HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.

Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.

Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

Chest CT screening of asbestos-exposed workers: lung lesions and incidental findings.

The objective of the present study is to determine the feasibility of chest computed tomography (CT) in screening for lung cancer among asbestos-exposed workers. In total, 633 workers were included in the present study and were examined with chest radiography and high-resolution CT (HRCT). A total of 180 current and ex-smokers (cessation within the previous 10 yrs) were also screened with spiral CT. Noncalcified lung nodules were considered positive findings. The incidental CT findings not related to asbestos exposure were registered and further examined when needed. Noncalcified lung nodules were detected in 86 workers. Five histologically confirmed lung cancers were found. Only one of the five cancers was also detected by plain chest radiography and three were from the group of patients with a pre-estimated lower cancer probability. Two lung cancers were stage Ia and were radically operated. In total, 277 individuals presented 343 incidental findings of which 46 required further examination. Four of these were regarded as clinically important. In conclusion, computed tomography and high-resolution computed tomography proved to be superior to plain radiography in detecting lung cancer in asbestos-exposed workers with many confounding chest findings. The numerous incidental findings are a major concern for future screenings, which should be considered for asbestos-exposed ex-smokers and current smokers.

Scoring CT/HRCT findings among asbestos-exposed workers: effects of patient's age, body mass index and common laboratory test results.

We studied the effects of age, body mass index (BMI) and some common laboratory test results on several pulmonary CT/HRCT signs. Five hundred twenty-eight construction workers (age 38-80, mean 63 years) were imaged with spiral and high resolution CT. Images were scored by three radiologists for solitary pulmonary nodules, signs indicative of fibrosis and emphysema, ground glass opacities, bronchial wall thickness and bronchiectasis. Multivariate statistical analyses were adjusted for smoking and asbestos exposure. Increasing age, blood haemoglobin value and erythrocyte sedimentation rate correlated positively with several HRCT signs. Increasing BMI was associated with a decrease in several signs, especially parenchymal bands, honeycombing, all kinds of emphysema and bronchiectasis. The latter finding might be due to the suboptimal image quality in obese individuals, which may cause suspicious findings to be overlooked. Background data, including patient's age and body constitution, should be considered when CT/HRCT images are interpreted.

Effects of tobacco smoking on findings in chest computed tomography among asbestos-exposed workers.

This study examined the effects of smoking on the findings in chest computed tomography (CT) in 587 asbestos-exposed construction workers (11 females, 576 males, mean age 62 yrs; 18 never-smokers, 406 exsmokers and 163 current smokers). The workers were imaged with spiral CT and high-resolution CT. A total of 13 radiological signs were scored by three radiologists independently. The workers' medical data, smoking habits and occupational exposures were collected at an interview. The effects of smoking status and smoked pack-yrs (0-87.5) on the CT signs were studied using multivariate analysis adjusted for confounding factors. Smoking increased all emphysema signs and contributed to bronchial wall thickening. Smoking was negatively associated with curvilinear and septal lines as well as with parenchymal bands. In persons who had smoked <10 pack-yrs, smoking was positively related to paraseptal emphysema and to bronchial wall thickening and negatively related to septal lines, subpleural nodules and honeycombing. Smoking was related to several abnormal computed tomography signs even among those with relatively small exposure. Computed tomography can detect changes due to smoking at an early stage.

Computed tomography of asbestos-related pleural abnormalities.

OBJECTIVES: To study the observer agreement in several asbestos-related pleural abnormalities and to define criteria to discriminate between pleural changes in workers with occupational disease, and those in controls. METHODS: Pleural abnormalities in spiral computed tomography of 602 construction workers with asbestosis or bilateral pleural plaques and 49 controls were reviewed by three radiologists using structured forms. RESULTS: Intra- and inter-observer agreement (weighted kappa) was 0.4 or better with regard to the calcification, extent and thickness of pleural disease. These factors all correlated positively with the duration of asbestos exposure. There were significant differences in these pleural changes between the workers (mean extent per side 83 cm(2)) and controls (mean extent per side 40 cm(2)). Of the controls, 84% showed pleural lesions with an estimated extent of 10 cm(2) or more, bilateral in 64%. The extent of 45 cm(2) in pleural disease was the best value for discriminating between the controls and diseased workers, with a sensitivity of 82% and a specificity of 66%. The degree of pleural calcification, however, was the best discriminator between these groups, but quantitative methods are necessary for its use in the diagnostics of individuals. CONCLUSIONS: The extent, calcification and thickness were well-repeatable indicators of benign pleural pathology and thus their use in future classification systems in computed tomography is recommended. In our material, the extent of 45 cm(2) and the degree of calcification were helpful in discriminating between pleural changes in workers with occupational disease, and those in controls who also presented marked pleural pathology.

Follow-up of asbestosis patients and predictors for radiographic progression.

OBJECTIVE: We followed a group of 85 Finnish asbestosis patients radiographically for an average of 6.5 (range 2-10) years to examine the progression of the disease and to assess possible explanations for the progression. METHODS: The examinations included full-size chest radiographs and a blood specimen analysis. The radiographs were classified according to the 1980 International Labor Office (ILO) classification. Progression was accepted if the second or third radiography was estimated (in a side-by-side comparison) to have more profusion of small opacities qualitatively than the first, even if the radiographs were classified into the same profusion category. RESULTS: In all, 38% of the patients showed progression during the follow-up period. The average progression of small opacities ranged from ILO 1/1 to ILO 2/2 (0.4 minor ILO categories/year). The asbestosis was progressive more often among the sprayers than among the insulators and asbestos factory workers [cross-tabulation, odds ratio (OR) 5.0, 95% confidence interval (95% CI) 1.2-20]. In the logistic regression model the ILO classification category at the beginning of the follow-up (OR 1.54; 95% CI 0.96-2.47), the fibronectin (OR 1.01; 95% CI 1.00-1.01) and angiotensin-converting enzyme (ACE; OR 1.10; 95% CI 1.00-1.20) levels, and the erythrocyte sedimentation rate (ESR; OR 1.05; 95% CI 1.00-1.10) were statistically associated with the radiographic progression of small opacities. Abnormalities of the pleura were found to progress more often among the patients with progressive parenchymal opacities. CONCLUSION: For the progression of small-opacity profusion the significant predictors in the logistic regression model were the ILO profusion category at the beginning of the follow-up period, the fibronectin level, the ACE value, and the ESR. The model correctly classified 94% of the patients with progression and 65% of those without progression. The differences in the mean values recorded for the biomarkers between the progressors and nonprogressors, however, were small and may therefore not be of any importance to the clinician.

Radiographic abnormalities among Finnish construction, shipyard and asbestos industry workers.

OBJECTIVES: The prevalence of asbestos-related radiographic abnormalities was surveyed among Finnish construction, shipyard, and asbestos industry workers. METHODS: The radiographic screening focused on active and retired workers who were under the age of 70 years and had been employed for at least 10 years in construction or for at least 1 year in shipyards or in the asbestos industry. In 1990-1992, 18,943 people participated in an X-ray examination of the lungs and an interview on work history and exposure. The criteria for a positive radiological finding were (i) small irregular lung opacities clearly consistent with interstitial pulmonary fibrosis (ILO 1/1 or higher), (ii) lung opacities indicating mild pulmonary fibrosis (ILO 1/0) with unilateral or bilateral pleural plaques, (iii) marked adhesions with or without thickening of the visceral pleura, or (iv) findings consistent with bilateral pleural plaques. RESULTS: Fulfilling the criteria were 4133 workers (22%) (22% from construction, 16% from shipyards, and 24% from the asbestos industry). The radiological findings included signs of pulmonary fibrosis (3%), changes in the visceral pleura (7%), bilateral plaques (17%), and unilateral plaques (10%). Occupational disease was diagnosed according to the Finnish insurance regulations for three-fourths of those referred for further examinations, 96% being abnormalities in the pleura and 4% being asbestosis. CONCLUSIONS: Exposure to asbestos dust has been common in ordinary construction work, and, consequently, radiographic abnormalities (mostly pleural) occur frequently among active and retired construction workers.

Progression of asbestosis predicts lung cancer.

STUDY OBJECTIVES: To explore whether the progression of asbestosis correlates with the risk of lung cancer among patients with asbestosis. DESIGN: A group of 85 asbestosis patients (78 men and 7 women) were radiographically followed up between 1979 and 1987. Two or three posteroanterior radiographs taken from each patient in 1978 to 1979, 1983 to 1984, and 1986 to 1987 were classified according to the International Labour Office 1980 classification and were used to divide the patients into progressors and nonprogressors. Follow-up for cancer was done automatically through the files of the Finnish Cancer Registry from the time of determination of the progression status to December 31, 1994. Predictors of lung cancer risk were studied with a logistic regression model, and the standardized incidence ratio (SIR) was calculated for lung cancer. RESULTS: Of the 24 male patients with progressive small opacity profusion, 11 (46%) developed lung cancer, as opposed to 5 (9%) of the 54 male patients without progression. The SIR for lung cancer was 37 (95% confidence interval, 18 to 66) for the progressors and 4.3 (1.4 to 9.9) for the nonprogressors. In both groups, all the lung cancer cases occurred among smokers or ex-smokers. None of the seven female patients showed progressive small opacity profusion. One of them developed lung cancer. In the logistic regression model including all 85 asbestosis patients, radiographic progression of small opacity profusion (p=0.0009) and current smoking (0.0021) were significant predictors of lung cancer morbidity. CONCLUSIONS: Asbestosis patients with radiographic progression of small opacity profusion over a few years are at a higher risk of lung cancer than those with a less aggressive course of the disease. The progression of pulmonary fibrosis may be an independent risk factor that, in addition to smoking history and the intensity of asbestos exposure, could be used to estimate lung cancer risk.

Respiratory health of cigar factory workers.

OBJECTIVES: To determine whether occupational exposure to raw tobacco causes respiratory or allergic diseases, an excess of respiratory symptoms, a decrease in lung function, or parenchymal changes in chest radiography among Finnish cigar workers. METHODS: This cross sectional study included all Finnish cigar workers (n = 106) exposed to raw tobacco and also a group of unexposed matched referents. Data were collected with a self administered questionnaire, flow volume spirometry, measurements of diffusing capacity of the lung for carbon monoxide, chest radiography and skin prick tests. A questionnaire was also sent to former workers of the factory. RESULTS: There were no significant differences between the groups in the prevalence of respiratory symptoms and chest radiography findings. Nine of 102 tobacco workers had pulmonary fibrosis of at least 1/0 (according to the International Labour Organisation (ILO) 1980 classification) and the corresponding figure was five for the referents. The tobacco workers tended to have a low forced vital capacity (FVC), and they had impaired forced expiratory volume in 1 second and lower means of the maximal expiratory flow at 25% of the FVC significantly more often than the referents. Diffusing capacity tended to be lower among the referents. The referents more often had atopy and earlier atopic diseases than the exposed workers. These results indicate the possibility of selection among the exposed workers. CONCLUSIONS: No excess of prevalence of respiratory symptoms in the tobacco workers was found. According to the questionnaire episodes of allergic alveolitis may have occurred in the cigar factory workers. However, in the absence of impairments in lung function and radiological changes it was not possible to distinguish humidifier fever and allergic alveolitis. In exposure conditions that include humidification of the air humidifier, fever and allergic alveolitis constitute a risk for tobacco workers. No effects were shown of exposure to tobacco dust on lung function.

Cancer incidence and mortality among Finnish asbestos sprayers and in asbestosis and silicosis patients.

Cohorts of Finnish asbestos sprayers and of asbestosis and silicosis patients were followed for cancer with the aid of the Finnish Cancer Registry in the period 1967-1994. Compared with the cancer incidence of the total Finnish population, asbestos sprayers had an increased risk for total cancer (standardized incidence ratio [SIR] 6.7, 95% confidence interval [95% CI] 4.2-10); lung cancer (SIR 17.95% CI 8.2-31); and mesothelioma (SIR 263, 95% CI 85-614). The SIR of the asbestosis patients was 3.7 (95% CI 2.8-5.0) for all sites, 10 (95% CI 6.9-14) for lung cancer, and 65 (95% CI 13-188) for mesothelioma. The silicosis patients also had significantly high SIR values for all sites (1.5, 95% CI 1.0-2.1) and lung cancer (2.7, 95% CI 1.5-4.5). The values for the SIR and the standardized mortality ratio for all sites and lung cancer were very similar, and therefore it seems that both are reliable indicators of the occurrence of occupational cancer. It was concluded that pneumoconioses patients and asbestos-exposed workers have a markedly elevated risk for cancer. Asbestos-induced occupational cancers are not only diseases of the elderly, since the relative risk is high also for middle-aged people.

Screening for asbestos-induced diseases in Finland.

Screening for asbestos-induced diseases in Finland was carried out in 1990-1992 as a part of the Asbestos Program of the Finnish Institute of Occupational Health. The aim of the present study was to find the workers who had developed an asbestos-induced disease in certain occupations. Examination of active or retired workers included a personal interview on work history and asbestos exposure, and a chest X-ray. The target group for the screening comprised workers under 70 years of age who had worked at least for 10 years in construction, 1 year in a shipyard or in the manufacture of asbestos products. A preliminary questionnaire was sent to 54,409 workers, 18,943 of whom finally participated in the screening examination. The mean age of the workers was 53 years; 95% were employed in construction, 2% in shipyards, and 3% in the asbestos industry. The criteria for a positive screening result were (1) a radiographic finding clearly indicating lung fibrosis (at least ILO category 1/1), (2) a radiographic finding indicating mild lung fibrosis (ILO category 1/0) with unilateral or bilateral pleural plaques, (3) marked abnormalities of the visceral pleura (marked adhesions with or without pleural thickening), or (4) bilateral pleural plaques. The positive cases totalled 4,133 (22%) and were sent for further investigation. In addition to the screening, information on the presence of asbestos in the work environment, prevention of asbestos exposure, as well as on the health effects of asbestos exposure and smoking were given to the participating workers. The screening acted as a preliminary survey to prompt further national follow-up of asbestos-induced diseases among the workers who have been exposed to asbestos. This article presents the material, methods, and overall results of the screening.

Radiographic small lung opacities and pleural abnormalities as a consequence of asbestos exposure in an adult population.

OBJECTIVES: The purpose of this study was to estimate the role of past asbestos exposure as a cause of radiographic small lung opacities and pleural abnormalities in the Finnish adult population. METHODS: The study was conducted in 1978-1981 and was based on a population sample (N = 8000) representative of the Finnish population aged 30 years or over. Full-size chest radiographs and a complete job title history were available for 3811 women and 3274 men. The radiographs were classified according to the 1980 classification of radiographs of pneumoconioses published by the International Labour Office and the work histories according to the probability of occupational asbestos exposure. Age- and smoking-adjusted relative risks of radiographic parenchymal and pleural abnormalities were calculated with the analysis of covariance according to the probability of asbestos exposure. RESULTS: About 13% of the men and 0.8% of the women were classified as probably exposed to asbestos. There was more than 90% agreement in the repeated work history evaluations. The risk of small lung opacities was significantly increased among the probably exposed men [risk ratio (RR) 1.7 for ILO profusion category 1/1 or more and RR 1.6 for profusion category 1/0]. The risk of pleural plaques was increased both among the men (RR 3.0) and the women (RR 4.8) with probable exposure. The risk of thickened horizontal interlobar fissure was also increased among the probably exposed men (RR 1.7). Among the men, the etiologic fraction attributable to occupational asbestos exposure was about 30% for small lung opacities, about 40% for pleural plaques, and about 20% for thickened horizontal fissure. Among the women the etiologic fractions for asbestos were similar for pleural abnormalities, but much lower for parenchymal ones. CONCLUSIONS: Occupational asbestos exposure has been common among Finnish men, and it plays a significant role in the etiology of both pleural and parenchymal abnormalities also at the level of the general population.

Asbestos and cancer in Finland.

Primary prevention carried out today can reduce the disease incidence in the future decades. The present disease panorama is the consequence of past asbestos exposure mainly before the 1970s. The peak incidence of asbestos-induced diseases will be reached around 2010 in Finland. The number of asbestos-related premature deaths is at present annually about 150 which exceeds the figure of fatal work accidents. Asbestos-related cancer will increase still for 15-20 years and reach its maximum, about 300 cases, in 2010, and will start to decrease after that. More than 20,000 asbestos-exposed workers have participated in the medical screening and follow-up. The termination of exposure, antismoking campaigns, improved diagnostics and careful attention to compensation issues, as well as other potentials for prevention, were the central issue of the Asbestos Program of the Finnish Institute of Occupational Health. An important objective of research work is to improve early diagnostics, and thereby treatment prospects, in case of asbestos-induced cancers.

Finnish Institute of Occupational Health Asbestos Program 1987-1992.

In 1987-1992, the Finnish Institute of Occupational Health (FIOH) implemented a nationwide asbestos program aimed at preventing asbestos-related risks in good cooperation with governmental authorities, industry, trade unions, the health care and insurance systems, and mass media. The goals were to minimize all exposure to asbestos, identify people exposed at work, and improve the diagnostics of asbestos diseases, especially cancers. The program entailed several concrete actions and extensive dissemination of information, training, services, and scientific research. As proposed by the State Asbestos Committee, new use of asbestos products was banned and strict regulations were applied to renovation and inspection of old buildings. The screening study of asbestos-induced diseases included 18,943 current and retired workers from house building, shipyard, and asbestos industries. Pleural and parenchymal changes were found in 4,133 persons (22%), who were referred to further clinical examinations as suspected cases of an occupational disease. It was estimated that past exposure of asbestos among the Finnish population of 5 million causes > 150 mesotheliomas and lung cancers annually, totalling > 2,000 asbestos-induced cancer deaths by the year 2010. Although several major control actions were made or started during the program, the bulk of the preventive work still lies ahead.

Rheumatoid factor and HLA antigens in wrist tenosynovitis and humeral epicondylitis.

A matched case-referent study was undertaken to assess whether rheumatoid factor (RF) is associated with repeating tenosynovitis or peritendinitis and whether HLA-B27 predisposes to epicondylitis. The study subjects consisted of 25 workers in manually strenuous jobs with a history of at least two episodes of tenosynovitis or peritendinitis in the wrist or forearm, or humeral epicondylitis, and their matched referents. The latex agglutination test was positive in seven of the 23 cases with tenosynovitis and in one of the referents (p = 0.03). The corresponding figures for IgM-RF by enzyme immunoassay were ten and two, respectively (p = 0.008). HLA-B27 antigen was found in five of the 13 workers with epicondylitis and in one worker with no such history (p = 0.13). It is possible that RF-positive repeating tenosynovitis represents an incomplete form of rheumatoid disease.

Psychomotor capacity and occurrence of wrist tenosynovitis.

A case-referent study was carried out among meatcutters, sausage markers, and packers in a large meat-processing plant to investigate the association between psychomotor capacity and occurrence of tenosynovitis. Reaction time, movement time, manual dexterity, visual attention and visuospatial ability were measured in 26 cases with a history of two or more episodes of tenosynovitis and 26 referents of similar gender, occupation, age, and job seniority with no episodes of the disease. No differences were found between the cases and the referents in any of the tests of psychomotor capacity. The results suggest that psychomotor capacity, as measured with the tests of this study, is a poor predictor of wrist tenosynovitis.

Parenchymal and pleural fibrosis in construction workers.

Exposure to mineral dust was studied among construction workers (N = 437) with the aid of a questionnaire and a chest X-ray examination of the lungs. The results of the questionnaire showed that 81% of the construction workers had been exposed to asbestos. Exposure had occurred in all of the occupational groups studied. Pleural plaques and/or lung fibrosis (ILO greater than or equal to 1/1) were found in 26% of the examined workers; the prevalence varied from 18 to 40% among the various occupational groups. Comparison with a representative sample of the Finnish male population from another investigation indicates that the frequency of lung fibrosis (ILO greater than or equal to 1/1) is at least two times higher among the examined construction workers than among the general population. It seems likely that exposure to asbestos dust can be considered an etiological factor for an appreciable number of the X-ray findings.

Screening for occupational cancer.

The main strategy for preventing occupational cancer is an environmentally based approach or primary prevention. However, it should be combined with screening, early diagnosis, and treatment. This review discusses screening for occupational cancer but not from the point of view of medical screening. Instead it focuses on asbestos exposure and asbestos-related cancer in Finland and the role screening plays in the current Finnish asbestos program. For example it is the feeling in Finland that screening is a very effective way of preventing further occupational exposure to asbestos and of organizing antismoking campaigns. An individually oriented strategy in cancer prevention should include the modification of exposures by behavioral change, the monitoring of early effects of exposures, and health examinations. The termination of exposure, antismoking campaigns, improved diagnostics, and careful attention to compensation issues combined with the study of other opportunities for prevention are seen as the key issues in screening.