Respiratory disease and cardiovascular morbidity.

BACKGROUND: Work related dust exposure is a risk factor for acute and chronic respiratory irritation and inflammation. Exposure to dust and cigarette smoke predisposes to exogenous viral and bacterial infections of the respiratory tract. Respiratory infection can also act as a risk factor in the development of atherosclerotic and coronary artery disease. AIMS: To investigate the association of dust exposure and respiratory diseases with ischaemic heart disease (IHD) and other cardiovascular diseases (CVDs). METHODS: The study comprised 6022 dust exposed (granite, foundry, cotton mill, iron foundry, metal product, and electrical) workers hired in 1940-76 and followed until the end of 1992. National mortality and morbidity registers and questionnaires were used. The statistical methods were person-year analysis and Cox regression. RESULTS: Co-morbidity from cardiovascular and respiratory diseases ranged from 17% to 35%. In at least 60% of the co-morbidity cases a respiratory disease preceded a cardiovascular disease. Chronic bronchitis, pneumonia, and upper respiratory track infections predicted IHD in granite workers (rate ratio (RR) = 1.9; 95% CI 1.38 to 2.72), foundry workers (2.1; 1.48 to 2.93), and iron foundry workers (1.7; 1.16 to 2.35). Dust exposure was not a significant predictor of IHD or other CVD in any group. Dust exposure was related to respiratory morbidity. Thus, some respiratory diseases appeared to act as intermediate variables in the association of dust exposure with IHD. CONCLUSION: Dust exposure had only a small direct effect on IHD and other CVD. IHD morbidity was associated with preceding respiratory morbidity. A chronic infectious respiratory tract disease appeared to play an independent role in the development of IHD.

Pleural fluid lysozyme in human disease.

Lysozyme content was measured in the plasma and pleural fluid of 110 patients with pleural effusions of various causes. The concentration of pleural fluid lysozyme was significantly higher (P less than .001) in patients with tuberculous pleurisy than in those with primary pulmonary carcinoma, metastatic carcinoma of the lung, connective tissue disease, nonspecific pleurisy, or congestive heart failure. Tuberculous patients also had a significantly higher (P less than .001) pleural fluid-to-plasma lysozyme ratio than did the other patients. Plasma lysozyme activity did not differ significantly among the various patient groups. Lysozyme was identified immunohistochemically in epithelioid cell granulomas in tuberculosis, in activated macrophages in lymph nodes adjacent to tuberculous lesions, and in granulocytes in pleural empyema. No lysozyme was detected in neoplastic cells in pulmonary carcinoma. The results show that the determination of pleural fluid lysozyme is a simple, fast method for obtaining corroborative information in the differential diagnosis of tuberculous pleurisy.

Neutrophil and asbestos fiber-induced cytotoxicity in cultured human mesothelial and bronchial epithelial cells.

This study investigates reactive oxygen species generation and oxidant-related cytotoxicity induced by amosite asbestos fibers and polymorphonuclear leucocytes (PMNs) in human mesothelial cells and human bronchial epithelial cells in vitro. Transformed human pleural mesothelial cells (MET 5A) and bronchial epithelial cells (BEAS 2B) were treated with amosite (2 micrograms/cm2) for 48 h. After 24 h of incubation, the cells were exposed for 1 h to nonactivated or amosite (50 micrograms) activated PMNs, washed, and incubated for another 23 h. Reactive oxygen species generation by the PMNs and the target cells was measured by chemiluminescence. Cell injury was assessed by cellular adenine nucleotide depletion, extracellular release of nucleotides, and lactate dehydrogenase (LDH). Amosite-activated (but also to a lesser degree nonactivated) PMNs released substantial amounts of reactive oxygen metabolites, whereas the chemiluminescence of amosite-exposed mesothelial cells and epithelial cells did not differ from the background. Amosite treatment (48 h) of the target cells did not change intracellular adenine nucleotides (ATP, ADP, AMP) or nucleotide catabolite products (xanthine, hypoxanthine, and uric acid). When the target cells were exposed to nonactivated PMNs, significant adenine nucleotide depletion and nucleotide catabolite accumulation was observed in mesothelial cells only. In separate experiments, when the target cells were exposed to amosite-activated PMNs, the target cell injury was further potentiated compared with the amosite treatment alone or exposure to nonactivated PMNs. In conclusion, this study suggests the importance of inflammatory cell-derived free radicals in the development of amosite-induced mesothelial cell injury.

Viral antibodies in multiple sclerosis. A nationwide co-twin study.

Serum viral antibody titers against 21 viruses were studied in 19 of 23 same-sex twin pairs with multiple sclerosis derived from the Finnish Twin Cohort. Thorough neurologic examinations showed two monozygotic pairs to be concordant, whereas all dizygotic pairs were discordant. Special attention was given to measles, mumps, and rubella viruses, against which the antibody levels were determined with the complement fixation, hemagglutination inhibition, hemolysis-ingel, and enzyme immunoassay methods. Epstein-Barr virus antibody levels were determined by enzyme assay. In pairwise comparisons, the measles, mumps, and Epstein-Barr virus-IgG antibody levels were more often elevated in the patients with multiple sclerosis, compared with the healthy co-twins. The same antibody levels were more often above the median in the diseased twin, compared with the healthy twin, but the difference was not significant. No human T-cell lymphotropic virus type I antibodies were found in any of the individuals examined. The total IgG, IgA, and IgM levels did not differ between the diseased and healthy subjects. The HLA types, severity of the disease, and cell-mediated immunity parameters did not influence antibody levels.

Tissue distribution of lysozyme in man.

The distribution of lysozyme (LZM) in normal human tissues was determined with the use of the immunoglobulin-enzyme (peroxidase) bridge method. LZM was detected in the following cells and tissues: secretory cells of the lacrimal gland, ductal epithelial cells of the parotid gland and the serous parts of the mixed sublingual glands, the esophageal submucosal glands, bronchial serous submucosal glands, gastric and pyloric glands, Brunner's glands of the duodenum, the Paneth cells of the small intestine, Kupffer cells of the liver and renal proximal tubular cells. In addition, LZM was also found in the mononuclear or polymorphonuclear cells of the placenta, lung, lamina propria of the small intestine, lymph nodes and spleen. This distribution of LZM is discussed in relation to its possible physiologic role in human tissues and particularly to its known antibacterial properties.

Asbestos fibers induce release of collagenase by human polymorphonuclear leukocytes.

The asbestos fibers chrysotile and crocidolite cause a dose-dependent release of specific granule collagenase by human polymorphonuclear leukocytes (PMNL). Release of azurophil granule elastase was induced by the asbestos fibers at higher concentrations, suggesting that asbestos fibers primarily cause the release of specific granule contents of human PMNL. Wollastonite, a fibrous silicate mineral, causes a weaker collagenase release and no elastase release. The collagenase was released in inactive, latent form. Carboxymethyl cellulose (CMC), an agent known to blunt chrysotile-induced hemolysis and production of reactive oxygen metabolites by human PMNL, specifically inhibits chrysotile-induced release of collagenase. Chrysotile asbestos was found to bind the PMNL serine proteinase cathepsin G. A role of collagenase release, production of reactive oxygen metabolites and cathepsin G binding by chrysotile for the perpetuation of the asbestos-induced alveolitis is suggested.

PHA and PPD reactivity of lymphocytes in pleural effusions.

The functional properties of lymphocytes in pleural fluid were studied in 23 patients admitted to the hospital for the diagnostic evaluation of a unilateral or bilateral pleural effusion. The in vitro reactivities of the patients' pleural fluid lymphocytes and peripheral blood lymphocytes to phytohemagglutinin (PHA) and to purified protein derivative (PPD) were compared. In most patients with pleural effusion, the function of pleural fluid lymphocytes was intact and comparable to that of lymphocytes from peripheral blood. The PHA- and PPD-stimulated 3H-thymidine incorporation by peripheral blood lymphocytes did not differ significantly from that by pleural fluid lymphocytes in any of the patient groups. Similarly, the comparison of PHA- and PPD-stimulated 3H-thymidine uptake by peripheral blood or pleural fluid lymphocytes from patients with pleural effusions of various causes revealed no significant differences. In vitro reactivity to PPD by peripheral blood and pleural fluid lymphocytes correlated positively with the in vivo intradermal reactivity to PPD.

Concentration of hyaluronic acid in pleural fluid as a diagnostic aid for malignant mesothelioma.

Hyaluronic acid (HA) was determined with a radiometric assay in the serum and pleural fluid of 85 patients with pleural effusions, including 15 with malignant mesothelioma, 32 with other cancer, 31 with nonmalignant inflammatory diseases, and seven with congestive heart failure. With a cutoff level at 100 mg/L, the pleural fluid concentration of HA was raised in 73 percent of patients (11 of 15) with malignant mesothelioma and in 23 percent with nonmalignant inflammatory diseases, but in none with other cancer and in none with congestive heart failure. The median concentration of pleural fluid HA was significantly higher in patients with mesothelioma than in those with other cancer (p less than 0.005). Determination of carcinoembryonic antigen (CEA) in pleural fluid further helped to differentiate between mesothelioma and other types of cancer; concentrations of CEA above 10 micrograms/L were found in four of 15 (27 percent) patients with mesothelioma, but in 38 percent of the patients with other cancer. We concluded that in the differential diagnosis of pleural effusions associated with malignant tumors a high concentration of HA in pleural fluid combined with a low concentration of CEA suggests malignant mesothelioma as opposed to other types of cancer.

Serum adenosine deaminase in viral and bacterial pneumonia.

We measured the activity of serum adenosine deaminase (ADA) in paired sera from 171 military conscripts with radiographically verified pneumonia. Patient serum samples were selected on the basis of serologic analyses identifying as single etiologic agents Streptococcus pneumoniae in 29 patients, Haemophilus influenzae in 7, Mycoplasma pneumoniae in 43, adenovirus in 24, influenza A or B in 12, and parainfluenza in 5 patients. In 14 patients Neisseria meningitidis and in 31 Chlamydia spp were considered the main etiologic agent. Compared with a control group of 45 healthy men, the ADA activity in patients with pneumonia was significantly higher (p less than 0.001) in all patient groups except those with meningococcal pneumonia. The highest ADA levels were seen in patients with pneumonia caused by M pneumoniae (27.4 +/- 9.7 U/L), Chlamydia spp (26.3 +/- 9.1 U/L), and adenovirus (28.5 +/- 10.9 U/L) compared with the controls (11.1 +/- 3.0 U/L). In patients with meningococcal pneumonia, the ADA activity was significantly decreased (p less than 0.001). Serum ADA activity probably reflects differences in cellular immune response to different infectious agents. The ADA determinations may give corroborative information on the etiologic agent of pneumonia.

Concentration of tumor-associated trypsin inhibitor (TATI) in pleural effusions.

We measured the concentration of tumor-associated trypsin inhibitor (TATI) in plasma and pleural fluid of 84 patients with pleural effusions of various causes. We observed elevated (greater than 30 micrograms/L) TATI levels in pleural fluid in 45 percent of patients with pleural effusion associated with malignant disease and in 15 percent of patients with benign disease. Similar results were obtained for TATI in plasma. The concentration of TATI in pleural fluid closely parallelled that in plasma. In patients with renal insufficiency and in patients with biliary obstruction, the TATI levels were elevated both in plasma and pleural fluid. A positive correlation was seen between the concentration of TATI and the activity of alkaline phosphatase in plasma. The results show that simultaneous determination of TATI in plasma and pleural fluid improves the diagnosis of cancer only marginally. Our results also support the hypothesis that elevated TATI levels may reflect an acute phase reaction caused by inflammatory disease or tissue destruction associated with cancer not only in inflammatory conditions, but also in malignant disease where the tumor itself is not producing TATI.

T and B lymphocytes in pleural effusions.

To determine the diagnostic significance of the determination of T and B lymphocytes in pleural fluid, we studied these cells in peripheral blood and in pleural fluid by means of surface markers. Our study comprised 30 patients suffering from pulmonary tuberculosis, pulmonary malignancy, connective tissue disease, nonspecific pleurisy or congestive cardiac failure. In pulmonary tuberculosis, both the percentage and absolute numbers of T lymphocytes in pleural fluid were significantly higher than in peripheral blood. In patients with pulmonary tuberculosis, pulmonary malignancy or nonspecific pleuritis, the percentages and absolute numbers of B lymphocytes were significantly lower in pleural fluid than in peripheral blood. Considered together with other clinical and laboratory indices, these determinations may aid in the differential diagnosis of pleurisy of various etiology.

High concentrations of eosinophil cationic protein and eosinophil protein X in eosinophilic pleural effusions.

To analyze the association of the eosinophil granulocyte with pleural effusions, we measured the concentrations of two eosinophil proteins, eosinophil cationic protein (ECP) and eosinophil protein X (EPX), in pleural fluid and serum of 92 patients with pleural effusions of various causes. We observed significantly higher ECP and EPX concentrations in eosinophilic than in noneosinophilic pleural effusions (p < 0.001 and p < 0.05, respectively) and a positive correlation between the concentrations of both eosinophil proteins in pleural fluid and the total number of eosinophils in pleural fluid (ECP: r = 0.66, p < 0.0001; and EPX: r = 0.62, p < 0.0001). There was a positive correlation between the concentrations of ECP in pleural fluid and serum (r = 0.74, p < 0.0001) and between the concentrations of EPX in pleural fluid and serum (r = 0.41, p < 0.001). High ECP and EPX concentrations in pleural fluid indicated nonspecific etiology and not tuberculosis as the cause of the effusion. Our results suggest that eosinophils in pleural effusions release eosinophil proteins and probably actively participate in the local inflammatory reaction.

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.

Quartz-induced production of reactive oxygen metabolites by activated human monocyte-derived macrophages.

Quartz but not titanium dioxide (TiO2) induced the production of reactive oxygen metabolites (ROM) by human monocyte-derived macrophages, as measured by lucigenin dependent chemiluminescence. Activation of the macrophages with BCG, bacterial lipopolysaccharide and macrophage-activating factor (MAF) caused a prominent increase of quartz-induced ROM production, MAF having the strongest effect. The activation did not affect the TiO2 responses to the same extent. Assuming that ROM have a role in the pathogenesis of silica-induced disease in man, we suggest that enhancement of quartz-induced production of ROM by activated pulmonary macrophages may at least partly explain the experimental and epidemiological data indicating that activation of the immune system during infection promotes the development of silicosis.

Increased mineral dust-induced production of reactive oxygen species by blood monocytes from patients with malignant diseases.

Mononuclear leukocytes were isolated from the peripheral blood of 15 patients with malignant pulmonary diseases, 17 patients with pulmonary infections, 18 patients with chest film abnormalities of non-malignant, non-infectious etiology, and 15 healthy persons. The cells were exposed to zymosan yeast, BCG vaccine, quartz, or chrysotile asbestos, and the subsequent production of reactive oxygen species (ROS) was measured by luminol-dependent chemiluminescence. All the stimulants caused significantly higher ROS production in the patient groups than in the healthy control group, and the asbestos-induced ROS production was significantly more pronounced in the cancer group than in the two non-cancer patient groups combined. After one-year follow-up, 5 of the 15 cancer patients were alive, and these patients had significantly lower mineral dust-induced ROS responses at the time of diagnosis than were found in the patients who died. This result was verified in a subsequent study comprising 19 patients with malignant pulmonary disorders (6 alive after one year). In conclusion, monocytes from patients with malignant diseases seem to be primed for an increased ROS production, and high ROS responses seem to correlate with a poor one-year survival of the patients.

Production of reactive oxygen metabolites induced by asbestos fibres in human polymorphonuclear leucocytes.

The ability of quartz and various asbestos fibres to induce the production of reactive oxygen metabolites in human polymorphonuclear leucocytes was assessed. A chemiluminescence assay showed that the activation of polymorphonuclear leucocytes was induced in the following order of effect: quartz; chrysotile A; crocidolite; chrysotile B; amosite; and anthophyllite. Only slight chemiluminescence was produced by cells exposed to wollastonites and titanium dioxide. A positive correlation was seen between production of chemiluminescence and red cell haemolysis. Our results suggest that the potential of various environmental particles and mineral fibres to induce inflammation, fibrosis, and cancer of the lung could be related to their ability to induce inflammatory cells to produce reactive oxygen metabolites.

Pleural fluid ferritin concentrations in human disease.

The concentration of ferritin was measured in the pleural fluid of 108 patients with pleural effusions. In all groups of patients the ferritin concentration was higher in pleural fluid than in serum. The greatest differences, with up to 100 times more ferritin in the pleural fluid, were found for patients with rheumatoid pleurisy, malignant effusions, and empyema. In patients with non-malignant inflammatory pleural effusions the concentration of ferritin in pleural fluid correlated significantly with other pleural fluid indices of inflammation: there was a positive correlation with lactate dehydrogenase activity and a negative correlation with concentrations of glucose and complement components C3 and C4. Ferritin was detected immunocytochemically only in the macrophages found among the pleural fluid cells. Our study shows that large amounts of ferritin accumulate locally in the pleural cavity in certain types of pleural inflammation. The accumulation is probably partly the result of increased local reticuloendothelial system activity. Determination of the concentration of ferritin in pleural fluid may provide corroborative information for differential diagnosis and may further our understanding of the pathogenetic events that lead to the perpetuation of inflammatory activity in pleural effusions.

Fibronectin in exudative pleural effusions.

Fibronectin is a glycoprotein found in body fluids, loose connective tissue matrix and in basement membranes. Fibronectin in pleural effusion was found to be immunologically indistinguishable from the plasma form, as shown by double-diffusion analysis. Fibronectin isolated from pleural fluid by affinity chromatography on gelatin-Sepharose had a polypeptide pattern similar to that of plasma fibronectin in SDS-polyacrylamide gel electrophoresis. In 28 patients with infectious or non-specific pleural effusion fibronectin concentrations in pleural fluid were 335 +/- 104 micrograms/ml (mean +/- SD), in 15 patients with malignant disease the concentrations were 369 +/- 173 micrograms/ml and in 26 patients with tuberculosis 441 +/- 103 micrograms/ml. The highest concentrations, 605 +/- 252 micrograms/ml, of fibronectin in pleural fluid were detected in 14 patients with connective tissue diseases. The results suggest that increased fibronectin concentrations reflect the presence of a pleurisy due to connective tissue disease or tuberculosis rather than other infectious or malignant disease.

Clearance ratios of amylase and isoamylase to creatinine in renal disease.

Amylase to creatinine clearance ratios were measured in 66 patients with a variety of moderate and severe renal diseases including 10 patients with renal transplants, and in 13 healthy controls. Only in patients with severe renal insufficiency (serum creatinine level above 660 micronmoles/1) were the amylase to creatinine ratios significantly raised. The ratios correlated neither with the type of renal disease, i.e. glomerular or tubulointerstitial, nor with the degree of proteinuria. Patients with renal transplants did not differ from other patients. Clearance ratios of pancreatic and salivary isoamylase to creatinine changed in parallel to that of total amylase. The results suggest that in severe renal failure the loss of nephrons results in decreased fractional reabsorption of amylase in the tubules.

Individualised multifactorial lifestyle intervention trial for high-risk cardiovascular patients in primary care.

BACKGROUND: The multiprofessional teams in Finnish health centres are well placed to carry out interventions aimed at the prevention of cardiovascular diseases. AIM: To evaluate the effectiveness of an individually tailored multifactorial lifestyle intervention in primary care for individuals at high risk for cardiovascular disease. DESIGN OF STUDY: A randomised controlled trial was conducted over 24 months with interim assessments at six and 12 months. SETTING: A health centre in Finland with a patient population of 11,000. METHOD: One hundred and fifty adults aged 18 to 65 years old with existing cardiovascular disease or multiple risk factors were randomised to active multiprofessional risk factor intervention or to standard care. The main outcome measure was a change in cardiovascular risk-factor score. Secondary outcomes were changes in blood pressure, weight, body-mass index, serum cholesterol, blood glucose, smoking cessation, and exercise habits. RESULTS: The cardiovascular risk score decreased by 28% in the intervention group (23% in the control group), body weight decreased by 3.7% (2%) and total cholesterol decreased by 10.8% (6.5%), while time engaged in exercise increased by 39% (43%). Differences were not significant. CONCLUSIONS: Cardiovascular risk levels of high-risk individuals decreased in both intervention and control groups. Primary care prevention should be targeted to high-risk persons. Long-term follow-up studies are needed.