Inflammatory proteins in nasal lavage of workers exposed to occupational agents.

BACKGROUND: Low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have been recognized as causes of occupational rhinitis (OR). Immunological mechanisms underlying OR differ according to the type of exposure. While HMW agents act mainly through IgE-mediated mechanisms, LMW agents appear to act through both immunological and non-immunological mechanisms. OBJECTIVE: The objective of this study was to identify potential differences in the upper airways inflammatory response after exposure to LMW and HMW agents by specific inhalation challenge test (SIC). METHODS: Nasal lavage (NL) samples from 20 subjects who were exposed to HMW (n = 10, Group I) and LMW (n = 10, Group II) at their workplaces were collected after SIC with control and specific occupational agents. These samples were analysed for 47 inflammatory markers using multiplex bead technology. RESULTS: After exposure to specific agent, Group I exhibited higher concentrations of the following proteins compared to Group II: fibrinogen (median (interquartile range) Group I: 0.09 (0.00) µg/mL, Group II: 0.04 (0.05) µg/mL, P = .05); haptoglobin (Group I: 0.86 (0.01) µg/mL, Group II: 0.14 (0.20) µg/mL, P = .02); vascular cell adhesion molecule-1 (VCAM-1) (Group I: 0.34 (0.67) ng/mL, Group II: 0.11 (0.11) ng/mL, P = .01); vascular endothelial growth factor (VEGF) (Group I: 157.0 (154.0) pg/mL, Group II: 98.0 (20.25) pg/mL, P = .01); and vitamin D (VDBP) (Group I: 0.06 (0.13) µg/mL, Group II: 0.03 (0.03) µg/mL, P = .04). No statistically significant differences in proteins profiles were observed between the groups after exposure to control agent. Also, subjects exposed to HMW agents showed a significant increase in NL levels of C-reactive protein compared to control-day exposure. CONCLUSIONS AND CLINICAL RELEVANCE: Exposure to HMW and LMW agents by SIC induced a differential nasal airway response including acute-phase reactants proteins (fibrinogen, haptoglobin and CRP), cell adhesion molecules (VCAM-1), endothelial growth factors (VEGF) and VDBP.

Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis.

OBJECTIVES: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). METHODS: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ≥2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. RESULTS: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ± 1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. CONCLUSION: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.

Occupational asthma and allergy in snow crab processing in Newfoundland and Labrador.

BACKGROUND: Risk factors and prevalence of occupational asthma (OA) and occupational allergy (OAl) in the snow crab-processing industry have been poorly studied. OBJECTIVE: To estimate the prevalence of OA and OAl in snow crab-processing workers and determine their relationship with exposure to snow crab allergens and other potential risk factors. METHODS: A total of 215 workers (120 female/95 male) were recruited from four plants in Newfoundland and Labrador, Canada in 2001-2002. Results from questionnaires, skin-prick tests to snow crab meat and cooking water, specific IgEs against the latter, spirometry and peak flow monitoring were used to develop a diagnostic algorithm. An index based on work history and exposure measurements of snow crab aeroallergens was developed to estimate the cumulative exposure for each worker. RESULTS: The prevalences of almost certain or highly probable OA and OAl were 15.8% and 14.9%, respectively. A high cumulative exposure to crab allergens, in jobs mostly held by women, was associated with OA (odds ratio (OR) = 14.0, 95% CI 3.0 to 65.8) (highest vs lowest Cumulative Exposure Index) and with OAl (OR = 7.1, 95% CI 1.9 to 29.0); job held when symptoms started (cleaning, packing, freezing) also predicted OA (OR = 3.9, 95% CI 1.6 to 8.7) and OAl (OR = 3.2, 95% CI 1.4 to 7.5). Atopy (OR = 2.8, 95% CI 1.2 to 6.8), female gender (OR = 10.7, 95% CI 3.6 to 32.1) and smoking were significant determinants for OA (OR = 3.1, 95% CI 1.3 to 7.4). CONCLUSIONS: The prevalences of OA and OAl are high in snow crab-processing workers of Canada's East Coast. Cumulative exposure to snow crab allergens was related to the prevalences of OA and OAl in a dose-response manner taking into account atopy, gender and smoking.

Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors.

AIMS/HYPOTHESIS: We previously reported that the plasma levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in a cohort of viscerally obese men are directly correlated with visceral adipose tissue (VAT) accumulation and metabolic risk factors including low HDL-cholesterol and high triacylglycerol. It is not known, however, if such correlations persist after vigorous lifestyle interventions that reduce metabolic risk factors. We analysed the changes in endocannabinoid levels in a subsample from the same cohort following a 1 year lifestyle modification programme, and correlated them with changes in VAT and metabolic risk factors. METHODS: Forty-nine viscerally obese men (average age 49 years, BMI 30.9 kg/m(2), waist 107.3 cm) underwent a 1 year lifestyle modification programme including healthy eating and physical activity. Plasma levels of 2-AG and the other most studied endocannabinoid, anandamide, were measured by liquid chromatography-mass spectrometry. Anthropometric and metabolic risk factors, including VAT, insulin resistance and glucose intolerance, HDL-cholesterol and triacylglycerol, were measured. RESULTS: Most risk factors were improved by the intervention, which led to a significant decrease in body weight (-6.4 kg, p < 0.0001), waist circumference (-8.0 cm, p < 0.0001) and VAT (-30%, p < 0.0001), and in plasma 2-AG (-62.3%, p < 0.0001) and anandamide (-7.1%, p = 0.005) levels. The decrease in levels of 2-AG but not those of anandamide correlated with decreases in VAT and triacylglycerol levels, and with the increase in HDL(3)-cholesterol levels. Multivariate analyses suggested that decreases in 2-AG and VAT were both independently associated with decreases in triacylglycerol. CONCLUSIONS/INTERPRETATION: This study shows that a strong correlation exists between 2-AG levels and high plasma triacylglycerol and low HDL(3)-cholesterol in viscerally obese men.

Malt can cause both occupational asthma and allergic alveolitis.

Specific inhalation challenge can help differentiate occupational asthma from allergic alveolitis caused by malt.

Cell detachment modulates TRAIL resistance in ovarian cancer cells by downregulating the phosphatidylinositol 3-kinase/Akt pathway.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis but many ovarian cancer cells display intrinsic resistance to TRAIL. The molecular determinants regulating TRAIL sensitivity in these resistant tumor cells are still incompletely understood. We observed that cell detachment enhances TRAIL-induced apoptosis in two TRAIL-resistant ovarian cancer cell lines. This process was accompanied by an increase of caspase activation, which could be blocked by caspase-8 inhibitor IETD. Cell detachment inhibited Akt phosphorylation. Phosphatidylinositol 3-kinase inhibition by LY294002 also enhanced TRAIL-induced apoptosis. Further decreased Akt activity by LY294002 in detached cells translated to increased cell death after TRAIL treatment. Our data indicate that cell detachment enhances TRAIL-induced killing by decreasing Akt activity in TRAIL-resistant ovarian carcinoma cells and suggest that Akt inhibition primes TRAIL-resistant cells to TRAIL-induced apoptosis.

Can access to spirometry in asthma education centres influence the referral rate by primary physicians for education?

BACKGROUND AND OBJECTIVES: Asthma remains uncontrolled in a large number of asthmatic patients. Recent surveys have shown that a minority of asthmatic patients are referred to asthma educators. The objective of the present study was to assess the influence of increased access to spirometry in asthma education centres (AECs) on the rate of patient referrals to these centres by general practitioners. METHODS: A one-year, prospective, randomized, multicentric, parallel group study was conducted over two consecutive periods of six months each, with added spirometry being offered in the second six-month period to the experimental group. Ten AECs were enrolled in the project. An advertisement describing the AECs' services was sent by mail to a total of 303 general practitioners at the start of each period, inviting them to refer their patients. Measures of the frequency of medical referrals to the AECs were assessed for each period. RESULTS: The group of AECs randomly selected for spirometry in the second six-month period received 48 medical referrals during the first period and 32 during the second one, following proposed spirometry. AECs that had not offered spirometry received five referrals during the first period and seven during the second period. One AEC withdrew a few weeks after the study began and others encountered administrative problems, reducing their ability to provide interventions. CONCLUSIONS: Referral to AECs is not yet integrated into the primary care of asthma and offering more rapid access to spirometry in the AECs does not seem to be a significant incentive for such referrals.

Gene expression in a rarely studied intraabdominal adipose depot, the round ligament, in severely obese women: A pilot study.

Gene expression (qPCR) was compared in round ligament (RL), omental (OME) and mesenteric (MES) ATs from 48 severely obese women (BMI, 54±11 kg/m(2); 38±9 yrs). The mRNA levels of enzymes of lipid metabolism (LPL, HSL, and PDE-3B), cortisol production (11ßHSD-1), adipogenesis (PPAR-γ1/2), thrombosis and inflammation (PAI-1, IL-6, TNF-α and adiponectin) were determined. AT-LPL mRNA was highest in RL. The highest PDE-3B and lowest PAI-1 mRNA levels were observed in RL and MES. The lowest IL-6 and TNF-α and the highest adiponectin and PPAR-g1/2 mRNA levels were found in RL AT. 11ßHSD-1 was highest in RL and OME. A higher lipogenic and adipogenic, and lower pro-inflammatory and pro-thrombotic profiles of the RL suggest a lesser deleterious impact on obesity-related complications.

The herpes simplex virus-1 Us3 protein kinase blocks CD8T cell lysis by preventing the cleavage of Bid by granzyme B.

The Us3 kinase is part of the antiapoptotic arsenal that salvages herpes simplex virus (HSV)-1-infected cells from damage caused by different stimuli. We demonstrate that Us3 protects HSV-1-infected cells from lysis by MHC class I-restricted CD8T cells without affecting antigen presentation. Expression of Us3 was associated with inhibition of caspase activation and reduced cleavage of the proapoptotic protein Bid. Recombinant granzyme B (GrB) failed to cleave Bid in cytosolic extracts from Us3 positive cells, while recombinant Bid served as substrate for Us3 phosphorylation, suggesting that modification of Bid by Us3 blocks its processing by GrB. Our data illustrate a new strategy of viral escape, where modification of a cellular proapoptotic substrate may prevent lysis of the infected cells without affecting other T-cell functions.

Gene expression of different adipose tissues of severely obese women with or without a dysmetabolic profile.

Despite well-established variations in the health risks posed by visceral vs. subcutaneous abdominal (SCABD) fat depots, surprisingly little is known on the differences within a given adipose tissue (AT) among severely obese patients displaying varying metabolic dysfunction. We thus compared, by quantitative PCR, the expression profile of a number of genes in the SCABD, omental (OME), and mesenteric (MES) depots of severely obese women with (DYS; n = 25) or without (NDYS; n = 23) a dysmetabolic profile. Fasting insulinemia and HOmeostasis Model Assessment-insulin resistance (HOMA-IR) were higher and plasma adiponectin level lower in DYS women (p < 0.05). Among enzymes involved in fatty acid metabolism and local cortisol production, phosphodiesterase-3B expression was lower in SCABD and MES fat, while 11ß-hydroxysteroid dehydrogenase type 1 mRNA levels were higher in visceral depots of DYS women (p < 0.05). Regarding vascular homeostasis and inflammation, plasminogen activator inhibitor-1 and interleukin-6 mRNA levels were higher in OME fat, while adiponectin expression was lower in SCABD and OME ATs of DYS women (p < 0.05). Finally, HOMA-IR was positively associated with SCABD AT IL6 mRNA, only in DYS women (r = 0.47; p < 0.05). In conclusion, although metabolic and secretory characteristics of all depots vary with subjects' metabolic profile, we find little evidence for a protective role of SCABD AT and no evidence for a further deleterious role of MES fat in DYS vs. NDYS severely obese women. Regional variation in the overall gene expression revealed that OME and MES fat were more closely related to each other in DYS women, while SCABD and MES depots showed greater resemblance in NDYS women.

Heterogeneity of hepatic microsomal UDP-glucuronosyltransferase activities. Conjugations of phenolic and monoterpenoid aglycones in control and induced rats and guinea pigs.

In this report we present evidence that the heterogeneity of hepatic microsomal UDP-glucuronosyltransferase(s) (UDPGT) activities depends on the chemical structures of the aglycones as well as their biophysical constants. Three animal models were used: Wistar rats, which have active UDPGTs; Gunn rats, in which some of the UDPGT activities are reduced, but which can be induced by phenobarbital; and guinea pigs. In Wistar rats, we found that some coumarins were poor substrates of UDPGT (GT1) and that twenty monoterpenoid alcohol activities showed typical phenobarbital-inducible behavior. In Gunn rats, we showed that substitution of the phenolic aglycone by bulky (alkyl- or methoxy-) groups in the 2-position of the phenolic ring decreased UDPGT (GT1) activity, whereas substitution in the 4-position resulted in an increase in this activity. We also showed that, in this particular strain, activities toward terpenes were less affected than activities toward flat (aromatic) aglycones. Induction by phenobarbital in Gunn rats increased the activity and limited the deficiency for monoterpenoid alcohols. In guinea pigs, we confirmed that phenobarbital selectively increased the activities of UDPGT towards twenty monoterpenoid alcohols without affecting other typical phenobarbital-induced activities such as those for conjugation of morphine. Finally, we showed that orientation of the aglycone molecule in the active site was apparently related to its dipole moment and that the distance between "acceptor-oxygen" (hydroxyl) and the carbons out of the general plane of the molecule was an important factor. These studies clearly suggest that rat and guinea pig contain a UDPGT(monoterpenoid alcohols) with restricted specificities and also that UDPGT(GT1) comprises at least two or three different isoenzymes, each with a slightly different restricted specificity towards flat aromatic aglycones.

Occupational asthma due to fumes of galvanized metal.

Two solderers exposed to fumes of galvanized metal reported a history of shortness of breath and fever which occurred during the evening and night of days spent at work. Specific inhalation challenges performed by asking subjects to do soldering on galvanized iron revealed a late bronchospastic reaction. One subject also demonstrated a significant increase in oral temperature and peripheral neutrophils. Environmental measurements revealed the presence of zinc after soldering on galvanized metal. This contaminant was not present after a control exposure while soldering on iron. Although metal fume fever has been described in workers exposed to fumes of galvanized metal, this is the first account of occupational asthma due to this agent.

Single-dose effect of astemizole on bronchoconstriction induced by histamine in asthmatic subjects.

STUDY OBJECTIVE: Astemizole, administered for seven days to asthmatic subjects, had an effect of bronchoconstriction induced by inhaled histamine for a mean period of 42 days. This study evaluates whether a single dose of astemizole would have the same effect. SUBJECTS: Sixteen adult asthmatic subjects took part in the study. DESIGN: They first underwent three inhalation tests and skin prick tests with histamine on three different days. On the last day, a methacholine inhalation test was also performed. They subsequently received either a placebo or an active preparation of astemizole. The histamine inhalation test was repeated one day, two days, one week, and/or ten days after administering the drug. RESULTS: Overall, no significant change in mean PC20 or in the mean diameter of the skin reaction to histamine was observed. However, three out of the eight subjects (38 percent) receiving active and none receiving placebo medication showed significant increases in PC20 histamine (p = 0.05). This effect lasted for one to two days. CONCLUSIONS: We conclude that a single dose of 10 mg/ml of astemizole can have a significant effect on bronchial but not cutaneous reactivity to histamine. This effect is of short duration (one to two days).

The reversibility of airway obstruction to an inhaled beta 2-adrenergic agent is less satisfactory after methacholine testing in asthmatic subjects.

AIMS: The aim of this work was to compare the response to an inhaled beta 2-adrenergic agent in two situations: (1) spontaneous airway obstruction in asthmatic subjects who had withheld treatment with the medication for more than 12 hs; and (2) after methacholine-induced airway obstruction once airway caliber had recovered to the premethacholine test value. SUBJECTS AND METHODS: Sixteen asthmatic subjects who showed a 20% or more improvement in FEV1 after inhaled beta 2-adrenergic agent (B2) (salbutamol, 200 micrograms) entered a double-blind crossover randomized trial in which the following tests were carried out: (1) FEV1 response after inhaling a placebo or active B2; (2) FEV1 response after inhaling a placebo or active B2 after a methacholine test that had induced a 20% or more reduction in FEV1, once FEV1 had recovered to the premethacholine value after inhaling salbutamol in an open fashion. RESULTS: As expected, the mean percent improvement in FEV1 in the spontaneous airway obstruction situation was 21.7 +/- 8.5% after inhaling the active B2 and 2.2 +/- 1.8% after placebo B2 (p < 0.001). Following recovery after methacholine challenge, the FEV1 was slightly superior (mean difference of 146 mL) to the premethacholine value before inhaling the active or placebo B2. In this situation, the percent improvement in FEV1 after inhaling the active B2 was only 7.5 +/- 4.4% and not significantly different from after inhaling placebo B2 (4.9 +/- 5.4%). Consequently, the end FEV1 value after inhaling active B2 was significantly higher in a situation of spontaneous airway obstruction than after methacholine-induced airway obstruction (mean difference = 110 mL; p = 0.02). CONCLUSION: After a methacholine test, the reversibility of an inhaled beta 2 agent is not significantly different from a placebo and is less satisfactory than in a situation of spontaneous airway obstruction. The mechanism for this needs to be explored but it is not secondary to persisting airway obstruction.

Validation of an exposure system to particles for the diagnosis of occupational asthma.

STUDY OBJECTIVE: We previously described a closed-circuit system for exposure to particles in humans. This system has three components: a particle generator, an exposure chamber connected to an orofacial mask, and monitors. We describe results of challenges in 56 subjects who underwent challenges with the apparatus using occupational sensitizers in particles. SUBJECTS: Fifty-six consecutive subjects referred for the investigation of occupational asthma to occupational sensitizers in particles were included. The agents were the following: flour and grains (n = 19), cedar (n = 10), psyllium (n = 9), guar gum (n = 9), drugs (n = 3), persulfate (n = 2), and miscellaneous (n = 4). INTERVENTION: The duration of exposure was progressive and varied from one breath to a maximum of 180 min depending on the reaction. When no significant fall in FEV1 occurred after exposure with the aerosolization device, the standard approach of tipping particles from one tray to another was used. RESULTS: Twenty-nine subjects (52 percent) had a significant (greater than or equal to 20 percent) fall in FEV1 after exposure. This includes 18 subjects with isolated immediate reactions, four with dual asthmatic reactions, and two with atypical reactions. In 20/24 instances (83 percent), the percentage of fall in FEV1 did not exceed 30 percent, thus showing that dose-response curves can generally be obtained in a safe way. In all instances except one (26/27 cases), subsequent exposures using the traditional method did not result in significant falls in FEV1. CONCLUSION: This new procedure results in safe tests in terms of the percentage of changes in FEV1 during the immediate reactions and very rare false-negative challenges.

Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent: relevance of the length of the interval from cessation of exposure.

STUDY OBJECTIVE: We set the hypothesis that follow-up surveys of occupational asthma (OA) could now show better improvement in the asthmatic condition because of a more prolonged interval since removal from exposure than in previously reported studies. PATIENTS/METHODS: Ninety-nine subjects with OA were assessed and were separated into two groups according to the duration of cessation of exposure: (1) group removed for > or = 5 years: 48 subjects studied 8.9+/-2.2 years after cessation of exposure; (2) group removed for <5 years: 51 subjects with OA, comparable in terms of history and functional results at time of diagnosis, with a time lapse from last exposure of 3.1+/-1.2 years. On the follow-up visit, questionnaires including information on the current and previous use of inhaled steroids, spirometry, and methacholine tests were administered and results were compared with those obtained at the time of diagnosis. RESULTS: At the follow-up visit, no significant changes in spirometry were observed in the two groups. However, a significant improvement in provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) from a mean value of 1.5 to 3.7 mg/mL was documented (p<0.001). The proportion of subjects having normal PC20 at the follow-up visit was significantly higher in the group removed from exposure for >5 years than in the group removed for < or = 5 years (16/33 vs 8/42; p=0.01). Stepwise logistic regression showed that follow-up PC20 could be predicted from baseline PC20 (p<0.001, odds ratio [OR]=4.1, 95% confidence interval [CI]=1.8 to 9.1), duration of exposure (p=0.04, OR=0.9, 95% CI=0.8 to 1.0), the interval since removal from exposure (p=0.002, OR=1.7, 95% CI=1.2 to 2.5), and the type of agent; subjects with OA due to high-molecular-weight agent showed a less favorable outcome (p=0.04, OR=0.2, 95% CI=0.03 to 1.0). Current and past treatments with inhaled steroids were not significant predictors. CONCLUSION: Results obtained in the group of this study removed for >5 years show better prognostic figures than those reported in most previous studies. Comparison with the group removed for a shorter interval and the stepwise logistic regression analysis suggest that the longer duration of the interval from cessation of exposure appears to be a factor determining this difference.

Patient handling of a multidose dry powder inhalation device for albuterol.

BACKGROUND: Studies have suggested that novel inhaling devices may be misused by patients and medical personnel in the clinical setting soon after their introduction. to assess the adequacy of patient handling of a newer multidose dry powder albuterol inhaler, we conducted a comprehensive survey of use in primary and respiratory practices. METHODS: Patients 6 years of age and older and requiring inhaled beta 2-agonist for the treatment of stable obstructive airways disease were recruited from the practices of primary care and specialist physicians. After instruction from their physician or clinic staff in the use of a multidose dry powder albuterol inhalation device (Diskhaler), patients used the device in unblinded fashion for 2 weeks instead of their usual beta 2-agonist. After 2 weeks, patient use of the device was assessed at a return clinic visit. RESULTS: A total of 4,529 patients with reversible airways obstruction participated in a 2-week assessment of the device and compared it with their previous beta 2-agonist delivery system. Significantly more patients preferred the dry powder device (54 percent) over their previous device (29 percent) (p < 0.001), with 17 percent expressing no preference. After instruction, 98.5 percent of patients could demonstrate adequate use at the initial visit. Performance difficulties at the initial visit resulting in exclusion from the trial were infrequent but more common in the elderly (3 percent vs 0.2 percent for all other age groups combined, p < 0.001). Despite adequate use at the initial visit, at the conclusion of the trial, incorrect use of the device was noted in 10.2 percent of the elderly vs 3.2 percent of all other age groups combined (p < 0.001). Albuterol delivered by Diskhaler was well tolerated in all patient groups. CONCLUSIONS: A majority of patients are able to use a multidose dry powder albuterol inhaler device in the clinical setting, and prefer the device to previously used beta 2-agonist inhalation devices. However, follow-up shows that problems with device handling may become apparent in as little as 2 weeks after initial instruction, thereby mandating the need for periodic follow-up and reinstruction.

Isolated late asthmatic reaction after exposure to a high-molecular-weight occupational agent, subtilisin.

High-molecular-weight agents generally induce immediate asthmatic reactions. We report the case of a subject who experienced a reaction that started after the first hour following exposure to subtilisin, a high-molecular-weight occupational agent. Any occurrence of immediate reaction was ruled out by measuring both FEV1 and lung volumes every 10 min in the first hour. This reaction was IgE-mediated as shown by immediate skin reactivity and increased specific IgE levels.

Occupational asthma due to various agents. Absence of clinical and functional improvement at an interval of four or more years after cessation of exposure.

We have previously shown that in some subjects with occupational asthma caused by various agents, there is no improvement approximately two years after exposure ended. These results could be explained by the short interval between diagnosis and follow-up. In the current study, we saw 28 subjects with occupational asthma at two intervals, 2.3 years (range, three months to 5.7 years) and 5.8 years (range, 4.3 to 10.9 years) after the cessation of exposure. Various causes of occupational asthma were included. The diagnosis was confirmed in 26 of the cases by specific inhalation challenges in the laboratory, and in the remaining two cases by combined monitoring of peak expiratory flow rates and bronchial responsiveness. All subjects had symptoms of asthma at both follow-up assessments. There were no changes in the need for medication, spirometry, or bronchial hyperresponsiveness. Depending on the interval of the follow-up, four to six subjects required inhaled steroid agents in addition to the usual bronchodilators, 11 had FEV1 less than 80 percent of predicted, and 26 or 27 had an abnormal PC 20 histamine. Only two subjects demonstrated sustained improvement in PC 20 at the first and second follow-ups, and one other showed changes during the second follow-up assessment which were not present at the first. We conclude that except for three subjects, the need for medication did not diminish, nor did airway obstruction and hyperresponsiveness improve in this group of subjects with occupational asthma long after exposure ended. These results differ from other studies, which demonstrated that some recovery takes place in a greater proportion of individuals.

Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction.

BACKGROUND: Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an "as required" basis (n=15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 microg; n=15) in addition to salbutamol to control their asthma. METHODS: Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 microg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV1 (PS20) was evaluated on a modified Borg scale from 0 to 10. RESULTS: Subjects using regular beclomethasone had a higher baseline PS20 than those using only salbutamol (means: 3.06 0.06 and 2.01+/-0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS20 compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS20 did not vary significantly throughout the study. CONCLUSION: These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.