Important non-disease-related determinants of exhaled nitric oxide levels in mild asthma - results from the Swedish GA(2) LEN study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has a potential clinical role in asthma management. Constitutive factors such as age, height and gender, as well as individual characteristics, such as IgE sensitization and smoking, affect the levels of FeNO in population-based studies. However, their effect on FeNO in subjects with asthma has been scarcely studied. OBJECTIVE: To study the effects on FeNO of these commonly regarded determinants, as demonstrated in healthy subjects, as well as menarche age and parental smoking, in a population of asthmatics. MATERIAL AND METHODS: Fractional exhaled nitric oxide was measured in 557 subjects with asthma from the Swedish GA(2) LEN study. Allergic sensitization was assessed by skin prick tests to most common aeroallergens. Upper airway comorbidities, smoking habits, smoking exposure during childhood and hormonal status (for women) were questionnaire-assessed. RESULTS: Male gender (P < 0.001), greater height (P < 0.001) and sensitization to both perennial allergens and pollen (P < 0.001) are related to higher FeNO levels. Current smoking (P < 0.001) and having both parents smoking during childhood, vs. having neither (P < 0.001) or only one parent smoking (P = 0.002), are related to lower FeNO. Women with menarche between 9 and 11 years of age had lower FeNO than those with menarche between 12 and 14 years of age (P = 0.03) or 15 and 17 years of age (P = 0.003). CONCLUSIONS AND CLINICAL RELEVANCE: Interpreting FeNO levels in clinical practice is complex, and constitutional determinants, as well as smoking and IgE sensitisation, are of importance in asthmatic subjects and should be accounted for when interpreting FeNO levels. Furthermore, menarche age and parental smoking during childhood and their effects on lowering FeNO deserve further studies.

A case-control study of the relation between plasma selenium and asthma in European populations: a GAL2EN project.

BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

Relationship of fish and cod oil intake with adult asthma.

BACKGROUND: A diet rich in fish or cod oil might possibly reduce the risk for asthma and atopic diseases. However, previous studies show conflicting results and no studies have assessed the potential long-term effects of childhood fish intake on adult asthma. OBJECTIVE: To investigate whether childhood and adult fish and cod oil intake was related to adult asthma. METHODS: In a large population-based study, Respiratory Health in Northern Europe (RHINE), 16 187 subjects aged 23-54 years answered a postal questionnaire. The relations of fish and cod oil intake with asthma symptoms and asthma were analysed using multiple logistic and Cox regression analyses, with adjustment for gender, adult hayfever, smoking, age, body mass index, household size, dwelling, parental education and centre, and for maternal smoking and family history of hayfever and asthma in a subsample (n=2459). RESULTS: Subjects from Iceland and Norway reported much more frequent intake of fish both in childhood and adulthood as compared with subjects from Sweden, Estonia and Denmark. Current fish intake less than weekly in adults was associated with more asthma symptoms, while more frequent fish intake did not appear to decrease the risk further. No dose-response association was found between childhood fish intake and adult asthma, but those who never ate fish in childhood had an increased risk for asthma and earlier asthma onset. Adult consumption of cod oil had a u-shaped association with asthma, with the highest risks in those taking cod oil never and daily. CONCLUSION: A minimum level of weekly fish intake in adulthood was associated with protection against asthma symptoms in this large North-European multi-centre study. Subjects who never ate fish in childhood were at an increased risk for asthma. Both indicate a possible threshold effect of fish on asthma.

Geographical variation in the prevalence of positive skin tests to environmental aeroallergens in the European Community Respiratory Health Survey I.

BACKGROUND: Many studies have reported the prevalence of sensitization using skin prick tests. However, comparisons between studies and between regions are difficult because the number and the type of allergens tested vary widely. Using the European Community Health Respiratory Survey I data, the geographical variation of sensitization to environmental allergen as measured by skin tests was established. METHODS: Adults aged 20-44 years, living in 35 centres in 15 developed countries, underwent skin tests for allergy to nine common aeroallergens: Dermatophagoides pteronyssinus, timothy grass, cat, Cladosporium herbarium, Alternaria alternata, birch, Olea europea, common ragweed and Parietaria judaica. The age-sex standardized prevalence of sensitization was determined and centres with high (95% confidence interval above and excluding study median) and low prevalence (95% confidence interval below and excluding study median) of sensitization to each allergen and to any of the nine allergens were identified. RESULTS: There was substantial geographical variation in the prevalence of sensitization to each of the nine allergens tested and in the prevalence of sensitization to any allergen (lowest 17.1%, median 36.8% and highest 54.8%). Sensitization to D. pteronyssinus, grass pollen and cat were usually the most prevalent (median between centre 21.7%, 16.9% and 8.8%, respectively). Timothy grass sensitization was higher than that for any other pollen species. CONCLUSIONS: As expected, geographical variations of sensitization to environmental allergen were observed across centres. These findings were compatible for those observed with serum-specific IgE. Skin tests can be used to assess the geographical distribution of allergens in a multicentric epidemiological survey.

Atopy and allergic disorders among adults in Tartu, Estonia compared with Uppsala, Sweden.

BACKGROUND: Recent studies in children and adults indicate that the prevalence of atopy and allergic disorders is lower in previously socialist countries in Eastern Europe compared with countries with a market economy while revealed risk factors are similar. OBJECTIVES: To estimate the prevalence of atopy among adults in Tartu, Estonia and to compare the prevalence of risk factors for atopy and allergic respiratory diseases in Estonia and Sweden. METHODS: As a part of cross-sectional study-European Community Respiratory Health Survey-random samples of 20-44 year olds (n = 351 in Tartu and n = 470 in Uppsala) and persons of the same age with asthma like symptoms or on current asthma medication according to a postal questionnaire (n = 95 in Tartu and n = 201 in Uppsala) were interviewed and circulating IgE antibodies were measured. RESULTS: The prevalence of atopy was 19% in Tartu and 32% in Uppsala (P < 0.001). The prevalence of sensitization to pollen was twice lower (11.5 vs 23.2; P<0.001) and the prevalence of pollen associated asthma symptoms was four times lower (1.7 vs 6.8; P<0.001) in Tartu than in Uppsala while sensitization to pollen was an equally large risk factor for asthma in both centres. Age was inversely related to cat and pollen associated symptoms of rhinoconjunctivitis in Uppsala (OR 0.6 and 0.7, respectively, P < 0.05) but not in Tartu. CONCLUSIONS: The prevalence of atopy was lower in Tartu, Estonia than in Uppsala Sweden. Perception of allergic disorders seemed to be lower in Tartu than in Uppsala. Age did not influence the prevalence of atopy nor allergic disorders in Tartu, while in Uppsala age was inversely related to clinical allergy. This could suggest a cohort effect underlying the increasing prevalence of allergy in Western Europe.

Physician-diagnosed asthma and drug utilization in the European Community Respiratory Health Survey.

The aim of this analysis was to estimate the geographical variation in the prevalence of physician-diagnosed asthma and treatment practice for asthma in young adults. The results are based on an ecological analysis of 34 centres in 14 countries, in which a total of 17,029 randomly selected subjects (52% females, age 20-48 yrs) underwent a structured interview and spirometry as part of the European Community Respiratory Health Survey. The sample was enriched with 2,903 symptomatic subjects when investigating treatment in subjects with physician-diagnosed asthma. The prevalence of physician-diagnosed asthma was highest in New Zealand and Australia (11-13%) and lowest in Erfurt, Germany (1.2%) and Spain (1.5-3.0%). The reported use of antiasthma medication in the last 12 months was also highest in New Zealand and Australia (12-16%) and correlated closely with the prevalence of diagnosed asthma (r=0.89, p<0.001). Herbal remedies against breathing problems had been used by 13% of subjects in Hamburg but the reported use of alternative remedies for breathing problems was low in most other centres. The use of inhaled anti-inflammatory drugs in subjects with physician-diagnosed asthma ranged from 49% in the UK to 17% in Italy and correlated with the prevalence of doctors' consultations within the last 12 months (r=0.66, p<0.05). The prevalence of anti-inflammatory treatment was positively related to the prevalence of nocturnal asthma symptoms (p<0.05). We conclude that there is a wide geographical variation in the prevalence of physician-diagnosed asthma and use of antiasthma medication. The geographical variation in the use of anti-inflammatory drugs among individuals with diagnosed asthma may be related to variations in asthma severity, as well as differences in treatment practices between countries.

Seasonal variation in serum eosinophilic cationic protein (S-ECP) in a general population sample.

The aim of this investigation was to study the seasonal variation in the serum levels of eosinophil cationic protein (S-ECP). The study population comprised a general population sample of 379 individuals (range: 20-45 years) who were investigated with blood sample for the measurement of S-ECP, skin prick test and methacholine challenge. The examination took place between May and October 1991. Of the 379 subjects investigated, 137 (36%) were atopic. A significant seasonal variation in S-ECP was found in the group of birch-pollen-positive subjects (P < 0.05), but not in the non-atopic or birch-negative atopic group. The mean level of S-ECP in birch-positive subjects was about twice as high in June as in birch atopic subjects examined during other months. It is concluded that seasonal variation in birch-pollen-positive subjects must be taken into account when using S-ECP clinically or in epidemiological research.

Synthesis and biological evaluation of novel 2,6-diaminobenz[cd]indole inhibitors of thymidylate synthase using the protein structure as a guide.

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.