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Background: Prior studies suggest that physical activity lowers circulating C-reactive protein (CRP) levels. However, little is known about the association between regular active commuting, i.e. walking or cycling to work, and CRP concentrations. This study examines whether active commuting is associated with lower CRP., Methods: We conducted a cross-sectional study using population-based FINRISK data from 1997, 2002, 2007 and 2012. Participants were working adults living in Finland (n = 6208; mean age = 44 years; 53.6% women). We used linear and additive models adjusted for potential confounders to analyze whether daily active commuting, defined as the time spent walking or cycling to work, was associated with lower high-sensitivity (hs-) CRP serum concentrations compared with passive commuting., Results: We observed that daily active commuting for 45 min or more (vs. none) was associated with lower hs-CRP [% mean difference in the main model: -16.8%; 95% confidence interval (CI) -25.6% to -7.0%), and results were robust to adjustment for leisure-time and occupational physical activity, as well as diet. Similarly, active commuting for 15-29 min daily was associated with lower hs-CRP in the main model (-7.4; 95% CI -14.1 to -0.2), but the association attenuated to null after further adjustments. In subgroup analyses, associations were only observed for women., Conclusions: Active commuting for at least 45 min a day was associated with lower levels of low-grade inflammation. Promoting active modes of transport may lead not only to reduced emissions from motorized traffic but also to population-level health benefits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Purpose: Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609., Methods: We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness., Results: High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype., Main Conclusions: Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility., (© Endocrine Society 2020.)

Objective: We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes., Methods: We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP)., Results: The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO., Conclusions: Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA., (Copyright © 2019 Endocrine Society.)

Context: Early prediction of dysglycemia is crucial to prevent progression to type 2 diabetes. The 1-hour postload plasma glucose (PG) is reported to be a better predictor of dysglycemia than fasting plasma glucose (FPG), 2-hour PG, or glycated hemoglobin (HbA1c)., Objective: To evaluate the predictive performance of clinical markers, metabolites, HbA1c, and PG and serum insulin (INS) levels during a 75-g oral glucose tolerance test (OGTT)., Design and Setting: We measured PG and INS levels at 0, 30, 60, and 120 minutes during an OGTT in 543 participants in the Botnia Prospective Study, 146 of whom progressed to type 2 diabetes within a 10-year follow-up period. Using combinations of variables, we evaluated 1527 predictive models for progression to type 2 diabetes., Results: The 1-hour PG outperformed every individual marker except 30-minute PG or mannose, whose predictive performances were lower but not significantly worse. HbA1c was inferior to 1-hour PG according to DeLong test P value but not false discovery rate. Combining the metabolic markers with PG measurements and HbA1c significantly improved the predictive models, and mannose was found to be a robust metabolic marker., Conclusions: The 1-hour PG, alone or in combination with metabolic markers, is a robust predictor for determining the future risk of type 2 diabetes, outperforms the 2-hour PG, and is cheaper to measure than metabolites. Metabolites add to the predictive value of PG and HbA1c measurements. Shortening the standard 75-g OGTT to 1 hour improves its predictive value and clinical usability., (Copyright © 2019 Endocrine Society.)

Objective: Type 2 diabetes arises from the interaction of physiological and lifestyle risk factors. Our objective was to develop a model for predicting the risk of T2D, which could use various amounts of background information., Research Design and Methods: We trained a survival analysis model on 8483 people from three large Finnish and Spanish data sets, to predict the time until incident T2D. All studies included anthropometric data, fasting laboratory values, an oral glucose tolerance test (OGTT) and information on co-morbidities and lifestyle habits. The variables were grouped into three sets reflecting different degrees of information availability. Scenario 1 included background and anthropometric information; Scenario 2 added routine laboratory tests; Scenario 3 also added results from an OGTT. Predictive performance of these models was compared with FINDRISC and Framingham risk scores., Results: The three models predicted T2D risk with an average integrated area under the ROC curve equal to 0.83, 0.87 and 0.90, respectively, compared with 0.80 and 0.75 obtained using the FINDRISC and Framingham risk scores. The results were validated on two independent cohorts. Glucose values and particularly 2-h glucose during OGTT (2h-PG) had highest predictive value. Smoking, marital and professional status, waist circumference, blood pressure, age and gender were also predictive., Conclusions: Our models provide an estimation of patient's risk over time and outweigh FINDRISC and Framingham traditional scores for prediction of T2D risk. Of note, the models developed in Scenarios 1 and 2, only exploited variables easily available at general patient visits., (© 2018 European Society of Endocrinology.)

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined., Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP)., Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype., Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia., Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant., Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies., (Copyright © 2017 Endocrine Society)

The aim of the study was to assess occupational exposure to bisphenol A in Finland. Five companies took part in the research project: two paint factories (liquid and powder paints), a composite product factory, a thermal paper factory, and a tractor factory. Exposure was assessed by measuring total bisphenol A excretion (free and conjugated) from urine samples, and its concentrations in the air. The results revealed the specific work tasks in two of five companies in which significant occupational exposure to bisphenol A may occur. In the manufacturing of liquid paint hardener, urine samples collected after the working day showed bisphenol A levels of up to 100-170 µg l-1. Workers in thermal paper manufacturing were also exposed to bisphenol A, especially those working in the manufacture of coating material and operating coating machines. Median concentrations of the post-shift urine samples of coating machine workers were in the range of 130-250 µg l-1. The highest bisphenol A concentrations were in the range of 1000-1500 µg l-1. Recommendations for more effective personal protection resulted in decreased exposure, particularly among coating machine operators. In the rest of the companies, urinary bisphenol A levels were typically in the range of those of the general population. Bisphenol A concentrations in air samples were typically low (<40 µg m-3), except in some short-term duties related to the handling of solid bisphenol A (maximum 17.6 mg m-3). Low air levels, even in the companies with high urinary levels, suggest exposure via dermal contact. According to the results, exposure to bisphenol A may occur particularly in work tasks that involve the use of pure bisphenol A. In these tasks, special attention should be paid to the prevention of skin exposure. Inhalation exposure may become relevant in dusty work tasks. Since skin exposure is of potential concern in these tasks, biomonitoring is recommended as the method for assessing occupational exposure to bisphenol A., (© The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Objective: Sweetened beverage intake is associated with increased risk of type 2 diabetes, but its association with autoimmune diabetes is unclear. We aimed to investigate sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA); autoimmune diabetes with features of type 2 diabetes., Design/methods: Data from a Swedish population-based study was used, including incident cases of LADA (n = 357) and type 2 diabetes (n = 1136) and randomly selected controls (n = 1371). Diabetes classification was based on onset age (≥35), glutamic acid decarboxylase autoantibodies (GADA) and C-peptide. Sweetened beverage intake information was derived from a validated food frequency questionnaire. ORs adjusted for age, sex, family history of diabetes, education, lifestyle, diet, energy intake and BMI were estimated using logistic regression., Results: Daily intake of >2 servings of sweetened beverages (consumed by 6% of participants) was associated with increased risk of LADA (OR: 1.99, 95% CI: 1.11-3.56), and for each 200 mL daily serving, OR was 1.15 (95% CI: 1.02-1.29). Findings were similar for sugar-sweetened (OR: 1.18, 95% CI: 1.00-1.39) and artificially sweetened beverages (OR: 1.12, 95% CI: 0.95-1.32). Similarly, each daily serving increment in total sweetened beverage conferred 20% higher type 2 diabetes risk (95% CI: 1.07-1.34). In type 2 diabetes patients, high consumers displayed higher HOMA-IR levels (4.5 vs 3.5, P = 0.0002), but lower HOMA-B levels (55 vs 70, P = 0.0378) than non-consumers. Similar tendencies were seen in LADA., Conclusions: High intake of sweetened beverages was associated with increased risk of LADA. The observed relationship resembled that with type 2 diabetes, suggesting common pathways possibly involving insulin resistance., (© 2016 European Society of Endocrinology.)

Objective: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. Our aim was to investigate whether alcohol consumption is associated with the risk of latent autoimmune diabetes in adults (LADA), an autoimmune form of diabetes with features of type 2 diabetes., Design: A population-based case-control study was carried out to investigate the association of alcohol consumption and the risk of LADA., Methods: We used data from the ESTRID case-control study carried out between 2010 and 2013, including 250 incident cases of LADA (glutamic acid decarboxylase antibodies (GADAs) positive) and 764 cases of type 2 diabetes (GADA negative), and 1012 randomly selected controls aged ≥35. Logistic regression was used to estimate the odds ratios (ORs) of diabetes in relation to alcohol intake, adjusted for age, sex, BMI, family history of diabetes, smoking, and education., Results: Alcohol consumption was inversely associated with the risk of type 2 diabetes (OR 0.95, 95% CI 0.92-0.99 for every 5-g increment in daily intake). Similar results were observed for LADA, but stratification by median GADA levels revealed that the results only pertained to LADA with low GADA levels (OR 0.85, 95% CI 0.76-0.94/5 g alcohol per day), whereas no association was observed with LADA having high GADA levels (OR 1.00, 95% CI 0.94-1.06/5 g per day). Every 5-g increment of daily alcohol intake was associated with a 10% increase in GADA levels (P=0.0312), and a 10% reduction in homeostasis model assessment of insulin resistance (P=0.0418)., Conclusions: Our findings indicate that alcohol intake may reduce the risk of type 2 diabetes and type 2-like LADA, but has no beneficial effects on diabetes-related autoimmunity., (© 2014 The authors.)

To protect the health of those occupationally exposed to respirable crystalline silica, the main industries in European Union associated with exposure to respirable silica, agreed on appropriate measures for the improvement of working conditions through the application of good practices, as part of 'The Agreement on Workers Health Protection through the Good Handling and Use of Crystalline Silica and Products Containing it' (NEPSI agreement), signed in April 2006. The present paper examines trends in exposure to respirable crystalline silica in Finland prior to and following the implementation of the NEPSI agreement and includes a working example of the NEPSI approach in the concrete industry. Data derived from workplace exposure assessments during the years 1994-2013 are presented, including 2556 air samples collected mostly indoors, from either the breathing zone of workers or from stationary points usually at a height of 1.5 m above the floor, with the aim to estimate average exposure of workers to respiratory crystalline silica during an 8-h working day. The aim was, to find out how effective this unique approach has been in the management of one of the major occupational hazards in the concerned industries. Application of good practices as described by the NEPSI agreement coincides with a strong decline in the exposure to respirable crystalline silica in Finnish workplaces, as represented by the clientele of Finnish Institute of Occupational Health. During the years followed in the present study, we see a >10-fold decrease in the average and median exposures to respirable silica. Prior to the implementation of the NEPSI agreement, >50% of the workplace measurements yielded results above the OEL8 h (0.2mg m(-3)). As of present (2013), circa 10% of the measurements are above of or identical to the OEL8 h (0.05mg m(-3))., (© The Author 2014. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Objective: Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults., Design and Methods: Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years., Results: The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ AND PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3-2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2-2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0-1 vs 2-3 vs 4-6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up., Conclusions: In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA.

The importance of nanotechnologies and engineered nanoparticles has grown rapidly. It is therefore crucial to acquire up-to-date knowledge of the possible harmful health effects of these materials. Since a multitude of different types of nanosized titanium dioxide (TiO(2)) particles are used in industry, we explored their inflammatory potential using mouse and cell models. BALB/c mice were exposed by inhalation for 2 h, 2 h on 4 consecutive days, or 2 h on 4 consecutive days for 4 weeks to several commercial TiO(2) nanoparticles, SiO(2) nanoparticles, and to nanosized TiO(2) generated in a gas-to-particle conversion process at 10 mg/m(3). In addition, effects of in vitro exposure of human macrophages and fibroblasts (MRC-9) to the different particles were assessed. SiO(2)-coated rutile TiO(2) nanoparticles (cnTiO(2)) was the only sample tested that elicited clear-cut pulmonary neutrophilia. Uncoated rutile and anatase as well as nanosized SiO(2) did not induce significant inflammation. Pulmonary neutrophilia was accompanied by increased expression of tumor necrosis factor-alpha (TNF-alpha) and neutrophil-attracting chemokine CXCL1 in the lung tissue. TiO(2) particles accumulated almost exclusively in the alveolar macrophages. In vitro exposure of murine and human macrophages to cnTiO(2) elicited significant induction of TNF-alpha and neutrophil-attracting chemokines. Stimulation of human fibroblasts with cnTiO(2)-activated macrophage supernatant induced high expression of neutrophil-attracting chemokines, CXCL1 and CXCL8. Interestingly, the level of lung inflammation could not be explained by the surface area of the particles, their primary or agglomerate particle size, or radical formation capacity but is rather explained by the surface coating. Our findings emphasize that it is vitally important to take into account in the risk assessment that alterations of nanoparticles, e.g., by surface coating, may drastically change their toxicological potential.

Water-miscible metalworking fluids (MWFs) are capable of causing respiratory symptoms and diseases. Recently, much emphasis has been put on developing new methods for assessing respiratory exposure to MWF emulsions. The air concentrations of ingredients and contaminants of MWF and inhalable dust were measured in 10 metal workshops in southern Finland. Oil mist was determined by infra red spectroscopy analysis after tetrachloroethylene extraction from the filter. Aldehydes were collected on Sep-Pak chemosorbents and analysed by liquid chromatography. Volatile organic compounds (VOCs) were collected on Tenax adsorbents and analysed by gas chromatography with mass spectrometric detection after thermal desorption. Endotoxins were collected on glass fibre filter and analysed by enzyme-based spectrophotometry, and viable microbes were collected on polycarbonate filter and cultured. Inhalable dust was collected on cellulose acetate filter and quantified gravimetrically. Associations between the different exposures were calculated with Spearman's correlations. The mean concentration of oil mist was 0.14 (range <0.010-0.60) mg m(-3). The mean total concentration of aldehydes was 0.095 (0.026-0.38) mg m(-3), with formaldehyde as the main aldehyde. The average total concentration of VOC was 1.9 (0.34-4.5) mg m(-3) consisting mainly of high-boiling aliphatic hydrocarbons. Several potential sensitizing chemicals such as terpenes were found in small quantities. The concentration of microbial contaminants was low. All the measured air concentrations were below the Finnish occupational exposure limits. The exposure in machine shops was quantitatively dominated by volatile compounds. Additional measurements of MWF components such as aldehydes, alkanolamines and VOCs are needed to get more information on the chemical composition of workshops' air. New air cleaning methods should be introduced, as oil mist separators are insufficient to clean the air of small molecular impurities.

Aim: To investigate the incidences and trends of occupational skin diseases (OSDs) and allergic respiratory diseases (ARDs) in machinists working in the fabrication of metal products., Methods: Data from the Finnish Register of Occupational Diseases during 1992-2001 were analysed. Incidence rates for skin and respiratory diseases of machinists were calculated and compared to the total working population. The patients investigated at the Finnish Institute of Occupational Health in the same period were described in detail., Results: A total of 279 dermatoses and 34 ARDs were reported. Skin diseases accounted for 27% of all occupational diseases. The incidences of the skin and respiratory diseases were 1.6 and 0.2 cases per 1000 person-years, respectively. This represents a 3-fold risk for getting an OSD compared to the total working population. The number of allergic contact dermatitis (ACD) increased 3-fold during the study period. The most common causes of ACD were metalworking fluids (MWFs) and their ingredients such as formaldehyde, ethanolamines and colophony. Eighty-five per cent of ARDs were asthmas. The commonest causes of asthma were metal dusts and fumes, epoxy resins and hardeners and MWFs and their components., Conclusions: Contact dermatitis is a common occupational health problem in metalworking machinists, whereas occupational respiratory disease is rare. Only a few specific chemicals in the metalworking have thus far been identified as respiratory allergens. Specific skin tests and inhalation challenge tests with MWFs and their ingredients are recommended if an OSD or a respiratory disease is suspected.

Overall exposure to alkanolamines in metal-working fluids (MWFs) in machine shops was studied by determining alkanolamines in air samples and in rinse-off samples from the hands of machinists. Methods for collecting airborne alkanolamines and alkanolamines absorbed to the skin of the hands were developed and tested. The exposure measurements were carried out in nine machine shops. After a 2 h working period the dominant hand of 37 machinists was rinsed with 200 ml of 20% isopropanol for 1 min in a plastic bag. Personal air samples were also collected during the 2 h working period onto acid-treated glass fibre filters. The filter samples were desorbed with methanol and analysed by liquid chromatography with mass spectrometric detection (LC-MS). The rinse-off samples were also analysed for alkanolamines by LC-MS. The median air concentration of monoethanolamine (EA) was 57 microg m-3, diethanolamine (DEA) 64 microg m-3 and triethanolamine (TEA) 6 microg m-3. The workers' overall exposure to alkanolamines was estimated by calculating the amount in inhaled air and the amount on the skin. The median amount of EA on the skin of the dominant hand was 9-43 times the median amount in inhaled air during 2 h exposure. The corresponding ratio for DEA was 100 and for TEA 170. According to this study the exposure to alkanolamines occurs mainly through the skin. EA was the only alkanolamine with a noticeable inhalation uptake compared to the skin uptake. Total exposure to MWFs may be reduced by reducing skin exposure. The hand rinsing method can be used to assess the efficiency of protective gloves.

Objectives: The Finnish Tobacco Act was amended on 1 March 2000 to include restrictions on smoking in restaurants and bars. To evaluate the effectiveness of the restrictions, environmental tobacco smoke (ETS) concentrations in restaurants and bars were measured prior and after the amended Act entered into force. The Act was enforced in stages so that all stages were effective on 1 July 2003. According to the Act, smoking is prohibited in all Finnish restaurants and bars with certain exceptions. Smoking may be allowed in establishments where the service area is not larger than 50 m(2) if the exposure of employees working there to ETS can be prevented. On premises with larger service area, smoking may be allowed on 50% of the service area, provided tobacco smoke does not spread into the area where smoking is prohibited. At bar counters or gambling tables smoking is not allowed, if the spreading of tobacco smoke cannot be restricted to the employee side of the counter. Therefore, according to the Act all areas where smoking is prohibited are to be smoke-free., Methods: Establishments with a serving area larger than 100 m(2) were selected for the present study. The evaluation both before and after the enforcement of the Act included the following: The ventilation rate was first measured in each establishment. Then 3-5 area samplers, depending on the layout, were placed in locations that best described the establishment and the working areas of the personnel. The measurements were performed twice at each establishment, during peak hours. The sample collection time was 4 h during which the guests and the cigarettes smoked were counted. The air samples were analysed for nicotine, 3-ethenylpyridine (3-EP) and total volatile organic compounds (TVOC) by thermodesorption-gas chromatography-mass spectrometry., Results: Altogether 20 restaurants and bars situated in three Finnish cities participated in the study out of which 16 participated during all four measurement periods. None of the establishments had introduced a total ban on smoking and they all had reserved only the smallest area allowed by the Finnish Tobacco Act as the smoke-free area. The measured geometric mean (GM) nicotine concentration in all participating establishments was 7.1 microg m(-3) before the amended act was in force and 7.3 microg m(-3) after all stages of the Act had been enforced. The GM concentration of nicotine in food and dining restaurants was 0.7 microg m(-3) before and 0.6 microg m(-3) after the enforcement of the Act, in bars and taverns the concentrations were 10.6 and 12.7 microg m(-3), and in discos and night-clubs 15.2 and 8.1 microg m(-3), respectively. The GM nicotine concentrations measured in the smoke-free sections varied between 2.9 and 3 microg m(-3). 3-EP concentrations measured correlated well with the nicotine concentrations and were approximately one-fifth of the nicotine concentrations. The measurements showed higher TVOC values in the smoking sections than in the smoke-free sections, but because there are many other sources of TVOC compounds in restaurants and bars TVOC cannot be regarded as a marker for ETS., Conclusions: The overall air nicotine concentration decreased in 10 out of the 18 establishments that participated in the study both before and after all stages of the amended Act had been in force. Structural changes or changes to the ventilation systems had been carried out in nine of these establishments, i.e. the smoke-free sections were actually non-smoking and were mainly separated from other sections by signs and very little was done to keep the smoke from spreading into the smoke-free sections. In four establishments, the highest air nicotine concentration was measured in the smoke-free section. In 10 establishments, the air nicotine concentration at bar counters had dropped after the Act. Exposure of the workers and the public to ETS was, therefore, not reduced as intended by the Finnish legislature. Thus, it seems obvious from the present study that improving ventilation will not be a solution to restricting tobacco smoke from reaching smoke-free areas and physical barriers separating smoking from smoke-free areas are required.

A case of acute permanent anosmia is described in a renovation worker during exposure to a waterproof coating chemical. The chemical consisted of several substances of which four (acetone, acrylates, butyl acetate and carbon disulfide) has been previously reported to induce hyposmia or anosmia in workers. Other aetiologies were clinically excluded but a large arachnoidea cyst in the frontal part of the left temporobasal fossa with possible compression of the left entorhinal cortex. The toxic aetiology of anosmia is supported by the acute onset and the temporal relationship with occupational exposure. The silent cyst as the cause of anosmia is improbable, but it may have had some contributory role. Our case illustrates both the challenges when clinically examining patients with work-related olfactory impairment and the importance of multi-disciplinary approach to such patients.

The prevalence of autoantibodies against nine intracellular enzyme autoantigens, namely 21-hydroxylase, side-chain cleavage enzyme (SCC), 17 alpha-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphatase-like protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, cytochrome P450 1A2, and against the extracellular calcium-sensing receptor, was assessed in 90 patients with autoimmune polyendocrine syndrome type I. A multivariate logistic regression analysis was performed for the presence of autoantibodies as independent predictors for different disease manifestations. Reactivities against 21-hydroxylase and SCC were associated with Addison's disease with odds ratios (ORs) of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against SCC with an OR of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with insulin-dependent diabetes mellitus with an OR of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, glutamic acid decarboxylase 65, were associated with intestinal dysfunction, with ORs of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an OR of 27.0. Hypoparathyroidism was not associated with reactivity against any of the autoantigens tested. No reactivity against the calcium-sensing receptor was found. Analysis of autoantibodies in autoimmune polyendocrine syndrome type I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease.

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF alpha gene could be such a modifying gene, we studied TNF alpha promoter polymorphisms (G-->A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF alpha(308) AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF alpha(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF alpha is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF alpha(308) polymorphism and the phenotype of common type 2 diabetes.

To study whether antibodies to glutamic acid decarboxylase (GADab) are associated with subclinical beta-cell damage and impaired insulin secretion, we screened 441 nondiabetic patients with autoimmune thyroiditis (AT) for GADab, and 15 (3.4%) were found positive. Antibodies to IA-2 were found in two GADab+ and one GADab- patients. We matched 11 GADab+ and 13 GADab- AT patients who were euthyroid on thyroxin supplementation, and 13 control subjects for sex, age, and body mass index and measured insulin, C-peptide, and glucagon response to glucose and arginine at three blood glucose concentrations (fasting, 14 mmol/liter, >25 mmol/liter). In the fasting state, all groups had similar blood glucose concentration and HbA1c level, but the serum insulin concentration was higher in the AT patients compared with the control subjects (P < 0.04). The acute insulin response to arginine was lower in GADab+ than in GADab- thyroiditis subjects at glucose concentration of 14 and >25 mmol/liter (AIR(14): 76.8 +/- 52.0 vs. 158.2 +/- 118.2 mU/liter, P = 0.040; AIR(>25): 84.3 +/- 64.4 vs. 167.9 +/- 101.5 mU/liter, P = 0.035). In conclusion, GADab were associated with a decreased insulin secretion capacity in nondiabetic subjects with thyroiditis, which suggests that GADab positivity could be a marker of subclinical insulitis.

We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab. We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.

Antibodies to glutamic acid decarboxylase (GAD) occur frequently in patients with APECED, although clinical insulin-dependent diabetes mellitus (IDDM) is seen only in a subgroup of the patients. We studied the cellular immunity to GAD, antibodies to GAD and their association with the HLA DQB1 risk alleles for IDDM in patients with APECED. Proliferation responses to GAD were enhanced in the patients with APECED when compared with the control subjects (P = 0.004), but autoimmunity to GAD was not associated with IDDM in APECED. The levels of interferon-gamma (IFN-gamma) secreted by GAD-stimulated T cells were higher in the patients than in control subjects (P = 0. 001). A negative correlation (r = - 0.436, P = 0.03) existed between the antibody levels and the stimulation indices (SIs) to GAD. In 14 non-diabetic patients no difference in insulin secretion was observed in intravenous glucose tolerance test (IVGTT) between the patients with and without T cell reactivity to GAD. We conclude that cellular immunity to GAD detected as T cell proliferation response to GAD or IFN-gamma secretion by GAD-stimulated T cells was frequent in patients with APECED (69%) and was not restricted to the patients with clinically detectable beta-cell damage.

To metabolically characterize patients with slowly progressing autoimmune diabetes (LADA) of short duration we measured insulin, C peptide, and glucagon responses to glucose and arginine at three blood glucose levels (fasting and 14 and 28 mmol/L) in 11 patients with LADA, 11 patients with type 2 diabetes, and 14 healthy control subjects matched for age and body mass index. The acute insulin response to arginine was impaired in LADA vs. type 2 diabetes at all glucose levels, with the greatest impairment in the maximally stimulated insulin concentrations (P<0.04). In contrast, beta-cell sensitivity to glucose was unaltered in LADA and type 2 diabetes. The glucagon concentrations were elevated in both LADA and type 2 diabetic patients compared with healthy control subjects (P<0.02), but did not differ between the diabetic groups. In conclusion, patients with LADA share insulin resistance with type 2 diabetic patients, but display a more severe defect in maximally stimulated beta-cell capacity than patients with type 2 diabetes.

Background: A method is described for the simultaneous analysis of nicotine and two of its major metabolites, cotinine and 3-hydroxycotinine, as well as for caffeine from urine samples. The method was developed to assess exposure of restaurant and hotel workers to environmental tobacco smoke., Methods: The method includes sample pretreatment and reversed-phase HPLC separation with tandem mass spectrometric identification and quantification using electrospray ionization on a quadrupole ion trap mass analyzer. Sample pretreatment followed standard protocols, including addition of base before liquid-liquid partitioning against dichloromethane on a solid matrix, evaporation of the organic solvent using gaseous nitrogen, and transferring to HPLC vials using HPLC buffer. HPLC separation was run on-line with the electrospray ionization-tandem mass spectrometric detection., Results: The detection limits of the procedure were in the 1 microg/L range, except for nicotine (10 microg/L of urine). Still lower detection limits can be achieved with larger sample volumes. Recoveries of the sample treatment varied from 99% (cotinine) to 78% (3-hydroxycotinine)., Conclusions: The method described is straightforward and not labor-intensive and, therefore, permits a high throughput of samples with excellent prospects for automation. The applicability of the method was demonstrated in a small-scale study on restaurant employees.

The satiety factor leptin is expressed in several reproductive tissues, but its role in the control of reproductive physiology is not well understood. We studied leptin concentrations in the sera and follicle fluids of 52 women [body fat mass percentage (BFM%) range, 19.6-38.8%] undergoing pituitary down-regulation and ovarian hyperstimulation for in vitro fertilization (IVF) treatment. Fasting serum samples were collected 1) at maximal suppression before the initiation of gonadotropin treatment, 2) at maximal ovarian hyperstimulation, 3) at the time of oocyte retrieval, and 4) 16 days later when all subjects were under exogenous luteal support using 600 mg progesterone daily. Follicular fluid (FF) was obtained at oocyte retrieval from two representative preovulatory follicles in both ovaries. During ovarian hyperstimulation there was a significant 60% increase in serum leptin concentrations from 10.9 +/- 1.1 (SEM) to 15.7 +/- 1.5 ng/mL (P < 0.01) between suppression and maximal hyperstimulation, demonstrating that the ovarian functional state can affect serum leptin concentrations. A serum leptin increase of 22-198% during ovarian hyperstimulation was evident in 43 subjects, whereas in 9, leptin concentrations remained unchanged. A positive correlation between leptin change and BFM% (r = 0.55; P < 0.0005) was observed in the 43 leptin responders. The follicular fluid leptin level was similar to that in serum. In separate linear regression analysis, BFM% contributed to 59-64%, body mass index to 46-56%, and weight to 46-55% (all P < 0.001) of the variability in leptin concentrations at the 4 time points. The 20-fold increase in serum estradiol concentrations during IVF was not significantly correlated with changes in leptin concentrations. On the contrary, the relative serum leptin increase was negatively associated with the ovarian response to hyperstimulation, as revealed by the numbers of follicles (b = -0.28; r2 = 8.1%; P < 0.05) and oocytes retrieved (b = -0.39; r2 = 15.2%; P < 0.01). This relationship was further reflected in a positive correlation between the percent increases in leptin and FSH concentrations (r = 0.39; P < 0.01). The significant relationship of high leptin and reduced ovarian response was also maintained when the cumulative dose of FSH was used as a covariable. Reduced ovarian response was not a function of body mass index, BFM%, basal leptin levels, or insulin concentrations. Fasting serum insulin concentrations remained unchanged in response to IVF, but were positively correlated to serum leptin concentrations at all four time points. Our data suggest that leptin production may be influenced by the ovarian functional state. During IVF a high relative leptin increase is associated with adiposity and a reduced ovarian response. These observations support the possibility that high leptin concentrations might reduce ovarian responsiveness to gonadotropins. Hence, leptin might explain in part why obese individuals require higher amounts of gonadotropins than lean subjects to achieve ovarian hyperstimulation.

Patients with autoimmune polyendocrine syndrome type I (APS I) have autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic beta-cells. The aim of the present study was to investigate the presence of anti-AADC antibodies in a large cohort of patients with APS I, and in patients with isolated insulin-dependent diabetes mellitus (IDDM). We found autoantibodies against AADC in 35 of 69 patients (51%) with APS I but in none of 138 patients with isolated IDDM or 91 healthy controls. Among the patients with APS I, anti-AADC antibodies were more often found in those with hepatitis (11/12, 92%), than in those without hepatitis (24/57, 42%) (P = 0.003). Similarly, of 15 patients with vitiligo, 12 (80%) had anti-AADC antibodies, compared with 23/54 (43%) without vitiligo (P = 0.021). Of the 9 APS I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Interestingly, AADC is present in relatively large amounts in the liver, where its function is unknown. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in APS I patients, whereas the role of AADC in the development of IDDM in these patients remains to be determined.

Glutamic acid decarboxylase (GAD) is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). This was initially identified as a 64-65 kD molecule according to migration in gels after immunoprecipitation from pancreatic islets. We studied the antigenicity of two different radiolabelled preparations of GAD, derived either by affinity purification from porcine brain and known to contain GAD 65 and GAD 67, or by expression from a cDNA for human GAD 65 by rabbit reticulocyte lysate (RRL). Radiolabelled immunoprecipitated pellets from the reaction of potent antisera to GAD from patients with IDDM were examined by autoradiography after SDS-PAGE under reducing or non-reducing conditions. Also, preparations of porcine brain GAD were "depleted' of GAD by exposure to antisera, and then similarly re-examined. Autoradiography of radiolabelled GAD either affinity purified from porcine brain, or expressed by RRL, showed that the immunoprecipitated protein migrated under non-reducing conditions according to a M(r) of approximately 110-130 kD, corresponding to dimeric forms of monomeric GAD of approximately 55-65 kD. Depletion by immunoprecipitation of this minor higher M(r) component from preparations of GAD left, in the supernatant, an abundance of GAD of M(r) 64-65 kD corresponding to monomer that was completely non-reactive with potent IDDM sera. We conclude that IDDM sera react with the GAD molecule in a dimeric (or oligomeric) form. Our findings have general connotations for self-tolerance and autoimmunity.

To evaluate the association of autoimmunity to glutamic acid decarboxylase (GAD) with insulin-dependent diabetes mellitus (IDDM) and IDDM-associated human leukocyte antigen (HLA) types, we studied a unique group of 47 patients with autoimmune polyendocrine syndrome type 1, a recessive disease not associated with HLA. GAD65 antibodies (GAD65-Ab), GAD67-Ab, islet cell antibodies, and HLA-DQA1, -DQB1, and -DRB1 were analyzed in relation to IDDM or a decreased insulin secretory capacity. GAD65-Ab were found in six of the eight diabetic patients 0.9-8.0 yr before the onset of IDDM and in 16 (41%) nondiabetic patients during a follow-up of 2.4-19.5 yr. Eleven (28%) nondiabetic patients had GAD67-Ab and islet cell antibodies. Fasting C peptide (mean +/- SD, 0.5 +/- 0.24 vs. 1.03 +/- 0.49 nmol/L; P = 0.003) and first phase insulin response (75.6 +/- 37.9 vs. 166.4 +/- 112.7 mU/L; P = 0.019) were lower in patients with than in those without GAD65-Ab. No HLA genotype predominated in the IDDM patients or GAD65-Ab-positive nondiabetic patients, but the IDDM high risk genotypes were decreased in frequency among the patients with GAD65-Ab. In conclusion, nondiabetic autoimmune polyendocrine syndrome type 1 patients frequently have GAD65-Ab together with a decreased insulin secretory capacity, suggesting subclinical islet cell inflammation not invariably progressing to diabetes. This is not associated with HLA haplotypes conferring susceptibility to or protection from IDDM.

Previous studies of patients with rheumatoid arthritis (RA) have shown a good correlation between results from immunoturbidimetric assays of rheumatoid factor (RF) and latex fixation tests. To extend the research to non-RA subjects, we tested sera from 1000 pregnant women, half each in the first and third trimesters. By turbidimetry, 24 non-RA sera were regarded as positive for RF (greater than or equal to 20 int. units/mL) and 18 sera as borderline (15-19 int. units/mL). By the latex fixation test, 28 non-RA sera gave a clear reaction (positive) and 17 sera a weak reaction (borderline). The association between the tests was statistically highly significant (P less than 0.001). All sera with positive and borderline reactions were tested by enzyme-linked immunosorbent assay for RF isotypes, together with a random subsample of about one-sixth of the original serum samples. Positive RF results by immunoturbidimetry were predominantly due to the presence of IgM-RF. In contrast to some earlier findings, we saw no difference in the prevalence of positive RF reactions between sera from the first and third trimesters.

In the search for differences between rheumatoid factors (RF) in patients with rheumatoid arthritis (RA) and in non-rheumatoid subjects, the reactivity of IgM- and IgA-class RF with rabbit IgG (rIgG) and Fc fragments of rabbit and human IgG (rFc, hFc) was studied by enzyme immunoassay. From a community-based cohort (n = 7124) representing the adult population of Finland, RA patients (n = 130), other subjects positive in the Waaler-Rose (WaRo, sensitized sheep cell agglutination) test (n = 137), and controls matched for age, sex and living area were selected for further study. In RA sera there was a good correlation between the results in the WaRo test and in the IgM-RF ELISA (rIgG, rFc and hFc). A considerable number of 'false positive' sera, though positive in the WaRo test and the rIgG-ELISA, were negative in the rFc-ELISA. Twenty-two per cent of the false positive sera reacted with either hFc or rFc, both types being equally common. IgA-RF reacted more frequently with hFc than with rFc in both the RA and the 'false positive' sera. In some sera, IgM- and IgA-RFs reacted differently with human and rabbit Fc, e.g. IgM-RF reacted only with human Fc, and IgA-RF reacted with both hFc and rFc, thus suggesting different regulation of their formation.