[The effect of nitric oxide on potassium channels of bronchial smooth muscle cells from asthmatic rats]

[Article in Chinese]

Liu XS.

Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Wuhan 430030, China.

OBJECTIVE: To investigate the effect of nitric oxide (NO) on resting membrane potential (Em) and potassium currents of bronchial smooth muscle cells (BSMC) from asthmatic rat models. METHODS: Sixteen male SD rats were randomly divided into two groups: a control group and an asthmatic model group. Single BSMC was obtained by acute enzyme-digestion separation method. All experiments were conducted in conventional whole-cell configuration of patch clamp technique. Em currents of Ca2+ activated potassium channels (BKCa) and voltage-dependent potassium channel (Kv) of two groups were separately measured, and the changes of The resting Em and potassium currents of BSMC before and after addition of NO donor sodium nitroprusside (SNP) were also measured. RESULTS: (1) The Em of the asthmatic model group [(-29 +/- 6) mV, n = 12] was significantly lower than that of the control group [(-35 +/- 6) mV, n = 15, P < 0.05]; SNP significantly increased Em of the asthmatic model group to [(-38 +/- 7) mV, n = 12, (P < 0.0 1)], there is no significant difference of Em between normal group and that of asthmatic model group after SNP treatment (P > 0.05), which meant that SNP could repolarize BSMC to normal. (2) The mean current density of BKCa from asthmatic model group [(44 +/- 17) pA/pF, n = 8] under pulse protocol was significantly lower than that of the control group [(73 +/- 20) pA/pF, n = 10, P < 0.01], and SNP significantly increased the mean current density of the asthmatic model group to [(79 +/- 16) pA/pF, n = 10, P < 0.01], which was close to control group (P > 0.05); under ramp protocol, the current densities of control and asthmatic model group were [(75 +/- 19) pA/pF, n = 10] and [(46 +/- 16) pA/pF, n = 8] respectively, there was significant difference between two groups (P < 0.01), SNP treatment significantly increased current density of asthmatic model group to [(82 +/- 21) pA/pF, n = 8, P < 0.01]. (3) The mean current density of Kv of the asthmatic model group [(32 +/- 9) pA/pF, n = 8] under pulse protocol was significantly lower than that of the control group [(58 +/- 10) pA/pF, n = 8, P < 0.05], and SNP significantly increased the mean current density of Kv of the asthmatic model group to [(45 +/- 13) pA/pF, n = 8, P < 0.05]. Under ramp protocol, current density of Kv of asthmatic model group was [(38 +/- 11) pA/pF, n = 8], which was significantly lower than that of control group [(62 +/- 14) pA/pF, n = 8, P < 0.05], SNP treatment significantly increased Kv current density of asthmatic model group to [(53 +/- 9) pA/pF, n = 8, P < 0.05]. there was a similar change. CONCLUSIONS: SNP can improve the resting membrane potential of BSMC from rat asthmatic models and increase the potassium channel activity of BSMC, which is impaired in asthma status. The result suggests that potassium channel mediates the relaxation effect of NO on asthmatic airway smooth muscle.

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High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma.

Chanez P.

Clinique des Maladies Respiratoires, INSERM U454, Hopital Arnaud de Villeneuve, 371 Av du Doyen Gaston Giraud, 34295 Montpellier 5, France.

Urinary LTE4 reflects the whole body production of the cysteinyl-leukotrienes (LTC4, LTD4 and LTE4) that are established mediators in asthma. The influence of chronic inhaled and oral glucocorticoid treatment on urinary excretion of leukotriene (LT) E4 was investigated in subjects with asthma. Enzyme immunoassay analysis of LTE4 was performed in spot urine samples collected from 40 patients with severe asthma, 25 patients with mild-moderate asthma and 20 non-asthmatic control subjects. Urinary LTE4 was significantly higher in patients with severe asthma (69.7 +/- 5.5) as compared to mild-moderate asthma (45.7 +/- 3.3 with P < 0.0004) and control (42.5 +/- 2.5 with P < 0.0001). Despite chronic systemic treatment with glucocorticoids, chronically severe asthma had presented with higher levels of LTE4 compared to mild moderate asthma and healthy controls. The findings support previous indications that one important component in asthmatic airway inflammation, the cysteinyl-leukotriene pathway remains relatively unopposed by oral glucocorticoids.

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[Prevalence of symptoms of asthma, allergic rhinitis, conjunctivitis and atopic eczema: ISAAC (International Study of Asthma and Allergies in Childhood) in a population of schoolchildren in Zagreb]

[Article in Croatian]

Custovic A.

Odjel za klinicku imunologiju i pulmologiju Opca boinica Sveti Duh Sveti Duh 64 10000 Zagreb, Hrvatska.

OBJECTIVE: Numerous studies of the population prevalence of asthma, allergic rhinitis, and atopic eczema revealed some international differences. However, the International Study of Asthma and Allergies in Childhood (ISAAC) was the first one using a standardized methodology to evaluate the prevalence of these diseases, and to make comparisons within and between countries. The results showed marked variations in 12-month prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms with 20-fold (range 1.6-36.8%), 30-fold (range 1.4-39.7%), and 60-fold (range 0.3-20.5%) differences between the centres with the highest and the lowest prevalence, respectively. AIM: Our aim was to gain the insight into the prevalence of allergic diseases in Zagreb, Croatia by the methods of internationally standardized protocol, proposed by the ISAAC Steering Committee. METHODS: Original questionnaires, translated from English into Croatian, consisting of questions about the child's demographic characteristics, core modules on wheezing, rhinitis and eczema, and supplementary modules, were completed by parents of 10-year-old children (4th grade) attending 18 elementary schools in a city of Zagreb. Total of 1047 questionnaires were returned and analysed after the inconsistent responses were eliminated by phone calling. DISCUSSION: Phase one of the ISAAC study has shown a wide variation in the prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms throughout the world, with differing international patterns for the different disorders. Four prevalence ranges have been established for better illustration of the geographic distribution of asthma prevalence: (I) < 5%; (II) 5 to < 10%; (III) 10 to < 20%; (IV) > or = 20%. The highest 12-month prevalences of asthma symptoms were found in developed countries (UK, Australia, New Zealand, Republic of Ireland, and most centres in North, Central, and South America), being in prevalence range IV. The lowest prevalences (range I) were found in several Eastern European countries, Indonesia, Greece, China, Taiwan, Uzbekistan, India, and Ethiopia. According to the results of our study, a continental part of Croatia with a 12-month prevalence of wheezing of 6.02% corresponds to range II. Prevalence of asthma symptoms was greater in males, which is consistent with the results of the younger age group previously analysed. For allergic rhinoconjunctivitis and atopic eczema symptoms grouping of centres with a high prevalences into specific regions was less well defined than for asthma. Centres with the highest prevalences were scattered across the world. In contrast, centres with the lowest prevalences were similar to those for asthma symptoms. Our results of the 12-month prevalence of allergic rhinoconjunctivitis (12.13%), and atopic eczema (7.83%) symptoms were somewhere between the two extremes. As with asthma symptoms, the prevalence of rhinoconjunctivitis symptoms was greater in males. Contrary, the difference in prevalence of atopic eczema symptoms between the sex groups has not been found. The worldwide variations in prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms suggest that environmental factors may be critical to the development of these disorders in childhood. Furthermore, different patterns of geographical distribution of particular disorders suggest that major risk factors for them may be different or may involve different latency periods and time trends. Therefore, studies that include objective clinical assessment are required. CONCLUSION: According to our results, Zagreb is a city with relatively low prevalence of allergic diseases symptoms. Larger sample size of at least 3000 subjects is required to provide sufficient precision for estimates of symptom severity, and to generate adequate number of subjects with particular disorders for further analyses. Therefore, we recently increased our sample size to more than 3000 subjects, and started ISAAC Phase two (clinical examination, measures of bronchial hyperresponsiveness, measures of atopy, measures of environmental exposure to aeroallergens, and genetic analyses) in Zagreb, Croatia.

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Socioeconomic status, stress, and immune markers in adolescents with asthma.

Strunk RC.

Washington University, St. Louis Children's Hospital, St. Louis, MO, USA.

OBJECTIVE: Previous research has demonstrated links between low socioeconomic status (SES) and clinical asthma outcomes, as well as links between stress and asthma. The objective of this study was to test whether adolescents with asthma from different SES backgrounds differed in biological profiles relevant to asthma, including immune and cortisol measures. The second objective was to test whether psychological stress and control beliefs could explain these differences. MATERIALS AND METHODS: Adolescents with persistent asthma from either low (N= 18) or high (N= 12) SES neighborhoods were interviewed about their stress experiences (chronic stress, acute life events, interpretations of ambiguous life events) and control beliefs. Blood was drawn to assess immune (cytokines, eosinophils, IgE) and neuroendocrine (cortisol) markers associated with asthma. RESULTS: Adolescents in the low SES group had significantly higher levels of a stimulated cytokine associated with a Th-2 immune response (IL-5), higher levels of a stimulated cytokine associated with a Th-1 immune response (IFN-gamma), and marginally lower morning cortisol values compared with the high SES group. Low SES adolescents also had greater stress experiences and lower beliefs about control over their health. Statistical mediational analyses revealed that stress and control beliefs partially explained the relationship between SES and IL-5/IFN-gamma. CONCLUSION: Our finding that low SES was associated with elevations in certain immune responses (IL-5/IFN-gamma) in adolescents with asthma suggests the importance of further exploration into relationships between SES and Th-2/Th-1 responses in asthma. Our findings also suggest that psychological stress and control beliefs may provide one explanation for links between SES and immune responses in childhood asthma.

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Genetic polymorphisms of the beta-2 adrenergic receptor in Israelis with severe asthma compared to non-asthmatic Israelis.

Navon R.

Department of Pulmonary Medicine, Meir Hospital, Sapir Medical Center, Kfar Saba, Israel.

BACKGROUND: It has been argued that arginine replacement in locus 16 (Arg16) of beta 2 adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population. OBJECTIVES: To investigate non-anglosaxic ethnic influences on beta 2AR polymorphisms and its correlations to asthma severity. METHODS: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of beta 2AR and compared to matched controls. The Jewish patients included both Ashkenazi (of European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis and non-asthmatic Anglo-Saxons described in the literature. RESULTS: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons. CONCLUSIONS: The genetic distribution of beta 2AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal.

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Asthma entities.

Calhoun WJ.

Asthma Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

Asthma is a syndrome characterized by variable airflow limitation, airway hyperresponsiveness and airway inflammation. Considering asthma in aggregate, it is clear that a number of distinct mechanisms underlie the development of this disorder. In some patients, the mechanistic distinctions can be clearly drawn, and important therapeutic insights can be gained. In other patients, several mechanisms may coexist, or it may be impossible to separate them with current methods and technology. To distinguish subsets of asthma is more than an academic exercise. For both clinicians and asthma researchers, it is valuable to distinguish asthma subtypes as clearly as possible. Clinicians strive to prescribe the most effective, most safe, and most cost effective therapy possible, and understanding asthma subsets and their underlying mechanistic differences can substantively facilitate achieving that objective. Asthma research is often limited by significant, and sometimes dramatic intersubject variability. It is likely that at least some of that variability may arise from the (unrecognized) mechanistic heterogeneity of asthma. Better definition and selection of more homogeneous subsets of asthma may then lead to greater statistical power, and more definitive conclusions from asthma investigations. (c) 1999 Prous Science. All rights reserved.

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Comparing asthma care provided to Medicaid-enrolled children in a Primary Care Case Manager plan and a staff model HMO.

Weiss KB.

Health Policy Institute, Georgetown University, Washington, DC 20007, USA. shieldsa georgetown.edu

OBJECTIVE: To examine differences in selected processes of asthma care provided to Medicaid-enrolled children in a state-administered Primary Care Case Manager (PCCM) plan and a staff model health maintenance organization (HMO). METHODS: Retrospective cohort study assessing performance on 6 claims-based processes of care measures that reflect aspects of pediatric asthma care recommended in national guidelines. Analyzed Medicaid and HMO claims and encounter data for 2365 children with asthma in the Massachusetts Medicaid program in 1994. RESULTS: There were no plan differences in asthma primary care visits, asthma pharmacotherapy or follow-up care after asthma hospitalization. Children in the HMO were only 54% as likely (confidence interval [CI]: 0.37-0.80; P<.01) as those in the PCCM plan to experience an asthma emergency department (ED) visit or hospitalization. HMO-enrolled children were only half as likely (CI: 0.38-0.64; P<.001) to meet the National Committee for Quality Assurance (NCQA) definition for persistent asthma and only 32% as likely (CI: 0.19-0.56; P<.001) to have prior asthma ED visits or hospitalizations relative to children in the PCCM plan. Controlling for case mix and other covariates, children in the HMO were 2.9 times as likely (CI: 1.09-7.78; P<.05) as children in the PCCM plan to receive timely follow-up care (within 5 days) after an asthma ED visit and 1.8 times as likely (CI: 1.05-3.01; P<.05) as those in the PCCM plan to receive a specialist visit during the year. CONCLUSIONS: In this study, the HMO served a less sick pediatric asthma population. After controlling for case mix, the staff model HMO provided greater access to asthma specialists and more timely follow-up care after asthma ED visits relative to providers in the state-administered PCCM plan. Further understanding of the impact of these differences on clinical outcomes could guide asthma improvement efforts.

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Elevated serum melatonin is associated with the nocturnal worsening of asthma.

Martin RJ.

Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.

BACKGROUND: Increased airway inflammation at night contributes to the nocturnal worsening of asthma. In vitro studies have shown exogenous melatonin to be pro-inflammatory in asthma, but it is unknown whether endogenous melatonin levels are a controller of airway inflammation in nocturnal asthma. OBJECTIVE: Our aim was to determine 24-hour patterns of serum melatonin and their relationship to overnight decline in physiology in subjects with nocturnal asthma, non-nocturnal asthma, and in healthy controls. METHODS: Observational study of pulmonary physiology and melatonin levels in patients with nocturnal asthma (n = 7), non-nocturnal asthma (n = 13), and healthy controls (n = 11). Subjects maintained a constant sleep-wake regimen for 7 days. On day 8, serum melatonin was measured every 2 hours by radioimmunoassay and analyzed by cosinor modeling. The correlation between serum melatonin levels and overnight change in spirometry was evaluated by Spearman's rank correlation analysis. RESULTS: In subjects with nocturnal asthma, peak melatonin levels were significantly elevated compared with healthy controls (67.6 +/- 5.0 pg/mL versus 53.5 +/- 4.0 pg/mL, P =.03). Melatonin acrophase was delayed in nocturnal asthma (02:54 versus 01:58 in healthy controls, P =.003, and 02:15 in non-nocturnal asthma, P =.01). In subjects with nocturnal asthma, increasing melatonin levels were significantly and inversely correlated with overnight change in FEV(1) (r = -.79, P =.04), a relationship that was not observed in non-nocturnal asthma or healthy controls. CONCLUSIONS: Nocturnal asthma is associated with elevation and phase delay of peak serum melatonin levels. Elevated melatonin levels might contribute to the pathogenesis of nocturnal asthma.

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