells in the induction of BHR in mice. METHODS: The effects of glucocorticosteroid dexamethasone on airways eosinophilia and BHR were observed. RESULTS: Administration of dexamethasone at the dose of 1.25 mg/kg i.p. 1 h before each of four antigen provocations suppressed the airways eosinophilia and BHR in response to intravenous 5-HT and to aerosolized methacholine, as well as IL-5 production in the BALF and in the serum. By contrast, dexamethasone failed to reduce anaphylactic bronchoconstriction. CONCLUSIONS: These results suggest that dexamethasone exerts its inhibitory effects on antigen-induced airways eosinophilia in mice by inhibiting IL-5 production, but that it does not block the liberation of anaphylactic mediators in mice.
Assuntos
Brônquios/efeitos dos fármacos , Brônquios/patologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Dexametasona/uso terapêutico , Eosinófilos/patologia , Anafilaxia/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos , Fatores de TempoRESUMO
The eosinophilic inflammatory response in asthma is associated with protein nitration, detected as immunostaining for 3-nitrotyrosine (3NT). As the presence of 3NT is strongly correlated with upregulation of the inducible form of nitric oxide synthase (NOS II), it has been hypothesized that 3NT formation results from the action of peroxynitrite (ONOO-), a highly reactive NO derivative produced from the reaction of molecular NO and O2-. However, recent observations have suggested that the action of peroxidases, including eosinophil peroxidase (EPO), may be responsible for protein nitration. In this study, we used murine models of allergic asthma to address the relative contribution of EPO and NOS II to protein nitration. We studied EPO-deficient New Zealand White (NZW) mice, which were sensitized and challenged intranasally with ovalbumin (OVA). Despite comparable levels of eosinophilia, NO, and superoxide production, NZW mice exhibited markedly decreased 3NT staining around the airways after OVA challenge when compared with two other strains (A/J and C57BL/6J). Immunocytochemical analysis of bronchoalveolar lavage (BAL) cells and lung sections suggested that 3NT staining was largely confined to eosinophils. This was confirmed by Western Blot analysis of proteins from different subsets of BAL cells that demonstrated a marked decrease in 3NT formation in eosinophils from NZW mice. These results contrast with those obtained in OVA-sensitized and -challenged NOS II deficient mice, which despite decreased NO production, exhibited similar 3NT staining in the airways after OVA challenge as in wild-type control mice. In this model, protein nitration was thus not a function of NO production by NOS II. We conclude that in the mouse, 3NT formation after specific allergen challenge is dependent on EPO activity, particularly in eosinophils themselves. In contrast, 3NT formation is not driven by upregulation of NOS II expression in this model and does not appear to depend on increases in the level of NO production.
Assuntos
Asma/metabolismo , Eosinófilos/enzimologia , Peroxidases/metabolismo , Proteínas/metabolismo , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar , Peroxidase de Eosinófilo , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem , Peroxidases/análise , Superóxidos/metabolismoRESUMO
A murine model for antigen-induced bronchial hyperreactivity (BHR) and airway eosinophilia, two hallmarks of asthma, was developed using ovalbumin-immunized mice, which produce large amounts of IgE (named BP2, "Bons Producteurs 2," for High Line of Selection 2). A single intranasal ovalbumin challenge failed to modify the bronchial responses, despite the intense eosinophil recruitment into the bronchoalveolar lavage fluid and airways. When mice were challenged twice a day for 2 days or once a day for 10 days, BHR in response to i.v. 5-hydroxytryptamine or to inhaled methacholine was induced in BP2 mice but not in BALB/c mice. Histological examination showed that eosinophils reached the respiratory epithelium after multiple ovalbumin challenges in BP2 mice but remained in the bronchial submucosa in BALB/c mice. Total IgE titers in serum were augmented significantly with immunization in both strains, but much more so in BP2 mice. Interleukin 5 (IL-5) titers in serum and bronchoalveolar lavage fluid of BP2 mice were augmented by the antigenic provocation, and a specific anti-IL5 neutralizing antibody suppressed altogether airway eosinophilia and BHR, indicating a participation of IL-5 in its development. Our results indicate that the recruitment of eosinophils to the airways alone does not induce BHR in mice and that the selective effect on BP2 mice is related to their increased IgE titers associated with antigen-driven eosinophil migration to the epithelium, following formation and secretion of IL-5.
Assuntos
Antígenos/imunologia , Brônquios/imunologia , Hipersensibilidade a Drogas/imunologia , Eosinófilos/imunologia , Imunoglobulina E/biossíntese , Interleucina-5/fisiologia , Cloreto de Metacolina/imunologia , Serotonina/imunologia , Animais , Brônquios/patologia , Hipersensibilidade a Drogas/patologia , Epitélio/imunologia , Imunoglobulina E/sangue , Interleucina-5/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Mucosa/imunologia , Mucosa/patologia , Ovalbumina/imunologiaRESUMO
Eosinophils are recruited to the airways during allergic reactions, but animal models have shown that their mere presence is not sufficient for the development of bronchopulmonary hyperreactivity. Other factors, such as immunoglobulin (Ig)E, seem to be required. Using mice selected for the production of large amounts of IgE, the effects of antibody neutralization of IgE on antigen-induced lung recruitment of eosinophils and induction of bronchopulmonary hyperreactivity and of other indicators of inflammation were studied. A monoclonal non-anaphylactogenic rat anti-mouse IgE (mAb1-5), given within 24 h of the challenge with antigen, reduced tissue eosinophilia, the recruitment of IgE-bearing cells identified as basophils, mucous cell metaplasia, anaphylactic bronchoconstriction and bronchopulmonary hyperreactivity. mAb1-5 inhibited interleukin (IL)4 titres in the bronchoalveolar lavage fluid, but not those of I1-5. Inhibition by mAb1-5 may result from competitive displacement of immunoglobulin E from its different receptors, thus preventing cell stimulation. Moreover, the inhibition of the massive recruitment of immunoglobulin E-bearing basophils into the lungs within hours after challenge and of interleukin4 production by mAb1-5 may be important factors leading to the reduction of pulmonary eosinophilia and bronchopulmonary hyperreactivity. Thus, immunoglobulin (Ig)E and allergic IgE-bearing cells seem to play an essential role in the initial development of the late allergic airway responses.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Monoclonais/farmacologia , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Imunoglobulina E/imunologia , Animais , Anticorpos Anti-Idiotípicos/farmacologia , Asma/fisiopatologia , Basófilos/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Eosinófilos/imunologia , Imunoglobulina E/fisiologia , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Ovalbumina/imunologia , Ratos , Fatores de TempoRESUMO
BACKGROUND: Allergies and allergic asthma are believed to be mediated by allergen-specific IgE antibodies. We have investigated the therapeutic potential of inhibiting endogenous IgE by a non-anaphylactogenic anti-mouse IgE antibody 1-5 with respect to its effects on antigen-induced skin reaction, lung function changes and lung inflammation in mice. METHODS: Mice were immunized with benzylpenicillinoyl-KLH or ovalbumin, and antigen-mediated skin reaction, bronchoconstriction, bronchopulmonary hyperresponsiveness (BHR) and lung eosinophilic inflammation determined in anti-IgE 1-5-treated versus untreated animals. RESULTS: Application of anti-IgE 1-5 inhibited (by 90%) the serum IgE and, 3-4 days after onset of treatment, blocked the antigen-induced skin reaction. Furthermore, the antibody also inhibited (by 90%) the antigen-induced infiltration of eosinophils into the lung. This latter effect seems to be mediated by blocking the IgE-CD23 interaction and indicates that lung eosinophilic inflammation also depends on IgE. Moreover, when applied to rats passively sensitized with mouse IgE, antibody 1-5 inhibited the antigen-induced bronchoconstriction. A similar effect could be seen in actively immunized mice, where antibody 1-5 was able to inhibit (by 70%) the ovalbumin-induced bronchoconstriction as well as BHR. CONCLUSIONS: In summary, non-anaphylactogenic anti-IgE antibodies can markedly inhibit IgE levels and IgE-mediated allergic reactions. Since bronchoconstriction, BHR and lung eosinophilic inflammation can be suppressed, such antibodies may be attractive principles for the treatment of allergic asthma.