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.

Toxic acute hepatitis and hepatic fibrosis after consumption of chaparral tablets.

In this report we describe a young, previously healthy woman who developed severe acute hepatitis after consumption of chaparral tablets, a commonly used herbal product. In this case, the elimination-rechallenge event and the exclusion of other possible aetiologic factors strongly supported true causality between the herbal product and the liver damage. Primary liver biopsy showed severe toxic hepatitis consistent with previous reports of chaparral-induced liver damage. Later, 6 months after the liver function tests had normalized, permanent hepatic fibrosis could still be seen.

Clinical characteristics of collagenous and lymphocytic colitis.

BACKGROUND: Microscopic colitides (MC), collagenous colitis (CC) and lymphocytic colitis (LC) share clinical features, but their mutual relationship is unclear, and clinical comparative studies are rare. We aimed to examine the clinical features in CC and LC by focusing on concomitant diseases. METHODS: Patients with MC (30 with CC, 54 with LC) were identified in the pathology databases and by reviewing biopsies. Controls included 84 age- and sex-matched persons. The clinical data collected from patient records were prospectively completed by interviews. RESULTS: The female:male ratio was 2:1 in CC and 5.75:1 in LC. Mean age at diagnosis was 53 in CC and 55.4 years in LC. There were no differences in the pattern of symptoms. Concomitant autoimmune diseases were more common in CC (53.3%) than in LC (25.9%; P = 0.017). Celiac disease was common in both CC (20%) and LC (14.8%). Bronchial asthma was associated with LC (25.9%), but not with CC (6.7%; P = 0.042). Colon diverticulosis was rare in MC (16%) compared with the controls (39%; P = 0.001). Hypolactasia was common in MC (45%; 76% in CC, 54% in LC) compared to its prevalence in the Finnish general population (17%). CONCLUSIONS: CC and LC are largely similar clinically, but the differences in the occurrence of autoimmune conditions and bronchial asthma suggest that they differ in immunopathogenesis. MC is associated with reduced lactose tolerance and shows a negative association with diverticular disease, possibly related to the small intestinal pathology and abnormal stool consistency.

Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

Exposure-response analysis and risk assessment for silica and silicosis mortality in a pooled analysis of six cohorts.

AIMS: To study the relation between exposure to crystalline silica and silicosis mortality. Although mortality is an important endpoint for regulators, there have been no exposure-response studies for silicosis mortality, because of the relative rareness of silicosis as an underlying cause of death, and the limited availability of quantitative exposure estimates. METHODS: Data from six occupational cohorts were pooled with good retrospective exposure data in which 170 deaths from silicosis were reported. Standard life table analyses, nested case-control analyses, and risk assessment were performed. RESULTS: The rate of silicosis mortality in the combined data was 28/100 000 py, increasing in nearly monotonic fashion from 4.7/100 000 for exposure of 0-0.99 mg/m(3)-years to 233/100 000 for exposure of >28.1 mg/m(3)-years. The estimated risk of death up to age 65 from silicosis after 45 years of exposure at 0.1 mg/m(3) silica (the current standard in many countries) was 13 per 1000, while the estimated risk at an exposure of 0.05 mg/m(3) was 6 per 1000. Both of these risks are above the risk of 1 per 1000 typically deemed acceptable by the US OSHA. CONCLUSION: The findings from this pooled analysis add further support to the need to control silica exposure and to lower the occupational standards. Our estimates of lifetime silicosis mortality risk are probably underestimates as, in addition to exposure misclassification, our study might have suffered from outcome misclassification in that silicosis deaths might have been coded to other related causes, such as tuberculosis or chronic obstructive pulmonary disease.

Pooled exposure-response analyses and risk assessment for lung cancer in 10 cohorts of silica-exposed workers: an IARC multicentre study.

OBJECTIVES: Silica is one of the most common occupational exposures worldwide. In 1997 the International Agency for Research on Cancer (IARC) classified inhaled crystalline silica as a human carcinogen (group 1), but acknowledged limitations in the epidemiologic data, including inconsistencies across studies and the lack of extensive exposure-response data. We have conducted a pooled exposure-response analysis of 10 silica-exposed cohorts to investigate lung cancer. METHODS: The pooled cohort included 65,980 workers (44,160 miners, 21,820 nominees), and 1,072 lung cancer deaths (663 miners, 409 nonminers). Follow-up has been extended for five of these cohorts beyond published data. Quantitative exposure estimates by job and calendar time were adopted, modified, or developed to permit common analyses by respirable silica (mg/m3) across cohorts. RESULTS: The log of cumulative exposure, with a 15-year lag, was a strong predictor of lung cancer (p = 0.0001), with consistency across studies (test for heterogeneity, p = 0.34). Results for the log of cumulative exposure were consistent between underground mines and other facilities. Categorical analyses by quintile of cumulative exposure resulted in a monotonic trend with odds ratios of 1.0. 1.0, 1.3, 1.5, 1.6. Analyses using a spline curve also showed a monotonic increase in risk with increasing exposure. The estimated excess lifetime risk (through age 75) of lung cancer for a worker exposed from age 20 to 65 at 0.1 mg/m3 respirable crystalline silica (the permissible level in many countries) was 1.1-1.7%, above background risks of 3-6%. CONCLUSIONS: Our results support the decision by the IARC to classify inhaled silica in occupational settings as a carcinogen, and suggest that the current exposure limits in many countries may be inadequate. These data represent the first quantitative exposure-response analysis and risk assessment for silica using data from multiple studies.

Factors predictive of ischemic heart disease mortality in foundry workers exposed to carbon monoxide.

The potential predictors of ischemic heart disease mortality were studied for 931 male foundry workers in Finland who participated in a health examination in 1973. These workers were followed up to 1993 through registers and by using a questionnaire. In 1973, the systolic and diastolic blood pressures of workers exposed to carbon monoxide (CO) were slightly higher than those of unexposed workers. The prevalence of angina pectoris showed a clear dose-response relation to CO exposure. Electrocardiogram (ECG) findings indicating past myocardial infarction or suggesting coronary artery disease as a function of smoking and/or CO exposure were not evident. In the 1987 follow-up, the rate ratio for ischemic heart disease mortality was estimated as 4.4 for CO-exposed smokers compared with unexposed nonsmokers. Ischemic heart disease mortality in 1973-1993 was analyzed by using the Cox proportional hazards model. The statistically significant predictors were age, pathologic ECG findings in 1973, regular CO exposure, and abundant alcohol drinking. Of the ECG findings, changes in Q or QS and ST-J or ST waves and in ventricular extrasystoles were statistically significant. The risk of mortality from ischemic heart disease was increased by working in iron foundries, by hypertension, and by smoking.

Transdermal delivery of levosimendan.

The aim of this study was to determine if transdermal penetration of levosimendan, a novel positive inotropic drug, could be enhanced and controlled by formulation modifications. Penetration of levosimendan across human epidermis in vitro was determined using abdominal excised skin and diffusion cells. Predicted steady-state plasma concentrations of levosimendan were estimated using permeabilities and pharmacokinetic parameters of levosimendan. For penetration enhancement we used different pH values, co-solvents, cyclodextrins, surfactants, penetration enhancers, liposomes, and iontophoresis. Sodium lauryl sulfate, ethanol, oleic acid, and soya phosphatidylcholine or their combinations clearly increased levosimendan permeation across the skin in vitro. Iontophoresis was also an efficient method to increase transdermal permeation of levosimendan. A hydrophilic co-solvent/penetration enhancer is needed to achieve better permeability of levosimendan across the skin. In conclusion, transdermal delivery of levosimendan can be significantly increased by formulation modification. Based on kinetic calculations, therapeutic plasma concentrations may be achievable transdermally.

Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype.

A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.

Phospholipids affect stratum corneum lipid bilayer fluidity and drug partitioning into the bilayers.

Phospholipids, e.g. fluid-state EPC (l-alpha-phosphatidylcholine from egg yolk), may diffuse into the stratum corneum and enhance dermal and transdermal drug penetration, while many other phospholipids, e.g. gel-state DSPC (distearoylphosphatidyl choline), are not able to do this. These effects are suggested to be due to the interactions between the phospholipids and the skin lipid bilayers, and so an in vitro method was developed to evaluate the influence of phospholipids on the distribution of drugs to stratum corneum lipids. The distribution coefficients of estradiol, progesterone and propranolol between stratum corneum lipid liposomes (SCLLs) without phospholipids or with EPC, DSPC, SPC (l-alpha-phosphatidylcholine from soybean) or DOPE (dioleylphosphatidyl ethanolamine), and pH 7.4 buffer were determined. Fluid-state phospholipids in SCLLs increased the partitioning of drugs into SCLLs, while gel-state lipid, DSPC, did not. The increased distribution of drugs into the SCLLs was at least partially due to the increased fluidity of SCLL bilayers by phospholipids, which was shown using steady-state fluorescence anisotropy. This in vitro method enables screening of the effects of phospholipids and other permeation enhancers on stratum corneum bilayer fluidity and drug partitioning.

Liposome-skin interactions and their effects on the skin permeation of drugs.

The aim of the study was to evaluate the interaction of phospholipid liposomes with skin and stratum corneum lipid liposomes (SCLLs). The influence of phospholipid liposomes on the skin permeability of model drugs was also studied. The transdermal flux of the drugs applied in various phospholipid containing formulations through human epidermis was studied in diffusion chambers. Liposomes in water solutions did not enhance the skin permeability of the drugs, but when ethanol (32% w/v) was present in the donor with EPC (egg yolk lecithin), permeabilities of some model drugs were substantially increased. Confocal microscopy studies revealed that EPC do not penetrate into the skin from water solutions, while from ethanol solutions, EPC penetrates deeply into the stratum corneum. Also, resonance energy transfer between different liposome compositions and the release of calcein from SCLLs showed that interactions between phospholipid liposomes and SCLLs increased with increasing ethanol concentration in the liposome solutions.

Integrating clinical and laboratory data in genetic studies of complex phenotypes: a network-based data management system.

The identification of genes underlying a complex phenotype can be a massive undertaking, and may require a much larger sample size than thought previously. The integration of such large volumes of clinical and laboratory data has become a major challenge. In this paper we describe a network-based data management system designed to address this challenge. Our system offers several advantages. Since the system uses commercial software, it obviates the acquisition, installation, and debugging of privately-available software, and is fully compatible with Windows and other commercial software. The system uses relational database architecture, which offers exceptional flexibility, facilitates complex data queries, and expedites extensive data quality control. The system is particularly designed to integrate clinical and laboratory data efficiently, producing summary reports, pedigrees, and exported files containing both phenotype and genotype data in a virtually unlimited range of formats. We describe a comprehensive system that manages clinical, DNA, cell line, and genotype data, but since the system is modular, researchers can set up only those elements which they need immediately, expanding later as needed.

Mortality, morbidity and health selection among metal workers.

Workers are selected into and out of physically demanding jobs with regard to their health. The study of occupational mortality and morbidity is hampered by this selection. Furthermore, social selection and rapid turnover are involved in health selection. Because different stages of disease form only one continuum (dissatisfaction-death), the correct interpretation of the results also requires measures softer than mortality. Earlier studies have concluded that soft and hard measures of health follow one another as explanations for the termination-of-employment rate. The aim of this study was to determine which age and exposure categories are the most prone to health selection. Mortality and morbidity were studied on three different exposure levels defined primarily according to the physical demands of the work: heavy level (iron foundries); medium level (manufacture of metal products); and light level (manufacture of electrical devices). The population comprised 15,714 men hired in 1950-1976 to work in the three branches of the metal industry. Another cohort, a cross-sectional one, of 1292 workers (who had been hired earlier and were still working in 1950) in the three industrial branches was used to clarify selection due to disability and mortality. Data for the mortality and disability analyses were obtained from national death and disability registers. The period of follow-up was 1950-1978. A questionnaire on occupational history, morbidity, and the causes of turnover was sent to 400 current and 600 former workers from each industrial branch. A questionnaire concerning occupational history was also sent to the nearest relatives of a total of 450 decidents. The occupational histories of the current and former workers were compared for changes in the exposure level throughout their complete occupational histories. The occupations during the workers' life-times were also classified into three exposure levels on the basis of physical demands (heavy, medium, and light). The three exposure levels showed different patterns of change according to age throughout the workers' complete occupational histories. Selection into and out of jobs within and between different exposure levels appeared to be a continuous process, a chain of selection. This conclusion was ascertained when the complete occupational histories were analyzed according to the exposure levels (heavy, medium, light) of the occupations from which the workers came and to which they transferred. The foundry workers entered the industry from either heavy or medium-level occupations, and most of them sought lighter work in medium-level occupations. The metal product workers either began their work lives within the metal product industry or they transferred to it from work that entailed the same exposure level. After leaving a job, the metal product workers generally moved to medium (i.e., the same level) or light occupations. The electrical workers switched from medium-level work, or they began their worklives within that industrial branch. When they left a job, they chose medium or light work in the metal industry. Due to the chain of selection from one exposure level to another, the mortality and morbidity rates for a certain exposure level can be underestimated or overestimated if complete occupational histories are not available. The selection process was different for different diseases and was manifested as different stages of disease. Ache or pain in the musculoskeletal system within the last 12 months was more frequent among the foundry and metal product workers than among the electrical workers. Both the currently employed and former foundry workers had significantly more earlier-diagnosed musculoskeletal diseases than the electrical workers. The younger age classes of foundry workers (< 45 years) had a higher occurrence of musculoskeletal diseases than the metal product workers; in the older age classes the opposite was true. (ABSTRACT TRUNCATED)

Interaction of liposomes with human skin in vitro--the influence of lipid composition and structure.

Liposomes have been suggested as a vehicle for dermal and transdermal drug delivery, but the knowledge about the interaction between lipid vesicles and human skin is poor. Therefore, we visualized liposome penetration into the human skin by confocal laser scanning microscopy (CLSM) in vitro. Liposomes were prepared from phospholipids in different compositions and labeled with a fluorescent lipid bilayer marker, N-Rh-PE (L-alpha-phosphatidylethanolamine-N-lissamine rhodamine B sulfonyl). Fluorescently labelled liposomes were not able to penetrate into the granular layers of epidermis. However, the fluorescence from liposome compositions containing DOPE (dioleylphosphatidyl ethanolamine) was able to penetrate deeper into the stratum corneum than that from liposomes without DOPE. Pretreatment of skin with unlabeled liposomes containing DOPE or lyso-phosphatidyl choline (lyso-PC) enhanced the subsequent penetration of the fluorescent markers, N-Rh-PE and sulforhodamine B into the skin, suggesting possible enhancer activity, while most liposomes did not show such enhancement. Resonance energy transfer (RET) and calcein release assay between stratum corneum lipid liposomes (SCLLs) and the phospholipid vesicles suggested that the liposomes containing DOPE may fuse or mix with skin lipids in vitro and loosen the SCLL bilayers, respectively. Among the factors not affecting stratum corneum penetration were: negative charge, cholesterol inclusion and acyl chain length of the phospholipids. In conclusion, fusogenicity of the liposome composition appears to be a prerequisite for the skin penetration.

Mortality among Finnish sea pilots 1956-85: a retrospective cohort study.

The National Board of Navigation in Finland employed 942 sea pilots in 1956-85, during which time 262 of them died (SMR = 77, 95% CI = 68-86). The male population in southwest Finland served as control. The causes of deaths were collected from death certificates. The mortality rate for all cardiovascular diseases and lung cancer was lower among sea pilots than in the comparison population (SMR = 83, 95% = CI 69-97 and SMR = 67, 95% CI = 37-97) while for ischaemic heart diseases, it was similar to that of the population as a whole (SMR = 96, 95% CI = 77-115). Health selection due to ischaemic heart disease was seen in the lower mortality rates among young pilots who started work in 1956-85. Otherwise, the slightly higher rates may indicate a possibility of adverse health effects of sea piloting.

Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect.

A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; phi = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study..

Two-locus approach of segregation and linkage analysis in the study of complex traits.

A two-locus segregation and linkage-analysis approach was used to characterize the genetic control of a complex trait (Q1) and to localize the genes that have detectable effects. The results suggested that a two-locus Mendelian model fit the data significantly better than a one-locus model. The linkage results based on the most parsimonious two-locus model revealed linkage of Q1 to two areas (MG2 and MG3), while there was less evidence for linkage using one-locus models. Results also suggested that the subphenotypes (Q2 and Q3) provided useful information for further analysis of Q1 using two-locus models.

Silica dust exposure and lung cancer.

OBJECTIVE: The study evaluated the possibility of a direct association between silica dust exposure and lung cancer. METHODS: Mortality and morbidity among 1026 granite workers was followed in 1940-1989. Regional census data for 1970-1985 and lung cancer incidence data were also linked. The cytotoxicity of different granite fractions and their capacity to induce reactive oxygen species (ROS) in human leukocytes was studied in vitro. RESULTS: Excess lung cancer mortality was found during several follow-up periods. The rate ratios were 1.6-3.8 for different latency periods. Lung cancer risk increased with the length of exposure and latency. Lung cancer morbidity in 1953-1987 showed an excess for the red and grey granite areas, the rate ratio being 2.5 for > or = 20-year latency. Only one lung cancer case came from the black granite area. The cancer cases from the grey area had a shorter latency than those from the red area. The mineral composition differed for each area. The strongest ROS-inducing activity of grey and red granite was seen in the quartz-containing fractions. In the cytotoxicity tests the quartz-containing fractions of the grey and red granite also caused the strongest lactic dehydrogenase (LDH) release. However, plagioclase, the main constituent of black granite (60%), had approximately the same ability to induce ROS as the quartz-containing fractions of red and grey granite. CONCLUSIONS: The cancer morbidity and mortality figures of the three different granite areas, combined with the found differences in biological activity of granite dusts and a hypothesis that there is a cancer-inducing mechanism for ROS, point to a direct role for quartz in cancer induction.

Cardiovascular diseases among foundry workers exposed to carbon monoxide.

OBJECTIVES: The study investigated long-term effects of carbon monoxide (CO) exposure on foundry workers' morbidity and mortality from cardiovascular diseases. METHODS: The study population comprised a cohort of 2857 men hired in 1950--1972 by 20 Finnish foundries and also 931 men who were still active in 1972, exposed for at least 4.2 years, took part in a health examination in 1973; 653 of the 931 had also been members of the cohort. These groups were followed to the end of 1987. RESULTS: The age-standardized incidence density rate (ID/1000 person-years) for compensated medication for hypertension was 4.7 for the unexposed workers and 9.4 for those exposed [rate ratio (RR) 2.0, 95% confidence interval (95% CI) 1.28--2.92]; for the iron foundry workers the rates were 4.7 and 9.9 (RR 2.1, 95% CI 1.24--3.38), respectively. During 1950--1987, 255 cardiovascular deaths were observed (284 expected according to national rates). The observed number of deaths due to ischemic heart disease was 183 (203 expected). The iron foundry workers' mortality rate for cardiovascular deaths was 99% of the national expected value. No remarkable differences were found between the CO-exposure categories. For the health-examination group, the age-standardized incidence rate for compensated medication for hypertension was 9.1 for the unexposed nonsmokers and 21.4 for the exposed smokers (RR 2.3, 95% CI 0.97-6.35); the difference originated among the iron foundry workers, for whom the rates were 8.1 and 24.0 (RR 3.0, 95% CI 0.96--9.78), respectively. The age-standardized mortality rate (ID/1000 person-years) was 2.7 for nonsmokers with no or slight CO exposure and 9.2 for exposed smokers (95% CI 1.13--12.11). This difference was mainly caused by ischemic heart disease. CONCLUSIONS: The results indicate that CO exposure increases the risk of cardiovascular morbidity and mortality.