14 research outputs found
Inhaled corticosteroids in asthma : effects on inflammation and lung function
Many clinicians are frequently confronted with an adolescent who comes to the first
aid department in the middle of the night, complaining of breathlessness and chest
tightness. While he was in a smoky environment he became wheezy and felt out of
breath. After taking some bronchodilator puffs his complaints did not improve but got
even worse. Others are more familiar with the picture of the infant, out of breath
sitting on the bench during gymnastics whereas other kids are busy doing their
exercises. All clinicians will immediately recognize the clinical symptoms of an asthma
patient. Bul what exactly is going on wilhin the airways?
Asthma is one of the most common disorders, affecting approximately 10% of the
population in the Western countries. Asthma, was used to describe several disorders characterized by
breathlessness or pain in the chest. Sir John Floyer wrote in his "treatise of the
asthma" in 1698: "I have assigned the immediate cause of asthma to the straitness,
compression, or constriction of the bronchi". Laennec in the eighteenth century
attributed asthma to a spasm of the smooth muscle fibers of the bronchi. In spite of
the fact that our knowledge of the disease has increased since then and asthma is
now considered as a chronic inflammatory disease, we still do not know the fundamental
cause of asthma and all the factors that induce airway inflammation.
Airway inflammation in asthma is characterized by redness and swelling of the
mucosa. These classical signs of inflammation are easily visible at bronchoscopic
examination. Bronchial biopsies not only show activated mast cells, eosinophils
and lymphocytes, but also epithelial shedding and fragility. Structural changes
include hypertrophy and hyperplasia of airway smooth muscle, and thickening of the
basement mem-brane due to the deposition of collagen in the lamina reticularisb
Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma
Asthma is characterized by both local infiltration of eosinophils in the
bronchial mucosa and bronchial hyperreactivity (BHR). A detailed
characterization of BHR implies analysis of a histamine or methacholine
dose-response curve yielding not only the dose at 20% fall of baseline
forced expiratory volume in 1 s (FEV1), but also a plateau (P)
representing the maximal narrowing response in terms of percent change in
FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling
dose). In the baseline condition, the specific airway conductance (sGaw)
may be considered closely related to airway lumen diameter. In 20
nonsmoking asthmatic patients, methacholine dose-response curves were
obtained, and a sigmoid model fit yielded the BHR indexes.
Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used
to recognize the total number of eosinophils and activated eosinophils,
respectively. The number of activated eosinophils was significantly
correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05),
whereas weaker and nonsignificant correlations were found for dose at 20%
fall of baseline FEV1 and the total number of eosinophils. We conclude
that the number of activated eosinophils can be considered a marker of the
inflammation-induced decrease of airway lumen diameter as represented by
the plateau index and sGaw
Effects of fluticasone propionate on methacholine dose-response curves in nonsmoking atopic asthmatics
Methacholine is frequently used to determine bronchial hyperresponsiveness
(BHR) and to generate dose-response curves. These curves are characterized
by a threshold (provocative concentration of methacholine producing a 20%
fall in forced expiratory volume in one second (PC20) = sensitivity),
slope (reactivity) and maximal response (plateau). We investigated the
efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate
in a double-blind, placebo-controlled study in 33 atopic asthmatics. The
outcome measures used were the influence on BHR and the different indices
of the methacholine dose-response (MDR) curve. After 2 weeks run-in,
baseline lung function data were obtained and a MDR curve was measured
with doubling concentrations of the methacholine from 0.03 to 256 mg x
mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently
developed, sigmoid cumulative Gaussian distribution function was fitted to
the data. Although sensitivity was obtained by linear interpolation of two
successive log2 concentrations, reactivity, plateau and the effective
concentration at 50% of the plateau value (EC50) were obtained as best fit
parameters. In the fluticasone group, significant changes occurred after 6
weeks with respect to means of PC20 (an increase of 3.4 doubling doses),
plateau value fall in forced expiratory volume in one second (FEV1) (from
58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to
3.75 L) in contrast to the placebo group. Stabilization occurred after 12
weeks. Changes for reactivity were less marked, whereas changes in log,
EC50 were not significantly different between the groups. We conclude that
fluticasone is very effective in decreasing the maximal airway narrowing
response and in increasing PC20. However, it is likely that part of this
increase is related to the decrease of the plateau of maximal response
Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness
Symptoms of atopic asthma often decrease or even seem to disappear around
puberty. The aim of this study was to investigate whether this so-called
clinical remission is accompanied by remission of airway inflammation,
since symptoms relapse in a substantial proportion of subjects later in
life. To assess indicators of inflammation and/or structural damage of the
airways, exhaled nitric oxide (eNO) and bronchial responsiveness to
adenosine-5'-monophosphate (AMP) and methacholine (MCh) were determined in
21 subjects in clinical remission of atopic asthma. Clinical remission was
defined as complete absence of symptoms of asthma without the use of any
medication in the year preceding the study. Results were compared with
those of 21 patients with current asthma and 18 healthy control subjects.
We found significantly higher eNO values in the remission group than in
healthy controls (geometric mean, 18.9 and 1.0 ppb, respectively; p <
0.001) whereas eNO values of the remission group and those of the subjects
with current asthma (geometric mean, 21.9 ppb) were similar (p = 0.09).
The responsiveness to both AMP and MCh of subjects in clinical remission
was significantly higher as compared with responsiveness of healthy
controls, and lower than responsiveness of subjects with current asthma. A
significant correlation could be established between eNO and
responsiveness to AMP, but not between eNO and responsiveness to MCh. The
results of this study are suggestive of persistent airway inflammation
during clinical remission of atopic asthma. We speculate that subclinical
inflammation is a risk factor for asthma relapse later in life, and that
eNO and responsiveness to both AMP and MCh can be used as different,
noninvasive indices of the inflammatory process of the airways
Dyspnoea perception during clinical remission of atopic asthma
Symptoms of atopic asthma often disappear around puberty. The authors
recently demonstrated that this clinical remission is accompanied with
ongoing airways inflammation in most subjects. The discrepancy between
lack of symptoms and persistent airway inflammation suggests that
perception of the symptoms is unclear. In the present study, young adults
in clinical remission of atopic asthma assigned themselves a modified Borg
score during methacholine and adenosine-5'-monophosphate induced
bronchoconstriction. Borg scores of subjects in clinical remission were
compared with those of symptomatic asthmatic subjects. A marked variation
in the Borg scores at a 20% fall in the forced expiratory volume in one
second was found. Significant differences in Borg scores between remission
patients and asthmatics could not be detected. It was concluded that
perception of dyspnoea, induced with methacholine and adenosine challenge,
is similar in young adults in clinical remission of atopic asthma compared
to that of patients with symptomatic asthma. Hence, an unclear perception
seems to be an unlikely explanation for the discrepancy between lack of
symptoms and ongoing inflammation. Other factors, including both physical
and psychological ones, may play a role in the apparent absence of
symptoms, thereby potentially leading to undertreatment
Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients
Allergic rhinitis and asthma often coexist and share a genetic background.
Pathophysiologic connections between the nose and lungs are still not
entirely understood. This study was undertaken to compare allergic
inflammation and clinical findings in the upper and lower airways after
segmental bronchial provocation (SBP) in nonasthmatic allergic rhinitis
patients. Eight nonasthmatic, grass pollen-sensitive patients with
allergic rhinitis and eight healthy controls were included. Bronchial
biopsies and blood samples were taken before (T(0)) and 24 h (T(24)) after
SBP. Nasal biopsies were obtained at T(0), 1 h after SBP (T(1)), and
T(24). Immunohistochemical staining was performed for eosinophils (BMK13),
interleukin (IL)-5, and eotaxin. The number of eosinophils increased in
the challenged and unchallenged bronchial mucosa (p < 0.05) and in the
blood (p = 0.03) of atopic subjects at T(24). We detected an increase of
BMK13-positive and eotaxin-positive cells in the nasal lamina propria and
enhanced expression of IL-5 in the nasal epitheliu
Simulating an integrated critiquing system
OBJECTIVE: To investigate factors that determine the feasibility and
effectiveness of a critiquing system for asthma/COPD that will be
integrated with a general practitioner's (GP's) information system.
DESIGN: A simulation study. Four reviewers, playing the role of the
computer, generated critiquing comments and requests for additional
information on six electronic medical records of patients with
asthma/COPD. Three GPs who treated the patients, playing users, assessed
the comments and provided missing information when requested. The GPs were
asked why requested missing information was unavailable. The reviewers
reevaluated their comments after receiving requested missing information.
MEASUREMENTS: Descriptions of the number and nature of critiquing comments
and requests for missing information. Assessment by the GPs of the
critiquing comments in terms of agreement with each comment and judgment
of its relevance, both on a five-point scale. Analysis of causes for the
(un-)availability of requested missing information. Assessment of the
impact of missing information on the generation of critiquing comments.
RESULTS: Four reviewers provided 74 critiquing comments on 87 visits in
six medical records. Most were about prescriptions (n = 28) and the GPs'
workplans (n = 27). The GPs valued comments about diagnostics the most.
The correlation between the GPs' agreement and relevance scores was 0.65.
However, the GPs' agreements with prescription comments (complete
disagreement, 31.3%; disagreement, 20.0%; neutral, 13.8%; agreement,
17.5%; complete agreement, 17.5%) differed from their judgments of these
comments' relevance (completely irrelevant, 9.0%; irrelevant, 24.4%;
neutral, 24.4%; relevant, 32.1%; completely relevant, 10.3%). The GPs were
able to provide answers to 64% of the 90 requests for missing information.
Reasons available information had not been recorded were: the GPs had not
recorded the information explicitly; they had assumed it to be common
knowledge; it was available elsewhere in the record. Reasons information
was unavailable were: the decision had been made by another; the GP had
not recorded the information. The reviewers left 74% of the comments
unchanged after receiving requested missing information. CONCLUSION: Human
reviewers can generate comments based on information currently available
in electronic medical records of patients with asthma/COPD. The GPs valued
comments regarding the diagnostic process the most. Although they judged
prescription comments relevant, they often strongly disagreed with them, a
discrepancy that poses a challenge for the presentation of critiquing
comments for the future critiquing system. Requested additional
information that was provided by the GPs led to few changes. Therefore, as
system developers faced with the decision to build an integrated,
non-inquisitive or an inquisitive critiquing system, the authors choose
the former
Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: Downregulation by inhaled corticosteroids
Background. Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and stimulators of T cells. Dendritic cells are also likely to be essential for the initiation of allergic immune responses in the lung. However, there are not many data on the presence of dendritic cells in the airways of patients with atopic asthma and on the effects of corticosteroid-treatment on such dendritic cells. Objective. We investigated the distribution of dendritic cells in the bronchial epithelium and mucosa of 16 non-smoking atopic asthmatic patients and eight healthy control subjects using detailed immunohistochemistry (CD1a, HLA-DR, L25 as markers for dendritic cells). Methods. Eleven asthmatics were treated for 2.5 years with bronchodilators only and five with bronchodilators and inhaled beclomethasone dipropionate (BDP), 800 ÎĽg daily. The patients were randomly sampled from a double-blind multicentre study. Results. There were higher numbers of CD1a+ DC (P = 0.003), L25+ DC (P = 0.002) and HLA-DR expression (P = 0.042) in the bronchial mucosa of asthmatic patients compared with healthy controls. After 2.5 years of treatment, we found a significant increase in flow expiratory volume in 1 second (FEV1) (P = 0.009) and a significant decrease in hyperresponsiveness (PC20 histamine) (P = 0.013) in the corticosteroid group (n = 5) compared with the bronchodilator group (n = 11). This clinical improvement in the corticosteroid-treated group was accompanied by significantly lower numbers of CD1a+ DC (P=0.008), and HLA-DR expression (P=0.028) in the bronchial mucosa than in the bronchodilator-treated group. Conclusion. Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulate the number of dendritic
Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers in nasal and bronchial mucosa
Mast cells and basophils are cells that play an important role in the
initiation and control of allergic inflam
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk