The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.

The most prevalent malignancy among women is breast cancer. Phytochemicals and their derivatives are rapidly being recognized as possible cancer complementary therapies because they can modify signaling pathways that lead to cell cycle control or directly alter cell cycle regulatory molecules. The phytochemicals' poor bioavailability and short half-life make them unsuitable as anticancer drugs. Applying PLGA-PEG NPs improves their solubility and tolerance while also reducing drug adverse effects. According to the findings, combining anti-tumor phytochemicals can be more effective in regulating several signaling pathways linked to tumor cell development. The point of the study was to compare the anti-proliferative impacts of combined artemisinin and metformin on cell cycle arrest and expression of cyclin D1 and apoptotic genes (bcl-2, Bax, survivin, caspase-7, and caspase-3), and also hTERT genes in breast cancer cells. T-47D breast cancer cells were treated with different concentrations of metformin (MET) and artemisinin (ART) co-loaded in PLGA-PEG NPs and free form. The MTT test was applied to assess drug cytotoxicity in T47D cells. The cell cycle distribution was investigated using flow cytometry and the expression levels of cyclin D1, hTERT, Bax, bcl-2, caspase-3, and caspase-7, and survivin genes were then determined using real-time PCR. The findings of the MTT test and flow cytometry revealed that each state was cytotoxic to T47D cells in a time and dose-dependent pattern. Compared to various state of drugs (free and nano state, pure and combination state) Met-Art-PLGA/PEG NPs demonstrated the strongest anti-proliferative impact and considerably inhibited the development of T-47D cells; also, treatment with nano-formulated forms of Met-Art combination resulted in substantial downregulation of hTERT, Bcl-2, cyclin D1, survivin, and upregulation of caspase-3, caspase-7, and Bax, in the cells, as compared to the free forms, as indicated by real-time PCR findings. The findings suggested that combining an ART/MET-loaded PLGA-PEG NP-based therapy for breast cancer could significantly improve treatment effectiveness.

Increased sputum levels of thymus and activation-regulated chemokine in children with asthma not eosinophilic bronchitis

BACKGROUND: Thymus and activation-regulated chemokine (TARC), a member of the CC chemokine family, plays a crucial role in Th2-specific inflammation. We aimed to determine the concentration of sputum TARC in children with asthma and eosinophilic bronchitis (EB) and its relation with eosinophilic inflammation, pulmonary function, and bronchial hyper-responsiveness. METHODS: In total, 90 children with asthma, 38 with EB, and 45 control subjects were enrolled. TARC levels were measured in sputum supernatants using an ELISA. We performed pulmonary function tests and measured exhaled fractional nitric oxide, eosinophil counts in blood, and sputum and serum levels of total IgE in all children. RESULTS: Sputum TARC levels were significantly higher in children with asthma than in either children with EB (p = 0.004) or the control subjects (p = 0.014). Among patients with asthma, sputum TARC concentration was higher in children with sputum eosinophilia than in those without sputum eosinophilia (p = 0.035). Sputum TARC levels positively correlated with eosinophil counts in sputum, serum total IgE levels, exhaled fractional nitric, and the bronchodilator response. Negative significant correlations were found between sputum TARC and FEV1/FVC (the ratio of forced expiratory volume in one second and forced expiratory vital capacity) or PC20 (the provocative concentration of methacholine causing a 20% decrease in the FEV1). CONCLUSION: Elevated TARC levels in sputum were detected in children with asthma but not in children with EB. Sputum TARC could be a supportive marker for discrimination of asthma from EB in children showing characteristics of eosinophilic airway inflammation

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Simpatectomía dorsal bilateral en el tratamiento de la hiperhidrosis esencial: efectos a los 3 años sobre la función pulmonar / Bilateral dorsal sympathectomy for the treatment of primary hyperhidrosis: effects on lung function at 3 years

Introducción La hiperhidrosis esencial se caracteriza por un exceso de sudoración en la palma de las manos, la planta de los pies y las axilas, debida a una hiperestimulación del sistema nervioso simpático que pasa a través del segundo y tercer ganglios torácicos simpáticos. El tratamiento de elección es la simpatectomía dorsal bilateral (SDB) por videotoracoscopia. El objetivo de nuestro estudio ha sido evaluar si las modificaciones en la función respiratoria halladas previamente en un grupo de pacientes intervenidos por SDB se mantenían a los 3 años de la cirugía. Pacientes y métodos Del grupo de 20 pacientes estudiados previamente, pudimos reunir a 18 (3 varones y 15 mujeres) con una edad media de 35 años. Se les realizaron una espirometría y una prueba de provocación bronquial con metacolina, y se determinó la concentración de óxido nítrico en aire espirado. Los resultados se compararon con los de las pruebas efectuadas antes de la cirugía. Resultados A los 3 años se detectó un incremento estadísticamente significativo del porcentaje de la capacidad vital forzada basal, que pasó de un valor medio (±desviación estándar) del 96±10% al 101±11% (p=0,008). Respecto a las cifras iniciales del flujo máximo mesoespiratorio, se halló un descenso estadísticamente significativo a los 3 años de la cirugía: de un valor basal de 3,8±0,9l/s se pasó a 3,5±0,9l/s (p=0,01). La prueba de provocación bronquial con metacolina y la concentración de óxido nítrico en aire espirado no experimentaron cambios a los 3 años. Conclusiones Las modificaciones en la función pulmonar indican una mínima afectación de la pequeña vía aérea, que persiste a los 3 años de la SDB, como consecuencia de la denervación simpática producida por la cirugía, pero sin ninguna significación clínica(AU)

Introduction Primary hyperhidrosis is characterized by excessive sweating of the palms, soles, and axillae due to overactivity of the sympathetic nervous system at the level of the second and third sympathetic thoracic ganglia. The treatment of choice is bilateral dorsal sympathectomy performed using video-assisted thoracic surgery (VATS). The objective of our study was to determine whether lung function changes observed in a group of patients prior to bilateral dorsal sympathectomy performed using VATS were still evident 3 years after surgery. Patients and methods Of the 20 patients studied at baseline, we were able to obtain data for 18 (3 men and 15 women; mean age, 35 y). They underwent spirometry and a bronchial challenge test with methacholine, and the fraction of exhaled nitric oxide (FENO) was measured. The results were compared with those of the tests performed before surgery. Results At 3 years from baseline, we detected a statistically significant increase in forced vital capacity from a mean (SD) of 96% (10%) to 101% (11%) (P=.008), and a statistically significant decrease in midexpiratory flow rate from 3.8 (0.9)L/s to 3.5 (0.9)L/s (P=.01). The results of the bronchial challenge test with methacholine and the FENO remained unchanged. Conclusions The lung function changes detected point toward minimal, clinically insignificant small airway alterations due to sympathetic denervation following bilateral dorsal sympathectomy performed 3 years earlier(AU)

Parietaria sublingual allergoid immunotherapy with a co-seasonal treatment schedule

Background: Sublingual immunotherapy (SLIT) with monomeric allergoid, given according to the standard scheme, resulted effective and safe. However, the achievement of a clinical benefit requires a long time. We thus performed this study using an administration protocol starting in the co-seasonal period with a 3-day build-up phase and lasting only 6 months, in order to obtain the above benefit in a shorter time. Methods and results: The study, prospective, randomised and controlled versus drug therapy, was conducted on 65 rhinitic and/or asthmatic patients allergic to Parietaria with or without other sensitisations. Twenty-four were allocated to 1,000 AU/week, 21 to 3,000 AU/week and 21 to drug therapy. They were treated from April to September 2006. At baseline, 3 and 6 months a Visual Analogue Scale (VAS) was performed to assess the patients' well-being. Drug consumption was evaluated by means of monthly diary cards. Bronchial reactivity was investigated at baseline and 6 months by methacholine challenge test. There was a greater VAS improvement in both the SLIT groups than in the controls after 6 months (p < 0.05). In patients taking 3,000 AU/week this was already evident after 3 months. There was a significant reduction in rescue medication consumption between 3 and 6 months (p < 0.05) in all three groups. The bronchial reactivity was reduced only in the SLIT groups (p < 0.001). No adverse events were observed. Conclusions: At 6 months the allergoid SLIT showed itself to be effective and safe. In addition the subjective clinical benefit was obtained in a more rapid period, i.e. 3 instead of 6 months, when a higher maintenance dose was administered

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Asociación entre colonización-infección crónica por Pseudomonas aeruginosa e hiperreactividad bronquial en pacientes con fibrosis quística / Association Between Chronic Colonization or Infection With Pseudomonas aeruginosa and Bronchial hyperreactivity in patients with cystic fibrosis

Objetivo: La hiperreactividad bronquial (HRB) es un hallazgo común en la fibrosis quística (FQ), que no se ha relacionado de forma concluyente con la atopia. El objetivo del estudio ha sido investigar la relación existente entre la colonización-infección crónica por Pseudomonas aeruginosa y la HRB en un grupo de pacientes con FQ. Pacientes y métodos: Se realizó la prueba de broncoprovocación inespecífica con histamina a un grupo de 32 pacientes con FQ cuya edad media ± desviación estándar era de 11,25 ± 3,7 años. Además se investigó en estos pacientes la existencia de atopia y colonización-infección crónica por P. aeruginosa. Resultados: De los 32 pacientes estudiados, se encontró HRB en 9 (28,1%), cuya situación clínica era significativamente peor. Estos 9 pacientes con HRB presentaron todos colonización-infección crónica por P. aeruginosa. Tenían atopia 17 pacientes (53,1%) de la muestra estudiada, pero sólo 3 (33,3%) de los 9 con HRB. La HRB se asoció significativamente con la colonización-infección crónica por P. aeruginosa (p < 0,001), pero no con la atopia (p = 0,12). Entre los pacientes sin atopia, la colonización se asoció significativamente con HRB (p = 0,017). Además, en el grupo de pacientes con función pulmonar normal (volumen espiratorio forzado en el primer segundo ≥ 80%) esta asociación fue también significativa (p = 0,044), mientras que la asociación entre HRB y atopia no lo fue (p = 0,11). Conclusiones: Los resultados del presente estudio indican que en pacientes con FQ la HRB podría estar relacionada con la colonización-infección crónica por P. aeruginosa, que podría ser un factor de riesgo de HRB más importante que la atopia

Objective: In patients with cystic fibrosis, bronchial hyperreactivity is a common finding that has not been conclusively associated with atopy. The objective of the present study was to determine the relationship between chronic colonization or infection with Pseudomonas aeruginosa and bronchial hyperreactivity in a group of patients with cystic fibrosis. Patients and methods: A nonspecific histamine bronchial provocation test was administered to a group of 32 cystic fibrosis patients with a mean (SD) age of 11.25 (3.7) years. The presence of atopy and of chronic colonization or infection with P aeruginosa was also studied. Results: Nine of the 32 patients (28.1%) studied showed bronchial hyperreactivity. The clinical status of these 9 patients was significantly worse and all were colonized or infected with P aeruginosa. Atopy was present in 17 of the 32 patients (53.1%) in the study group, but in only 3 of the 9 patients (33.3%) with bronchial hyperreactivity. Bronchial hyperreactivity was significantly associated with colonization or infection with P aeruginosa (P<.001), but not with atopy (P=.12). In the patients without atopy, colonization was significantly associated with bronchial hyperreactivity (P=.017). In the group with normal lung function (forced expiratory volume in 1 second ≥80%) this association was also significant (P=.044), while the association between bronchial hyperreactivity and atopy was not (P=.11). Conclusions: The results of the present study suggest that in patients with cystic fibrosis, bronchial hyperreactivity may be associated with colonization or infection with P aeruginosa, and that this may be a more important risk factor for bronchial hyperreactivity than atopy

El tratamiento según la guía de la Global Initiative for Asthma (GINA) reduce la morbimortalidad de los pacientes con asma de riesgo vital / Management according to the global initiative for asthma guidelines of patients with near-fatal asthma reduces morbidity and mortality

Objetivo: Valorar el efecto de un adecuado tratamiento ambulatorio, de acuerdo con las recomendaciones de la guía de la Global Initiative for Asthma (GINA), en la evolución a largo plazo del asma de riesgo vital (ARV). Pacientes y métodos: Durante una media de 49 meses se realizó el seguimiento de 53 pacientes que habían sobrevivido a una crisis de ARV y que se trataron de acuerdo con las recomendaciones de la GINA (grupo de intervención). Se obtuvieron datos clínicos y espirométricos retrospectivos y prospectivos (antes y después del ataque de ARV, respectivamente) y se compararon con los de 40 pacientes con ARV que no fueron tratados según las recomendaciones de la GINA (grupo control histórico) y cuyo seguimiento medio fue de 51 meses. Resultados: No se registraron fallecimientos en el grupo de intervención, mientras que en el grupo control murieron 6 pacientes (15%) (p = 0,005). Los nuevos ataques de ARV fueron significativamente menores (p < 0,001) en el grupo de intervención, con una media ± desviación estándar de 0,17 ± 0,61, frente a 1,6 ± 1 en el grupo control. En el grupo de intervención las visitas a urgencias descendieron de 0,9 ± 1,8 a 0,3 ± 0,6 después de la crisis de ARV (p = 0,03), y los ingresos hospitalarios pasaron de 3,4 ± 5,1 a 0,5 ± 1,4 (p < 0,001); el recuento de eosinófilos en sangre periférica descendió de 390 ± 411 a 159 ± 121 células x 109/l (p = 0,01) y el volumen espiratorio forzado en el primer segundo aumentó del 68 ± 23% al 76 ± 20% (p = 0,006). Conclusiones: En los pacientes que han presentado una crisis de ARV el tratamiento siguiendo las recomendaciones de la GINA se asocia a un descenso de la morbilidad y la mortalidad del asma

Objective: To assess the effect of adequate outpatient care as defined by guidelines of the Global Initiative for Asthma (GINA) on the long-term outcome of near-fatal asthma. Patients and methods: Fifty-three patients who had experienced a near-fatal attack of asthma were treated according to the GINA guidelines and followed for a mean of 49 months (intervention group). Clinical and spirometric measurements corresponding to the periods before the attack (obtained retrospectively) and after the attack (obtained prospectively) were compared to measurements from 40 near-fatal asthma patients who had not been managed according to the GINA guidelines and who were followed for a mean of 51 months (historic control group). Results: There were no deaths in the intervention group and 6 deaths (15%) in the control group (P=.005). The mean (SD) number of new near-fatal asthma attacks was significantly lower in the intervention group (0.17 [0.61]) than in the control group (1.6 [1]) (P<.001). Emergency visits following a near-fatal asthma attack decreased from 0.9 (1.8) to 0.3 (0.6) in the intervention group and hospital admissions decreased from 3.4 (5.1) to 0.5 (1.4) (P<.001). Eosinophil count decreased from 390 (411) x l09 cells/L to 159 (121) x l09 cells/L (P=.01) and forced expiratory volume in 1 second increased from 68% (23%) of predicted to 76% (20%) (P=.006). Conclusions: Management according to the GINA guidelines of patients who had experienced a near-fatal asthma attack was associated with a decrease in asthma morbidity and mortality

Estudio de la función pulmonar en el paciente colaborador. Parte II / Respiratory function assessment in cooperative patients. Part II

El análisis de la hiperrespuesta bronquial mediante pruebas de provocación bronquial es uno de los pilares fundamentales para el diagnóstico de asma, así como un instrumento válido para la monitorización de la enfermedad, valoración de su gravedad, su evolución y la respuesta al tratamiento. Revisamos las pruebas de provocación bronquial inespecíficas tanto por estímulos físicos (ejercicio físico, soluciones hiperosmolares, y la hiperventilación con aire frío) como por fármacos (metacolina y adenosina). Aunque hay una cierta correlación entre las respuestas a diferentes tipos de prueba, hay niños que responden de forma diferente. La elección de la prueba que hay que utilizar dependerá de los fines diagnósticos o epidemiológicos que persigamos, de la experiencia de su utilización, dándonos frecuentemente información complementaria. Las pruebas de provocación indirectas como los estímulos físicos y la adenosina son más específicas del asma

Analysis of bronchial hyperresponsiveness using bronchial provocation tests are a key feature in the diagnosis of asthma, as well as a valid tool for monitoring disease severity, clinical course, and treatment response. We review non-specific bronchial challenge tests, including pharmacological stimuli (methacholine, adenosine) and physical stimuli (exercise, hypertonic saline, cold air hyperventilation). Although there is some correlation among responses to the distinct tests, individual responses are also observed. The indication for a single test will depend on whether the procedure will be used for diagnostic or epidemiologic purposes, and on experience of its use. Frequently, complementary information will be obtained. Indirect airway challenges tests such as physical stimuli and adenosine are more specific for asthma diagnosis

Bronchial challenge, assessed with forced expiratory manoeuvres and airway impedance.

OBJECTIVE: The Methacholine concentration at which a 20% decrease of the forced expiratory volume in 1s (PC20_FEV1) or a 40% increase in airway resistance (PC40_Rrs6) occur are accepted indicators for airway hyperresponsiveness. We hypothesised that the level of detection of bronchial hyperresponsiveness will differ between the two methods. METHODS: The response to Methacholine was assessed by forced oscillation technique (FOT) and spirometry in 20 stable hyperresponsive asthmatics. The effects of repeated lung function measurements on respiratory muscle fatigue were measured from maximal inspiratory mouth pressure (MIP). After each dose, patients scored their perception of dyspnoea on a BORG scale. Differences in patient's burden were measured by comparing the BORG-score at PC40_Rrs6 (BORG-PC40_Rrs6) and at PC20_FEV1 (BORG-PC20_FEV1). Reproducibility was also evaluated. RESULTS: The PC20_FEV1-values were 2.2 (0.4) doubling dose higher as compared to the PC40_Rrs6 (P<0.001). The mean BORG-score at PC40_Rrs6 was 1.7 points lower as compared to the BORG-score at PC20_FEV1 (P<0.001). The difference (mean(sd)) between the PC20_FEV1 of measurement 1 and 2 was -0.1 (1.4) doubling dose, and -0.3 (2.7) doubling dose for PC40_Rrs6. The MIP after Methacholine provocation was 1.0(0.2) kPa lower as compared to the MIP before the challenge test (P<0.001), suggesting respiratory muscle fatigue. CONCLUSION: Measuring PC40_Rrs6 shortens the challenge test and lowers the concentrations of bronchoconstrictor agents as compared to measurements of PC20_FEV1. The FOT-method was less strenuous for patients. In spite of the fact that the reproducibility is two-fold worse than measuring PC20_FEV1, it still remains quite acceptable at a mean of 0.3 doubling dose. The respiratory muscle strength was deteriorated after the challenge test.

Long-term follow-up of toluene diisocyanate-induced asthma.

Eighty-seven cases of occupational asthma induced by toluene diisocyanate (TDI) were diagnosed by an inhalation challenge with TDI and methacholine. After an average follow-up interval of 11 yrs, all subjects were re-examined. Of the 87 subjects examined, 13 (15%) had remained in the same job, 44 (50.5%) had been removed from exposure for <10 yrs and 30 (34.5%) had been removed for >10 yrs. The proportion of subjects who experienced symptoms of asthma and those who were hyperresponsive to methacholine was significantly lower. Of the patients, 59% used short-acting bronchodilators, 8% long-acting bronchodilators and 18% were on regular inhaled glucocorticoids. Thus, multiple regression analysis showed a positive correlation between forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at follow-up and FVC and FEV1 at diagnosis, and a negative correlation with smoking and with therapy with bronchodilators. Stepwise logistic regression showed that the follow-up provocative dose causing a 20% fall in the FEV1 (PD20) could be predicted from baseline PD20. These results indicate that respiratory symptoms and airway hyperresponsiveness to methacholine persist in subjects removed from exposure to TDI for >10 yrs. A more favourable prognosis was associated with a better lung function and a lower degree of airway hyperresponsiveness to methacholine at diagnosis.

Oropharyngeal angioedema induced by inhaled histamine.

Inhaled histamine used to measure airway responsiveness produces some side effects more frequently than does methacholine. It is possible that the inhaled histamine induces the side effects in asthmatics with increased end organ responsiveness to histamine. A 56-yr-old woman with chronic idiopathic angioedema presented with asthma-like symptoms. Methacholine challenge test was performed, with a negative result. Five days later, histamine inhalation test was done. FEV1 fell by 37% after inhalation of histamine concentration of 8 mg/mL. Immediately thereafter, severe angioedema on face, lips, and oropharyngeal area, foreign body sensation at throat, and hoarseness occurred. To assess end organ responsiveness to histamine, skin prick tests with doubling concentrations of histamine (0.03-16 mg/mL) were carried out on the forearm of the patient and six age- and sex-matched asthmatic controls. The wheal areas were measured. The patient showed greater skin responses than the controls. Regression analysis showed that the intercept and slope were greater than cut-off levels determined from six controls. The patient showed an increased skin wheal response to histamine, indicating the enhanced end organ responsiveness to histamine, which is likely to contribute to the development of the oropharyngeal angioedema by inhaled histamine.

Oropharyngeal Angioedema Induced by Inhaled Histamine

Inhaled histamine used to measure airway responsiveness produces some side effects more frequently than does methacholine. It is possible that the inhaled histamine induces the side effects in asthmatics with increased end organ responsiveness to histamine. A 56-yr-old woman with chronic idiopathic angioedema presented with asthma-like symptoms. Methacholine challenge test was performed, with a negative result. Five days later, histamine inhalation test was done. FEV1 fell by 37% after inhalation of histamine concentration of 8 mg/mL. Immediately thereafter, severe angioedema on face, lips, and oropharyngeal area, foreign body sensation at throat, and hoarseness occurred. To assess end organ responsiveness to histamine, skin prick tests with doubling concentrations of histamine (0.03-16 mg/mL) were carried out on the forearm of the patient and six age- and sex-matched asthmatic controls. The wheal areas were measured. The patient showed greater skin responses than the controls. Regression analysis showed that the intercept and slope were greater than cut-off levels determined from six controls. The patient showed an increased skin wheal response to histamine, indicating the enhanced end organ responsiveness to histamine, which is likely to contribute to the development of the oropharyngeal angioedema by inhaled histamine.

[The effects of ozone and toxic air particles on airway function in mice]. / Vplyv ozonu ta toksychnykh chastok povitria na dykhal'ni shliakhy myshei.

We tested the hypothesis that exposures to particulate matter and ozone can produce asthma-like symptoms. Balb/c mice received a single intratracheal instillation of particulate matter and TiO2 or they were exposed to low concentration of ozone. We have established that exposure to particulate matter produces increased responsiveness to methacholine in mice. Exposure to ozone and TiO2 did not produce changes in respiratory mechanics. These data are spreading our understanding about mechanisms of environmental influence on airways.

TNF-alpha dysregulation in asthma: relationship to ongoing corticosteroidtherapy.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is a major proinflammatory cytokine that is thought to be important in the pathogenesis of asthma. However, alterations in systemic regulation of this cytokine in asthma have not been examined in the context of corticosteroid therapy. OBJECTIVES: To examine the ability of peripheral blood mononuclear cells (PBMC) from three different groups of patients with asthma requiring varying amounts of inhaled corticosteroids (ICS) for clinical control, and to examine cells from age- and sex-matched nonasthmatic patients to produce TNF-alpha. DESIGN: All patients with asthma had a positive methacholine challenge test. 'High dose' ICS patients with asthma required ICS greater than or equal to 800 microg/day. 'Medium dose' patients with asthma were on less than or equal to 500 microg/day of ICS, whereas 'no ICS' patients with asthma had received no ICS for at least three months. Each patient with asthma was examined in parallel with an age- and sex-matched, nonasthmatic, nonatopic control subject. Cells were cultured (with or without the addition of potential stimulators phytohemagglutinin, lipopolysaccharide, formyl-methionine-leucine-phenylalanine or antihuman CD3), and TNF-alpha production was assessed by ELISA. MAIN RESULTS: PBMC from both high dose ICS (n=8) and no ICS (n=11) patients with asthma produced more than twice the amount of TNF-alpha than cells from matched nonasthmatic control patients (P<0.01) when cultured alone or in the presence of each stimulus (P<0.05). In contrast, there was no significant difference in TNF-alpha production between medium dose ICS patients with asthma and control patients. A group of asymptomatic atopic patients (n=6) did not have an increased level of TNF-alpha production. CONCLUSIONS: Increases in TNF-a production within the PBMC compartment can be observed in both patients with asthma receiving high dose ICS and in a group of patients with mild asthma receiving no ICS therapy, but not in patients with asthma receiving a medium dose of ICS or atopic patients.

Perception of bronchoconstriction and bronchial hyper-responsiveness in asthma.

The inter-relationship between the perception of bronchoconstriction, bronchial hyper-responsiveness and temporal adaptation in asthma is still a matter of debate. In a total of 52 stable asthmatic patients, 32 without airway obstruction ¿forced expiratory volume in 1 s (FEV(1))/vital capacity (VC) 84.1% (S.D. 7.9%), and 20 with airway obstruction [FEV(1)/VC 60% (4%)], we assessed the perception of bronchoconstriction during methacholine inhalation by using: (i) the slope and intercept of the Borg and VAS (Visual Analog Scale) scores against the decrease in FEV(1), expressed as a percentage of the predicted value; and (ii) the Borg and VAS scores at a 20% decrease in FEV(1) from the lowest post-saline level (PB(20)). Bronchial hyper-responsiveness was assessed as the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)FEV(1)). The reduction in FEV(1) was significantly related to the Borg and VAS scores, with values for the group mean slope and intercept of this relationship of 0.13 (S.D. 0.08) and -1.1 (3.02) for Borg, and 1.5 (1.19) and -12.01 (35) for VAS. PB(20) was 3 (1.75) with Borg scores and 34.6 (20.5) with VAS scores. Compared with the subgroup without airway obstruction, the obstructed subgroup exhibited similar slopes, but lower Borg and VAS intercepts. For similar decreases in FEV(1) (5-20% decreases from the lowest post-saline values), the Borg and VAS scores were lower in the non-obstructed than in the obstructed subgroup. PC(20)FEV(1) was significantly related to both Borg PB(20) and VAS PB(20) when considering all patients. When assessing the subgroups, PC(20)FEV(1) was related to Borg PB(20) and VAS PB(20) in the non-obstructed subjects, but not in the obstructed subjects. In neither subgroup was the log of the cumulative dose related to the Borg and VAS scores at the end of the test. We conclude that, unlike in previous studies, the ability to perceive acute bronchoconstriction may be reduced as background airflow obstruction increases in asthma. Bronchial hyper-responsiveness did not play a major role in perceived breathlessness in patients without airway obstruction, and even less of a role in patients with obstruction. The cumulative dose of agonist did not appear to influence the perception of bronchoconstriction.

Induced sputum: comparison of postinfectious cough with allergic asthma in children.

BACKGROUND: Cough persisting after a respiratory infection is common in children and is often managed as asthma. However, little is known about the pathophysiologic mechanisms of such cough and how it compares with asthma. OBJECTIVE: We used the technique of induced sputum to examine the inflammatory index values associated with persistent cough or allergic asthma in children. We hypothesized that the sputum from children with persistent postinfectious cough would differ from that of children with allergic asthma in that the former would lack eosinophils compared with the latter. STUDY DESIGN: Sputum production was induced with hypertonic saline solution in 34 children: 12 with cough persisting for 1 month or more after an apparent respiratory tract infection, not treated with corticosteroid; 11 with untreated atopic asthma, not using inhaled corticosteroid; and 11 with treated atopic asthma using inhaled corticosteroid. RESULTS: The percentage of eosinophils in the sputum of children with cough was significantly lower than in the sputum of children with untreated allergic asthma (median 0.5% vs 14.5%, P <.0001). Similarly, the percentage of eosinophils in the sputum of children with asthma treated with inhaled steroids was significantly lower compared with untreated asthmatic children (1.5% vs 14.5%, P <.0001). The peripheral blood eosinophils, serum eosinophil cationic protein, and nasal percent eosinophils of the patients with cough were also significantly lower than those from patients with untreated asthma. Methacholine challenge in 6 of the 11 cough patients tested showed mild-to-moderate hyperresponsiveness, whereas the other 5 had a negative methacholine challenge. CONCLUSIONS: Children with persistent postinfectious cough do not have airway eosinophilia typical of untreated asthma. Despite the absence of eosinophilic inflammation, some of the patients with chronic cough had reactive airways. These results suggest that postinfectious cough in children has different pathophysiologic features than allergic asthma and probably represents a different disease.

The relationship between airways inflammation and asthma severity.

In order to investigate the relationship between airways inflammation and disease severity, and improve the understanding of persistent asthma, 74 asthmatics, with disease severity ranging from intermittent, to mild to moderate and severe persistent (classified according to the Global Initiative for Asthma [GINA] guidelines), and 22 nonatopic control subjects were studied using the method of induced sputum. Sputum was analyzed for total and differential cell counts concentrations of albumin, and levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and tryptase, inflammatory mediators reflecting eosinophil, neutrophil, and mast cell activation. Asthma severity (assessed by FEV(1), peak expiratory flow [PEF] variability, and daily symptom scores) and methacholine airways responsiveness were related to sputum eosinophilia and ECP. In addition, sputum neutrophilia and MPO levels correlated, albeit weakly, with PEF variability and symptom scores, respectively. Tryptase concentrations were raised in mild to moderate asthmatics. Albumin concentrations were significantly raised across the spectrum of asthma severity and correlated with those of tryptase and ECP. Despite treatment with either high doses of inhaled corticosteroids or oral corticosteroids, prominent eosinophilic inflammation with raised ECP was noted. This study points to persistent, disease severity-related airways inflammation in asthma, involving eosinophils, mast cells, and neutrophils, which is evident despite treatment with corticosteroids.

Hiperreactividad en 30 niños sin asma con dermatitis atópica / Bronchial hyperreactivity in children with atopic dermatitis

Introducción. La importancia de la dermatitis atópica (DA) no sólo radica en su alta morbilidad, con topografía y morfología dérmica características, sino que además existen manifestaciones extracutáneas, de las cuales la hiperreactividad bronquial (HRB) puede estar presente expresándose posteriomente como asma bronquial, por este motivo el objetivo del trabajo fue determinar la presencia de HRB en 30 niños con DA sin diagnóstico de asma o afección pulmonar previa. Material y métodos. Se realizó un estudio prospectivo, transversal, en 30 niños de 6 a 16 años de edad que acudieron al Hospital Infantil de México Federico Gómez con diagnóstico de DA. Para determinar la presencia de HRB se realizaron pruebas de función pulmonar (espirometría basal y posterior al reto con diferentes concentraciones de metacolina). El análisis estadístico se llevó a cabo por la prueba t de Student pareada con corrección de Kurtosis. Resultados. La edad media fue de 11 años, con una relación femenino/masculino de 1.5: 1. De los 30 pacientes, 21 tuvieron reto positivo, demostrado por el descenso del VEF1 con respecto a la basal de 20 por ciento acompañándose de tos, opresión torácica y sibilancias. Al analizar los valores del VEF1 se encontró significancia estadística (P=0.0125) de los basales comparados con cada reto. De esta manera se observa que 70 por ciento tuvo HRB, concordando con lo reportado por otros autores, en los cuales más de la mitad de los pecientes con DA presentan HRB. Conclusión. Es necesario vigilar estrechamente a los pacientes con DA ya que como se demostró en este estudio, existe la posibilidad de que en algún momento de la vida pudieran presentar asma bronquial y aunque no se pueda evitar en su totalidad sí se podrían tomar las medidas necesarias para disminuir esta posibilidad basados en la pevención

Occupational asthma and food allergy due to carmine.

Carmine (E120), a natural red dye extracted from the dried females of the insect Dactylopius coccus var. Costa (cochineal), has been reported to cause hypersensitivity reactions. We report a case of occupational asthma and food allergy due to carmine in a worker not engaged in dye manufacturing. A 35-year-old nonatopic man, who had worked for 4 years in a spice warehouse, reported asthma and rhinoconjunctivitis for 5 months, related to carmine handling in his work. Two weeks before the visit, he reported one similar episode after the ingestion of a red-colored sweet containing carmine. Peak flow showed drops higher than 25% related to carmine exposure. Prick tests with the cochineal insect and carmine were positive, but negative to common aeroallergens, several mites, foods, and spices. The methacholine test was positive. Specific bronchial challenge test with a cochineal extract was positive with a dual pattern (20% and 24% fall in FEV1). Double-blind oral challenge with E120 was positive. The patient's sera contained specific IgE for various high-molecular-weight proteins from the cochineal extract, as shown by immunoblotting. Carmine proteins can induce IgE-mediated food allergy and occupational asthma in workers using products where its presence could be easily overlooked, as well as in dye manufacture workers.

Determinants of bronchial responsiveness in the European Community Respiratory Health Survey in Italy: evidence of an independent role of atopy, total serum IgE levels, and asthma symptoms.

The aim of the analysis was to test whether total serum IgE levels, specific serum IgE levels, and asthma symptoms are independent predictors of bronchial hyperresponsiveness (BHR), after controlling for known risk factors or potential confounders. The study was carried out on a sample of 875 young adults, 20-44 years old, who took part in the European Community Respiratory Health Survey in Italy. The subjects underwent a dose-response methacholine challenge test. We also measured airway caliber as the baseline FEV1 in absolute terms and as percentage of forced vital capacity (FVC); skin wheal response to 11 common environmental allergens; and total and specific serum IgE levels to mites, molds, pets, and respiratory symptoms by means of a standardized questionnaire. Atopy (positive skin prick test and/or positive specific IgE assay), total IgE, asthma symptoms, airway caliber, and age appeared to be independent predictors of BHR. When all the other risk factors were taken into account, atopy and total IgE were associated with a threefold increase in BHR risk and thus emerged as the main determinants of BHR. The importance of symptom status as a determinant of BHR decreased remarkably after controlling for atopy and IgE: the odds ratio of current asthmatics to asymptomatic subjects decreased from 15.3 to 8.8. When controlling for symptoms and atopy, a family history of allergic diseases and early respiratory infections was not found to be associated with BHR. Both FEV1 and FEV1/FVC were strongly and inversely associated with BHR. When airway caliber was taken into account, older age was associated with decreased responsiveness, and the level of responsiveness did not differ significantly between males and females and between smokers and nonsmokers. The results from this analysis indicate that at any given age, irrespective of sex and smoking habits, total serum IgE, specific IgE, airway caliber, and asthma symptoms are the main independent factors influencing the occurrence of BHR in a young adult sample.