Search PubMed⌕ Search

Biomedical subjects

D S Postma

Publications and source records attributed to D S Postma.

At least 145 records · Page 8Linked to original sources
PubMed1999

The importance of genetic influences in asthma.

Asthma is a complex genetic disorder in which the mode of inheritance is not known. Many segregation studies suggest that a major gene could be involved in asthma, but until now different genetic models have been obtained. Twin studies, too, have shown evidence for genetic influences in asthma, but have also revealed substantial evidence for environmental influences, in which nonshared environmental influences appeared to be important. Linkage, association studies and genome-wide screening suggest that multiple genes are involved in the pathogenesis of asthma. At least four regions of the human genome, chromosomes 5q31-33, 6p21.3, 11q13 and 12q14.3-24.1, contain genes consistently found to be associated with asthma and associated phenotypes. Not only genes associated with asthma but also genes which are involved in the development and outcome of asthma will be found in the future. This will probably provide greater insight into the identification of individuals at risk of asthma and early prevention and greater understanding for guiding therapeutic intervention in asthma. Exchange of information between researchers involved in the genetics of asthma is important because of mandatory agreement on phenotypes and analytical approaches. Genetics will contribute to the a better understanding and management of asthma in the future.

Asthma↗
PubMed1999

Proteoglycan changes in the extracellular matrix of lung tissue from patients with pulmonary emphysema.

To characterize the changes in the extracellular matrix in smoking-related pulmonary emphysema, we undertook immunohistochemical studies in lung tissues from controls (n = 7), from patients with mild (n = 11) and severe (n = 8) emphysema, and from patients with lung fibrosis (n = 6). We studied collagens, laminin, fibronectin, proteoglycans (PGs), and beta1-integrins. The majority of the patients with severe emphysema showed diminished staining for the interstitial PGs, decorin and biglycan, in the peribronchiolar area, compared with patients in the control and fibrosis groups. Only a minority of patients with mild emphysema showed this diminished staining. In contrast, decorin and biglycan were well preserved in the perivascular area of all of the specimens from the emphysema group. Heparan sulfate PG staining was diminished in the respiratory airspace walls of patients with emphysema and fibrosis. Staining for Types I, III, and IV collagen, as well as for laminin, fibronectin, and the integrins, showed no differences between the four groups. The specific loss of interstitial PGs may be crucial for elastic recoil loss and subsequent bronchiolar obstruction, as seen in patients with smoking-related emphysema.

Adolescent↗
PubMed1999

Cytotoxic changes in hair cells secondary to pneumococcal middle-ear infection.

To determine whether the bacterial toxins associated with otitis media could induce morphologic changes in the organ of Corti, we inoculated the middle-ear cavities of healthy guinea pigs with either Streptococcus pneumoniae or sterile saline and then examined the organ of Corti histologically at 1, 2, and 3 weeks postinoculation. We found that the outer hair cells (OHCs) in the infected ears underwent several changes that were dependent on both the length of time following inoculation and also the position of the OHCs in the cochlea. At 2 weeks postinoculation, 7.0 to 20% of the OHC nuclei from the infected animals became very swollen, with the most significant swelling occurring in the basal turn. At 3 weeks postinoculation, 2.5 to 3.5% of the OHCs were missing in the infected animals, with the most significant loss occurring in the basal and middle turns. These results suggest that bacterial otitis media can produce cytotoxic changes in the cochlea. These changes may be a clinically significant factor in the temporary and permanent sensorineural hearing loss that has been associated with bacterial otitis media.

Acute Disease↗
PubMed1999

[Current opinions about asthma: genetic factors].

Asthma is a common disease which prevalence has been rising over the last years. It is therefore not a surprise that researchers have tried to set up genetics study in order to better understand the disease and hopefully find new ways for treatment and possibly prevention. Asthma has been found to run in families in many studies. Recently evidence has been gained that it segregates in families, when assessed by several phenotypes like atopy and hyperresponsiveness. Moreover, studies have shown that the inheritance of high levels of total serum IgE, a marker of atopy, are better fitted in a segregation analysis when a two locus model was applied than when a one locus model was applied. This suggests that more than one gene is involved in this complex disease. The search for genes in asthma has now led to several locations on the genome, including genes on chromosome 5, 11 and 12. The latter chromosomal regions have been replicated in several studies. Not all studies show these positive linkages, which may due to family selection, the number of families under study, the definition of the asthma phenotype under study and the prevalence of the phenotype in the general population. Apart from a genome wide search, several groups have looked for specific regions of interest, like the Fc epsilon receptor for IgE on chromosome 11 and the cluster of cytokines on chromosome 5q. Association studies have shown that several polymorphisms in chromosomal regions are linked to atopy, hyperresponsiveness and asthma. Data today suggest that several genes will be involved and current knowledge points at the possibilities for genetic analyses to further unravel asthma subtypes, like severe asthma, aspirin-sensitive asthma etc. A polymorphism in the beta-receptor has recently been found to be associated with nocturnal asthma. Moreover, polymorphisms in this receptor are also more prevalent in patients who respond less to beta-agonist therapy. A recent observation that a polymorphism in the 5-Lipoxygenase gene is linked to less responsiveness to a leukotrien-antagonist shows that the future perspectives of genetic studies may lie also in revealing the chromosomal map of the best therapy for an individual patient with asthma. Although, this may sound far fetched, it will become within our reach in the future. Finally, gene-environment interaction will be of interest for further prevention of asthma.

Amino Acid Sequence↗
PubMed1999

Defining asthma in genetic studies.

Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define asthma in genetic studies. These approaches include narrowing of the disease definition and use of intermediate phenotypes of asthma. Future studies are required to apply these approaches in genetic studies of asthma and, most likely, this will facilitate the search for genes for asthma.

Asthma↗
PubMed1998

Identifying asthma and chronic obstructive pulmonary disease in patients with persistent cough presenting to general practitioners: descriptive study.

OBJECTIVE: To determine the prevalence of asthma and chronic obstructive pulmonary disease in patients not known to have these disorders, who present in general practice with persistent cough, and to ascertain criteria to help general practitioners in diagnosis. DESIGN: Descriptive study. SETTING: Primary healthcare centre in the Netherlands. SUBJECTS: 192 patients aged 18-75 years, not known to have asthma or chronic obstructive pulmonary disease, attending their general practitioner with cough persisting for at least 2 weeks. : A diagnosis of asthma or chronic obstructive pulmonary disease was based on the recurrence of airway symptoms in the past year accompanied by spirometric measurements (including bronchodilator testing) and methacholine provocation tests. A scoring formula to estimate the probability of asthma or chronic obstructive pulmonary disease, based on history and physical examination, was generated by means of logistic regression. RESULTS: 74 patients (39%) were classified as having asthma, 14 (7%) as having chronic obstructive pulmonary disease. The best formula for predicting asthma or chronic obstructive pulmonary disease used scores for three symptoms: (reported) wheeze, (reported) dyspnoea, and allergen induced symptoms, together with prolonged expiration, pack years of smoking, and female sex. Variables were scored 1 when present and 0 when absent, except for allergen induced symptoms (1.5) and number of pack years of smoking (n/25). With a cut off value of 3 on the scoring formula, 76% of the patients could be classified correctly. CONCLUSIONS: About half of patients with persistent cough who present to a general practitioner have asthma or chronic obstructive pulmonary disease. With a simple formula based on three symptoms and prolonged expiration, pack years of smoking, and female sex, most patients may be identified correctly in general practice.

Adolescent↗
PubMed1998

Prostaglandin E2 differentially modulates IL-5 gene expression in activated human T lymphocytes depending on the costimulatory signal.

BACKGROUND: Protein kinase A (PKA) activation is documented to be inhibitory for T helper cell (T[H1])-like cytokines (IL-2, IFN-gamma), whereas T(H2)-like cytokines (IL-4, IL-5) are not affected or upregulated. We have recently shown that IL-4 gene expression can be inhibited by PKA activation but depends on the mode of T-cell activation. For IL-5 gene expression, we hypothesized that the mode of T-cell activation also determines the ultimate effect of simultaneous PKA activation. OBJECTIVES: The objective of this study was the examination of IL-5 gene expression in healthy T cells activated with various mitogenic stimuli after simultaneous activation of PKA by dibutyryl-cAMP or prostaglandin E2 (PGE2). METHODS: IL-5 mRNA was measured by semiquantitative reverse transcription-polymerase chain reaction or Northern analysis. IL-5 protein was measured by ELISA. Transcriptional mechanisms involved in IL-5 gene expression were determined by nuclear run-on experiments and electrophoretic mobility shift assays. Posttranscriptional mechanisms were determined by actinomycin D chase studies. RESULTS: Anti-CD2-, anti-CD3-, and anti-CD3 plus anti-CD28-induced IL-5 mRNA were completely inhibited by dibutyryl cyclic AMP (10[-3] mol/L) and PGE2 (10[-5] mol/L), whereas concanavalin A-induced IL-5 mRNA was partially reduced. The effect of PGE2 was accomplished at the transcriptional level, probably as the result of inhibition of DNA binding of nuclear factor-kappaB. Anti-CD3 plus anti-CD28-induced IL-5 protein (504 +/- 56 pg/ml) was significantly reduced by PGE2 (122 +/- 42 pg/ml, p < 0.001). Addition of cytokines that use the IL-2 receptor gamma(C) chain (IL-2, IL-7, IL-15) abrogated the PGE2-induced inhibition of IL-5 protein. In contrast, concanavalin A plus PMA-induced IL-5 protein (75 +/- 8 pg/ml) was significantly upregulated by the simultaneous addition of PGE2 (128 +/- 17 pg/ml, p < 0.03). CONCLUSIONS: PKA activation differentially modulates IL-5 gene expression and depends on the mode of T-cell activation.

Bucladesine↗
PubMed1998

The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): recruitment methods and strategies.

The European Respiratory Society's study on chronic obstructive pulmonary disease (EUROSCOP) is a multicentre study performed initially in 12 countries to assess the effect of 3 years' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease (COPD). It aimed at recruiting 50 subjects in 50 European centres. This study discusses the most successful, countrywise, recruitment strategies, an important issue since many multicentre European studies may follow in the future. The total number of recruited subjects was 2147 in 39 participating centres. In total, at least 25,000 screening spirometries were performed, and about 80,000 hospital records were checked. The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns (eight out of nine countries). Others used workplace screenings and different types of population survey, and only a few centres successfully recruited participants by hospital records. Inclusion criteria were slightly changed upon low initial accrual rate. Initial surveys in one country, where 2405 subjects were screened by spirometry, gave an important indication for the change of the inclusion criteria. Extension of the upper age limit from 60 to 65 yr considerably improved recruitment, as did a change of the upper limit of FEV1 from below 80% predicted normal to below 100% predicted normal, while maintaining the FEV1/VC ratio below 70%. A tremendous effort is needed to recruit individuals with preclinical COPD, but this is certainly feasible with adequate strategies adjusted to each country.

Administration, Inhalation↗
PubMed1998

Seasonal variations in cyclic AMP production by peripheral blood mononuclear cells in allergic asthmatics.

BACKGROUND: Dysfunction of the beta-adrenoceptor (betaAR)/adenylyl cyclase (AC) system can impair the response of different cell types, including lymphocytes. In asthma, impairment of this system as well as changes in cytokine production by lymphocytes have been described. Because the severity of asthma can change over the year, a circannual pattern of the betaAR/AC system activity may also exist. OBJECTIVES: We set out to examine the activity of this betaAR/AC signal transduction system in peripheral blood mononuclear cells (PBMCs) of allergic asthmatics to asses whether differences existed between seasons. We investigated whether changes were associated with asthma severity and circannual changes in serum cortisol levels. METHODS: During 19 months, 41 allergic asthmatics (mean age 28 years) with nocturnal airway obstruction were enrolled in the study. AC activity was measured by cyclic AMP production. Resting, stimulated and potentiated AC activities and their relationships with clinical parameters, seasonal influences and serum cortisol levels were assessed. RESULTS: The AC activity in resting, stimulated and potentiated cells varied during the year. AC activity was relatively low in the periods June-August and September-November, and higher in December-February and March-May. Receptor-mediated and potentiated responses expressed as percentage of the resting response were equivalent throughout the year. Serum cortisol levels were positively related to AC activity. No relationships were found between clinical parameters and AC activity or serum cortisol levels. CONCLUSIONS: These results indicate that AC activity in PBMCs of allergic asthmatics shows a seasonal variation. However, seasonal differences in AC activity seems to be unrelated with clinical parameters. Other factors such as serum cortisol levels may have a modulating influence on AC activity. Future studies of AC systems in blood cells of asthmatic patients need to take into account these seasonal influences.

Adenylyl Cyclases↗
PubMed1998

Exclusion of chromosome 11q and the FcepsilonRI-beta gene as aetiological factors in allergy and asthma in a population of Dutch asthmatic families.

BACKGROUND: The beta subunit of the high-affinity receptor for IgE (FcepsilonRI-beta) is localized to chromosome 11q13 and has been reported by Cookson et al. to be in close genetic linkage with a gene for atopy. A maternally inherited association was found between the presence of a variant of FcepsilonRI-beta, Ile181Leu, and high total serum IgE levels (IgE > 100 IU). In a previous study of 20 Dutch families, we found no evidence for linkage of atopy or bronchial hyperresponsiveness (BHR) to chromosome 11q. OBJECTIVE: Recently segregation analysis in 92 families has given us evidence for two independent major loci accounting for 78% of the observed variance in total serum IgE levels, and linkage analysis using both sib-pair and LOD score methods has identified one major locus for regulation of IgE levels and BHR near the cytokine gene complex on chromosome 5q. The objective of this study is to pursue the identification of the second major locus. METHODS: We have studied markers in the area of the high affinity IgE receptor (FcepsilonRI-beta) on chromosome 11q (D11S1314, FcepsilonRI-beta and D11S987) in 83 families for whom DNA was available. Furthermore, our families have been examined for variance in the FcepsilonRI-beta gene, specifically for Leu181 and Leu181/Leu183 mutations. RESULTS: By sib-pair analysis, there is no evidence for linkage of total serum IgE levels or number of positive skin tests to these markers in our population. Similar negative results were obtained for affected sib-pair analysis of BHR, with the exception of D11S1314, which was significant at P=0.046. The FcepsilonRI-beta gene in 36 female probands, 44 male probands and 46 female spouses was sequenced for these mutations. For each of these 126 individuals sequencing of FcepsilonRI-beta demonstrated a wild-type sequence pattern, with no mutations found in anyone, male or female. CONCLUSION: We are unable to confirm the presence of significant mutations in FcepsilonRI-beta gene in our population, and we cannot confirm that the FcepsilonRI-beta gene is crucial to the pathogenesis of allergic inflammation in asthma.

Asthma↗
PubMed1998

The importance of serum IgE for level and longitudinal change in airways hyperresponsiveness in COPD.

BACKGROUND: Airways hyperresponsiveness (AHR) is an important feature of patients with chronic obstructive pulmonary disease (COPD). Little is known about factors that modulate AHR in COPD. OBJECTIVE: To study these factors, we performed a long-term, double-blind, parallel intervention study in 58 male, non-allergic patients with COPD. METHODS: During a period of 2 years, patients were treated with inhaled budesonide (1600 microg/day), inhaled budesonide (1600 microg/day) plus oral prednisolone (5 mg/day), or placebo. PC20 histamine was measured at 4-monthly intervals. The influence of treatment, smoking, age, level of lung function, initial serum IgE level and peripheral blood eosinophils on level and longitudinal change of PC20 histamine was analysed. RESULTS: During follow-up, PC20 decreased in our group, and this decrease was not influenced by treatment. PC20 tended to decrease faster in current smokers than in ex-smokers. PC20 was significantly associated with pre-challenge FEV1 at each time point. Level nor decline of PC20 were significantly related to age. A higher initial serum IgE level was independently associated with a lower PC20. Moreover, a higher initial serum IgE level was associated with a slower annual decline of PC20, regardless of treatment, pre-challenge FEV1, and other modulating factors. No significant associations were found between initial blood eosinophils and level or decline of PC20. CONCLUSION: We conclude that AHR increases over time in non-allergic patients with COPD. Treatment with an inhaled corticosteroid alone or in combination with oral prednisolone does not change this increase. Our study suggests an important role for IgE in the course of the disease, since a higher initial serum IgE level predicts a more favourable course with regard to annual decline of PC20 histamine.

Aged↗
PubMed1998

Vascular adhesion molecules in nocturnal asthma: a possible role for VCAM-1 in ongoing airway wall inflammation.

BACKGROUND: Increased airway inflammation at night is thought to be one of the underlying mechanisms in nocturnal asthma. Vascular adhesion molecules may be important for the recruitment of inflammatory cells in the process of asthmatic airway inflammation. OBJECTIVE: To determine the possible role of vascular adhesion molecules in increased airway inflammation at night in subjects with nocturnal asthma. METHODS: Bronchial biopsies were obtained at 16.00 h and 04.00 h from 13 healthy controls, 15 asthmatic patients with PEF variation < or = 15% and 10 asthmatic patients with PEF variation > 15%. Biopsies were snap-frozen and double-immunostained for CD31 in combination with P-selectin, E-selectin, ICAM-1 or VCAM-1. RESULTS: No significant day-night differences in expression of adhesion molecules were found in any of the three groups. The percentage of VCAM-1 positive vessels in biopsies of asthmatic patients was higher than in biopsies of healthy controls: 5.8 vs 2.5% (P < 0.05) at 16.00h and 11 vs 0% (P<0.05) at 04.00 h. In asthma, VCAM-1 expression was correlated with the number of EG2 positive cells: at 16.00 h (rho = 0.57, P < 0.01) as well as at 04.00 h (rho = 0.64, P< 0.01). Moreover, VCAM-1 expression was correlated with the number of CD25 positive cells at 16.00 h (rho = 0.43, P < 0.05) and at 04.00 h (rho = 0.41, P < 0.05). CONCLUSION: Increased nocturnal airway obstruction in asthma is not associated with an increased nocturnal expression of vascular E-selectin, P-selectin, ICAM-1 or VCAM-1. The relationship between vascular VCAM-1 expression and sub-mucosal EG2 and CD25 positive cells, both at 16.00 h and 04.00 h, suggests a role for VCAM-1 in the ongoing airway wall inflammation of asthma.

Adult↗