The Swedish National Airway Register (SNAR): development, design and utility to date.

BACKGROUND: The Swedish National Airway Register (SNAR) was initiated in 2013 to ensure and improve the quality of care for patients with asthma and COPD. AIM: To describe the development and design of SNAR, and to study the 2019 data to evaluate its potential utility related to improvement of quality of care. METHODS: SNAR includes data from patients with asthma (both children and adults) and COPD from primary, secondary and tertiary care, and also, for COPD inpatient care. Data on diagnostic investigations (e.g. spirometry, blood sample, skin prick test), symptom-scores, comorbidities and prescribed treatments are registered. The registrations are entered manually by healthcare professionals, or directly transferred from electronic medical records to a web-based platform. RESULTS: In 2019, 1000 clinics participated and data were directly transferred by about 88% of them. The register included data on 205,833 patients with asthma and 80,372 with COPD (of these, 5% had both diagnoses). Registrations of new patients and follow-up visits from primary and secondary/tertiary care in 2019 were completed for 75,707 patients with asthma (11,818 children <12 yr, 6545 adolescents 12-17 yr, and 57,344 adults >17 yr) and 38,117 with COPD. Depending on age and disease group, 43-77% had performed spirometry, 36-65% Asthma Control Test, and 60% COPD Assessment Test. The prevalence of current smoking was about 2% in adolescents, 10% in adults with asthma, and 34% in COPD. For these, smoking cessation support was offered to 27%, 38% and 51%, respectively. Overall, limited data were available on investigation of allergy, 6-min walk test, patient education and written treatment plans. Regarding asthma, sex-differences in disease management were evident. CONCLUSION: SNAR has cumulatively registered data from over 270,000 individuals, and the register is important for patients, caregivers, authorities, politicians and researchers to evaluate the effect of treatment and to ensure high and equal quality of care nationwide.

A multicenter photoprovocation study to identify potential biomarkers by global peptide profiling in cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease in which abnormal photosensitivity is an important pathogenetic factor but is difficult to predict, creating a challenge in determining treatment efficacy. Although photosensitivity in CLE patients may change over time, photoprovocation testing with ultraviolet (UV) A and UVB irradiation can be a helpful tool to explore differences between responders and nonresponders during photoprovocation. To identify biomarkers that could substitute for the clinical endpoint lesion development, we performed a global peptidomics profiling analysis of CLE subjects in a controlled photoprovocation study. Plasma and skin biopsy samples were collected before and after UV-irradiation from 13 healthy volunteers and 47 CLE subjects. Twenty-two of the 47 CLE subjects developed skin lesions. The samples were analyzed using a label-free quantitative peptidomics workflow combined with univariate and multivariate statistical analyses. The primary finding was identification of a specific plasma peptide signature separating responders versus nonresponders at baseline. The peptide signature consisted of beta 2-microglobulin (B2MG), human beta-defensin-1, and peptides derived from CD99, polymeric immunoglobulin receptor, and immunoglobulin kappa light chains. In skin, elevated B2MG levels correlated with lesion formation. Our results show that the peptidome is a rich source of potential biomarkers for predicting photosensitivity in CLE.

Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids.

During recent decades, the increasing use of opioids for chronic non-cancer pain has raised concerns regarding tolerance, addiction, and importantly cognitive dysfunction. Current research suggests that the somatotrophic axis could play an important role in cognitive function. Administration of growth hormone (GH) to GH-deficient humans and experimental animals has been shown to result in significant improvements in cognitive capacity. In this report, a patient with cognitive disabilities resulting from chronic treatment with opioids for neuropathic pain received recombinant human growth hormone (rhGH) replacement therapy. A 61-year-old man presented with severe cognitive dysfunction after long-term methadone treatment for intercostal neuralgia and was diagnosed with GH insufficiency by GH releasing hormone-arginine testing. The effect of rhGH replacement therapy on his cognitive capacity and quality of life was investigated. The hippocampal volume was measured using magnetic resonance imaging, and the ratios of the major metabolites were calculated using proton magnetic resonance spectroscopy. Cognitive testing revealed significant improvements in visuospatial cognitive function after rhGH. The hippocampal volume remained unchanged. In the right hippocampus, the N-acetylaspartate/creatine ratio (reflecting nerve cell function) was initially low but increased significantly during rhGH treatment, as did subjective cognitive, physical and emotional functioning. This case report indicates that rhGH replacement therapy could improve cognitive behaviour and well-being, as well as hippocampal metabolism and functioning in opioid-treated patients with chronic pain. The idea that GH could affect brain function and repair disabilities induced by long-term exposure to opioid analgesia is supported.

Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer.

Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 µg/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.

The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism.

OBJECTIVE: An elevated level of total plasma homocysteine (tHcy) has been associated with risk of coronary heart disease (CHD). The level of tHcy is affected by lifestyle, in addition to genetic predisposition. The methylene tetrahydrofolate reductase (MTHFR) 677C>T polymorphism (rs1801133) is among the strongest genetic predictors of tHcy. We examined whether the association between tHcy and CHD is modified by the MTHFR 677C>T polymorphism. DESIGN AND SETTING: Data from two case-control studies of first-time myocardial infarction (MI), Stockholm Heart Epidemiology Programme (SHEEP), and for MI and unstable angina, INTERGENE, were analysed in parallel. PATIENTS: THcy was determined in a total of 1150 cases and 1753 controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The outcome comprised first-time MI and unstable angina, subsumed as CHD. Logistic regression was used to investigate the association between tHcy and CHD, and its modification by genotype. RESULTS: High tHcy was confirmed to be a risk factor for CHD in both studies. In SHEEP, the association between tHcy and MI was observed in MTHFR 677 C-homozygotes (OR=1.4, 95% CI 1.2 to 1.6, for a difference by 1 SD of log tHcy) and in heterozygotes (OR=1.3, 95% CI 1.1 to 1.6) but not in T-homozygotes, independent of smoking, physical activity and obesity. An effect modification of similar magnitude was observed but not statistically significant in the smaller INTERGENE study, and confirmed in a meta-analysis of both studies. CONCLUSIONS: Two Swedish case-control studies showed that the association between elevated tHcy and CHD was confined to carriers of the MTHFR 677 C-allele, which could have implications for the efficiency of tHcy-lowering treatment.

Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden.

BACKGROUND: Numerous case reports about drug-induced (DI) subacute cutaneous lupus erythematosus (SCLE) have been published. Various drug types with different latencies has been proposed as triggers for this autoimmune skin disease. OBJECTIVES: To evaluate the association between exposure to certain suspected drugs (previously implicated to induce SCLE) and a subsequent diagnosis of SCLE. METHODS: We performed a population-based matched case-control study in which all incident cases of SCLE (n=34) from 2006 to 2009 were derived from the National Patient Register. The control group was selected from the general population, matched (1:10) for gender, age and county of residence. The data were linked to the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the association between exposures to certain suspected drugs and the development of SCLE. RESULTS: During the 6 months preceding SCLE diagnosis, 166 (71%) of the patients with SCLE had at least one filled prescription of the suspected drugs. The most increased ORs were found for terbinafine (OR 52.9, 95% CI 6.6-∞), tumour necrosis factor-α inhibitors (OR 8.0, 95% CI 1.6-37.2), antiepileptics (OR 3.4, 95% CI 1.9-5.8) and proton pump inhibitors (OR 2.9, 95% CI 2.0-4.0). CONCLUSIONS: We found an association between drug exposure and SCLE. More than one third of the SCLE cases could be attributed to drug exposure. No significant OR was found for thiazides, which might be due to longer latency and therefore missed with this study design. DI-SCLE is reversible once the drug is discontinued, indicating the importance of screening patients with SCLE for potentially triggering drugs. A causal relationship cannot be established from this study and the underlying pathogenesis remains unclear.

Increased risk of cancer among 3663 patients with cutaneous lupus erythematosus: a Swedish nationwide cohort study.

BACKGROUND: Other autoimmune diseases have been associated with higher risks for cancer, and numerous case reports of cutaneous lupus erythematosus (CLE) and different cancer types are available. OBJECTIVES: To estimate the overall and specific cancer risks in a nationwide cohort study of patients diagnosed with CLE in Sweden and compare that risk with that in a control cohort without CLE. METHODS: A cohort of 3663 individuals with CLE and a matched control cohort from the general population (three controls to each CLE case) without a diagnosis of CLE were derived from the Swedish National Patient Register, 1997-2007, and were electronically linked to the Swedish Cancer Register and the Swedish Cause of Death Register. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to compare the observed vs. the expected numbers of cancers. RESULTS: A total of 183 incident cancers occurred within the observation interval, yielding a HR of 1·8 (95% CI 1·5-2·2) for cancer overall. Median follow-up was 4·1 years. About a fourfold risk increase was seen for buccal cancer, lymphomas, respiratory cancer and nonmelanoma skin cancer. CONCLUSIONS: Patients with CLE appear to have an elevated risk for certain cancer types, an increase that remains when excluding patients also diagnosed with systemic lupus erythematosus. Our findings point to the importance of counselling about not smoking and sun avoidance, and underscore the need for specialized monitoring of this patient group along with bench-to-bedside research efforts to clarify pathogenesis.

Cutaneous manifestations and serological findings in 260 patients with systemic lupus erythematosus.

The prevalence and prognostic value of cutaneous manifestations in patients with systemic lupus erythematosus (SLE) is not clear due to a lack of distinct criteria. Our aim was to investigate the prevalence of cutaneous manifestations in SLE patients according to strict dermatological classification, compare the results with other studies and to assess differences in serological markers between patients with and without cutaneous lupus erythematosus (CLE). Secondary aims were to investigate the validity of the criteria 'malar rash' and 'photosensitivity' for SLE diagnosis. We included 260 consecutive SLE patients, and 164 with skin complaints were examined by a dermatologist. CLE was found in 23% of the 260 SLE patients. There was agreement on the presence of malar rash in only 60% of patients seen by both rheumatologists and dermatologists. A history of polymorphous light eruption (PLE) was found in 42% of patients. Raynaud's phenomenon was significantly more common in patients with CLE. In addition, four malignant melanomas were found. Based on our findings, we suggest that the American College of Rheumatology (ACR) criteria for SLE diagnosis include histopathologically confirmed CLE as one criterion, and that the criteria photosensitivity and malar rash should be re-defined. Regular examination by a dermatologist is called for in SLE patients.

Novel findings of Langerhans cells and interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with pustules, erythema and scaling localized to the palms and soles. To date, no specific treatment is known. Earlier findings indicate the acrosyringium as the target for the inflammation. OBJECTIVES: To identify specific features of the PPP inflammatory cell infiltrate and mediators of inflammation, which might provide insight into the pathogenesis and possible future treatment of the disease. METHODS: Skin biopsies were taken from 23 patients with typical PPP (23 from involved skin and seven from noninvolved skin) and from 18 healthy controls (10 nonsmokers, eight smokers). Cell infiltrates and inflammation mediators were studied with immunohistochemistry. RESULTS: A strong inflammation was observed in lesional skin of PPP. Our main findings of Langerhans cells and interleukin-17 close to or in the acrosyringium differs from findings in psoriasis vulgaris. Other inflammatory cells such as CD4+, CD8+, regulatory T cells and CD11a+ cells were also accumulated close to the sweat duct in epidermis and papillary dermis. More CD4+, CD8+, Langerhans cells, plasmacytoid dendritic cells and a higher proportion of regulatory T cells/CD3+ cells were seen in noninvolved palmar skin from patients with PPP compared with healthy controls. CONCLUSIONS: Our novel findings indicate that the inflammation in PPP is initiated by the 'stand-by' innate immune system at the acrosyringium.

Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing.

BACKGROUND: Children exposed to tobacco smoke early in life have a higher risk of wheeze. Individual susceptibility may depend on genetic factors. OBJECTIVE: We studied whether variations in single nucleotide polymorphisms (SNPs) in the TNF, glutathione S transferase P1 (GSTP1) and beta2-adrenoreceptor (ADRB2) genes modify the effect of early maternal smoking on the development of childhood asthma, wheeze and allergic sensitization. METHODS: In the Swedish prospective birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) (n=4089), data collection included questionnaires to measure tobacco smoke exposure and clinical outcomes up to age 4 and medical examinations with blood sampling for specific IgE measurements and genotyping. We defined early maternal smoking as daily smoking by the mother during pregnancy and/or postnatally. We investigated five TNF, six GSTP1 and three ADRB2 SNPs in 982 selected wheezers and non-wheezers. RESULTS: An interaction with early maternal smoking was found for three TNF SNPs (-857C/T, Intron 1, Intron 3) with respect to early wheeze (up to 2 years of age). For example, the odds ratio (OR) for developing early wheeze related to early maternal smoking was 2.4 [95% confidence interval (CI) 1.6-3.7] in children with a wild-type CC homozygote genotype of the TNF-857 SNP, while no tobacco-related risk was seen in children carrying the rare T allele. A clear dose response was observed in children with the CC genotype, with an OR of 1.3 (95% CI 1.1-1.5) per each additional pack per week smoked by the mother during pregnancy. A suggestive interaction with early maternal smoking was also seen for three GSTP1 SNPs (Intron 5, Intron 6 and Ile105Val) with respect to transient wheeze, but not for ADRB2 and wheeze phenotypes. No effect modifications were observed for allergic sensitization. CONCLUSION: Our results suggest that the risk of early childhood wheeze associated with early maternal smoking may be modified by TNF and GSTP1 polymorphisms.

Fine specificity of the Ro/SSA autoantibody response in relation to serological and clinical findings in 96 patients with self-reported cutaneous symptoms induced by the sun.

Anti-Ro/SSA assays assist the clinician in distinguishing autoimmune diseases such as Sjögrens syndrome (SS), systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE). The objective of the study was to investigate the fine specificity of the autoantibodies in relation to clinical presentation as well as environmental and endogenous factors such as photosensitivity, smoking and immunoglobulin (Ig) levels in patients with Ro/SSA autoantibodies. Serum samples from 96 anti-Ro/SSA positive photosensitive patients were tested for autoantibody levels by enzyme-linked immunosorbent assay (ELISA) using purified recombinant Ro52 kd, Ro60 kd and La proteins as antigens. The highest levels of anti-Ro52 and anti-La were observed in patients with primary SS, and the lowest levels of anti-Ro52 in chronic cutaneous lupus erythematosus (CCLE). SCLE patients with systemic disease (SLE and/or SS) showed higher levels of anti-Ro52 than SCLE limited to the skin. A correlation between high serum levels of IgG and anti-Ro52 (P < 0.01) and between IgA and anti-Ro52 (P < 0.05) and anti-Ro60 (P < 0.05) was found. Polymorphic light eruption (PLE) was common in all diagnostic groups but did not correlate with autoantibody levels. Smoking was more common in lupus patients than in SS patients. Our findings thus propose different mechanisms for different clinical presentations of Ro/SSA positive patients. The testing of anti-Ro52 antibodies might serve as a prognostic tool in photosensitive cutaneous diseases.

Peptide conversion--a potential pathway modulating G-protein signaling.

Previous and current research has revealed that most neuropeptides induce their actions on cellular systems through specific receptors located on the cell surface. These receptors are known as G-protein coupled receptors, which exert their effects through interaction with ion channels or enzymes located within the cell membrane. Following receptor stimulation and exerting their effects the peptides are inactivated by enzymatic degradation. However, in many cases the active neuropeptides are enzymatically converted to products with retained bioactivity. These bioactive fragments may mimic but also counteract the action of the parent peptide. Thus, the released fragment may serve as a modulator of the response of the original compound. This phenomenon has been found to occur in a number of peptide systems, including the opioid peptides, tachykinins, as well as peptides belonging to the renin-angiotensin system, such as angiotensin II. In some cases the conversion product interacts with the same receptor as the native compound but sometimes it appears that the released fragment interacts with receptors or binding sites distinct from those of the original peptide. This review is focused on peptide fragments released from opioid related peptides, substance P and angiotensin II, that have been shown to modulate the action of their parent compounds.

Role of soluble and cell surface molecules in the pathogenesis of autoimmune skin diseases.

The skin is one of the most commonly involved tissue in rheumatic autoimmune diseases. Different mechanisms are thought to be implicated in the pathogenesis of skin lesions. In genetically predisposed individuals, ultraviolet (UV) light can contribute to the induction of skin lesions via an inflammatory process. UV light promotes the release of cytokines by keratinocytes and the induction of adhesion molecules on the surface of epidermal cells initiating a cascade of inflammatory events and recruiting immunoinflammatory cells into the skin. In this review data regarding the expression of TNF-alpha in lesional skin tissue from subacute cutaneous lupus erythematosus patients and the role of interferons in the pathogenesis of skin manifestations of rheumatic autoimmune diseases are reported. In addition, an overview on the expression of cellular adhesion molecules in these diseases is provided.UV light can also induce apoptosis in keratinocytes. During this cell death several enzymes became activated. Among them, desoxyribonuclease (DNase) is an enzyme involved in degrading DNA during apoptosis. Data regarding the activity of DNAse in patients with cutaneous lupus erythematosus as a possible risk factor for the development of systemic disease are here reported.

Synthesis and AT2 receptor-binding properties of angiotensin II analogues.

The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2-8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 microM). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.

The epidemiology of interstitial lung disease and its association with lung cancer.

The criteria and terminology for diagnosing interstitial lung disease (ILD), a diverse range of pulmonary fibrotic disorders that affect the alveoli of the lungs, have been variable and confusing; however, there have been recent major improvements to an internationally agreed classification. Evidence from recent analyses of populations suggests that the incidence and prevalence rates of ILD are on the increase, particularly when the broad definition of ILD is used. In most patients with ILD a cause is not identified; nevertheless, among the established causes are a number of drug therapies and infections. Occupational causes are lessening in importance, while cigarette smoking is now an established risk factor. Radiation therapy for cancer is a well-established cause of ILD that usually, but not always, localises within the radiation portal and may occur later after completion of therapy. Similarly, exposure to drugs long after radiation therapy may be an aetiological factor for the development of ILD later in life, although the magnitude of this risk requires further epidemiological investigation. The possibility that ILD and lung cancer are associated has been recognised for >50 years, but it remains unclear whether ILD precedes lung cancer or vice versa. In this review, we examine the epidemiology of ILD and the basis for its association with lung cancer.

The cumulative risk of lung cancer among current, ex- and never-smokers in European men.

Recent analyses based on UK data indicate that people who stop smoking, even well into middle age, avoid most of their subsequent risk of lung cancer. We investigated whether similar absolute risks of lung cancer in men are found in other European countries with different smoking patterns and at different stages of their lung cancer epidemic. Using data for men from a multicentre case-control study of lung cancer in the UK, Germany, Italy and Sweden, and including 6523 lung cancer cases and 9468 controls, we combined odds ratio estimates with estimates of national lung cancer incidence rates to calculate the cumulative risk of lung cancer among men by age 75. Lung cancer cumulative risks by age 75 among continuing smokers were similar for the UK, Germany and Italy at 15.7, 14.3 and 13.8% respectively, whereas the cumulative risk among Swedish male smokers was 6.6%. The proportion of the risk of lung cancer avoided by quitting smoking before the age of 40 was comparable between the four countries, at 80% in Italy and 91% in the UK, Germany and Sweden. Similarly, the proportion of the excess risk avoided by quitting before the age of 50 ranged from 57% in Italy to 69% in Germany. Our results support the important conclusion that for long-term smokers, giving up smoking in middle age avoids most of the subsequent risk of lung cancer, and that lung cancer mortality in European men over the next three decades will be determined by the extent to which current smokers can successfully quit smoking.

Environmental tobacco smoke and myocardial infarction among never-smokers in the Stockholm Heart Epidemiology Program (SHEEP).

An increased risk for myocardial infarction (MI) related to environmental tobacco smoke (ETS) exposure has previously been reported, but several aspects of the association are still uncertain. We studied the MI risk associated with ETS exposure among 334 nonfatal never-smoking MI cases and 677 population controls, 45-70 years of age, in Stockholm County. A postal questionnaire with a telephone follow-up provided information on ETS exposure and other potential risk factors for MI. After adjustment for age, gender, hospital catchment area, body mass index, socioeconomic status, job strain, hypertension, diet, and diabetes mellitus, the odds ratio for MI was 1.58 (95% confidence interval = 0.97-2.56) for an average daily exposure of 20 cigarettes or more from the spouse. Combined exposure from spouse and work showed an increasing odds ratio for MI, up to 1.55 (95% confidence interval = 1.02-2.34) in the highest category of weighted duration, that is, more than 90 "hour-years" of exposure (1 "hour-year" = 365 hours, or 1 hour per day for 1 year). In addition, more recent exposure appeared to convey a higher risk. Our data confirm an increased risk of MI from exposure to ETS and suggest that intensity of spousal exposure, combined exposure from spouse and work, and time since last exposure are important.

Using geographic information systems to assess individual historical exposure to air pollution from traffic and house heating in Stockholm.

A specific aim of a population-based case-control study of lung cancer in Stockholm, Sweden, was to use emission data, dispersion models, and geographic information systems (GIS) to assess historical exposure to several components of ambient air pollution. Data collected for 1,042 lung cancer cases and 2,364 population controls included information on residence from 1955 to the end of follow-up for each individual, 1990-1995. We assessed ambient air concentrations of pollutants from road traffic and heating throughout the study area for three points in time (1960, 1970, and 1980) using reconstructed emission data for the index pollutants nitrogen oxides (NO(x)/NO(2)) and sulfur dioxide together with dispersion modeling. NO(2) estimates for 1980 compared well with actual measurements, but no independently measured (study-external) data were available for SO(2), precluding similar validation. Subsequently, we used linear intra- and extrapolation to obtain estimates for all other years 1955-1990. Eleven thousand individual addresses were transformed into geographic coordinates through automatic and manual procedures, with an estimated error of < 100 m for 90% of the addresses. Finally, we linked annual air pollution estimates to annual residence coordinates, yielding long-term residential exposure indices for each individual. There was a wide range of individual long-term average exposure, with an 11-fold interindividual difference in NO(2) and an 18-fold difference in SO(2). The 30-year average for all study subjects was 20 microg/m(3) NO(2) from traffic and 53 microg/m(3) SO(2) from heating. The results indicate that GIS can be useful for exposure assessment in environmental epidemiology studies, provided that detailed geographically related exposure data are available for relevant time periods.