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Background and Aim: KL-6 and SP-D are potential serum markers in interstitial lung diseases. Their discriminative value, and ability to reflect pulmonary disease activity and prognosis in bird fancier's lung were analyzed., Methods: We studied 49 patients, 38 unexposed and 9 exposed controls. Serum KL-6 and SP-D concentrations were measured at presentation and a second sample, taken after antigen avoidance, was available in 17 patients. Pulmonary function tests were analyzed at presentation and 2-year follow-up., Results: KL-6 and SP-D were significantly elevated in patients compared to controls (p < 0.0001). ROC curve analysis revealed that both are equally useful in discriminating patients from controls. Analysis of their value as activity markers showed that both correlated with pulmonary function impairment; however, KL-6 correlated best with diffusing capacity. Evaluation of their predictive value showed that higher levels at onset were associated with improvement of diffusing capacity during follow-up. Further, it was noted that KL-6 and SP-D levels decreased after more than one month of allergen avoidance., Conclusions: KL-6 and SP-D appear useful serum markers in bird fancier's lung. Since higher levels are associated with more severe lung function impairment at presentation, and better recovery over time, we postulate that in this disease they are especially markers of disease activity.

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.

Previously, an association between susceptibility to sarcoidosis and a polymorphism in the interleukin (IL-18) gene (IL-18 -607A/C) has been reported in Japanese. The aim of the present study was to validate this association in a clinically well-characterized population of Dutch Caucasians. Three other polymorphisms at positions -656, -137, and 1248 were included in order to extend the mapping of the IL-18 gene and to enable the construction of haplotypes. Polymorphisms were determined using sequence-specific primers (SSPs) and polymerase chain reaction (PCR). A total of 236 individuals was studied (133 patients and 103 controls). No significant differences were observed in the distribution of the -607 and the other polymorphisms between Dutch sarcoidosis patients and controls. However, significant differences in IL-18 -607 genotype and allele frequency distributions were found between the Dutch and the Japanese. From the investigated IL-18-promoter polymorphisms, we were able to deduce four haplotypes. No differences were observed in haplotype frequencies between Dutch sarcoidosis patients and controls. In conclusion, IL-18 polymorphisms do not appear to influence the susceptibility to sarcoidosis in Dutch Caucasians. Important differences in allele frequencies were observed between Japanese and Dutch sarcoidosis patients and controls., (Copyright 2004 Blackwell Munksgaard)

Study Objectives: To determine the discriminative value of serum Clara cell 16 (CC16), KL-6, and surfactant protein (SP)-D as markers of interstitial lung diseases, and their ability to reflect pulmonary disease severity and prognosis in sarcoidosis., Subjects: Seventy-nine patients with sarcoidosis and 38 control subjects., Measurements: Serum CC16, KL-6, and SP-D concentrations at disease presentation were measured. Pulmonary function tests and chest radiographs were analyzed at presentation and 2-year follow-up., Results: All markers co-correlated, and a significant difference was found between CC16, KL-6 (Krebs von den Lungen-6), and SP-D levels in patients with sarcoidosis and control subjects (p < 0.0001). Receiver operating characteristic curve analysis revealed largest area under the curve for KL-6. Significantly higher levels of CC16 and KL-6 were found in patients with parenchymal infiltration (stage II, III) compared to patients without parenchymal infiltration (stage I). In concordance, CC16 and KL-6 levels inversely correlated with diffusion capacity and total lung capacity, and KL-6 also with inspiratory vital capacity. Moreover, higher KL-6 levels were weakly but significantly associated with persistence or progression of parenchymal infiltrates at 2-year follow-up., Conclusion: In this study, KL-6 appears to be the best discriminative marker in differentiating patients with sarcoidosis from healthy control subjects; however, as it is not a specific marker for this condition, this quality is unlikely to be useful as a diagnostic tool. Both CC16 and KL-6 may be of value in reflecting disease severity, and KL-6 tends to associate with pulmonary disease outcome.

Sarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-Löfgren sarcoidosis, 47 Löfgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1-9). In patients with Löfgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-Löfgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and Löfgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for Löfgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and Löfgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.

The aetiology of sarcoidosis is uncertain; current thinking implicates exposure of genetically susceptible hosts to environmental factors. The nuclear factor kappa B (NF-kappaB) family of transcription factors are critical regulators of immediate transcriptional responses in inflammatory situations and immune responses. Inhibitor kappa B-alpha (IkappaB-alpha) inhibits NF-kappaB and plays a major role in controlling its activity. We investigated IkappaB-alpha promoter polymorphisms using sequence-specific primer-polymerase chain reaction, at positions -881 (A/G), -826 (C/T), and -297 (C/T) in Caucasian sarcoidosis patients (UK and Dutch [NL]), each with their own controls. Disease severity at presentation was assigned using chest radiography and pulmonary function indices. In the combined populations, the -297T allele carriage was more prevalent in patients than in controls (P=0.008). Three common haplotypes were found, of which haplotype 2 (GTT) was significantly associated with sarcoidosis in comparison with control subjects (P=0.01). Subgroup analysis revealed that the -826T allelic carriage was most prevalent in stage II disease, and more prevalent in stage III than in stage IV (P=0.01). The -826T allelic carriage did not show any association with lung function. These results indicate that the NF-kappaB activation pathway might be associated with the inflammation of sarcoidosis.

Objectives: To date, insufficient evidence is available to recommend serum soluble interleukin-2 receptor (sIL-2R) measurement as a routine test in the assessment of sarcoidosis. Therefore, we evaluated the clinical value of this test., Design: Forty-seven patients with sarcoidosis, all presenting with active disease, were included in the study. Initial serum sIL-2R levels were determined by enzyme-linked immunosorbent assay, and clinical data at presentation and follow-up were collected retrospectively., Results: The median follow-up period of all patients was 44 months (range, 6 to 100 months), and 38 patients had follow-up data present over at least 24 months. The median sIL-2R level was 1,068 U/mL (range, 248 to 4,410 U/mL; upper limit of normal, 710 U/mL). A positive correlation was found between serum sIL-2R levels and the number of CD4+ T lymphocytes in BAL (rs = 0.53, p < 0.001). In accordance with this result, both sIL-2R level and the number of CD4+ T lymphocytes were elevated in stage I compared to stage III disease (p < 0.05). Patients with extrapulmonary disease (ED) [excluding Löfgren's syndrome] showed higher sIL-2R levels than those presenting with only pulmonary sarcoidosis (p = 0.001). No relation was found between sIL-2R level and response to treatment, and there was no association between sIL-2R levels and radiographic evolution and lung function outcome., Conclusions: Our data suggest a role for serum sIL-2R as marker of pulmonary disease activity and ED in patients with sarcoidosis.

Background: Proinflammatory cytokines are a major determinant in the inflammatory events leading to sarcoidosis. Genetic variations in the genes encoding these cytokines might contribute to sarcoidosis susceptibility, disease severity and outcome., Methods: In the present study we genotyped two clinically well-defined cohorts of Caucasian sarcoidosis patients from different European countries (each with their own controls) for the following polymorphisms using SSP-PCR: IL6 -174(G/C), IL6 intron 4(A/G) and IL1A-889(C/T). In total, 516 individuals were studied (147 UK + 102 Dutch patients, 101 UK + 166 Dutch controls). Disease severity data at presentation included chest radiographic stage, FVC, DL(CO), and extrapulmonary manifestations. Disease progression was evaluated on follow-up chest radiographs and sequential lung function measurements (2, 4 years)., Results: No differences in genotype, carriage and allele frequencies of the investigated polymorphisms were found in either of the populations. Analysis of genotype data in relation to disease severity data, however, showed a slightly increased carrier frequency of the rarer-174C allele in patients with Stage IV sarcoidosis (p = 0.03, Pc = 0.09). Pulmonary function progression analysis did not reveal significant associations., Conclusions: Although the investigated polymorphisms are unlikely to contribute to sarcoidosis susceptibility, the IL6-174C allele might have a role in the genetics underlying sarcoidosis severity or the progression towards pulmonary fibrosis in a particular subgroup.

Human leukocyte antigen (HLA)-DQB1 is one of the intriguing candidate genes in sarcoidosis. We performed high resolution molecular HLA-DQB1 typing on two groups of white patients (British [UK] and Dutch [NL]) in order to investigate the relationship between 19 DQB1 alleles and disease severity and progression. A total of 803 individuals were studied (133 UK and 102 NL patients, and 354 UK and 214 NL control subjects). Disease severity data included extrapulmonary disease, chest X-ray stage, lung diffusing capacity for carbon monoxide, and FVC. Progression was evaluated on follow-up chest radiographs (2 and 4 yr). The results showed DQB1*0201 to be strongly protective against severe sarcoidosis in both populations; in other words, it localized to Stage I at all time points (P < 0.0001, P(corrected) (P(c)) = 0.002), whereas another DQB1 allele, *0602, tended to have opposite effects. Further, a clear association was found between the *0201 allele and Löfgren's syndrome (P < 0.0001, P(c) = 0.001). More importantly, carriage of this allele reduced the risk of disease progression. In contrast, the other common split of DQB1*02, *0202, did not affect disease severity but was mildly protective against sarcoidosis in the UK population (P = 0.02, p(c) not significant). In conclusion, this study shows that DQB1*0201 is a strong marker for mild sarcoidosis. Additional mapping across the DQB1*0201-DRB1*0301 haplotype, including specific alleles at genes such as DRB3, tumor necrosis factor, lymphotoxin-alpha, I-kappa-B-like protein, and B-associated transcript 1, is necessary for a final localization of the protective effect on this haplotype.

Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C), -863(C/A), -857(C/T), -307(G/A), and -237(G/A) in two clinically well-defined groups of white patients (British [UK] and Dutch [NL]) with sarcoidosis, each with their own control subjects. Polymorphisms were determined using SSP-PCR. A total of 772 individuals were studied (96 UK patients, 354 UK control subjects, 100 NL patients, 222 NL controls). A significant increase in the rarer TNF -857T allele was found in both sarcoidosis populations. In total 25.5% of the sarcoid patients carried the TNF -857T allele versus 14.1% of the control subjects (p = 0.003, p(c) = 0.02). In the sarcoidosis group the allele frequency of this polymorphism was 13.5% versus 7.3% in the control subjects (p = 0.0003, p(c) = 0.002). Subgroup analysis showed a significant increase in the rarer TNF -307A (TNF-2) allele in patients with Löfgren's syndrome (p = 0.006, p(c) = 0.03). Our finding does not necessarily imply that the two polymorphisms relate to different functions; it may be that one or both are in linkage disequilibrium with the causal site. This requires further studies of functionality and linkage disequilibrium.

A 75-yr-old female presented with platypnoea and orthodeoxia, shortly after laying down an old and pinching corset. The injection of activated Haemaccel in the right cubital vene during transoesophageal echocardiography, in the upright position, revealed a direct blood flow from the superior caval vein at a patent foremen ovale, consequently opening it and causing a large right-to-left shunt which was calculated at 28.5%. In the supine position there was only a minimal opening of the patent foremen ovale with a calculated right-to-left shunt of 9.5%. The patent foremen ovale was successfully closed percutaneously with a CardioSEAL.

Eosinophils play an important role in the pathogenesis of asthma. Several pro-inflammatory responses of eosinophils are primed in vivo in this disease. The aim of the present study was to investigate whether regular antiasthma treatment could modulate priming-sensitive cytotoxic mechanisms of human eosinophils. In a randomized, two-centre, double-blind parallel group study, the effect of 8 weeks of treatment with salmeterol xinafoate 50 microg b.i.d., beclomethasone dipropionate 400 microg b.i.d. or both on pulmonary function and the activation of priming-sensitive cytotoxic mechanisms of eosinophils, i.e. degranulation of eosinophil cationic protein (ECP) in serum, and activation of isolated eosinophils in the context of induction of the respiratory burst and release of platelet-activating factor (PAF) were tested. These effects were evaluated in 40 allergic asthmatics before and 24 h after allergen inhalation challenge. Whereas baseline forced expiratory volume in one second (FEV1) improved in all treatment groups, only treatment with a combination of salmeterol and beclomethasone significantly inhibited the allergen-induced increase in serum ECP, and (primed/unprimed) PAF-release, suggesting inhibition of eosinophil priming after allergen challenge. In contrast to the combination therapy, monotherapy with beclomethasone had no influence on allergen-induced PAF-release, suggesting an additional anti-inflammatory effect of salmeterol during combination therapy. Monotherapy with beclomethasone inhibited the prechallenge serum-treated zymosan (STZ) (0.1 mg mL(-1))-induced respiratory burst and the allergen-induced increase in serum ECP levels, reflecting pre- and postchallenge anti-inflammatory effects. During monotherapy with salmeterol, an allergen-induced increase in serum ECP concentration and STZ (0.1 mg x mL(-1))-induced respiratory burst was observed, suggesting that treatment with salmeterol alone had no effect on priming-sensitive eosinophil cytotoxic mechanisms. In conclusion, this study shows that standard asthma therapy leads to inhibition of eosinophil priming of cytotoxic mechanisms in vivo.

Background: Sarcoidosis is generally characterized by a CD4+ lymphocyte predominance in bronchoalveolar lavage fluid (BALF), whereas in extrinsic allergic alveolitis (EAA) a CD8+ lymphocyte predominance is found. However, we have previously demonstrated an increase in CD4+ lymphocytes in BALF obtained from EAA patients as well. The aim of this study was to evaluate whether in sarcoidosis and EAA the BALF cellular profile-even without the help of cytokine detection-might reflect differences in the CD4+ T-lymphocyte subpopulations, i.e. T helper (TH)-1 and TH2 lymphocytes., Methods: For this purpose, we analyzed BALF analysis results obtained from 77 nonsmoking patients with histologically proven sarcoidosis and 54 nonsmoking patients suffering from EAA., Results: Patients with EAA showed the highest mean absolute numbers of lymphocytes, CD8+ as well as CD4+ T lymphocytes, whereas the percentage of CD4+ T lymphocytes in BALF was low. In contrast, patients with sarcoidosis showed the lowest absolute and relative number of CD8+ T lymphocytes, the highest percentage of CD4+ T lymphocytes and CD4+/CD8+ ratio. Moreover, patients with Löfgren's syndrome demonstrated an alveolitis suggesting a TH1 lymphocyte-subset-like predominant related profile, characterized by lower numbers of eosinophils and mast cells, whereas sarcoidosis patients with respiratory symptoms formed a more mixed TH1/TH2 pattern. Patients with EAA showed a cellular BALF profile suggesting a functional predominance of TH2 lymphocytes., Conclusion: These preliminary data suggest a different distribution of the CD4+ T lymphocyte subtypes characterized by a functional heterogeneity of CD4+ T lymphocytes between-as well as within-these various pulmonary disorders. The exact role of this imbalance of TH1 and TH2-like activity in the lung with regard to the pathogenesis and prognosis needs to be further elucidated.

No systematic data are available about the long-term follow up of breast cancer patients treated with amino-hydroxypropylidene bisphosphate (APD) for hypercalcaemia and about the results of APD treatment of recurrent hypercalcaemia in these patients. Treatment with intravenous APD (10-15 mg daily until normalization of the serum calcium level) normalized serum calcium in 29 of 31 patients with hypercalcaemia due to advanced breast cancer. Survival in these 29 patients varied between 8 and 693 days (median 140 days) and 7 patients achieved a partial remission or stabilisation of disease during subsequent anti-tumor therapy. In 16 of the 29 patients in whom APD treatment was initially successful, hypercalcaemia recurred after a median period of 65 days. Eleven of these patients received a second course of APD, which was equally successful as the first in terms of percentage of patients with normalization of serum calcium, total dose of APD needed, and duration to normalization of serum calcium. Recurrent hypercalcaemia occurred significantly faster after the second successful APD course (median 17 days) than after the first (median 65 days). When only patients with progressive disease were taken into account, recurrence of hypercalcaemia usually occurred early, both after a first (median 23 days) and after a second successful APD course (median 17 days). Normalization of serum calcium occurred in 4 of 6 patients receiving a third APD course, in all 3 patients receiving a fourth, and in 1 of 2 patients receiving a fifth course.(ABSTRACT TRUNCATED AT 250 WORDS)