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Appropriate parameters are needed for the monitoring of children with pulmonary arterial hypertension (PAH). Various biologic markers seem to be of use in adults with PAH. No data are available on their value in children with PAH. In this study, the relation between serum markers, functional parameters, and hemodynamic variables in pediatric PAH and their ability to predict survival is determined. Serum N-terminal pro brain natriuretic peptide (NT-proBNP), uric acid, norepinephrine, and epinephrine were measured and correlated with invasive hemodynamics, functional parameters, and outcome in 29 pediatric patients with PAH who visited a tertiary reference center for pediatric PAH between 1997 and 2005. NT-proBNP correlated with functional class (R = 0.36; p = 0.03) and 6-min walking distance (6MWD) (R = -0.53; p

Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis.

A role of Wnt signaling in Dupuytren disease, a fibroproliferative disease of the hand and fingers, has not been fully elucidated. We examined a large set of Wnt pathway components and signaling targets and found significant dysregulation of 41 Wnt-related genes in tissue from the Dupuytren nodules compared with patient-matched control tissue. A large proportion of genes coding for Wnt proteins themselves was downregulated. However, both canonical Wnt targets and components of the noncanonical signaling pathway were upregulated. Immunohistochemical analysis revealed that protein expression of Wnt1-inducible secreted protein 1 (WISP 1), a known Wnt target, was increased in nodules compared with control tissue, but knockdown of WISP I using small interfering RNA (siRNA) in the Dupuytren myofibroblasts did not confirm a functional role. The protein expression of noncanonical pathway components Wnt5A and VANGL2 as well as noncanonical coreceptors Ror2 and Ryk was increased in nodules. On the contrary, the strongest downregulated genes in this study were 4 antagonists of Wnt signaling (DKK1, FRZB, SFRP1, and WIF1). Downregulation of these genes in the Dupuytren tissue was mimicked in vitro by treating normal fibroblasts with transforming growth factor beta 1 (TGF-beta 1), suggesting cross talk between different profibrotic pathways. Furthermore, siRNA-mediated knockdown of these antagonists in normal fibroblasts led to increased nuclear translocation of Wnt target p-catenin in response to TGF-beta 1 treatment. In conclusion, we have shown extensive dysregulation of Wnt signaling in affected tissue from Dupuytren disease patients. Components of both the canonical and the noncanonical pathways are upregulated, whereas endogenous antagonists are downregulated, possibly via interaction with other profibrotic pathways.

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Objective, Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis, This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. Methods, The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine, ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3), Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing, Results. No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA, There were no findings suggestive of vasculitis in any of these patients. Conclusion. From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine, However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.

Objective, Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis, This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials.Methods, The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine, ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3), Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing,Results. No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA, There were no findings suggestive of vasculitis in any of these patients.Conclusion. From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine, However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.

Objective. To identify the optimal dose of oral iloprost bn the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. Design. Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. Setting. European university hospitals. Patients. A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. Intervention. Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 mu g or oral iloprost 100 mu g. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 mu g. Measurements. The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. Results. A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 mu g and 35 received iloprost 100 mu g. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment:differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 mu g and 64% iloprost 100 mu g (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 mu g and 97% on oral iloprost 100 mu g. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. Conclusion. The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 mu g oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 mu g iloprost dose was better tolerated in this patient group.

Objectives: Crystalline silica occurs as a significant component of many traditional materials used in restoration stonework, and stoneworkers who work with these materials are potentially exposed to stone dust containing respirable crystalline silica (RCS). Exposure to RCS can result in the development of a range of adverse health effects, including silicosis and lung cancer. An understanding of the determinants of RCS exposure is important for selecting appropriate exposure controls and in preventing occupational diseases. The objectives of this study were to quantify the RCS exposure of stoneworkers involved in the restoration and maintenance of heritage properties and to identify the main determinants of RCS exposure among this occupational group. Methods: An exposure assessment was carried out over a 3-year period amongst a group of stonemasons and stone cutters involved in the restoration and maintenance of heritage buildings in Ireland. Personal air samples (n 103) with corresponding contextual information were collected. Exposure data were analysed using mixed-effects modelling to investigate determinants of RCS exposure and their contribution to the individuals mean exposure. Between-depot, between-worker, and within-worker variance components were also investigated. Results: The geometric mean (GM) RCS exposure concentrations for all tasks measured ranged from < 0.02 to 0.70mg m(3). GM RCS exposure concentrations for work involving limestone and lime mortar were < 0.020.01mg m(3), tasks involving granite were 0.010.06mg m(3), and tasks involving sandstone were < 0.020.70mg m(3). Sixty-seven percent of the 8-h time-weighted average (TWA) exposure measurements for tasks involving sandstone exceeded the Scientific Committee on Occupational Exposure Limits recommended occupational exposure limit value of 0.05mg m(3). Highest RCS exposure values were recorded for the tasks of grinding (GM 0.70mg m(3)) and cutting (GM 0.70mg m(3)) sandstone. In the mixed-effects analyses, task was found to be significantly associated with RCS exposure, with the tasks of grinding and cutting resulting in average exposures of between 32 and 70 times the exposures recorded for the task of stone decorating. The between-depot, between-worker, and within-worker variance components were reduced by 46, 89, and 49%, respectively, after including task in the mixed effects model. Conclusion: Restoration stoneworkers are regularly overexposed (compared with 0.1 and 0.05mg m(3) 8-h TWA) to RCS dust when working with sandstone. The results indicate that the tasks of cutting and grinding sandstone are predictors of increased exposure to RCS dust. In order to decrease exposure to RCS, efforts should be focused on developing and implementing interventions which focus on these high-risk tasks.

Background: Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs. Methods: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control lung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis. Results: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-β response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group. Conclusions: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.

Background and Design: Morphea is an inflammatory skin disease seen more frequently than systemic sclerosis in pediatric patients. Important functional deficiencies and cosmetic deformities may develop especially due to linear morphea. Patients may have accompanying extracutaneous involvement, family history of rheumatologic diseases and abnormalities in laboratory parameters like positive ANA and RF. It is important to evaluate pediatric patients accordingly and to carry out further examinations. Data about pediatric morphea in Turkish population could not be found in the literature. We aimed to evaluate epidemiological, clinical and laboratory findings, to compare the data with those in the literature and to propose a model for Turkish pediatric morphea which can be supported by future multicenter national studies. Materials and Methods: Fourteen pediatric morphea patients, 3 males and 11 females under the ageof 18, followed up at Uludag University, Medical Faculty, Dermatovenereology Department between 2000-2010 were enrolled in the study. Inclusion criterion was age under 18 years at diagnosis. Epidemiological, clinical and laboratory findings were analyzed retrospectively. Results: Only 3 patients were males. The mean age at disease onset was 9.5 years. The mean duration of disease was 21 months. Most frequent type was linear morphea. Two patients had contracture, one had shortness in the left lower extremity, and 4 patients had livedo reticularis. Raynaud's phenomenon was positive in one case. Trauma and sunburn were the trigger factors detected. Behcets disease was reported in the father of one patient. One case was RF positive. Five patients had positive ANA in titers of 1/100, while a patient with generalised morphea had significantly higher titer (1/1000). Antihistone antibodies were positive in one patient and 2 cases were Lyme IgM positive. Conclusion: Early diagnosis and therapy are important since childhood morphea can cause cosmetic deformities. Patients should be evaluated for accompanying systemic symptoms and, extracutaneous involvement should be investigated when the disease is suspected. Morfea (lokalize skleroderma) çocuklarda sistemik sklerozdan daha sık görülen inflamatuvar bir deri hastalığıdır. Özelikle lineer skleroderma bazen önemli fonksiyonel yetersizlik ve kozmetik bozukluklara neden olmaktadır. Ayrıca hastalarda ekstrakutanöz bulgular, ailede romatolojik hastalık öyküsü ve ANA ve RF pozitifliği gibi patolojik laboratuvar bulguları izlenebilir. Pediyatrik hastaların bu açıdan sorgulanması ve ileri tetkiklerin yapılması önem taşımaktadır. Literatürde ülkemizdeki morfealı çocukların verileriyle ilgili bilgi bulunmamaktadır. Bu çalışmayla kliniğimize başvuran olguların epidemiyolojik, klinik ve laboratuvar bulgularının incelenmesi, literatür verileriyle karşılaştırılması ve Türk popülasyonuna ait ileride çok merkezli ulusal çalışmalarla desteklenebilecek bir modelin oluşturulabilmesi amaçlanmıştır. Gereç ve Yöntem: Çalışmaya 2000-2010 yılları arasında Uludağ Üniversitesi Tıp Fakültesi Deri ve Zührevi Hastalıkları Anabilim Dalına başvuran, tanı anında 18 yaşın altında olan 3 erkek, 11 kız, toplam 14 pediyatrik morfealı hasta alındı. Hastaların epidemiyolojik, klinik ve laboratuvar verileri retrospektif olarak incelenerek kaydedildi. Bulgular: On dört hastanın 3’ü erkekti. Ortalama hastalık başlangıç yaşı 9,5 olarak değerlendirildi. Başvuru anında hastalık süresi ortalama 21 aydı. En sık görülen klinik tip lineer morfeaydı. İki hastada kontraktür, bir hastada sol ekstremitede kısalık mevcuttu. Dört hastada livedo retikülaris saptandı, 1 hastada Raynaud fenomeni pozitifti. Tetikleyici faktör olarak travma ve güneş yanığı öyküsü vardı. Bir hastada babada Behçet hastalığına rastlandı. Bir hastada RF pozitifti. Beş hastada ANA 1/100 titrede pozitif saptanırken yaygın morfealı bir hastada 1/1000 titrede anlamlı pozitiflik mevcuttu. Antihiston antikor bir olguda, Lyme Ig M ise 2 olguda pozitifti. Sonuç: Çocukluk çağında morfeanın erken tanı ve tedavisi deformitelere neden olabilmesi nedeniyle önemlidir. Hastalar detaylı bir anamnezle eşlik edebilecek sistemik bulgular açısından sorgulanmalı ve şüphelenildiğinde ekstrakutanöz tutulum araştırılmalıdır.

Background β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β4, β4 sulfoxide, and β10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. Methods β-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. Results Thymosin β4, β4 sulfoxide, and β10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β4 levels seem to have a protective role against lung tissue damage. Thymosin β4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. Conclusions We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status.

ContextHashimoto's thyroiditis (HT) and Graves' disease (GD), two autoimmune thyroid diseases (AITD), occur more frequently in women than in men and show an increased incidence in the years following parturition. Persisting fetal cells could play a role in the development of these diseases.ObjectiveAim of this study was to detect and characterize fetal cells in blood of postpartum women with and without an AITD.ParticipantsEleven patients with an AITD and ten healthy volunteers, all given birth to a son maximum 5 years before analysis, and three women who never had been pregnant, were included. None of them had any other disease of the thyroid which could interfere with the results obtained.MethodsFluorescence in situ hybridization (FISH) and repeated FISH were used to count the number of male fetal cells. Furthermore, the fetal cells were further characterized.ResultsIn patients with HT, 7 to 11 fetal cells per 1.000.000 maternal cells were detected, compared to 14 to 29 fetal cells in patients with GD (p=0.0061). In patients with HT, mainly fetal CD8(+) T cells were found, while in patients with GD, fetal B and CD4(+) T cells were detected. In healthy volunteers with son, 0 to 5 fetal cells were observed, which was significantly less than the number observed in patients (pConclusionThis study shows a clear association between fetal microchimeric cells and autoimmune thyroid diseases.

BACKGROUND: Biologic predictors or biomarkers of survival in pulmonary fibrosis with a worse prognosis, more specifically in idiopathic pulmonary fibrosis would help the clinician in deciding whether or not to treat since treatment carries a potential risk for adverse events. These decisions are made easier if accurate and objective measurements of the patients' clinical status can predict the risk of progression to death. METHOD: A literature review is given on different biomarkers of survival in interstitial lung disease, mainly in IPF, since this disease has the worst prognosis. CONCLUSION: Serum biomarkers, and markers measured by medical imaging as HRCT, pertechnegas, DTPA en FDG-PET are not ready for clinical use to predict mortality in different forms of ILD. A baseline FVC, a change of FVC of more than 10%, and change in 6MWD are clinically helpful predictors of survival. ispartof: Respiratory Research vol:11 issue:1 ispartof: location:England status: published

Objectives. To quantify nailfold capillary density and dimensions in patients with idiopathic inflammatory myopathy (IIM) and compare them with those in healthy controls; to look for associations with microvascular disease in IIM; and to determine whether nailfold capillary density and dimensions change over time. Methods. Nailfold video microscopy (x300 magnification) was performed on 24 patients with IIM and 35 healthy controls. Capillary density and dimensions (total width and apical width) were quantified. Patients were clinically assessed and disease activity recorded using the Myositis Disease Activity Assessment Tool. Disease severity and physical function were assessed using the myositis damage index and Stanford HAQ, respectively. Findings were analysed using linear and logistic regression, adjusted for age and sex. In a subgroup of 16 patients with IIM and 27 controls, the process was repeated 6-12 months later and the results were analysed using Student's t-test. Results. Capillary density was lower and dimensions were higher in patients with IIM compared with healthy controls (P < 0.001 for all). Anti-Jo-1 antibody was associated with reduced capillary density. In the longitudinal cohort, the mean change in capillary density was -1.4 in patients vs -0.4 in controls (P = 0.07). Mean change in capillary dimensions did not differ between patients and controls, but some patients demonstrated pronounced changes in capillary morphology over time. Conclusions. Reduced capillary density and increased dimensions in patients with IIM can be quantified using nailfold capillaroscopy, suggesting that nailfold capillaroscopy may be useful as an outcome measure of microvascular disease in studies of IIM.

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Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis.

Molecular mimicry between infectious agents and normal human host cell components is one of the mechanisms responsible for autoimmunity. Among infectious agents, some viruses represent ideal candidates for their ability to infect human cells, where they are harbored for the duration of the life of the host in a latent state. Human cytomegalovirus (hCMV) infection has been implicated in the pathogenesis of vascular damage in systemic sclerosis (SSc) and atherosclerosis. Based on recent data describing a cause and effect relationship between hCMV and endothelial cell damage in SSc and atherosclerosis, we propose that the immune response to particular hCMV proteins might result in autoaggression through a mechanism of molecular mimicry of normally expressed endothelial cell surface molecules.

Objective. To identify the optimal dose of oral iloprost bn the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. Design. Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. Setting. European university hospitals. Patients. A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. Intervention. Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 mu g or oral iloprost 100 mu g. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 mu g. Measurements. The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. Results. A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 mu g and 35 received iloprost 100 mu g. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment:differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 mu g and 64% iloprost 100 mu g (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 mu g and 97% on oral iloprost 100 mu g. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. Conclusion. The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 mu g oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 mu g iloprost dose was better tolerated in this patient group.

Background Transforming growth factor beta (TGFβ), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFβ on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown. Methods We used Affymetrix oligonucleotide microarrays U95v2, containing approximately 12,000 human genes, to study the transcriptional profile in response to a four hour treatment with TGFβ in control lung fibroblasts and in fibroblasts from patients with idiopathic and scleroderma-associated pulmonary fibrosis. A combination of the Affymetrix change algorithm (Microarray Suite 5) and of analysis of variance models was used to identify TGFβ-regulated genes. Additional criteria were an average up- or down- regulation of at least two fold. Results Exposure of fibroblasts to TGFβ had a profound impact on gene expression, resulting in regulation of 129 transcripts. We focused on genes not previously found to be regulated by TGFβ in lung fibroblasts or other cell types, including nuclear co-repressor 2, SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), bone morphogenetic protein 4, and angiotensin II receptor type 1 (AGTR1), and confirmed the microarray results by real time-PCR. Western Blotting confirmed induction at the protein level of AGTR1, the most highly induced gene in both control and fibrotic lung fibroblasts among genes encoding for signal transduction molecules. Upregulation of AGTR1 occurred through the MKK1/MKK2 signalling pathway. Immunohistochemical staining showed AGTR1 expression by lung fibroblasts in fibroblastic foci within biopsies of idiopathic pulmonary fibrosis. Conclusions This study identifies several novel TGFβ targets in lung fibroblasts, and confirms with independent methods the induction of angiotensin II receptor type 1, underlining a potential role for angiotensin II receptor 1 antagonism in the treatment of lung fibrosis.

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y α-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs 2.9 ± 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

Background: TGF-beta 1 controls many pathophysiological processes including tissue homeostasis, fibrosis, and cancer progression. Together with its latency-associated peptide (LAP), TGF-beta 1 binds to the latent TGF-beta 1-binding protein-1 (LTBP-1), which is part of the extracellular matrix (ECM). Transmission of cell force via integrins is one major mechanism to activate latent TGF-beta 1 from ECM stores. Latent TGF-beta 1 mechanical activation is more efficient with higher cell forces and ECM stiffening. However, little is known about the molecular events involved in this mechanical activation mechanism.