Re-evaluation of diagnostic parameters is crucial for obtaining accurate data on idiopathic pulmonary fibrosis.

BACKGROUND: The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. METHODS: We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31(st) of December in 2012 was calculated using the reported population in each university hospital city as the denominator. RESULTS: Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group - on the basis of patient records assessed by pulmonologists only 20-30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients' mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. CONCLUSIONS: Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports.

Preoperative assessment of endometrial carcinoma by three-dimensional power Doppler angiography.

OBJECTIVE: Preoperative evaluation of the depth of myometrial invasion in endometrial carcinoma is challenging. The objective of this study was to evaluate the usefulness of three-dimensional power Doppler angiography (3D-PDA) in this setting. METHODS: Sonographic and histological data on 100 consecutive cases of endometrial carcinoma were analyzed. The endometrial and myometrial vascular indices VI (vascularization index), FI (flow index) and VFI (vascularization flow index) were calculated by 3D-PDA. The results were compared with a complete surgical staging. RESULTS: The mean ( ± SD) age of patients was 67.1 ± 8.8 (range, 33-87) years. Forty-six patients had deep (≥ 50%) myometrial invasion. Eight patients had metastases, seven of them with deep invasion. Three patients were found to have carcinomas of non-uterine origin on histology, and these were excluded from further statistical analysis. The median endometrial and myometrial vascular indices were higher in the group with deep invasion than in the group without. Following multivariable analysis of the indices only the endometrial FI was independently associated with deep invasion (OR, 1.061; 95% CI, 1.023-1.099; P = 0.001). However, a greater endometrial volume was also an independent predictor of deep invasion (OR, 1.109; 95% CI, 1.011-1.215; P = 0.028). CONCLUSION: Our study suggests that endometrial and, to a lesser degree, myometrial vascular indices and endometrial volume correlate with the depth of myometrial invasion in endometrial carcinoma.

No increase in the prevalence of COPD in two decades.

Relevant information on the prevalence of chronic obstructive pulmonary disease (COPD) and its trends is scarce. In the present study, we compare the prevalence rates and potential determinants of COPD in two national population samples that were surveyed 20 yrs apart. In 1978-1980, a sample of 8,000 people was surveyed; subjects were representative of the Finnish population and were aged ≥30 yrs. Among those aged 30-74 yrs, acceptable spirometry was obtained from 6,364 (87%) subjects. In a similar survey conducted in 2000-2001, comparable spirometry was obtained from 5,495 (80%) participants. Airway obstruction was defined as forced expiratory volume in 1 s (FEV(1))/forced vital capacity below the lower limit of normal and staged for severity on the basis of FEV(1) % predicted. The age-adjusted prevalence rates of obstruction (stages I-IV) were rather similar in both surveys in males (4.7 versus 4.3%; p = 0.25), but were almost significantly higher in females in the later survey (2.2 versus 3.1%; p = 0.06). The rates of COPD stage II or higher were 3.9% in 1978-1980, and 3.6% in 2000-2001 (p = 0.36) for males, and 1.4 and 1.5% (p = 0.93), respectively, for females. In conclusion, no significant difference was found in the prevalence of COPD stages II-IV between similar population based surveys performed 20 yrs apart. Since COPD is mostly mild or moderate there is a strong case for early prevention.

Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD.

High levels of exhaled nitric oxide (NO) predict favourable response to inhaled corticosteroids in asthma, but the ability of exhaled NO or inflammatory markers in exhaled breath condensate (EBC) to predict steroid responsiveness in chronic obstructive pulmonary disease (COPD) is not known. We measured alveolar and bronchial NO output, levels of leukotriene B(4) (LTB(4)), cysteinyl leukotrienes (cysLTs) and 8-isoprostane in EBC, spirometry, body plethysmography and symptoms in 40 subjects with COPD before and after 4 weeks of treatment with inhaled fluticasone (500 microg b.i.d.). Five subjects (12.5%) with COPD had significant improvement in lung function during fluticasone treatment, whereas 20 subjects (50%) had significant decrease in symptoms. High baseline bronchial NO flux was associated with higher increase in forced expiratory volume in 1 s to forced vital capacity ratio (r = 0.334, p = 0.038) and more symptom relief (r = -0.317, p = 0.049) during the treatment. Baseline EBC levels of LTB(4), cysLTs or 8-isoprostane were not related to response to fluticasone treatment. Inhaled fluticasone decreased bronchial NO flux but not alveolar NO concentration or markers in EBC. High levels of bronchial NO flux are related to symptom relief and improvement of airway obstruction during treatment with inhaled fluticasone in COPD. Markers of inflammation or oxidative stress in EBC are not related to steroid responsiveness in COPD.

Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.

BACKGROUND: Although knowledge of the IgE cross-reactivity between allergens is important for understanding the mechanisms of allergy, the regulation of the allergic immune response and the development of efficient modes of allergen immunotherapy, the cross-reactivity of animal allergens is poorly known. OBJECTIVE: The aim of this study was to characterize IgE cross-reactivities between lipocalin proteins, including five animal-derived lipocalin allergens and one human endogenous lipocalin, tear lipocalin (TL). METHODS: The recombinant proteins were validated by chromatography and mass spectrometry. The IgE-binding capacity of the allergens was confirmed by IgE. immunoblotting and IgE immunoblot inhibition. IgE ELISA was performed with sera from 42 atopic patients and 21 control subjects. The IgE cross-reactivities between the lipocalin proteins were determined by ELISA inhibition. RESULTS: ELISA inhibition revealed IgE cross-reactivities between Can f 1 and human TL, between Can f 1 and Can f 2, and between Equ c 1 and Mus m 1. Low levels of IgE to human TL were found in the sera of seven dog-allergic patients of whom six were IgE-positive for Can f 1. CONCLUSION: Several lipocalins exhibited IgE cross-reactivity, probably due to the sequential identity of the proteins and also due to similarities in their three-dimensional structures. The clinical significance of the findings needs to be elucidated. Low-level IgE cross-reactivity can play a role in regulating immune response to lipocalin allergens.

Cancer families with children: factors associated with family functioning--a comparative study in Finland.

OBJECTIVE: The objective is to examine the factors associated with family functioning in families with children where a parent has cancer in comparison to families without cancer. SAMPLE AND METHODS: Eighty-five families including 85 cancer patients, 61 healthy spouses and 68 children between 11 and 17 years of age, and a control group of 59 families including 105 adults and 65 children were given a set of questionnaires including a background variable questionnaire, the Family Assessment Device, the Beck Depression Inventory and the Sense of Coherence (SOC). A statistical multilevel model allowing the use of data from several informants belonging to the same family was constructed for the analysis of associations between variables. RESULTS: Maternal depression and SOC of family members were associated with family functioning; maternal depression impaired family functioning and family members' SOC improved it. No difference was found between the clinical group and the control group. CONCLUSION: In clinical work with cancer families with children, maternal depression and SOC should be focused on.

The major horse allergen Equ c 1 contains one immunodominant region of T cell epitopes.

BACKGROUND: Despite the fact that most significant mammalian respiratory allergens are lipocalin proteins, information on the human T cell reactivity to these allergenic proteins is largely missing. OBJECTIVE: Knowing the T cell epitopes in allergens is a prerequisite for developing novel preparations for allergen immunotherapy. METHODS: Specific T cell lines were generated with recombinant Equ c 1 from the peripheral blood mononuclear cells (PBMCs) of 10 horse-allergic subjects. For determining T cell epitopes, the lines were stimulated with 16mer synthetic Equ c 1 peptides overlapping by 14 amino acids. The binding capacity of Equ c 1 peptides to human leucocyte antigen class II molecules was determined by the competitive ELISA. RESULTS: The major horse allergen Equ c 1 resembles two other lipocalin allergens, the major cow allergen Bos d 2 and the major dog allergen Can f 1, in that it is weakly stimulatory for the PBMCs of sensitized subjects. Moreover, the T cell epitopes of Equ c 1 are clustered in a few regions along the molecule, as is the case with Bos d 2 and Can f 1. Similar to Bos d 2, Equ c 1 contains one immunodominant epitope region at the carboxy-terminal end of the molecule. The T cell lines of eight horse-allergic subjects out of 10 showed strong reactivity to one or both of the two overlapping peptides, p143-158 and p145-160, in this region. The region probably contains two overlapping epitopes. CONCLUSION: The 18mer peptide p143-160 from the immunodominant region of Equ c 1 is a potential candidate for the peptide-based immunotherapy of horse-sensitized subjects.

Chest CT screening of asbestos-exposed workers: lung lesions and incidental findings.

The objective of the present study is to determine the feasibility of chest computed tomography (CT) in screening for lung cancer among asbestos-exposed workers. In total, 633 workers were included in the present study and were examined with chest radiography and high-resolution CT (HRCT). A total of 180 current and ex-smokers (cessation within the previous 10 yrs) were also screened with spiral CT. Noncalcified lung nodules were considered positive findings. The incidental CT findings not related to asbestos exposure were registered and further examined when needed. Noncalcified lung nodules were detected in 86 workers. Five histologically confirmed lung cancers were found. Only one of the five cancers was also detected by plain chest radiography and three were from the group of patients with a pre-estimated lower cancer probability. Two lung cancers were stage Ia and were radically operated. In total, 277 individuals presented 343 incidental findings of which 46 required further examination. Four of these were regarded as clinically important. In conclusion, computed tomography and high-resolution computed tomography proved to be superior to plain radiography in detecting lung cancer in asbestos-exposed workers with many confounding chest findings. The numerous incidental findings are a major concern for future screenings, which should be considered for asbestos-exposed ex-smokers and current smokers.

The DR4-DQ8 haplotype and a specific T cell receptor Vbeta T cell subset are associated with absence of allergy to Can f 1.

BACKGROUND: The significance of specific T cell receptor (TCR) Vbeta subtypes and human leucocyte antigen (HLA) class II alleles for the development of allergy to lipocalin allergens such as the major dog allergen Can f 1 is not clear at present. OBJECTIVE: To characterize the TCR Vbeta usage in the Can f 1-specific T cell lines and the HLA class II genotypes of Can f 1-allergic and non-allergic subjects. METHODS: T cell lines were induced with recombinant Can f 1 from the peripheral blood mononuclear cells of 12 non-atopic dog owners and 26 dog-allergic patients. Thirteen of the dog-allergic subjects were sensitized to Can f 1. Expression of the TCR Vbeta subtypes on CD4(+) T cells in the T cell lines was measured by flow cytometry. The subjects were HLA genotyped for DRB1, DQB1 and DPB1 loci. RESULTS: Can f 1-specific T cell lines were obtained from 18 subjects, with either positive (n=8) or negative (n=10) skin prick tests (SPTs) to recombinant Can f 1. The frequency of TCR Vbeta5.1(+) T cells was significantly higher in the T cell lines of subjects with negative SPTs to the allergen. Moreover, DR4-DQ8 haplotype was over-represented among these subjects. CONCLUSION: The DR4-DQ8 haplotype and the TCR Vbeta5.1(+) CD4(+) T cells may be protective against allergy to Can f 1.

Long-term follow-up study of pulmonary findings in patients with primary Sjögren's syndrome.

BACKGROUND: In a previous study pulmonary hyperinflation was observed frequently in patients with primary Sjogren's syndrome (pSS) and elevated serum beta-2 microglobulin (beta2m) concentrations were associated with hyperinflation. OBJECTIVE: To evaluate the significance of baseline serum beta2m concentration and to identify other possible risk factors for pulmonary involvement in long-term follow-up of patients with pSS. METHODS: Nineteen pSS patients whose pulmonary function tests (PFTs) had been previously studied were reexamined after a median follow-up of 10 years. Pulmonary symptoms were recorded, chest radiograph, and high-resolution computed tomography (HRCT) were evaluated and methacholine provocation and PFTs including flow-volume spirometry, body plethysmography, and diffusing capacity performed. RESULTS: Baseline serum beta2m concentrations correlated inversely with follow-up total lung capacity (TLC), vital capacity (VC), and diffusing capacity (DL), and positively with residual volume (RV), all expressed as percentage of predicted values. Diminished airways resistance (Raw) and, correspondingly, elevated specific conductance (SGaw) were frequent findings in pSS patients at follow-up, indirectly implying stiffness of the lungs and a restrictive decrease in lung volumes. Baseline serum protein concentration was higher and IgG concentration tended to be higher in pSS patients who at follow-up had elevated SGaw compared with others. Interstitial changes in HRCT were found more frequently in patients with elevated SGaw than in those without. CONCLUSION: Our results suggest that subtle restrictive changes in pulmonary function are more prone to develop in the long term in pSS patients with elevated serum beta2m concentration and other signs of immunological activity at baseline.

Assessment of recombinant dog allergens Can f 1 and Can f 2 for the diagnosis of dog allergy.

BACKGROUND: The use of recombinant allergens for the diagnosis and immunotherapy of allergy may offer several advantages over allergen extracts. OBJECTIVE: To produce recombinant dog allergens Can f 1 and Can f 2 in Pichia pastoris yeast and to assess their suitability for the diagnosis of dog allergy. METHODS: Clinically diagnosed dog-allergic patients' and healthy non-atopic dog owners' reactivities against recombinant Can f 1 and Can f 2 and commercial dog epithelial extract were studied by a panel of methods including skin prick test (SPT), ELISA and IgE immunoblotting. RESULTS: Recombinant Can f 1 and Can f 2 were found immunologically functional: they bound dog-allergic patients' IgE in immunoblotting and inhibited specifically the binding of IgE to their natural counterparts in the dog allergen extract. Moreover, patients' IgE reactivity in immunoblotting to natural Can f 1 and their SPT with the recombinant allergen were perfectly concordant (phi coefficient 1.0, P<0.001). The concordance was slightly lower with recombinant Can f 2 (phi coefficient 0.92, P<0.001). A lower number of dog-allergic patients, 52%, reacted against Can f 1 than previously reported. About one-third of the patients reacted to Can f 2. In immunoblotting, the highest prevalence of reactivity, 60%, was directed to an 18 kDa component. Aminoterminal sequencing showed this to be a previously unidentified allergenic protein. CONCLUSIONS: The recombinant allergens can be used reliably to identify Can f 1 and Can f 2-sensitized individuals. However, the two allergens are insufficient as reagents for diagnosing dog allergy.

Probing the mechanisms of low immunogenicity of a lipocalin allergen, Bos d 2, in a mouse model.

BACKGROUND: Bos d 2, a major bovine allergen of the lipocalin family, stimulates very weakly cow dust-asthmatic subjects' peripheral blood mononuclear cells and the spleen cells of several inbred mouse strains immunized with the allergen. OBJECTIVE: To identify the immune mechanisms accounting for the weak stimulatory capacity of Bos d 2. METHODS: The spleen cell responses of BALB/c mice immunized with the allergen and with hen egg lysozyme and tetanus toxoid as control antigens were examined using several in vitro methods. RESULTS: Analysis of the numbers of spleen cells in the antigen-stimulated in vitro cultures with the vital dye 7-amino-actinomycin D showed that Bos d 2 induced a smaller expansion of cells in comparison with the control antigens. Increased cell death in vitro did not account for the weak response against Bos d 2. The number of spleen cells reacting against Bos d 2 also proved to be the lowest when they were analysed by labelling the stimulated cells with 5-6-carboxyfluorescein diacetate succinimidyl ester or by enumerating cytokine-secreting cells by ELISPOT. Eliminating CD8+ cells in the in vitro culture did not enhance the response against Bos d 2. Bos d 2 was also the weakest of the antigens to stimulate the production of soluble cytokines. Adding IL-2, IL-4 or antibody against TGF-beta in the antigen-stimulated spleen cell cultures enhanced the proliferative responses against all the antigens, whereas adding IL-12 or antibody against IL-4 or IL-10 did not enhance the responses. CONCLUSION: The results exclude several mechanisms of peripheral tolerance as an explanation for the poor immune response against Bos d 2, and suggest that the allergen is recognized by a low number of specific T cells. The weak immunogenicity of Bos d 2 may be related to its allergenicity.

Increased alveolar nitric oxide concentration in asthmatic patients with nocturnal symptoms.

Nocturnal asthma symptoms and impaired lung function at night are related to inflammatory activity in the peripheral lung compartment. Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates can be used to separately assess alveolar and bronchial NO production and inflammation. The authors hypothesised that asthmatic patients with nocturnal symptoms have a higher alveolar NO concentration than those with only daytime symptoms. The authors asked 40 patients with newly-diagnosed steroid-naïve asthma about their nocturnal asthma symptoms through the use of a written questionnaire. Alveolar NO concentration and bronchial NO flux were assessed in the 40 asthmatics and 40 healthy controls. Nineteen of the 40 patients reported nocturnal symptoms. Patients with nocturnal symptoms had a higher alveolar NO concentration (1.7+/-0.3 (mean+/-SEM) parts per billion (ppb)) than patients without nocturnal symptoms (0.8+/-0.3 ppb, p=0.012) or healthy controls (1.0+/-0.1 ppb, p=0.032). Bronchial NO flux was higher both in patients with (2.4+/-0.4 nL x s(-1), p<0.001) and without (2.6+/-0.4 nL x s(-1), p<0.001) nocturnal symptoms, compared to controls (0.7+/-0.1 nL x s(-1)). Nocturnal symptoms in asthmatic patients are related to a higher alveolar nitric oxide concentration. The results suggest that assessment of alveolar nitric oxide concentration can be used to detect the parenchymal inflammation in asthmatic patients with nocturnal symptoms.

Inhaled fluticasone decreases bronchial but not alveolar nitric oxide output in asthma.

Exhaled nitric oxide (NO) concentration is a noninvasive measure of airway inflammation and is increased in asthma. Inhaled glucocorticoids decrease exhaled NO concentration, but the relative contributions of alveolar and bronchial levels to the decrease in exhaled NO concentration are unknown. Alveolar NO concentration and bronchial NO flux can be separately approximated by measuring exhaled NO at several exhalation flow rates. The effect of steroid treatment on alveolar and bronchial NO output in asthma was studied. Alveolar NO concentration and bronchial NO flux were assessed in 16 patients with asthma before and during treatment with inhaled fluticasone for 8 weeks and in 16 healthy controls. Before the treatment, asthmatics had increased bronchial NO flux (mean+/-SEM: 3.6+/-0.4 versus 0.7+/-0.1 nL x s(-1), p<0.001) but normal alveolar NO concentration (1.2+/-0.5 versus 1.0+/-0.2 parts per billion (ppb), p>0.05) compared with controls. Inhaled fluticasone decreased bronchial NO flux from 3.6+/-0.4 to 0.7+/-0.1 nL x s(-1) (p<0.01) but had no effect on alveolar NO concentration (before: 1.2+/-0.5; after: 1.2+/-0.1 ppb, p>0.05). The forced expiratory volume in one second improved, whereas asthma symptom score and serum levels of eosinophil cationic protein and eosinophil protein X decreased during the treatment. In conclusion, inhaled fluticasone decreases bronchial but not alveolar nitric oxide output simultaneously with clinical improvement in patients with asthma.

Extended exhaled NO measurement differentiates between alveolar and bronchial inflammation.

Lower respiratory tract inflammation can be detected by measuring exhaled nitric oxide (NO) concentration at a single exhalation flow rate, but this does not differentiate between alveolar and bronchial NO production. We assessed alveolar NO concentration and bronchial NO flux with an extended method of measuring exhaled NO at several exhalation flow rates in 40 patients with asthma, 17 patients with alveolitis, and 57 healthy control subjects. Bronchial NO flux was higher in asthma (2.5 +/- 0.3 nl/s, p < 0.001) than in alveolitis (0.7 +/- 0.1 nl/s) and healthy control subjects (0.7 +/- 0.1 nl/s). Alveolar NO concentration was higher in alveolitis (4.1 +/- 0.3 ppb, p < 0.001) than in asthma (1.1 +/- 0.2 ppb) and healthy control subjects (1.1 +/- 0.1 ppb). In asthma, bronchial NO flux correlated with serum level of eosinophil protein X (EPX) (r = 0.60, p < 0.001) and bronchial hyperresponsiveness (r = 0.55, p < 0.001). In alveolitis, alveolar NO concentration correlated inversely with pulmonary diffusing capacity (r = -0.55, p = 0.022) and pulmonary restriction. Glucocorticoid treatment or allergen avoidance normalized bronchial NO flux in asthma and decreased alveolar NO concentration toward normal in alveolitis. In conclusion, extended exhaled NO measurement can be used to separately assess alveolar and bronchial inflammation and to assess disease activity/severity in asthma and alveolitis.

Increased bronchial nitric oxide production in patients with asthma measured with a novel method of different exhalation flow rates.

The concentration of nitric oxide (NO) in exhaled air is increased in patients with asthma, suggesting that measuring fractional exhaled NO concentration (FE(NO)) may be used to monitor asthmatic airway inflammation. However, increased FE(NO) is not specific for asthma, as other inflammatory lung diseases may also increase FE(NO). To augment the specificity of FE(NO) measurement, we tested a novel theoretical modelling of pulmonary NO dynamics that allows the approximation of alveolar NO concentration and bronchial NO flux separately by measuring FE(NO) at several exhalation flow rates. We measured FE(NO) at four exhalation flow rates in 10 steroid-naive asthmatics, 5 patients with extrinsic allergic alveolitis, and in 10 healthy controls. Both the asthmatics and the patients with alveolitis had significantly higher FE(NO) than the healthy controls. The increased NO concentration originated from the bronchial level in the asthmatics and from the alveolar level in the patients with alveolitis. In the second part of the study we assessed the repeatability of FE(NO) test, within-day and day-to-day (during two weeks) variation in FE(NO), and the effects of mouth pressure and cigarette smoking on FE(NO) in healthy volunteers. Repeatability of 10 subsequent measurements was high (coefficient of variation (CV) 4.6% +/- 0.4%), and no diurnal variation was found. The day-to-day variation during a 2-week period gave a CV of 10.6% +/- 1.0%. The magnitude of mouth pressure (5-20 cmH2O in adults, 5-40 cmH2O in children) during measurement had no effect on FE(NO). Smoking a cigarette caused a small and transient but statistically significant increase in FE(NO) at 1 and 5 min after smoking. In conclusion, FE(NO) measurement is highly repeatable with low day-to-day variation among healthy subjects. Our results also suggest that the present novel method of measuring FE(NO) at several exhalation flow rates can be used to approximate alveolar and bronchial contributions to FE(NO) separately and thus increase the clinical value of this test.