text:
*From the Department of General Practice and Social Medicine (Drs. Cloosterman, Bijl-Hofland, and Akkermans), University of Nijmegen, and Department of Pulmonology (Drs. van Herwaarden and Folgering), Medical Centre Dekkerswald, University of Nijmegen, Nijmegen; the Department of Pulmonology (Dr. Elshout), Rijnstate Hospital, Arnhem; and University of Maastricht (Dr. van Schayck), Maastricht, The Netherlands.
Correspondence to: Sonja G. M. Cloosterman, MSc, PhD, Department of General Practice and Social Medicine, 229, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands; e-mail: firstname.lastname@example.com
Background: Some recent studies suggest that
regular β2-agonist use may result in inadequate control
of asthma. It has been hypothesized that this occurs particularly in
allergic asthmatic patients exposed to relevant allergens. Moreover, it
is still unclear whether this occurs during the use of both
short-acting and long-acting β2-agonists.
Methods: Asthmatic patients (n = 145) allergic to house
dust mite (HDM) were randomly allocated to monotherapy with a
short-acting β2-agonist (SA; n = 48), a long-actingβ
2-agonist (LA; n = 50), or placebo (n = 47), double
blind, double dummy. The study covered three periods: (1) a 4-week
run-in period, in which no changes took place; followed by (2)
cessation of treatment with asthma medication including inhaled
corticosteroids, introduction of allergen avoidance measures
(active/placebo treatment) to lower HDM exposure in the active group,
and an 8-week washout period to adjust patients to these changes;
followed by (3) a 12-week study medication period. At the start of the
12-week medication period, and every 4 weeks thereafter,
spirometric measurements (FEV1 and provocative
concentration of histamine causing a 20% fall in FEV1[
PC20]) were performed. Peak flow and asthma symptoms
were recorded daily. Additionally, at the start and every 6 weeks
thereafter, dust samples were collected from mattresses and living room
and bedroom floors to assess HDM (der p 1)
concentrations. Effects on FEV1, PC20, peak
flow, and asthma symptoms were analyzed with repeated-measurement
analysis and corrected for the exposure to HDM allergens.
Results: There were no significant differences among the
three medication groups after 12 weeks for FEV1. However, a
significant decrease in mean FEV1 percent predicted (95%
confidence interval [CI]) was observed within the SA group: − 6.6
(− 10.4 to − 2.8) (p = 0.0002). A decrease in geometric mean
PC20 (95% CI) of − 1.2 (− 1.96 to − 0.44) doubling
concentration was observed within the SA group (p = 0.05). No
significant changes in FEV1 and PC20 were
observed > 12 weeks within the LA group or the placebo group. There
were neither changes in peak flow and asthma symptom scores among the
three medication groups nor within the groups. Moreover, none of the
parameters showed interactive effects with allergen exposure.
Conclusion: There were no significant differences
among the three medication groups for FEV1 and
PC20. The within-treatment group comparison showed a
significant small decline in FEV1 for the SA group (but not
for the LA group), which could indicate that monotherapy with SAs might
have negative effects on FEV1. This was not seen during
regular use of LAs. No clear pathophysiologic mechanism can explain
these findings at the moment. Relatively high or low exposure to
allergens did not alter these findings.
In the last
to 10 years, interest in the possible detrimental effects of regularβ
2-agonist use for treating asthma has
increased. This started with the observation that there was a
connection between the increased use of β2-agonists
and death from asthma.1–3 The concern grew when clinical
trials reported increased bronchial hyperresponsiveness
(BHR),4–6 increased decline in lung
function,7and less overall control of asthma during
continuous use ofβ
Several studies observed that regular use ofβ
2-agonists led to tolerance to its protective
effects against bronchoconstrictive stimuli, whereas its
bronchodilatory properties remained unchanged.6,9–10
Bronchoconstrictive stimuli can act either directly on smooth muscles
or indirectly by stimulating the release of mediators. It has been
found that tolerance to direct bronchoconstrictive stimuli is of
a smaller magnitude compared to indirect stimuli.11
Tolerance is thought to be due to a downregulation ofβ
2-receptors on airway smooth
muscle,5 or on mast cells.11–12 O'Connor and
colleagues11found that after regular use of terbutaline,
the protective effect against adenosine monophosphate was more
diminished than the protective effect against methacholine (a direct
bronchoconstrictor). Cockcroft and colleagues12 found
similar results: after regular use of salbutamol for 2 weeks, airway
responsiveness to allergens (mast cell mediator release-induced
bronchoconstriction) had increased, whereas responsiveness to
methacholine had not changed. Furthermore, they found that regular use
of salbutamol caused tolerance to the protective effect of salbutamol
on bronchoconstriction induced by both methacholine and allergens.
These findings support the possibility of β2-receptor
downregulation on airway smooth muscle and probably to an even greater
extent on mast cells or other inflammatory cells. The latter may result
in an enhanced effect of the late asthmatic response, which is the more
important consequence of allergen inhalation. Consequently, it is
hypothesized that regular use of β2-agonists in
conjunction with allergen exposure might result in increased
Several other studies did not find any deleterious effect of the
regular use of short-acting β2-agonists
(SA)15–16 or long-actingβ
2-agonists (LA).20 One of the
possible explanations for the controversy might be that some asthmatic
patients are more sensitive to the deleterious effects of
bronchodilators than others. Reanalyzing our original data of patients
who used bronchodilators continuously during 2 years7
showed that especially asthmatic patients who were allergic and also
had a high reversibility of obstruction had an increased decline in
lung function.14 This result, together with the findings
of O'Connor et al11and Cockcroft et al12–13
indicate that, especially in allergic asthmatic patients, there might
be an interactive effect on inflammation between regular use ofβ
2-agonists and the exposure to allergens,
resulting in an increased airway responsiveness. We have proposed a
hypothesis that might explain the observed deleterious effects in some
studies, assuming a high exposure to specific and nonspecific irritants
during regular use of bronchodilators (Fig 1
).14 Thus far, this hypothesis has not been investigated in
everyday life. It is questionable whether the above-mentioned
laboratory findings (tolerance) result in negative effects on clinical
parameters in the long term. Furthermore, it is questionable whether
this hypothesis applies to LA as well as to SA.21 To test
this hypothesis and investigate these aspects, we performed a study in
allergic asthma patients to answer the following questions: (1) Does
regular use of β2-agonists result in
detrimental effects, and do these effects become worse when allergic
asthmatic patients are at the same time exposed to a high allergen
concentration? (2) Is there a difference between SA and LA?
We selected asthmatic patients allergic to house dust mite (HDM)
who should not use inhaled corticosteroids or should be able to cease
treatment with this medication, so that we would be able to study the
isolated effects of regular bronchodilator use. Patients were first
selected from an allergy laboratory (HDM positive). Secondly, patients
were examined by their general practitioner (GP) for having bronchial
symptoms or diagnosed asthma.22 Eligible patients
(n = 456) visited the lung function laboratory for an inclusion
assessment, where they had to meet the following criteria: (1)
FEV1 > 50% of predicted and > 65% of
predicted after inhalation of 800 μg of salbutamol; (2a) provocative
concentration of histamine causing a 20% fall in
FEV1 (PC20) ≤ 8 mg/mL
and/or (2b) reversibility of obstruction ≥ 15% after inhalation of
800 μg of salbutamol; (3) positive intradermal allergen test finding
for HDM (histamine equivalent wheal size > 0.7 on 10,000
biological units); and (4) treatment with bronchodilator monotherapy
possible, according to GP and lung physician (if applicable).
Additional selection criteria to avoid possible confounding of other
allergens include the following: (1) patients with a positive reaction
to dogs, rabbits, guinea pigs, or birds that was greater than the
reaction to HDM were excluded when these pets were still present in the
domestic situation; (2) patients allergic to cats, irrespective of the
magnitude of the reaction, were excluded when the cat was present in
the domestic situation at the time, or had been so in the 12 months
before the start of the study. Eventually, 258 patients met these
inclusion/exclusion criteria, of whom 204 agreed to participate in the
study (Table 1
). The study protocol was approved by the Medical Ethical Committee of
the Department of Pulmonology Dekkerswald, University of Nijmegen,
and all patients gave written informed consent.
Selected patients were randomly allocated to an active or
placebo allergen avoidance group and simultaneously to the use of SA
(salbutamol via metered-dose inhaler; two inhalations of 100 μg qid),
LA (formoterol via metered-dose inhaler; one inhalation of 12 μg
bid), or placebo treatment (Fig 2
The study involved three periods: (1) a 4-week run-in period with
no interventions, (2) an 8-week washout period during which time
allergen avoidance measures (active and placebo treatments) were
implemented and treatment with all pulmonary medication apart fromβ
2-agonists was discontinued, and (3) a 12-week
double-blind, double-dummy treatment period with study medications.
Allergen avoidance measures were performed in order to achieve a wide
range in allergen exposure (blinded for patient and lung function
technician). Patients who used pulmonary medication (inhaled
corticosteroids, cromoglycates, bronchodilators, etc) discontinued this
use and were instructed to use only the rescue medication on demand
(fenoterol/ipratropium combination via dry powder inhaler). The
fenoterol/ipratropium combination was chosen because it primarily
contains an anticholinergic bronchodilator (ipratropium bromide, 40μ
g) and a low dose of a β2-agonist
(fenoterol hydrobromide, 100 μg). Rescue medication use was carefully
recorded during the whole study period, and the record was subsequently
used as an effect parameter indicating asthma control. During the
8-week washout period, the patients could adjust to the changes in
allergen load and the cessation of treatment with their medications.
After those 8 weeks, the patients received the study medication but
rescue medication use was still allowed. The patients were carefully
instructed how to use the study medication (inhaler technique and time
schedule), and this use was checked every time the patient visited the
lung function laboratory. Used canisters were collected and were
weighed before and after use in order to check compliance.
If any of the patients had an exacerbation, as judged by their GP, they
were treated with an oral prednisone course and, if necessary, with
antibiotics in a standardized way. Prescribed prednisone courses were
also seen as an effect parameter indicating asthma control. If this
treatment was not sufficient and patients had to resume their
medication of inhaled steroids because of a further deterioration of
their asthma, this was considered an end point; these patients no
longer met the inclusion criteria and were therefore withdrawn.
Spirometry and BHR were measured during inclusion, at the start
of the study medication period, and after every 4 weeks of follow-up,
each time at least 12 h after stopping treatment with the study
medication. Spirometric parameters (FEV1,
postbronchodilator FEV1) were measured by means
of a microspirometer (HI-298; Chest Corporation; Tokyo,
Japan).23BHR was determined by stepwise inhalation of
increasing concentrations of histamine solution in accordance with the
European Respiratory Society standards.24 Doubling
concentrations of histamine acid phosphate, from 0.03 to 16.0 mg/mL,
were administered. PC20 from baseline was
obtained from the log-concentration response curve by linear
interpolation. After spontaneous recovery to ≥ 90% of the
prehistamine value, bronchodilator response was measured before and 15
min after 400 μg of salbutamol via metered-dose inhaler. This
reversibility of FEV1 was calculated as a
percentage of the prebronchodilator value.
During the entire study period, the patients recorded rescue medication
use, asthma symptoms, and peak flow values (Pocket Peak Flow Meter;
Micro Medical; Rochester, Kent, UK) on a diary card. Before the start
the study, they had been trained in performing peak flow maneuvers.
Three readings were performed each morning before breakfast and each
evening before dinner. The highest of three measurements (both in the
morning and in the evening) was recorded. Asthma symptoms included
cough, breathlessness, wheezing, expectoration, tiredness, and sleep
disturbance (due to nocturnal asthma symptoms) and were scored on a
modified Borg scale (0 = no symptoms to 10 = severe
Active HDM avoidance measures were performed in order to create
a lower exposure to HDM allergens. These measures consisted of
treatment of carpets and rugs in bedrooms and living rooms with an
acaricidal moist powder (Acarosan; Allergopharma; J. Ganzer KG;
Hamburg, Germany) in accordance with the instructions of the
manufacturer. Smooth floors (eg, parquet, flagstones) were
not treated. Mattresses, duvets, and pillows were enclosed in covers
impermeable to HDM and its allergens (Intervent Bedding Systems; W.L.
Gore & Associates; Livingstone, UK). The patients' environment without
HDM allergen avoidance served as an environment with a relatively high
allergen exposure. However, to blind the patients, placebo measures
were performed, which consisted of spraying a small volume of water on
the carpets and rugs from a bottle with an acaricide label, and
encasement of mattresses with mite- and allergen-permeable cotton
covers (specially designed for easy penetration by house dust by
Intervent Bedding Systems).
Separate dust samples were collected from the living room floor,
bedroom floor, and mattresses with a vacuum cleaner (Philips Turbo
Exclusive TC836, 1400 W; Philips; Eindhoven, the Netherlands). This was
done prior to the introduction of the avoidance measures and 8 weeks,
14 weeks, and 20 weeks later as follow-up. Floors were vacuumed totally
(intensity, 1 min per square meter) in a standardized way. For the
baseline assessment, the upper surface of the bare mattress of both the
patient and the partner (if present) was sampled, again in a
standardized way (intensity, 5 min per square meter). After encasing
the mattresses, follow-up samples were taken from the upper surface of
the encasing.
Detection of Der p 1 was performed by radioallergosorbent
testing as described by Van der Heide et al26 and
expressed in nanograms per gram.
PC20 values were log2-transformed to
achieve a normal distribution. Changes in PC20
could then be interpreted as doubling concentrations.
FEV1 was presented as a percentage of the
reference value (European Respiratory Society/European Community
for Coal and Steel standard).27 Compliance rates for
medication were assessed by comparing the used medication with the
prescribed medication (percentage). Der p 1 concentrations
were ln-transformed to achieve a normal distribution and presented as a
geometric mean (95% confidence interval [CI]). Der p 1
concentrations of the three follow-up measurements were averaged for
mattresses, living room floor, and bedroom floor independently. These
factors then described the whole range of allergen loads, from low to
high levels. This continuous factor "der p
1-concentration" was included in the analysis, not the dichotomous
factor "high exposure vs low exposure."
Repeated-measurement analysis of variance was performed to assess
effects during use of β2-agonists.
PC20 was used as dependent variable, and type of
medication (SA, LA, placebo) as the independent variable. Subsequently,
allergen concentration (mattresses, living room floor, and bedroom
floor, independently) was added as a second independent variable,
together with a term defining the interaction between the medication
parameters and the allergen parameter. In this way, we could assess
whether there was interaction between medication use and allergen
concentration on BHR. Finally, a variable defining measurements over
time was incorporated to see whether this possible interaction was
changing over time. Consequently, the following three models were
Patients were included in the analysis as far as they had completed the
study, according to the intention-to-treat principle, but with a
minimum condition of two measurements (baseline plus one follow-up
measurement). The data are presented as mean (95% CI).
A power calculation was performed on the basis that a difference of one
doubling dose (with a between-patient SD of two doubling dose) could be
detected between the two groups. A power of 0.90 was used and was set
at 0.05. The sample size of the groups should then be at least 53.
After applying the inclusion/exclusion criteria, 204 patients
started the 8-week washout period (Table 1). During this period, 42
subjects dropped out; consequently, 162 patients started the medication
period. During this medication period, five subjects dropped out
because they had to restart their use of inhaled corticosteroids before
the first follow-up measurement (SA group, n = 2; LA group, n = 0;
placebo group, n = 3). Five subjects stopped taking the study
medication within 4 weeks after the start (SA group, n = 2; LA group,
n = 1; placebo group, n = 2). Six patients stopped due to
motivational factors within 4 weeks after the start (SA group, n = 4;
LA group, n = 1; placebo group, n = 1). One subject (LA group) had
only one suitable measurement. Consequently, these 17 subjects (SA
group, n = 8; LA group, n = 3; placebo group, n = 6) performed
only the baseline measurement and could not be included in the
analysis. Eventually, 145 subjects completed the study. Patient
characteristics are shown in Table 2
To assess whether the avoidance measures successfully resulted in
a discrimination between low and high allergen exposures, the der
p 1 values after the intervention were compared. Geometric mean
der p 1 concentration on the encased mattresses in the
low-exposure group was 158 (94 to 266) ng/g and 686 (444 to 1061) ng/g
in the high-exposure group, which was significantly different
(p = 0.00). Geometric mean (95% CI) der p 1 concentration
on the bedroom floor was 568 ng/g (387 to 834 ng/g) in the low-exposure
group and 585 ng/g (394 to 870 ng/g) in the high-exposure group
(p = 0.92). For the living room floor, these concentrations were 520
ng/g (322 to 841 ng/g) for the low-exposure group and 413 ng/g (271 to
630 ng/g) for the high-exposure group (p = 0.47). Only the
HDM-impermeable covers reduced allergen exposure.
Repeated measurements analysis showed that there was a tendency
toward a difference in the course of BHR over time among the three
medication groups (p = 0.07; Fig 3
, top). Because the course over time tended to be different
among the three groups (interaction between time and medication group),
repeated-measurements analyses were also performed within each of the
three medication groups independently. These analyses showed that there
was no significant trend in BHR over time within the placebo group or
within the LA group. However, BHR showed a significant increasing trend
over time within the SA group, geometric mean (95% CI)
PC20 values decreased by − 1.2 mg/mL (− 1.96
to − 0.44 mg/mL), doubling concentration during the 12 weeks
(p = 0.05). When these analyses were corrected for allergen
concentrations of mattresses, bedroom floors, and living room floors,
no interactive effects were observed between medication use and
allergen concentration (all three p values > 0.05).
After 12 weeks of follow-up, there were no differences among the
three medication groups in the course of FEV1
over time (p = 0.17; Fig 3, bottom). Looking at the result
in the figure, we were interested in repeated-measurement analyses
within each of the three medication groups independently. These
analyses showed that there was a significant decreasing trend in
FEV1 within the SA group:
FEV1 percent predicted decreased by − 6.6
(− 10.4 to − 2.8) during the 12 weeks (p = 0.00). No significant
trends in FEV1 were observed within the placebo
or within the LA group. When corrections for allergen concentrations
were made, no interaction between medication use and allergen
concentration was observed (for all three samples sites p values>
As baseline peak flow variability was slightly, but significantly,
different among the three groups (higher in the placebo group),
corrections for baseline values were made for this variable during the
analysis by adding the baseline value as a covariant. First, only
medication effects were tested. There was no significant difference in
course time among the three medication groups for morning peak flow
(p = 0.34), evening peak flow (p = 0.52), and peak flow variability
(p = 0.87). Moreover, there were no significant trends within each of
the three medication groups for all three parameters (all p values>
0.10). No interactive effects between medication use and allergen
concentrations of the three sample sites were observed.
Because all symptom scores showed the same tendencies, only the
overall symptom score was presented. The simple model showed that there
was no difference among the three medication groups (p = 0.15) in
overall symptom score. When the overall symptom score was tested within
each medication group, no significant trends were observed. When
analyses were done with corrections for allergen concentrations, no
interactions were observed for each sample site.
The number of oral prednisone courses used and the amount of
rescue medication used in the three medication groups were taken as
indicators for asthma control. There were nine prednisone courses
prescribed during the study medication period (Table 3
). There was no difference in the number of prescribed prednisone
courses among the three study groups.
During the visits to the lung function laboratory, the patients handed
over the remaining capsules of the fenoterol/ipratropium combination,
which were counted, so that an indication about the rescue medication
could be obtained (median plus interquartile range). During the washout
period, the SA group used 0.12 (0.0 to 1.0) capsules a day and the LA
group and placebo group used 0.09 (0.0 to 0.41) and 0.25 (0.0 to 1.22)
capsules per day, respectively, which did not lead to any difference
among the three groups (p = 0.56). During the medication period, the
SA group used a median of 0.07 (0.0 to 0.75) capsules per day. During
LA use, this use was 0.04 (0.0 to 0.41) capsules per day, and during
placebo use, it was 0.15 (0.0 to 0.95) capsules per day, again not
significant among the three groups (p = 0.22). These data showed that
there was no excessive use of rescue medication in any of the three
medication groups before and during the study medication period.
This study indicates that regular use of the SA, salbutamol, may
result in a deterioration of BHR and lung function, which was not the
case during regular use of the LA, formoterol. Although no significant
difference was observed between groups, significant effects were
observed within the SA group, but not within the LA group.
Whereas some studies found deleterious effects of regularβ
2-agonist use,4–8 others did
not.9,16,20 This contradiction might be a result of
selecting different study populations. We hypothesized that asthmatic
patients with a high reversibility of obstruction who are exposed to a
high allergen level are the most vulnerable for these detrimental
effects.14 This was also hypothesized by Cockcroft et
al12–13: the regular use ofβ
2-agonist is especially deleterious when
allergen exposure occurs at the same time. However, no interactive
effects between allergen exposure and the regular use ofβ
2-agonists on lung function and BHR during
both SA and LA use were observed in this study.
Both FEV1 (− 6.6%) and BHR (− 1.2 doubling
concentration) deteriorated during regular SA use. Cockcroft et
al12 found no increase in BHR after regular use of
salbutamol for 2 weeks, when tested with methacholine. However, they
did find an increased BHR (− 0.91 doubling concentration) when tested
with allergen. They also showed that there was reduced protection, both
for methacholine and allergen, but this was not measured during the
present study. Wahedna et al28 observed a decrease in
FEV1 (absolute) of 10% and a decrease in
PC20 of 1.47 doubling concentration, after 3
weeks use of albuterol. Although these studies investigated a shorter
period of regular use of β2-agonists, these
findings are comparable with our findings.
We found no statistically significant difference among the three
medication groups. It might be possible that with slightly larger
sample sizes and a longer follow-up period, differences would have
become significant. This is suggested by the fact that the
within-treatment group effect of SA was highly significant for
FEV1 (p = 0.0002) and nearly significant for
PC20 (p = 0.05) and clinically relevant for
both, and the fact that differences among groups were more pronounced
at the end of the 12 weeks.
Several authors10–12 suggest that these negative effects
are caused by tolerance to the protective effect ofβ
2-agonists. This reduced protection is thought
to be due to β2-receptor downregulation on
smooth muscle cells and inflammatory cells, such as mast cells. This
would indicate that subjects are becoming less and less protected
against bronchoconstrictive stimuli (direct and indirect), resulting in
a deterioration of pulmonary parameters in the long term, which will
probably become even greater when subjects are exposed to allergens.
Several laboratory studies,11–12 did indeed find reduced
protection after regular β2-agonist use but
also found that there remained still a considerable amount of
protection. Most of these studies,5,10–12,17,29–
investigated a period of 1 to 8 weeks of regular use. Therefore, the
clinical relevance of these findings for the long term remains
uncertain.30 We did not measure the protective effects ofβ
2-agonists in this study; instead, we assessed
the clinical consequence of this possible tolerance during a period of
12 weeks. It was assumed that if a clinical relevant and persistentβ
2-receptor downregulation (tolerance) occurs
after regular β2-agonist use, resulting in
reduced protection, clinical consequences (a deterioration of
FEV1 and PC20) should
become manifest in the long term. This study shows this is the case to
a certain extent for the regular use of SA.
Theoretically, the use of LA produces prolonged occupancy onβ
2-receptors,21 which could result
in greater downregulation, compared with regular use of
SA.21 This is even more plausible for formoterol, because
this is nearly a full agonist, whereas salbutamol and salmeterol are
not.31 However, several studies5,11–12 showed
that both SA and LA (including formoterol) led to persistentβ
2-receptor downregulation (tolerance). In our
study, downregulation was noted in the SA group (with negative clinical
effects), but not in the LA group. Detrimental effects were found
for both SA and LA in laboratory settings,,10–12,32–33
but, in clinical studies, no adverse effects have been attributed to
LA.19,34The effect of inhaled corticosteroids might
confound these findings, as they might overcome a possible
An explanation for the differences between SA and LA found in the
present study is hard to give, as there is no clear pathophysiologic
mechanism. One explanation might be that the persistentβ
2-receptor downregulation caused by regular
use of SA, resulting in reduced protection in the long term, does
result in detrimental clinical effects. During use of LA, this
persistent β2-receptor downregulation still
seems to give enough protection, and consequently does not result in
detrimental effects. Furthermore, it has been found that formoterol has
a greater mast cell-stabilizing effect than albuterol36–
and salmeterol,37which might explain the effects of
formoterol in the present study. Finally, the time of measurement after
the last doses of study medication might have influenced our data.
Patients had to stop taking their medication for at least 12 h. It
is suggested in the literature that LAs have effects far beyond 12
h.38–39 So it might be that medication was still partly
active in this group at the time of measurement, which might result in
slightly elevated values. The median time of stopping treatment with
the study medication in the total LA group was 15 h at all
occasions. Additionally, we analyzed a subgroup of subjects who stopped
treatment with their medication for at least 20 h and 24 h.
Analyses of these subgroups did not result in different findings,
implicating that the β2-agonist activity was
probably marginal at the time of measurement for the whole LA group. We
therefore believe that the time of measurement did not seriously
confound the results of this study. Nevertheless, the LA group was
measured each time in this (probably partly) protected stage.
Several studies5,28,40 observed a rebound decrease in
FEV1 and PC20 during the
period just after stopping treatment withβ
2-agonists, which is thought to subsequently
recover within a few hours. These observations indicate that
detrimental effects might not be a structural effect of regular use ofβ
2-agonists, but rather a temporal
pharmacologic consequence of this regular use. If our observations are
due to a rebound effect, it seems that this only occurs after
discontinuing regular use of SA, and not after discontinuing use of LA.
This discrepancy is also observed in the
literature.,5,10,32 It is possible that the results of this
study are (partly) due to this rebound effect, especially in the SA
group, because pulmonary parameters were measured between 12 h and
15 h after the last concentration of study medication. This was
done to avoid still existing bronchodilating effects of theseβ
2-agonists (functional antagonism), though
this might not be the case in the LA group. To assess whether the
deterioration is structural after discontinuing regular use of SA or
recovers after a certain time, parameters should be additionally
measured at least 72 h after stopping treatment with the
medication and not only in this possible rebound period. Whether or not
a rebound effect occurs after discontinuing LA therapy cannot
completely be ruled out by this study, as there might be a possibility
that subjects were still in a partly protected stage. To give a better
answer to this, longer periods of discontinuation (eg,
24 h) are necessary. However, this period should also not be too
long; otherwise, this possible rebound effect might be missed.
We deliberately studied patients who did not use inhaled
corticosteroids or were able to stop using this medication, as we
wanted to investigate the isolated effects of regular use ofβ
2-agonists. One could argue that this study is
mostly theoretical, as regular monotherapy withβ
2-agonists is not generally advocated in
guidelines nowadays. Because we wanted to select only patients who
could do without inhaled steroids, a considerable number of patients
dropped out, as several of them could not do without their inhaled
steroids. So, it is likely that the patients who remained in the study
were those with less severe asthma, because they were steroid
independent. Consequently, these patients may be considered as not
fully representative of the total allergic asthmatic population.
Nevertheless, the present study population is probably more
representative of the subjects who do sometimes rely onβ
2-agonist monotherapy. Although inhaled
steroids are also advised in guidelines for this group of patients, it
might be that, because these patients have relatively mild conditions
and consequently have lesser symptoms, their compliance toward inhaled
corticosteroids is diminished and, consequently, they only useβ
2-agonists in their daily
As mentioned before, and in contrast to our original hypothesis, we
found no additional deteriorating effect of relatively high allergen
exposure. It might be that the exposure to HDM allergens in this study
was not high enough to evoke a possible interacting effect. The mean
(geometric) HDM allergen loads found in this study were just below
1,000 ng/g. Compared with other countries, for instance Australia or
South Africa, this is relatively low.42–43 Although
measured der p 1 concentrations are generally low in the
Netherlands, the prevalence of HDM allergy is 21.8% for subjects< 45 years old.44 So, despite the relatively low
allergen levels, patients in this country are also sensitized to HDM,
and exposure to these allergens might result in possible interactive
effects during use of β2-agonists.
In conclusion, we can say that, in this study, we observed a worsening
of lung function and BHR within a group of asthmatic allergic patients
who received monotherapy with salbutamol. This was not observed during
the regular use of LAs. Effects were seen only within the medication
groups, while the effects between the medication groups were not
statistically significant. No interactive effects were observed between
allergen exposure and the regular use ofβ
2-agonists on the deterioration of lung
function during both LA and SA use.
Abbreviations: BHR = bronchial hyperresponsiveness;
CI = confidence interval; GP = general practitioner; HDM = house
dust mite; LA = long-acting β2-agonist;
PC20 = provocative concentration of histamine causing a
20% fall in FEV1; SA = short-actingβ
This study was supported by the Dutch Asthma Foundation,
Novartis Pharma, 3M Pharma Industries, and Boehringer Ingelheim.
IC = inhaled corticosteroids.
Exclusion criterion.
Due to not stopping treatment with study medication or
rescue medication on time, or because FEV1 ≤ 50% of
Data are presented as mean (SD) (tested with
analysis of variance) unless otherwise indicated.
Geometric mean (95% CI).
Peak flow variability: (evening–morning)/mean.
Median (25th–75th percentiles).
N = total number of subjects in each
group; n = the number of patients who used an oral prednisone course;
% = these totals in percentages.
We thank the research assistants for obtaining the
dust samples, Mr. H. Hovenga (University Hospital Groningen) for
analyzing all the dust samples, Professor R. Aalberse (University of
Amsterdam) for kindly supplying the cell line producing monoclonal
antibody against Der p 1, and the four lung function
technicians (Mrs. M. Habes, Mrs. I. Van Den Heuvel, Mrs. E. Snakenborg,
Mrs. M. Thies) for performing spirometric measurements.
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text:
I took the Wilton Class over a year ago and never finished the final cake... So I would like to consider this my first cake since I had the help of a few people from this site.. I would like to thank Aitza for the inspiration. Her cakes inspired me...
CakeCentral.com is the world's largest cake community for cake decorating professionals and enthusiasts.
(if this is a private computer)
Yes please, register now!

subset: commoncrawl


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Chamber selects Bainbridge Island leader as CEO
Business veteran Kevin Dwyer has been named as the Snoqualmie Valley Chamber of Commerce's new president and chief executive officer.
"I'm thrilled to be working in such a beautiful area," said Dwyer. "I'm looking forward to working with the chamber board, the Snoqualmie business community and the community at large, to lift the chamber to its next level of excellence in the areas of membership development, tourism and economic development."
The chamber board unanimously approved his hiring in late December. His first day on the job will be Tuesday, Jan. 3.
Dwyer spent the past decade as executive director of the Bainbridge Island Chamber of Commerce and prior to that working as a business recruiter and marketer for the Economic Development Council of Kitsap County. Before entering the ceconomic development arena, he spent more than 20 years in newspaper and magazine editing and reporting in the Midwest, California and the Seattle area. He is the former editor of the Puget Sound Business Journal and was founding editor of Washington CEO Magazine.
During his tenure with the Bainbridge Chamber, Dwyer oversaw a growth in membership from the 670 members he inherited in 2001 to more than 1,000 members at the height of economic expansion, to about 850 in the years since. He also was able to triple the chamber's revenue and added a number of new events and networking opportunities.
Rodger McCollum, Snoqualmie Valley Hospital District administrator and incoming 2012 chamber president, led an extensive selection process with Gregory Malcolm, Encompass executive director and 2011 chamber president. McCollum is thrilled to welcome Dwyer aboard.
"Kevin is perfectly suited to step into the role as the champion for our chamber," he said, "especially at a time when experience in economic development, tourism and job creation will be required for the chamber to meet its strategic goals, which include increasing the number of chamber members."
Dwyer succeeds Snoqualmie resident Susan Livingston, who filled in on a contract basis as management consultant for the chamber since last summer.
The CEO role was created, McCollum said, because chamber board members believed that the new top position needed to be at that level for the new leader to capitalize on opportunities for economic growth in the Valley. He added that the Snoqualmie Valley chamber is particularly fortunate to draw upon Dwyer's skill set.
Dwyer said he sees great potential in the Snoqualmie Valley for building what he calls the three-legged stool of chamber work: membership development, tourism, and economic development.
"The Valley has great amenities," he said. "When you take in Snoqualmie Falls, the Railroad Museum, Snoqualmie Casino, the North Bend Premium Outlets, TPC Snoqualmie Ridge, Mt. Si, the rivers and the ski resorts, you really have a package of great outdoor and indoor opportunities that have enormous appeal and potential."
Part of Dwyer's role will be working with local city and regional officials to attract new businesses and primary jobs to the region.
"Growth is coming to the Valley from the Eastside, and the challenge is, how do we capture some of that?" Dwyer said. "How do we attract technology companies and other kinds of businesses that will see the Valley as a great place to live, work and play?"
Dwyer said he thoroughly enjoyed the hiring process with the Snoqualmie Valley Chamber and is in-tune with the organization's goals and objectives.
"I was impressed that a city administrator and a city council member were involved in the interview," he said. "It will be refreshing to be in a community where it appears that everybody is rowing the same way on tourism, economic development and the business perspective."
Dwyer looks forward to taking advantage of the Valley's physical beauty and surroundings. He enjoys biking, hiking, golfing and skiing and is an avid sports fan. He is married and has an adult-aged daughter. He plans to relocate to the Snoqualmie Valley.
To contact Dwyer, visit him at the chamber office, 38767 S.E River St. starting Tuesday, Jan. 3, or call (425) 888-6362.
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McKiernan named publisher of Record
Jim McKiernan has been named publisher of the Snoqualmie Valley Record, a 4,600-circulation weekly newspaper operated by King County Journal Newspapers. McKiernan, 42, has served as general manager of the Record since the newspaper was purchased from him and his wife Karen in 2000.
"Jim's record of leadership with the Record and his deep commitment to the greater Snoqualmie Valley community make him the natural choice for this position," said John S. Perry, executive vice president of King County Journal Newspapers.
McKiernan has been a resident of the Snoqualmie Valley since 1966. He began working at the Record in 1996 after working for the Boeing Co. for 11 years. He and Karen purchased the newspaper in that year from her father, Bob Scott.
McKiernan has been active in the Snoqualmie community and the newspaper industry. He served as president of the Chamber of Commerce and Mount Si Alumni Association. Her has served on the board of directors for the Washington Newspaper Publisher Association.
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text:
Re: "State schools official fired; He sounded alarm on Abramson," Page B1, July 22.
Folwell Dunbar is a whistle-blowing employee of the state Department of Education who for more than a year has been seeking better oversight of the 30-plus operators of New Orleans charter schools. He's now developed written recommendations for a comprehensive school quality review system.
This is not someone who should be fired by an acting superintendent in the job for only a few weeks. I met Mr. Dunbar only once, in 2006, when we were both volunteers shoveling Katrina debris, and I noted then that he is a dedicated public servant.
Subsequently, I did enough research on charter schools to find out that their quality is wide-ranging, and New Orleans is the only U.S. city having the majority of its public schools operating as charters. Those two facts alone justify "calling for a greater level of scrutiny" of independent charter operators. Dunbar should be reinstated in his position, and his recommendations should be given serious consideration.
Bonnie C. Morel
New Orleans


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More property in the works for Freeland sewer project
The Freeland Water & Sewer District is close to acquiring another piece of property for its future sewer system.
Water district commission chairman Rocky Knickerbocker said Saturday that the district has agreed on a price for 10 acres to be used for a future sewage treatment plant.
The parcel is the same one earmarked for that purpose in the district's comprehensive plan, he said.
The owner has agreed to sell the property, off Bush Point Road between Highway 525 and Mutiny Bay Road, for $275,000, Knickerbocker said. Money for the purchase will come from a grant from the state Department of Ecology.
On Dec. 30, the district closed on an 80-acre piece of property formerly owned by the Trillium Corporation and, more recently, by Dogwood Whidbey Development, an Arlington company that had hoped to build a planned residential development called the Estates at Whidbey.
The company defaulted on its loans for the land, however, and the property was purchased by Shoreline Bank at auction.
The sale price for the Freeland district is $560,000, which will be drawn from $2.5 million in Island County sales-tax revenues set aside last month for the Freeland sewer project as part of a rural development program.
The property would be used for an outfall for the sewer system.
Knickerbocker said the next step is to conduct design studies to get the project shovel-ready and prepared to go out for bids once more funds are available.
Sewer system supporters hope to acquire a $30 million grant for the project from the U.S. Department of Agriculture.
The water district has worked for years to create a sewer system that would serve Freeland's commercial core, the center of economic activity on the South End.
The $38 million project has been stalled over the years, however, by extensive planning, legal wrangling and a quest for funding.
The project is envisioned in multiple phases. The first would be the commercial core, for an estimated $17 million.
Gary Hess, district engineer, said Monday that construction on the project could begin within two years, once funding is set.
Hess said the Bush Road treatment plant would be installed in a building about the size of a large house. He said the water reclamation facility would have no outdoor ponds, and would be designed to be odor-free.
"We're plugging along, trying to get this thing going," Hess said. "Nothing has been smooth on this project so far."
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text:
Choose Between Two Options
- $25 for 6 vitamin B12 injections or Slim Shots ($120 value)
- $49 for 12 vitamin B12 injections or Slim Shots ($240 value)
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text:
BUYING? Brand New Construction Underway!
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text: I liked the post's approach: very level-headed; and worked both sides of the argument. I don't mind aligning myself with the Paleo/Primal community, but the idea of attaching the label being a danger is true. By putting a label, one's setting up for a sense of expectation; something to live up to. In the end, this labeling could be detrimental; and against one of the precepts of Paleo/Primal living: don't overstress over the wrong details.


text:
GOWANDA - The annual Hollywood Happenings in Gowanda kicked off the weekend of festivities with a very wet motorcycle ride.
Gowanda Harley Davidson Owner John Reid said fewer bikers were there this year because of the rain. "Turnout is quite a bit lower than other years, obviously because of the weather, but I'm surprised so many people are here regardless of the weather. We have the real enthusiastic riders here tonight," he said.
The event was formerly called the Harley Happenings, but has been changed to support fund-raising efforts for the Hollywood Theater in Gowanda.
Article Photos
OBSERVER Photo by Shirley Pulawski
Turnout was lighter than other years due to the rain, according to Jim Reid, co-owner of Gowanda harley Davidson.
"Randy Rosen and Gowanda Harley had started all of this, but basically, after almost nine years of doing it on their own, they needed some help and we were able to facilitate a lot more volunteers to make things work," Sal Dicembre, vice-president of the Gowanda's Historic Hollywood Theater board, said.
"This is our largest fund-raiser. We have thousands of people come to the event every year, and this is our 14th year. ... If we have a good turnout, good weather, we'll net anywhere from $40-50,000 this weekend," Dicembre continued.
"One hundred percent of that money goes back into the theater," in addition to the grants and other matching funds the group has been able to secure Dicembre explained.
"The theater was built in 1927. It fell into disrepair in the '90s. It was shut down in the mid-90s," according to Dicembre, who said it was then purchased by Dan Gernatt Jr.
"At that time it was closed. What he wanted to do was turn it over to a group that would be able to restore the theater. A 501 3(c) non-profit was established, Gowanda's Historic Hollywood Theater was established. ... We have raised roughly $511,000 through the Hollywood Happenings and private donations," Dicembre said.
"We are just shy of having put $2 million into the building. We expect to spend close to $2.6 million once we expend the grants we have. We are well over the half-way mark as far as the restoration," Dicembre continued.
We would love to get (the theater) fired up in 2013 or some time in 2014 so we can get at least some cinema showing in there," Dicembre explained. The theater has undergone extensive required repairs and upgrades, including wheelchair accessibility features, wiring replacements and removal of the boiler.
"It was one of those old coal-fired steam boilers with a pile of coal you had to shovel into it," Dicembre said. He further explained most of the remaining renovations would be more cosmetic. "People will really see it start to shine," Dicembre noted.
Dicembre said that in addition to the rider fees from the bike parade riders, the beer garden, other events, corporate sponsors and raffle ticket sales for a custom Harley Davidson motorcycle are the key sources of revenue during the event.
Today's line-up of events begins at 10 a.m. with registration for the AMVET's charity ride which leaves the American Legion at 11:30 a.m. The beer garden opens at noon today and Sunday.
The Hollywood Theater is open for visitors, and a magician will be performing at the theater at 11:30 a.m., 1:30 p.m., 4 p.m. and 6:30 p.m. both today and Sunday.
At 12:30, 3 p.m. and 5:30 p.m., a motorcycle stunt show takes place on South Water Street on both days as well. Rock and country musicians will perform on the stages. Today's events include a tattoo contest, and Sunday's festivities will conclude with the drawing of the Harley Davidson raffle.
Comments on this article may be sent to firstname.lastname@example.com


text:
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text:
|[TowerTalk] Cushcraft 40 meter Beam ???
|firstname.lastname@example.com (firstname.lastname@example.com)
|Wed, 12 Nov 1997 12:39:56 -0500 (EST)
In a message dated 97-11-12 10:48:15 EST, email@example.com writes: > You may be getting interference from nearby broadcast stations. The MFJ > runs just microwatts, so it wouldn't take much to upset the readings, > especially at that height. I live withing 4 miles of a 50 kw AM station and > can see the effects with a tribander at 40 feet. And the AEA analyzer as well. I've got a coax jumper with stacked toroids on it to use in cases where I've probably got some nearby RF problems. I've got the MFJ 259 and I use it ALL the time. 73, Steve K7LXC -- FAQ on WWW: http://www.contesting.com/towertalkfaq.html Submissions: email@example.com Administrative requests: firstname.lastname@example.com Problems: email@example.com Search: http://www.contesting.com/km9p/search
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text:
Staten Island Sandy victims wary as NYC Parks clears trees
Friday, March 01, 2013 3:23 PM
New Dorp Beach resident Steven Buckley is pictured while heavy machinery is used to clear trees between Cedar Grove Avenue and the shoreline in New Dorp Beach leaving some area residents worried as their last line of defense against a rising tide and damaging winds will be gone in a post-Hurricane Sandy Staten Island. Friday March 1, 2013. (Staten Island Advance/Anthony DePrimo)
Related articles
- Flood-wary Staten Islanders worried about losing the last line of protection (video/photo gallery) March 04, 2013, 7:00 AM


text:
Zorro Baits Casting Booza Bug Jig
The Zorro Casting Booza Bug was designed by legendary angler Stan Sloan. The Booza Bug Casting Jig features an unique head design and dual wire weedguard, allowing the Booza Bug to be fished with minor hang-ups. The Booza Bug is backed with a 5/0 lazer point hook while the line tie is set at 28 degree angle. Each jig head is epoxy painted to match every skirt.
9 Colors
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text:
British researchers may have uncovered a partial answer to the age-old question, "what came first the chicken or the egg?"
According to a team, comprising researchers from the University of Warwick and the University of Sheffield, the answer is "chicken" or at least a particular chicken protein.
There is, however, a further twist – this particular chicken protein turns out to come both first and last. That neat trick it performs provides new insights into control of crystal growth which is key to egg shell production.
Copyright 2016 © Godem Online Inc. | Web and server solutions by NewTech Solutions.


text:
Next Level Games, the Canadian based development studio that brought us, Punch-Out!! Wii and Luigi's newest haunted romp, Luigi's Mansion: Dark Moon, has signed an exclusive development deal with Nintendo. This means Nintendo now has another second party developer under its belt.
This information was revealed in an interview at Gamasutra with Next Level Games' co-founder Jason Carr. He said, the studio staff was "super happy" to work with Nintendo on Dark Moon. Later, Carr made an official statement about the matter.
"We have worked with a lot of other companies before, and we're super happy with our relationship with Nintendo.There's no reason to look anywhere else. They keep giving us better and better IP to work with, and as long as we do our job and make good games for them there's no reason for us to venture out."
Next Level Games is probably well known for its Nintendo franchises it has worked on, but there are a couple of other games that caught my eye. Titles like, NHL Hitz Pro, Spider-Man: Friend or foe, and Captain America: Super Soldier. Now these titles aren't exactly triple a, but did have promise and were far from being terrible.
How do you feel having Next Level Games taking over some of Nintendo most beloved series?
[via Screwattack]
Continue reading:
- Analyst: Nintendo Switch could cost $250 and
- Check out these awesome themed Nintendo Switc
- Nintendo: Switch is a new platform, not a suc
- WiiUDaily's Big Switch
TAGS: Next-Level Games, Nintendo, wii u


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» No double posting
» No glitching/hacking while in a match unless the other members agree to it.
►How Do I Sign Up?
[table]

code

►Clan Ranks
»Trust Agent: Your not the best, but you have come along way.
»Drones: Your the middle man, good but not great.
»Mites: Your Pretty good.
»Newbie: Just started and getting better.
►Current Ranks
Simply declare a rank match against an opponent, and win. You must first tell one of the leaders, and until then the match is put on hold. You may only rank match every other day, and can challenge people above your status. When you win you rank up, and the loser ranks down.
Rank Standings
Mr Ford
Trust Agent
Mario Legend
►Chat Box
Here we can chat easily about our clan. This also helps for those without wii speak[like myself] and want to quickly chat during the game!
Spoiler: Graphics
- - - - - - - - - - - -
- - - - - - - -
Generic UB's
Conduit name:Justin
Conduit code:4039-4248-9102
Timezone: Pacific
The Conduit Name: Slicer
The Conduit FC: 1935-2995-1689
Timezone: PST
- - - - - - - -
Neo name: Reuben
Conduit name: reuben
Conduit code: 5113-2546-6631
Time zone: 10+ i think, well Australia
- - - - - - - -
Neo name:Torag62
Conduit name:Michael
Conduit Fc:3696-1336-7461
Time zone:EST
neo name:Mario Legend
Conduit name: DEMON09
Conduit fc: 1419 7397 4120
Timezone: N/A
Conduit name:Meeper
Conduit code:2364-7331-7935
neo-name:Weapons of Peace
Conduit name:[J.]
Conduit code:4469-0549-5266
neo-name: Darcshadow7
Conduit name: MatthewK
Conduit code: 2965-6643-1044
Timezone: Mountain Standard Time (MST)
neo-name: curtzilla
Conduit name:curtis
Conduit code:1290-9029-7167
Timezone:Eastern Standard Time (EST)
neo-name: Sasuke45
Conduit name:Sasuke45
Conduit code: 1162 3553 0814
Timezone: Eastern Standard Time (EST)
neo-name: VoltageHero
Conduit name:Voltage
Conduit code: 4770-0225-9274
Timezone: Eastern Standard Time (EST)
neo-name: CnduitKiller
Conduit name: Sean
Conduit code: 3910-7971-5777
Timezone: Eastern Standard Time (EST)
Neo-name: lonelord
Conduit Name: Avion
Conduit Code: 2192-5635-1897
Timezone: Eastern Standard time (EST)
neo-name: Jordn
Conduit name: Naos
Conduit code: 4726-5720-2388
Timezone: GMT -4
neo-name: DXD
Conduit Name: DXD
Friend Code: 0947 - 8239 - 1631
Timezone: Mountain Standard Time(MST)
- - - - - - - -
For the best second leader i can ask for
Neoname: Arie
The Conduit Name: Arie
Wii System Code: 6339 2457 1206 8499
The Conduit Friend Code: 1290-6591-1336
Timezone: Eastern Standard Time
|quote quick quote posts in thread
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Nov 20, 10 at 10:11pm ^re: Lcc • XXII | We're Still Hip!
Crew History:
October 26th:TCC has been made, Arie has joined, Stonecutter joins, Chatbox is made, Luminary joins.
Ocotober 27th: Insanity has joined, our 1~V~1 ladder begins,Our name Contest Begins
Ocotober 28th: Hugs4hackers joins, arie levels up.
October 30th: Euben0 joins the clan.
Ocotober 31st: Cnduitkiller joins the clan
November 1st: ConduitFreak joins, Stonecutter leaves
November 2nd:Hugs4Hackers leaves us
November 5-10: ShadowBolt, Sephiroth, and Seargent_Conduit have joined the clan. New alliances are also formed.
November 14th: Thread two is created by JDL22
November 17th: Insanity has resigned from this clan.
November 18th: Euben is leaving for vacation until December 16th
November 20th: our Thanksgiving Tournament has been created by JDL22
November 23rd: Our GameBattles account has been made.
November 25th: Clan War Has been made againstLeague Of Legends [gamebattles clan]
November 26th: Happy thanksgiving TLC, Our name has now been changed to The Last chance.
November 27th: A new Cool banner made by Arie, go check it out.
November 29th: Arie is promoted to leader alongside JDL22, our new Clan site is made!
November 30th: New ranking system
December 1st: Hugs 4 hackers rejoins us, and makes us an Awesome header!
December 2nd: Our first weekly event! Go us.
December4th: Seargent_Conduit&Shadow bolt are removed from the members list.Arie trains JDL22 to become better!
December5th: JDL22 has made gold rank! I'm soo pro. i also get on the roof glitch in streets. To fall down minutes after. Arie ranks up!
December6th: Pure Awesome joins, and then Pure Awesome leaves... And then he joins
December7th: Thread three is made by JDL22
December9th: Our second weekly practice happened and Arie emerged the winner
December11th: We scrimaged LOL and lost... it was close though! they're good.
December12th: We played a clan battle against LoL and lost, also Territory wars is made. Decemeber Tournament is made.
December15th: Ferret is kicked from this clan.
December18th: Break has started for the most of us. This means more events! Happy holidays
December19th: josefuentes, Shriken4, and Solid Snake join!
December20th: The Empire takes Complex from Kill Inc.
December21st: New rank system is added. Sephiroth is also promoted to Co-leader
December22nd: PureAwesome leaves
December23rd: Mario Legend joins, and Arie makes User Bars, JDL22 makes thread 4
December25th: Happy christmas LCC!
December27th: Curtzilla joins us!
December30th: Thread 5 is made by JDL22
January 1st: Happy new years, 2010!
January 5th: Slicer joins us.
January 9th: Thread 6 is made by JDL22, & lost against CC in a clan battle
January 11th: Mini Games are made.
January 12th: Thread is updated & fun week begins!
January 14th: Allies are dropped with The black nights. CC, our allies, are now recruiting again.
January 15th: Thread seven is made by JDL22, Arie wins the December tourney
January 16th: Slicer & Mikey are promoted to Co leader. Squall is demoted to normal member. Had some mini games today! Rad game was fun.
January 17th: Our clan is brought to Conduit Portal
January 19th: Msnyps joins
January 22nd: Suris joins
January 24th: Arie makes Thread 8
January 24th: Jdl22 is a thread nazi
January 26th: AK9ShootOut joins
January 30th:
January 31st slicer makes February tourneyWar against Blazing Killers, we lost
February 1st: Slicer makes February Tournament
February 2nd:JDL22 makes Thread 9, Squall leaves
February 4th: JDL22 clears out the members list... *Goodbye*
February 14th: JDL22 makes thread 10, he also cleans the member's list, and gives Slicer his trophy!
February 16th: Snake comes back! OMG! arie makes a SUPER GOOD outline of streets
February 21st: Stickdude joins
February 25th:thread 11 is made JDL22
February 26th: Happy birthday, me. Your wonderful leader. ^^
March 1st: February tourney is won by MOFO
March 5th Arie and Hugs announces their leave. D;
March 6th: thread 12 is made by JDL22. Slicer is promoted to leader, reuben is promoted to co-leader, and mario is promoted to tester.
March 7th: March/april tourney is made by Slicer.
March 16th: Thread 13 is made by Slicer.
March 29th: Thread 14, JDL22 cleans out the list... again.
April 5th: Thread 15 is made by jdl22.
April 10th: Torag joins!
April 24th: Thread 16 is made by Slicer.
May 7th: May tourney is made by Slicer.
May 15th: Thread 17 Is made by Euben0
May 30th: Darcshadow emerges victor in our tourney!
June 11: Thread 18 is made by Justin!
June 13th: Sasuke joins!
June 14th: Justin edits the first post, and cleans the members list once again!
July 7:Thread 19 Is made by Euben0!
July 23: Justin goes camping for 9 days, Reuben becomes more skilled in the Conduit.
July 24: Reuben makes thread 20.
September 20: Reuben makes Thread 21
September 28: DXD Joins LCC
Spoiler: Alliances
Chaos Commanders
~Led by xlXPunkRockerXIx
Spoiler: Wars
Clan War Against League of Legends ~Status~Lost
Clan War Against Blazing Killers~Status~Lost
Spoiler: Events to look forward to!
Tournament for the top~Status~Arie
thanksgiving Tourny~Status~Canceled
December monthly tournament~status~Arie
February monthly tourney~status~MOFO
March/April monthly tourney~status~Canceled
May's monthly tournament~status~ Darcshadow7
- - - - -
Clan Battles
Clan battle with CC~Status~Lost
Spoiler: RIP
Spoiler: Arie's farewell
This spoiler is made for Arie only. March 5th, 2010; Arie made his farewell speach. It is because of him, and justin, that this clan has made it up until this far. I give him my highest blessings on behalf of the whole clan. May he be be happy, where ever it is that he will go. This is to the best Tcon clan leader you can ask for. This is for the best Tcon player you will see. This is to, arie, the best person you'll ever find here on neoseeker. Arie, live well.
Time Zones:
|quote quick quote posts in thread
Nov 20, 10 at 10:12pm ^re: Lcc • XXII | We're Still Hip!
Famous Sayings, and proverbs:
Spoiler: Sayings/proverbs
Official Title:
i just thought of this, and i think it suits them very well.
CnduitFreak: Active Freak in honor of your activity and will in putting effort in to this clan. Congratz.
Arie: Co-leader of the century in honor of your willful attitide, and concern for us at TCC. Thanks, and what better co-leader could there be?
that doesn't really do anything but i just thought i should make something like that because they try to help all that they can.
- - - - - - - -
13 kill streak, 17 and 2! that's my best ever!!! lol
~JDL22(sad, isn't it?)
- - - - - - - -
Lol, sweet. I'll join jdl because my clan was deleted
Any other PC members interested? this is a golden opportunity to stimulate some of the lesser clans.
How 'bout it active people, Earth? Luminary? anyone else (cough Hugs cough)?
One suggestion jd, um.. can you make it a little more readable? The green text sorta hurts my brain lmao
~Arie(our first, but not our last.)
- - - - - - - -
I resignThis clan isn't going anywhereThere just aren't enough people in this forum.I might stop in every once in awhile though.For now*jumps in the millennium falcon and flies away*
~Hugs 4 Hackers
- - - - - - - -
this clan is going nearly to destruction. I really can't afford to lose anymore people.
"Have we decided to take the action to attempt a revival that is so close to impossible only gods can succeed?"
if only dreams did come true...
I'm keeping you on the list though Conduit Killer, we'll miss you. Thanks for everything you have done. I only wish our time could be just weeks longer...
~JDL22( fool's words.I was wrong, so so wrong.)
- - - - - - - -
We tried, played, and have gotten far. Clan this is not the end, nor will i let it be! We shall last until each member has given' up on this game! When will that happen? I'm not exactly sure. This game is not flawless, nor perfect. We are the few, the brave, the strong. May we succeed in all that we set out to do... Even if it is with few willing members. We shall attempt, as we have been. ~JDL22~
- - - - - - - -
I quit
~Pure Awesome~
- - - - - - - -
You're welcome
So like,tomorrow if I go Lazer Tagging,I'mma be thinking of you guys <3
Lazer Tagging is a lot similar to TCON,just that headshots aren't better like in TCON
- - - - - - - -
Later reuben? You're playing more then usual, and i seem to be away when you do =(
just 'cuz:
Really, this clan was made to be as a back up for all those who lost the option in having a clan when LZ Shnieder closed ours without warning. Takin' back, i asked some of the active members over there such as:
Arie,StoneCutter,Luminary,&earth Only Earth hadn't joined, but instead sent over stone cutter. The five us made quite the clan, and not long after more members joined. Those four were great, and i mean absolutely great at this game. The only one left standing, is well... Arie, so thank you so much Arie. You, along with earth, were the first people that i asked to join this clan, the clan that was built from literally nothing. You instantly responded nicely, and helped me out with the name contest, and making the chat which later grew into our own site and everything.
In short time, i met people that i can also say were great people. Conduit freak Hugs & Conduit killer both brung smiles to my face when i played along side them in public/private. Reuben, who lives so very far away, played with us also! a friend across the world =). Then people like Squall and Slicer, who succeeded in making me laugh every time with his woots and hollers joined, don't go...
Other people like Mario, curt, & Mikey joined not long ago, but continue to bring activity and fun.
There's also snake, who played along with me in so many nights. Where are you snake... where are you?
Basically, it's a thank you, for being here in my times of need.
- - - - - - - - -
I don't really feel like being a leader anymore, I'm quiting.
When I am carefree and spam about anime, I get yelled at, and when I try and be responsible by removing spam I am yelled at to quit arguing.
I wasn't really being controlling mario, I was just removing some unnecessary replies.
I haven't played this game in months, and I really have no intention of playing this game avidly again anytime soon.
Maybe if tcon 2 ever comes out I'll get that and team up with jd again, but I really don't feel like staying here anymore.
honestly the only reason I wanted to stay was to keep this alive, but most of us are gone and nobody is really respecting my authoritative moves.
The chatbox is dead, our games are dead, our tournies are half-filled with people who don't even belong to our forums.
I'm kinda dissapointed at how this turned out, but oh well it was fun while it lasted.
I'm sure jd is gonna start crying once he reads this,
so I'll write a bit about the people here. For jd's sake.
JDL22: at first glance, I thought you were a noob. An overenthusiastic newbie who joined a dead forum at the worst popular time.
When PC died, I got a PM from Justin about starting up a clan, and to be honest I had no intention of ever doing it.
The only reason I felt like attempting to start up a clan was because I was given a fairly high position and I wanted to be able to manipulate and work for our clan. After a few ideas, we were able to set up a chatbox, a website, a GB profile, and even a tourny or two, we would play a lot and I like to think that justin and I got along pretty well.
I'm sorry for leaving, I might still post some though, if you don't mind.
Ruby, I remember when you first joined too, I thought it was rediculous how far away you lived, and I thought you really sucked at tcon when we first played.
42 to 2, oh was that a fun match. I remember you asking "was it close?" everytime you were killed ^^ those were good times.
I believe ruby and I immediately hit it off, we got along great.
I even called dibs on your nickname, and I remember how hard it was to think of a nickname for someone named reuben... but it worked. We haven't really talked in weeks, and I'm sorry for that, but school and friends seperated us overtime.
I will miss kicking you.
SEPH: you were silent except on wiispeak, that was funny.
I liked you, but we never really spoke very often.
I honestly wasn't surprised when you left.
Pure Awesome: I know you aren't here, and you won't see this, but you were a great member PC and a fun guy when you joined us for like 3 weeks.
Tehferret: you were annoying, I was glad I banned you.
10 year olds shouldn't be on the internet, you were a good example.
I guess you were fun sometimes, but you were more work than you were worth.
Slicer: your sniping was fun, and I love how organized you were with everything.
please continue to take care of the tourneys while I'm gone (I still plan on partaking in the doubles one).
you are a good co-leader.
Mikey: I thought you were annoying with your always-right attitude, and your long and well written posts... but it seems like I've taken after you in a way recently.
when you joined our crew, things were different of course, you were one of my favorites as well, you were very dedicated and I hope you are doing well in college.
Sean: you aren't here but I did like you... sometimes.
you had a high voice and a short fuse, but you were like family to me ^^
thanks for hacking those beta levels for us~
ConduitFreak: I always loved your poorly translated sentances, and how useful you were to jd and I, you left us early for hockey, but I can't blame you.
Hockey is pretty badass.
Snake: you joined, you were fun for like 4 days, you got a laptop, and you pretty much left.
you were missed.
MarioLegend: This one is hard to write... because I have a lot of mixed feelings about you, mario.
when you joined I thought you would be another noob who would quick sign up and leave.
you turned out to be a great anime buddy, and even though I get after you and call you stupid, you should know that I call most people I am close to stupid.
my sister's nickname is baka-chan, and my cat's name is dumbshit.
I hope I didn't piss you off too much, but I did have the responsibility to remove spam, and that's what was presented.
I give to you my banhammer... well, on the other hand I'll give it to jd ^^ haha.
Sticky and Espeon: You guys are new here, and I really appreciate you joining. Our crew needs all the activity it can get, especially now that I'm gone.
Don't leave us please.
well, that pretty much covers it, and Jd: if you quit because I'm gone I will never forget you.
This crew needs you, so don't get overly upset. -hug-
and oh yeah, I might stop by or even participate in here now and again,
but probably just to visit or play a match or two.
Godspeed Last Chance Crew, Godspeed
if I lurk this forum, and find that you guys pick up on my words like hokay, mer, or start using gay as a synonym for stupid, I'll still kick your ass.
Practice time with us!
Haven't played for awhile? Maybe you just aren't all that good to begin with?
We have the answer! To help you get even better come on by and practice with me and Arie. We can help you with just about anything there is to playing Tcon.
Pm Arie
quote Territory Wars
MINI GAMESRadiation game/Towers/Pentagon War/Race/Tag
Radiation Game
Four Person Rules
Four+ Person Rules
Invader: He attacks the others' bases. Remember the rules invaders, or you'll be kicked out.
Defender: He defends your base. Using the SPAS he stands at the door way and keeps out all invaders.
Pentagon war
Spoiler: Streets 1st Floor
Black Box = Gun Respawn Point
Blue Box = Trust Weapons Cache
Orange Box = Drudge Weapons Cache
Yellow Box = Human Weapons Cache
Grey Wall = Window or Short Wall
Box with Green Plus = Health Box
Spoiler: Streets 2nd Floor
Black Box = Gun Respawn Point
Blue Box = Trust Weapons Cache
Orange Box = Drudge Weapons Cache
Yellow Box = Human Weapons Cache
Grey Wall = Window or Short Wall
Box with Green Plus = Health Box
Spoiler: double teamed
|quote quick quote posts in thread
Nov 21, 10 at 2:01am ^re: Lcc • XXII | We're Still Hip!
First post
I like the thread name
My internet was REALLY bad today :/ Don't expect me to be on TCon tonight I hope it gets better by tomorrow D:
Do you guys get midterm report cards in America? I got mine yesterday
marisa pls
|quote quick quote posts in thread
Nov 21, 10 at 2:27am ^re: Lcc • XXII | We're Still Hip!
My wii's internet is stuffing up too, I wouldn't worry too much.
I get quarters, but the semesters are the ones that really count.
|quote quick quote posts in thread
Nov 21, 10 at 3:08am ^re: Lcc • XXII | We're Still Hip!
My midterms are kind of like your quarters, then
I played campaign for a short while today. I glitched inside the president's helicopter, but there was nobody inside...
marisa pls
|quote quick quote posts in thread
|Mario Legend
Nov 21, 10 at 5:59am ^re: Lcc • XXII | We're Still Hip!
Hey guy's, I really don't know how to put it in any other way but I think I'm going to... Delete my account.
Has been baptized; praise the LORD Almighty.
|quote quick quote posts in thread
Nov 21, 10 at 6:06am ^re: Lcc • XXII | We're Still Hip!
Happy Birthday, Reuben!
I let my friend borrow TCON until Tuesday. Couldn't believe he asked me to borrow it since he has Black ops.
Well, it's your choice, Mario.
|quote quick quote posts in thread
Nov 21, 10 at 6:09am ^re: Lcc • XXII | We're Still Hip!
You mean, leave the clan?
Or just sell the game or something?
I'd hate it to be the first one, to be honest. You've been a great member, and it's not like you have to remain too active here. Glad to have you, none the less, and I hope to see you around.
It was really nice meeting you, playing with you, and hanging out with you via this thread, chat, and even game.
Forgot how that felt like, haven't had to do it for awhile. It's sad being a leader, y'know! I've always been bad at saying goodbye. Just looked at what I did when Arie left. God I miss him, squall, CFREAK, Condtuikiller, hugs4hackers, lum lum, Stone cutter, and everyone else.
That's all I can remember off the top of my head, and all but hugs hasn't been on neo for awhile, I think.
|quote quick quote posts in thread
Nov 21, 10 at 9:43am ^re: Lcc • XXII | We're Still Hip!
Your reminiscing can't be shared, I'm afraid, given I know none of those members.
@ Mario Legend: You mean leave Neoseeker permanently? It's your call.
quote SlicerI pass my good wishes as well. Here's to another year on this Earth, buddy!
[ Currently Playing ] - Splatoon
|quote quick quote posts in thread
Nov 21, 10 at 1:04pm ^re: Lcc • XXII | We're Still Hip!
Happeh burfdai, weubweubs
It was great having you, mario I'll remember playing with you, talking with you, trolling with you, and all that D: Not really the last one but still D:
Jay-dee D: I miss sean so much too Wiispeak just isn't the same without him
marisa pls
|quote quick quote posts in thread
Nov 21, 10 at 11:20pm ^re: Lcc • XXII | We're Still Hip!
Tell me about it. We have such a good history.
|quote quick quote posts in thread
|Mario Legend
Nov 22, 10 at 3:26am ^re: Lcc • XXII | We're Still Hip!
I don't know, neoseeker had gotten boring I've tried becoming a moderator for 2 years and nothings happening.
Has been baptized; praise the LORD Almighty.
|quote quick quote posts in thread
Nov 22, 10 at 3:30am ^re: Lcc • XXII | We're Still Hip!
Neoseeker isn't about becoming a Moderator, you know. The site isn't full of mods, it's full of members; that's where the site's fun!
Ultimately, it's up to you if you want to stay or go, but it'd be a shame to see you go 3;
|quote quick quote posts in thread
Nov 24, 10 at 8:28am ^re: Lcc • XXII | We're Still Hip!
quote AskaVerbal conversations between strangers?...8[
I got caught by some random kid off of ACC. Twas' pretty awkward.
[ Currently Playing ] - Splatoon
|quote quick quote posts in thread
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EFF Calls on Tunisian Court to Uphold Right of Free Expression
On February 15, a verdict will be handed down that determines whether or not the Tunisian Internet Agency (ATI) will need to censor pornography on the Internet. Last May, after receiving--and unsuccessfully attempting to block--an order to censor such websites, the ATI appealed the decision citing, among other things, a lack of financial resources. As a result, the case was sent to the Court of Cassation, Tunisia's highest court
All Tunisians have a reason to be concerned: Under the rule of Ben Ali, it wasn't just obscene content that was unavailable to citizens, but political opposition websites, information on human rights, even YouTube.
As a result, Tunisian digital rights activists are wary of letting the government force the ATI to re-install the tools that allowed such overreaching censorship (which in the Ben Ali era were made by American company SmartFilter, owned by Intel). For others--such as the activist community that was active in fighting censorship during the Ben Ali era--it's a matter of principle. Or as Moez Chakchouk, CEO of the ATI, has argued: "It's not a matter of pornography or not, it's a matter of whether we have censorship or not in Tunisia."
Indeed, though the current target may be pornography, installing a tool like SmartFilter would enable the ATI to block other categories of websites. And while Chakchouk has spoken out against the idea of any government-mandated censorship outside of the legal process, he is also concerned that putting the tools of censorship in place could easily allow the government to expand its reach.
EFF reiterates our support for Chakchouk and the Tunisian Internet Agency. Tomorrow's decision will not only affect the free speech of Tunisians, but could have broader implications for the region as well. We call on the Court of Cassation to uphold the right of free expression in their decision.
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text:
When I open a pdf file, Firefox opens a blank window, then the file opens in a Adobe Reader window. How can I stop the blank window?
Whether I am using Firefox 3.6.8 or Thunderbird 3.0.6, clicking on a pdf file opens a new window. After a few seconds the pdf file opens in a separate Adobe Reader window. When I am done with that and close it, I still have to go back and close out the blank window. Got to be a configuration issue some place. I have tried several settings under Tools/Options, but haven't found the right setting yet. Any suggestions?
Additional System Details
Installed Plug-ins
- Shockwave Flash 10.1 r53
- npmnqmp 07103010
- Office Plugin for Netscape Navigator
- np-mswmp
- Adobe PDF Plug-In For Firefox and Netscape
- The QuickTime Plugin allows you to view a wide variety of multimedia content in Web pages. For more information, visit the QuickTime Web site.
- Centra Updater Plugin: 7,6,2,1
- 18.104.22.1682
- RealPlayer(tm) LiveConnect-Enabled Plug-In
- RealJukebox Netscape Plugin
- Default Plug-in
- The Hulu Desktop Plugin allows Hulu.com to integrate with the Hulu Desktop application.
- iTunes Detector Plug-in
- 4.0.50524.0
- Office Authorization plug-in for NPAPI browsers
- The plug-in allows you to open and edit files using Microsoft Office applications
- Adobe PDF Plug-In For Firefox and Netscape "9.3.3"
- User Agent: Mozilla/5.0 (Windows; U; Windows NT 6.1; en-US; rv:18.104.22.168) Gecko/20100722 Firefox/3.6.8 ( .NET CLR 3.5.30729)
More Information
1. Start Acrobat or Adobe Reader.
2. Choose Edit > Preferences. 3. Select Internet on the left. 4. Select Display PDF In Browser Using [Acrobat application], and then click OK. 5. Quit Acrobat or Adobe Reader.
Good Luck! Hamid
Modified by hamidD
Question owner
Thank you very much for the reply. I followed your instructions. This fixed half of the problem. Links to pdf files that are on web pages now come up with a box that asks if I want to open or save the file, without a blank browser window in the background. That is great.
When I tested the fix with pdf file links in email, the problem still exists. I tested links in Outlook Express, Yahoo mail, and Gmail. Any time I click on a pdf link in an email, a blank Firefox window opens and then I get the small window that asks me if I want to open or save the file. Sounds like this is a configuration issue, not a technical problem. Thanks for your help.
I'm not wanting to open my pdf in a browser window; I want it to open in the adobe application (just like it already does). But I'd rather not have this extra blank Firefox window open as well that has to be separately closed.
I'm with robk1w1. That is the problem I am having - an extra click to close a blank page after downloading a document. FF did not used to do this. Very irritating. Might go back to Chrome.


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January 22, 2014
Sleepy Ocean
Dr. Jeffrey Thompson
Dr. Jeffrey Thompson is one of the most reliable names in the field of brainwave synchronization. His delta sleep systems incorporate subliminal brainwave entrainment sounds with soothing nature and are meant to be played as you drift off to slumber. Dr. Thompson's Sleepy Ocean is meant to lull even the most stressed-out listener to pleasant dreamland, and it does so with a solid hour of nothing but the ambient sound of gently lapping ocean waves and subliminal delta-wave entraining frequencies. While your upper brain responds to the tranquility of shore associations, your lower automatically adjusts its wavelength to match the delta waves on the disc, sending you deep into relaxation and sleep. This CD does everything but put the smell of brine in the air and the lotion on your back, and no chance of sunburn.
Even without the delta waves to help lull your mind into a reflective calm, the ocean waves are incredibly soothing. Nature's own stress-reducing machine, the ocean's ceaseless lapping of tide, is something we instinctively respond to; it's a million years of hard-wired evolution. It's the mother of us all; we feel protected, safe, when we're in her presence. Put on Dr. Thompson's Sleepy Ocean the next time you are feeling harried and overbooked. Let Mother Nature carry your weight awhile, and find yourself floating on a bed of pleasant impressions and calm. Add delta wave impulses and your agitation and anxiety haven't got a chance.
In addition to using Thompson's CD as a sleep aid, it's also great for napping inside on a peaceful afternoon when you can't get to the beach. Find a spot to lie down in where the sun is on your face. Close your eyes and--with Sleepy Ocean on in the background--put some coconut oil or your favorite suntan lotion on so you can smell it as you lie there. The sensory combination of smell (lotion), sight (sun behind closed eyes), and sound (Sleepy Ocean) will send the impression to your unconscious that you are in fact at the beach. You may even feel that weird floating feeling that can sometimes overtake you when falling asleep after a day of playing in the waves. How much more stress-reduction can you get when going to the beach doesn't involve traffic, finding a parking spot, or sunburn?
Listen to all sound clips from this CD Buy this CD
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