Search

Background: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F2α (PGF2α) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF2α in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF2α in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF2α, a stable metabolite of PGF2α. Methods: We measured plasma concentrations of 15-keto-dihydro PGF2α in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF2α concentrations with disease severity and mortality. Results: Plasma concentrations of 15-keto-dihydro PGF2α were significantly higher in IPF patients than controls (p<0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (Rs [correlation coefficient] = −0.34, p = 0.004), forced vital capacity (Rs = −0.33, p = 0.005), diffusing capacity for carbon monoxide (Rs = −0.36, p = 0.003), the composite physiologic index (Rs = 0.40, p = 0.001), 6-minute walk distance (Rs = −0.24, p = 0.04) and end-exercise oxygen saturation (Rs = −0.25, p = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, p = 0.002) and plasma 15-keto-dihydro PGF2α concentrations (relative risk = 1.005, p = 0.002) were independently associated with an increased risk of mortality. Conclusions: We demonstrated significant associations of plasma concentrations of PGF2α metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF2α in human IPF. [ABSTRACT FROM AUTHOR]

Abstract: The action of C60 fullerene and its derivatives as a radical-scavenging antioxidant has received much attention, but their reactivity toward free radicals and antioxidant capacity have not been well elucidated yet. In the present study, the reactivity of the two types of water-soluble, sugar-pendant C60 fullerenes, C60-1S and C60-2S, toward peroxyl radical and their effect against human plasma lipid peroxidation were measured. The rate constants for the reaction of C60-1S and C60-2S with peroxyl radicals were obtained from their effect on the bleaching of β-carotene in lipid-SDS micelle system as 4.6×103 and 8.0×103 M−1 s−1 at 37°C, respectively. They inhibited the free radical-induced lipid peroxidation in human plasma in a concentration-dependent manner. These results suggest that the sugar-pendant fullerenes C60-1S and C60-2S act as a radical-scavenging antioxidant with the activity similar to the phenolic antioxidants. [Copyright &y& Elsevier]

A 68-year-old man presented with right buccal ulceration along the facial artery, temporal pain, lagophthalmos, diplopia, and tongue deviation to the right. Contrast-enhanced computed tomography showed bilateral temporal artery and right maxillary artery wall thickening, and a diagnosis of giant cell arteritis (GCA) was made according to the American College of Rheumatology 1990 criteria. Treatment with corticosteroids ameliorated his symptoms. This is the first report of GCA with buccal skin ulceration along a facial artery. Because a delayed diagnosis can lead to irreversible damage, it is essential to notice rare symptoms, such as skin ulceration and multiple cranial neuropathy-like symptoms.

Reactive amyloidosis is a serious systemic disease in rheumatoid arthritis (RA). Amyloid protein can be deposited in kidneys, heart or gastrointestinal tract leading to organ failure. Renal involvement is a well-known complication in amyloidosis as this may culminate in end-stage renal disease (ESRD). Hemodialysis (HD) is always considered the treatment of choice for such patients; however, the prognosis is usually poor due to a large number of sudden deaths immediately following HD therapy. To circumvent the problem of HD initiation while instituting HD safety, we devised a plan to start HD and compare patient's survival with our previous data. Sixty-three patients were treated with HD. They were categorized according to the initiation of first dialysis. All patients were divided into planned, unplanned and programmed initiation groups. First dialysis that had been initiated as not urgent was considered 'planned' (20 patients). First dialysis that had been performed urgently for life-threatening renal insufficiency was considered 'unplanned' (31 patients). First dialysis that had been initiated as not urgent and according to our dialysis program was considered 'programmed' (12 patients). Survival of these 63 patients from the initiation of HD at 38 days was 75%, at 321 days was 50% and at 1,784 days was 25%. Patients with unplanned initiation of HD showed a significant poor survival compared with those of both planned and programmed initiation. Additionally, patients with planned and programmed initiation of HD showed no significant difference for the patients' survival. Our study demonstrates that patients with amyloidosis have a higher mortality rate. Nevertheless, programmed initiation of HD will improve the prognosis of patients with ESRD. Such possibility needs to be considered in more detail in the future.

Background: Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy., Results: We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype., Conclusion: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-beta1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-beta1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-beta1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-beta1 variants or haplotypes. The -509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the -509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the -509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the -509C and codon 10T, implicated in lower levels of TGF-beta1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-beta1, although future studies will be needed to correlate TGF-beta1 protein levels with known TGF-beta1 genotypes and assess whether there is a shared mechanisms for TGF-beta1 in these two granulomatous diseases.

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.

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.

Background: Genes encoding cytokine mediators are prime candidates for genetic analysis in conditions with T-helper (Th) cell disease driven imbalance. Idiopathic Pulmonary Fibrosis (IPF) is a predominantly Th2 mediated disease associated with a paucity of interferon-gamma (IFN-gamma). The paucity of IFN-gamma may favor the development of progressive fibrosis in IPF. Interleukin-12 (IL-12) plays a key role in inducing IFN-gamma production. The aim of the current study was to assess whether the 1188 (A/C) 3'UTR single nucleotide polymorphism (SNP) in the IL-12 p40 subunit gene which was recently found to be functional and the 5644 (G/A) 3' UTR SNP of the IFN-gamma gene were associated with susceptibility to IPF., Methods: We investigated the allelic distribution in these loci in UK white Caucasoid subjects comprising 73 patients with IPF and 157 healthy controls. The SNPs were determined using the polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3'-end., Results: Our results showed that these polymorphisms were distributed similarly in the IPF and control groups, Conclusion: We conclude that these two potentially important candidate gene single nucleotide polymorphisms are not associated with susceptibility to IPF.