21-hydroxylase autoantibodies are more prevalent in Turner syndrome but without an association to the autoimmune polyendocrine syndrome type I.

Turner syndrome (TS) is associated with an increased frequency of autoimmunity. Frequently observed autoimmune diseases in TS are also seen in the autoimmune polyendocrine syndrome type I (APS I), of which Addison disease is a key component. An overlapping antibody profile between TS and APS I could be considered. The aim of this work was to study women with TS regarding 21-hydroxylase (21-OH) antibodies and interferon omega (IFN-ω) antibodies, a highly specific marker for APS I, to determine if there are immunological overlaps between TS and APS I. Blood samples from 141 TS were assayed for 21-OH antibodies and IFN-ω antibodies using in-vitro-transcribed and translated autoantigen. Indices with a cut-off point of 57 and 200 for 21-OH antibody and IFN-ω antibody were used as reference. The median age of TS was 31·6 years (range = 11·2-62·2). Positive indices of 21-OH antibodies were present in six TS (4%), with a mean of 144·8 (range = 60-535). None had apparent adrenal insufficiency. There was no age difference comparing 21-OH antibody-positive TS (median age = 33·9 years, range = 17·7-44·7) and 21-OH antibody-negative TS (median age = 31·6 years, range = 11·2-62·2) (P = 0·8). No TS was positive for IFN-ω antibodies (mean = 42·4, range = -435-191). No overlapping autoimmune profile between TS and APS I was found. Autoimmunity against 21-OH among TS patients was more prevalent than previously identified, suggesting an increased risk of adrenal failure in TS. However, whether adrenal impairment will develop remains unknown.

Particulate matter air pollution components and risk for lung cancer.

BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow-up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important.

Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood.

PURPOSE: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. METHODS: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. RESULTS: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. CONCLUSION: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.

Consumption of lead-shot cervid meat and blood lead concentrations in a group of adult Norwegians.

Several recent investigations have reported high concentrations of lead in samples of minced cervid meat. This paper describes findings from a Norwegian study performed in 2012 among 147 adults with a wide range of cervid game consumption. The main aim was to assess whether high consumption of lead-shot cervid meat is associated with increased concentration of lead in blood. A second aim was to investigate to what extent factors apart from game consumption explain observed variability in blood lead levels. Median (5 and 95 percentile) blood concentration of lead was 16.6 µg/L (7.5 and 39 µg/L). An optimal multivariate linear regression model for log-transformed blood lead indicated that cervid game meat consumption once a month or more was associated with approximately 31% increase in blood lead concentrations. The increase seemed to be mostly associated with consumption of minced cervid meat, particularly purchased minced meat. However, many participants with high and long-lasting game meat intake had low blood lead concentrations. Cervid meat together with number of bullet shots per year, years with game consumption, self-assembly of bullets, wine consumption and smoking jointly accounted for approximately 25% of the variation in blood lead concentrations, while age and sex accounted for 27% of the variance. Blood lead concentrations increased approximately 18% per decade of age, and men had on average 30% higher blood lead concentrations than women. Hunters who assembled their own ammunition had 52% higher blood lead concentrations than persons not making ammunition. In conjunction with minced cervid meat, wine intake was significantly associated with increased blood lead. Our results indicate that hunting practices such as use of lead-based ammunition, self-assembling of lead containing bullets and inclusion of lead-contaminated meat for mincing to a large extent determine the exposure to lead from cervid game consumption.

Measuring autoantibodies against IL-17F and IL-22 in autoimmune polyendocrine syndrome type I by radioligand binding assay using fusion proteins.

Autoantibodies against interleukin (IL)-17A, IL-17F and IL-22 have recently been described in patients with autoimmune polyendocrine syndrome type I (APS I), and their presence is reported to be highly correlated with chronic mucocutaneous candidiasis (CMC). The aim of this study was to develop a robust high-throughput radioligand binding assays (RLBA) measuring IL-17F and IL-22 antibodies, to compare them with current enzyme-linked immunosorbent assays (ELISA) of IL-17F and IL-22 and, moreover, to correlate the presence of these antibodies with the presence of CMC. Interleukins are small molecules, which makes them difficult to express in vitro. To overcome this problem, they were fused as dimers, which proved to increase the efficiency of expression. A total of five RLBAs were developed based on IL-17F and IL-22 monomers and homo- or heterodimers. Analysing the presence of these autoantibodies in 25 Norwegian APS I patients revealed that the different RLBAs detected anti-IL-17F and anti-IL-22 with high specificity, using both homo- and heterodimers. The RLBAs based on dimer proteins are highly reproducible with low inter- and intravariation and have the advantages of high throughput and easy standardization compared to ELISA, thus proving excellent choices for the screening of IL-17F and IL-22 autoantibodies.

Flow cytometry study of blood cell subtypes reflects autoimmune and inflammatory processes in autoimmune polyendocrine syndrome type I.

Autoimmune polyendocrine syndrome type I (APS I) is a recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed in medullary epithelial cells where it activates transcription of organ-specific proteins in thymus, thereby regulating autoimmunity. Patients with APS I have, in addition to autoimmune manifestations in endocrine organs, also often ectodermal dystrophies and chronic mucocutaneous candidiasis. The aim of this study was to characterize immune cell subpopulations in patients with APS I and their close relatives. Extensive blood mononuclear cell immunophenotyping was carried out on 19 patients with APS I, 18 first grade relatives and corresponding sex- and age-matched healthy controls using flow cytometry. We found a significant relative reduction in T helper cells coexpressing CCR6 and CXCR3 in patients with APS I compared to controls (mean = 4.10% versus 5.94% respectively, P = 0.035). The pools of CD16(+) monocytes and regulatory T cells (Tregs) were also lower in patients compared with healthy individuals (mean = 15.75% versus 26.78%, P = 0.028 and mean = 4.12% versus 6.73%, P = 0.029, respectively). This is the first report describing reduced numbers of CCR6(+)CXCR3(+) T helper cells and CD16(+) monocytes in patients with APS I We further confirm previous findings of reduced numbers of Tregs in these patients.

AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I.

Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

Residential outdoor air pollution and allergen sensitization in schoolchildren in Oslo, Norway.

BACKGROUND: Epidemiological studies that have investigated the association between air pollution and atopy have found inconsistent results. Furthermore, often exposure to outdoor air pollution has had limited quality, and more individual exposure is needed. OBJECTIVE: To investigate the relations between early and lifetime exposure to residential outdoor air pollution and allergen sensitization in 9-10-year-old children in Oslo, Norway. METHODS: Sensitization to common allergens was measured by skin prick tests (SPTs), which were performed in 2244 children who had lived in Oslo since birth. Several definitions of positive SPT were used. Information on potential confounding variables was collected by a parental questionnaire. Exposure to outdoor air pollution was assessed by the EPISODE dispersion model, which calculates hourly concentrations of nitrogen dioxide (NO2), particulate matter (PM) with aerodynamic diameter <10 microm (PM10) and <2.5 microm (PM2.5), respectively. RESULTS: We found no associations between long-term air pollution exposure and sensitization to any allergen, any indoor or any pollen allergen. However, lifetime air pollution exposure was associated with sensitization to the house dust mite Dermatophagoides farinae. One interquartile increase of lifetime exposure to NO2, PM10 and PM2.5 was associated with 1.88 (adjusted odds ratio) (1.02, 3.47) [95% confidence interval (CI)], 1.61 (0.96, 2.72) and 1.46 (0.96, 2.22), respectively, for D. farinae. Lifetime exposure was also associated with sensitization to cat in a subpopulation. Both associations diminished after adjusting for a contextual socio-economic factor. CONCLUSION: Long-term exposure to traffic-related pollutants was generally not associated with allergen sensitization in 9-10-year-old Oslo children. However, lifetime exposure was associated with sensitization to D. farinae, and with sensitization to cat in a subpopulation, which may be explained by socio-economic confounding or multiple comparisons. The air pollution levels in Oslo may be too low to reveal associations with sensitization.

Lung cancer and air pollution: a 27 year follow up of 16 209 Norwegian men.

BACKGROUND: The well documented urban/rural difference in lung cancer incidence and the detection of known carcinogens in the atmosphere have produced the hypothesis that long term air pollution may have an effect on lung cancer. The association between incidence of lung cancer and long term air pollution exposure was investigated in a cohort of Oslo men followed from 1972/73 to 1998. METHODS: Data from a follow up study on cardiovascular risk factors among 16 209 40 to 49 year old Oslo men in 1972/73 were linked to data from the Norwegian cancer register, the Norwegian death register, and estimates of average yearly air pollution levels at the participants' home address in 1974 to 1998. Survival analyses, including Cox proportional hazards regression, were used to estimate associations between exposure and the incidence of lung cancer. RESULTS: During the follow up period, 418 men developed lung cancer. Controlling for age, smoking habits, and length of education, the adjusted risk ratio for developing lung cancer was 1.08 (95% confidence interval, 1.02 to 1.15) for a 10 micro g/m(3) increase in average home address nitrogen oxide (NO(x)) exposure between 1974 and 1978. Corresponding figures for a 10 micro g/m(3) increase in sulphur dioxide (SO(2)) were 1.01 (0.94 to 1.08). CONCLUSIONS: Urban air pollution may increase the risk of developing lung cancer.

Safety of the transpulmonary ultrasound contrast agent NC100100: a clinical and haemodynamic evaluation in patients with suspected or proved coronary artery disease.

OBJECTIVE: To evaluate the clinical and haemodynamic safety of NC100100, a new transpulmonary ultrasound contrast agent intended for vascular use. DESIGN: Pulmonary artery pressures and gas exchange, left ventricular and systemic blood pressure and ECG were measured at baseline, after saline injection, and after each of two increasing doses of NC100100 injected intravenously. PATIENTS: 30 patients who were evaluated for suspected coronary artery disease. RESULTS: No change was detected in any of the haemodynamic variables, or in haematological or clinical chemical parameters. Blood gases were unchanged, as were heart rhythm and arterial oxygen saturation. No serious adverse reactions were reported. CONCLUSIONS: NC100100 appeared to be haemodynamically inert and safe in patients with coronary artery disease.