Long-term follow-up of diisocyanate-induced occupational asthma has been occasionally reported.
We studied the outcome of toluene diisocyanate (TDI)-induced asthma in 46 patients at diagnosis and ...after a follow-up of 11 ± 3.6 years. Symptoms, anti-asthma therapy, forced expiratory volume in 1 s (FEV1) and bronchial hyperresponsiveness to methacholine were assessed.
A significant improvement in FEV1 (% predicted) and PD20FEV1 methacholine was observed at follow-up in comparison with diagnosis. Anti-asthma treatment was performed by 42% of patients at diagnosis and by 70% at follow-up. At the time of follow-up, 32 subjects had been removed from exposure for 6.0 ± 6.9 years, whereas 14 subjects continued to work with reduced exposure to TDI. There was a significant reduction in the prevalence of attacks of shortness of breath and dyspnoea at follow-up, but only in unexposed patients. PD20FEV1 was significantly improved only in patients with a lower FEV1 at diagnosis and in those who have ceased work. Logistic regression analysis, using different models with some independent variables, showed that there were no significant determinants of improvement in FEV1 at follow-up, while a shorter duration of symptoms before diagnosis was a significant predictor of improvement in PD20FEV1 at follow-up.
Asthma-like symptoms, bronchial hyperresponsiveness and airway obstruction improved, but did not normalize, after a long-term follow-up with cessation or reduction in TDI exposure, mainly in subjects with an early diagnosis of occupational asthma and in patients with a lower baseline FEV1 no longer exposed to TDI.
Few data are reported on the effects of a reduction of exposure to specific sensitizers in occupational asthma (OA). The objective of this study was to evaluate the clinical outcome of subjects with ...OA, comparing the effect of a reduction with that of the persistence or cessation of occupational exposure to the specific sensitizer.
Forty-one subjects with OA due to different sensitizers were diagnosed via a specific inhalation challenge. After a follow-up interval of 3.5 years, subjects were reexamined by clinical assessment, bronchial hyperresponsiveness (BH) and induced sputum.
At follow-up, subjects who had reduced occupational exposure (n = 22) showed a significant improvement in BH and a nonsignificant improvement in sputum eosinophilia (from 5.3 to 1.1%, n.s.), while subjects still exposed (n = 10) showed a significant decrease in FEV(1). Subjects who ceased work (n = 9) showed a trend of improvement in BH and sputum eosinophilia. Logistic analysis showed that the major determinant of improvement in BH at follow-up was the severity of BH at diagnosis, with a minimal contribution from the duration of exposure and treatment with inhaled corticosteroids during follow-up; reduction of work exposure did not enter into any model.
The reduction of occupational exposure could not be considered to be as effective as work cessation, which remained the best treatment for OA. However, it was not associated with a deterioration of FEV(1) as observed in subjects with persistent exposure.
The diagnosis of occupational asthma is usually performed in epidemiology using a combination of symptoms and bronchial hyperresponsiveness, while in a clinical setting the ‘gold standard’ for the ...diagnosis of occupational asthma is the specific bronchial challenge test in the laboratory. The aim of this study was to detect new cases of flour-induced occupational asthma (OA) in a group of workers exposed to grain and/or flour dust, by means of a step-by-step approach, as used in a clinical setting. In an epidemiological study, 111 millers and 186 bakers were examined by means of questionnaire, pulmonary function tests and skin-prick tests (SPT) to common allergens and to wheat flour dust extracts. From the whole sample, 82 subjects who showed asthma-like symptoms in the questionnaire and/or low forced expiratory volume in 1 sec (FEV1) were selected. Selected subjects underwent methacholine challenge test, and hyperreactive subjects underwent specific bronchial challenge with flour dust in the laboratory. Sixty-two of the selected subjects performed the methacholine challenge test, and 22 (33·8%) were hyperreactive (PD20 FEV1<1 mg of methacholine). Fifteen of 22 hyperreactive subjects underwent specific bronchial challenge test (sBCT) with flour dust; a positive response was elicited in six subjects. These subjects can be diagnosed as having flour-induced occupational asthma. Atopy and skin sensitivity to flour was partially related to the response to flour bronchial challenge. Bronchial hyperreactivity can be observed in a small percentage of subjects with asthma-like symptoms and/or low FEV1, and a positive response to sBCT was observed in a subgroup of hyperreactive subjects. Therefore, using these selection criteria, a diagnosis of flour-induced OA, as commonly performed in a clinical setting, can be performed in few previously undiagnosed subjects. This approach could be relevant for an early diagnosis of occupational asthma.
OBJECTIVES: To study the role of individual and occupational risk factors for asthma in furniture workers. METHODS: 296 workers were examined (258 men, 38 women) with a questionnaire of respiratory ...symptoms and diseases, baseline spirometry, bronchial provocative test with methacholine, and skin prick tests. Non-specific bronchial hyperreactivity was defined as when a provocative dose with a fall of 20% in forced expiratory volume in 1 second (PD20FEV1) was < 0.8 mg and atopy in the presence of at least one positive response to skin prick tests. Workers were subdivided into spray painters (exposed to low concentrations of diisocyanates and solvents), woodworkers (exposed to wood dusts), and assemblers (control group). RESULTS: The prevalences of attacks of shortness of breath with wheezing and dyspnoea were higher in spray painters (13.5% and 11.5% respectively) than in woodworkers (7.7% and 6.3%) or in assemblers (1.6% and 1.6%); prevalences of chronic cough, asthma, and rhinitis were also slightly but not significantly higher in spray painters and in woodworkers than in assemblers. The difference in the prevalence of respiratory symptoms among the job titles was due to the atopic subjects, who showed a higher prevalence of chronic cough, wheeze, shortness of breath with wheeze, dyspnoea, and asthma in spray painters than in the other groups. The prevalence of non-specific bronchial hyperreactivity in subjects who performed bronchial provocative tests was 17.7%, with no significant difference among groups. Asthma symptoms were significantly associated with non-specific bronchial hyperreactivity. Asthma-like symptoms plus non-specific bronchial hyperreactivity was found in 4% of assemblers, 10% of woodworkers, and 13.3% of spray painters (chi 2 = 2.6, NS). Multiple logistic analysis taking into account individual (smoke, atopy, age) and occupational (job titles) risk factors confirmed that spray painters had higher prevalence of chronic cough than assemblers, and a trend in increasing the prevalence of shortness of breath with wheeze, dyspnoea, and asthma. CONCLUSIONS: Painters in the furniture industry, particularly atopic subjects, are at higher risk of asthma-like symptoms than other job titles. In these workers asthma-like symptoms are more sensitive than non-specific bronchial hyperreactivity in detecting a negative effect of the occupational exposure.
Low molecular weight protein tyrosine phosphatase (LMW-PTP) is an enzyme involved in platelet-derived growth factor (PDGF)-induced mitogenesis and cytoskeleton rearrangement because it is able to ...bind and dephosphorylate the activated receptor. LMW-PTP presents two cysteines in positions 12 and 17, both belonging to the catalytic pocket; this is a unique feature of LMW-PTP among all protein tyrosine phosphatases. Our previous results demonstrated that in vitro LMW-PTP is oxidized by either H2O2or nitric oxide with the formation of a disulfide bond between Cys-12 and Cys-17. This oxidation leads to reversible enzyme inactivation because treatment with reductants permits catalytic activity rescue. In the present study we investigated the in vivo inactivation of LMW-PTP by either extracellularly or intracellularly generated H2O2, evaluating its action directly on its natural substrate, PDGF receptor. LMW-PTP is oxidized and inactivated by exogenous oxidative stress and recovers its activity after oxidant removal. LMW-PTP is oxidized also during PDGF signaling, very likely upon PDGF-induced H2O2 production, and recovers its activity within 40 min. Our results strongly suggest that reversibility of in vivo LMW-PTP oxidation is glutathione-dependent. In addition, we propose an intriguing and peculiar role of Cys-17 in the formation of a S–S intramolecular bond, which protects the catalytic Cys-12 from further and irreversible oxidation. On the basis of our results we propose that the presence of an additional cysteine near the catalytic cysteine could confer to LMW-PTP the ability to rapidly recover its activity and finely regulate PDGF receptor activation during both extracellularly and intracellularly generated oxidative stress.
To evaluate the morphologic basis of the different outcomes of toluene diisocyanate (TDI) asthma after quitting occupational exposure, we examined ten patients with TDI asthma who showed, at ...diagnosis, a positive TDI challenge test and nonspecific bronchial hyperresponsiveness (NSBH) to methacholine. After diagnosis, all patients ceased work and a 4- to 40-month follow-up was obtained with three to eight determinations of the cumulative dose producing a 15 percent fall in FEV1 (PD15FEV1) methacholine in each patient. Bronchoalveolar lavage (BAL) and biopsy of bronchial mucosa were performed 3 to 39 months after cessation of work, in the absence of acute exacerbations of the disease. Total cell count in BAL fluid was moderately increased in four of ten patients, eosinophils were increased in five of ten patients, and neutrophils were increased in eight of ten patients. Mucosal biopsy specimens of main or lobar bronchi were available in eight of ten patients; epithelial damage and thickening of basement membrane was observed in almost all patients, as well as a mild-to-moderate inflammatory reaction in the submucosa, mainly represented by lymphocytes, eosinophils, and neutrophils. No relationship was observed between the cellularity of BAL and the degree of NSBH at the time of BAL; mean values of total cells and differential count were not different between patients with presence or absence of the different histologic findings. Mucosal biopsy and BAL were performed also in four subjects exposed to dusts without respiratory symptoms or NSBH; similar findings were obtained except for the absence of eosinophils in BAL and a lesser degree of basement membrane thickening and inflammatory reaction in the submucosa. The study of the changes in NSBH after quitting exposure showed that five of ten patients had a significant improvement in NSBH to methacholine, as evaluated by a positive significant linear regression between months of work cessation and PD15FEV1 methacholine; only one of these five patients had an increased number of eosinophils in BAL fluid. By contrast, four of the five patients with persistent NSBH after quitting exposure had an increased number of eosinophils in BAL. We suggest that persistent NSBH in TDI asthma after cessation of work may be related to an inflammatory reaction in which eosinophil infiltration seems to be a major determinant.
Hematopoietic cells, particularly megakaryoblastic ones, display a high level of low
M
r phosphotyrosine protein phosphatase (LMW-PTP) expression; nevertheless, the role of this PTP in such cellular ...lineages has been scarcely investigated. Here, we demonstrate that LMW-PTP is able to associate and dephosphorylate signal transducer and activator of transcription-5 (STAT5) in DAMI megakaryocytic cells. Numerous researchers repeatedly hypothesized the association of a regulatory phosphotyrosine protein phosphatase with STAT5 C-terminus, but such phosphotyrosine protein phosphatase remained unknown. We show evidence indicating that the association of STAT5 and LMW-PTP does not exclusively involve the phosphatase active site and phosphotyrosine residue of STAT5, and we individuate an essential region of interaction at STAT5 C-terminus, coinciding with the previously hypothesized PTP-associating domain.
Beta-catenin plays a dual role as a major constituent of cadherin-based adherens junctions and also as a transcriptional coactivator. In normal ephitelial cells, at adherens junction level, ...beta-catenin links cadherins to the actin cytoskeleton. The structure of adherens junctions is dynamically regulated by tyrosine phosphorylation. In particular, cell-cell adhesion can be negatively regulated through the tyrosine phosphorylation of beta-catenin. Furthermore, the loss of beta-catenin-cadherin association has been correlated with the transition from a benign tumor to an invasive, metastatic cancer. Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) is a ubiquitous PTP implicated in the regulation of mitosis and cytoskeleton rearrangement. Here we demonstrate that the amount of free cytoplasmic beta-catenin is decreased in NIH3T3, which overexpresses active LMW-PTP, and this results in a stronger association between cadherin complexes and the actin-based cytoskeleton with respect to control cells. Confocal microscopy analysis shows that beta-catenin colocalizes with LMW-PTP at the plasma membrane. Furthermore, we provide evidence that beta-catenin is able to associate with LMW-PTP both in vitro and in vivo. Moreover, overexpression of active LMW-PTP strongly potentiates cadherin-mediated cell-cell adhesion, whereas a dominant-negative form of LMW-PTP induces the opposite phenotype, both in NIH3T3 and in MCF-7 carcinoma cells. On the basis of these results, we propose that the stability of cell-cell contacts at the adherens junction level is positively influenced by LMW-PTP expression, mainly because of the beta-catenin and LMW-PTP interaction at the plasma membrane level with consequent dephosphorylation.
OBJECTIVES--To compare the usefulness of high resolution computed tomography (HRCT) with chest radiography (CR) in the diagnosis and assessment of severity of silicosis. METHODS--27 workers exposed ...to silica underwent CR, HRCT, and pulmonary function tests. Two experienced readers independently evaluated CR by International Labour Office classification, and grouped the results into four categories. HRCT categories of nodule profusion and the extent of emphysema were graded on a four point scale; in 20 subjects the percentage distribution of lung densities were measured by HRCT. RESULTS--Concordance between readers was higher for HRCT than for CR (K statistic = 0.49 and 0.29 respectively). There was poor concordance between CR and HRCT in the early stage of silicosis. No significant difference in pulmonary function tests was found among different CR categories, but forced expiratory volume in one second (FEV1), maximal expiratory flow at 50% and 75% of FVC (MEF50, MEF75), and diffusion capacity significantly decreased with increasing HRCT categories. Subjects with simple silicosis detected by HRCT had a lower FEV1 than subjects without silicosis, whereas subjects with conglomerated silicosis showed higher residual volume and functional residual capacity than subjects with simple silicosis. These relations were not affected by smoking or symptoms of chronic bronchitis. Different grades of emphysema detected by HRCT were significantly different in diffusion capacity. Only the HRCTs of the lowest and the highest categories of profusion of parenchymal opacities were significantly different in their distribution of density classes. CONCLUSION--HRCT is more reproducible and accurate than CR, as suggested by the higher agreement between readers and the better correlation with pulmonary function tests, irrespective of smoking and chronic bronchitis; however, these data do not support the hypothesis that HRCT is more sensitive than CR in the early detection of silicosis.
The aim of this study was to evaluate the outcome of the specific inhalation challenge test (SIC) in 160 subjects with suspected baker's asthma and to assess its relation to total flour dust levels ...and to personal characteristics such as specific skin sensitisation, non-specific bronchial hyper-responsiveness (NSBH) and atopy.
We investigated the outcome of SIC tests performed with wheat flour in six Italian laboratories. For each subject, data was available regarding skin sensitisation to wheat flour, NSBH, atopy, forced expiratory volume at 1 s (FEV1) monitoring and airborne flour dust in the challenge chamber measured by the gravimetric method (total dust in mg/m(3)).
The SIC test was positive for early asthma in 42 subjects (26%) and for late/dual asthma in 18 (11%). Positive outcome to SIC was significantly associated with NBSH (odds ratio, OR: 3.5, 95% CI: 1. 6-7.7) and skin sensitisation to wheat flour (OR: 3.1, 95% CI: 1.3-7. 0). Exposure level to wheat flour was less than or equal to 10 mg/m(3 )in 12% of individuals, ranged between 11 and 30 mg/m(3) in 43% and exceeded 30 mg/m(3) in 45%. The outcome of SIC was always negative among workers not skin sensitised to wheat flour and without NSBH and atopy. An increasing prevalence of positive SIC was observed among workers with one or more of the above-mentioned personal characteristics whose challenge exposure was greater than 10 mg/m(3) (P < 0.001).
Procedures currently adopted for wheat flour dust exposure during SIC need to be better standardised in order to avoid excessive airborne dust exposure. Over-exposure seems to be of no use for the diagnosis and risks making the asthmatic reaction worse, particularly in patients who are both sensitised to wheat allergens and have NSBH and/or atopy.