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The article focuses on a prospective observational, single-center cohort study which evaluated the capability of multiple platelet function tests to predict clinical outcome in patients undergoing coronary stent implantation. The study used patients taking clopidogrel and undergoing elective coronary stent implantation between December 2005 and December 2009. At 1-year follow-up, occurrence of the primary end point is more frequent in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry.

Background: Various studies have described decreased serum angiotensin-converting enzyme (ACE) activity in patients with pneumonia. The aim of the present study was to evaluate the role of ACE in pneumonia by comparing ACE insertion/deletion (I/D) genotype corrected serum ACE activity and to establish whether the severity of the disease correlates with lower ACE activity. Methods: This was a prospective hospital-based observational study including 134 patients with pneumonia. Serum ACE activity was determined at admission, on days 2, 3, 5 and 10 of hospital stay, and at recovery. Based on ACE genotype and reference values, corresponding Z-scores were calculated. Disease severity, quantified by the acute physiology score (APS), and clinical outcome were compared between tertile groups of the Z-scores. Results: A significant decrease in serum ACE activity during an episode of pneumonia with return to control range during recovery was observed for all three genotypes (II, ID and DD). The calculated Z-scores showed a negative correlation with APS scores (p=0.050). No significant association between decreased serum ACE activity and clinical outcome was observed. Conclusions: Serum ACE activity is significantly decreased during the acute phase of pneumonia. Despite correction for ACE I/D genotype, decreased ACE activity did not show a prognostic value. Further studies are needed to examine the mechanisms behind and diagnostic value of decreased ACE activity in community-acquired pneumonia. Clin Chem Lab Med 2007;45:1326–31. [ABSTRACT FROM AUTHOR]

Background: Chymase is released from mast cells following activation. Evidence suggests that chymase plays an important role in tissue injury and remodeling of the lungs, heart and skin. Objective: We postulated that chymase gene (CMA1) polymorphisms are associated with pulmonary fibrosis in Dutch and with cardiac and skin involvement in Japanese sarcoidosis patients. Patients and Methods: Dutch (n = 153) and Japanese (n = 122) sarcoidosis patients with controls (Dutch, n = 309; Japanese, n = 111) were studied. Pulmonary involvement in Dutch patients as well as clinical manifestations in Japanese patients was evaluated for association with five CMA1 polymorphisms. Results: The CMA1 polymorphisms were not associated with disease susceptibility in either population, or with radiographic evolution in the Dutch or with cardiac or skin involvement in the Japanese patients. The –526 T allele was associated with a lower iVC in Dutch patients. Conclusions: The CMA1 polymorphisms studied do not contribute to disease susceptibility in Japanese or Dutch sarcoidosis patients. CMA1 polymorphisms do not influence radiographic evolution in Dutch sarcoidosis patients, nor do they predispose to cardiac or skin involvement in Japanese patients. However, the association between CMA1 –526 C/T and iVC in the Dutch patients suggests that chymase may modify the functional outcome of pulmonary sarcoidosis. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Study Objectives: Pulmonary fibrosis develops in approximately 25% of patients with chronic sarcoidosis. Transforming growth factor (TGF)-beta1 plays a central role in fibrosis, and accruing reports address the implication of TGF-beta2 and TGF-beta3 in this process. We determined whether single-nucleotide polymorphisms (SNPs) in the TGF-beta1, TGF-beta2, and TGF-beta3 genes might contribute to pulmonary fibrosis in sarcoidosis patients. Setting: A hospital in the Netherlands. Design: Five SNPs per TGF-beta gene were investigated. Patients and Control Subjects: Patients with either acute/self-remitting sarcoidosis (n = 50) and Löfgren syndrome (n = 46) or chronic disease with fibrosis (n = 24) and without fibrosis (n = 34) were assessed over a 4-year follow-up period. The control subjects included 315 individuals. Measurements and Results: Polymorphism frequencies were not discordant between the patients and control subjects. The TGF-beta3 4875 A allele was significantly higher in fibrotic patients (carrier frequency, 0.29) than in patients with acute/self-remitting (0.06) and chronic (0.03) sarcoidosis combined (corrected p = 0.01; odds ratio [OR], 7.9). The TGF-beta3 17369 C allele carrier frequency was significantly higher in fibrotic patients (0.29) compared to acute/self-remitting (0.08) and chronic (0.06) patients combined (corrected p = 0.05; OR, 5.1). Although not significant after correction, the TGF-beta3 15101 G allele carrier frequency was lower in fibrotic patients (0.79) compared to acute/self-remitting (0.94) and chronic (1.00) patients combined (p = 0.02; corrected p = 0.1; OR, 0.15). The TGF-beta2 59941 G allele was more abundant in fibrotic patients (carrier frequency, 0.62) compared to patients with acute/self-remitting (0.41) and chronic sarcoidosis combined (0.28) [p = 0.04; corrected p = 0.2; OR, 2.9]. TGF-beta1 gene polymorphisms were not associated with fibrosis. Conclusions: This study is the first to suggest the implication of genetic variation of TGF-beta3 in the predilection for pulmonary fibrosis developing in sarcoidosis patients. [ABSTRACT FROM AUTHOR]

Insulin can be measured by immunochemical methods using polyclonal or monoclonal antibodies. Monoclonal antibodies are specific in the detection of pure human insulin, and may show little to no cross reactivity with pro-insulin or recombinant insulin. Polyclonal antibodies, however, do show such cross reactivity. Most medical laboratories use commercial (monoclonal) methods to measure insulin 75% of which are not capable of detecting pro-insulin or exogenous insulin. This pitfall in diagnostics may lead to prolonged uncertainty for both patient and physician, which we illustrate with two patients. The first patient was a 45-year-old woman with DM type 1 who for years suffered from hypoglycaemic attacks. Factitious hypoglycaemia went undiagnosed because our monoclonal assay did not detect the overdose insulin analogues. The second patient was a 47-year-old woman with recurrent hypoglycaemic attacks. An insulinoma, which produced pro-insulin, was only detected after using polyclonal insulin and specific pro-insulin assays.

Survival rates after lung transplantation are the lowest among solid organ transplantations. Long-term survival is limited by the development of chronic rejection, known as bronchiolitis obliterans syndrome (BOS). Risk factors, such as acute rejection and cytomegalovirus infection, contribute to the development of BOS. However, these risk factors alone do not explain the interindividual variability seen in the development of BOS. There is growing evidence that genetic variations might contribute to an individual's susceptibility to rejection. In this systematic review, based on a literature search through Medline and Embase, an overview is given of the genetic polymorphisms that have been investigated in lung transplant recipients in relation to the devlopment of BOS. Functional genetic polymorphisms in the genes of IFNG (+874 A/T), TGFB1 (+915 G/C), and IL6 (-174 G/C) have been found to be associated with the development of BOS and allograft fibrosis after lung transplantation. However, confirmation was not consistent across all studied cohorts. Genetic polymorphisms in the genes of several Toll-like receptors, mannose-binding lectin, CD14, killer immunoglobulin-like receptors, and matrix metalloproteinase-7 were also found to be associated with the development of BOS, but these studies need to be replicated in independent cohorts. This review shows that there may be involvement of genetic polymorphisms in the development of BOS. Genetic risk profiling of lung transplant recipients could be a promising approach for the future, enabling individualized risk stratification and personalized immunosuppressive treatment after transplantation. Further studies are needed to define risk alleles.

Background: In a previous study, a relation between decreased serum angiotensin-converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community-acquired pneumonia., Methods: This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004-2006; n=157 and 2007-2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups., Results: A total of 265 patients were enrolled in this study. Mean age was 60±19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (≥20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57-9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality., Conclusions: This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia.

Background: The chitinase-like protein YKL-40 is a serum biomarker in diseases with fibrosis, inflammation and tissue remodelling. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that is hallmarked by these processes. The aim of this study was to investigate the potential of YKL-40 as a prognostic biomarker for survival in IPF patients., Methods: Serum and bronchoalveolar lavage fluid (BALF) levels of YKL-40 at the time of diagnosis and a promoter polymorphism in CHI3L1, the gene encoding YKL-40, were determined in 85 IPF patients and 126 controls. The relationship between YKL-40 levels and clinical parameters was evaluated. Kaplan-Meier and Cox regression analyses were used to examine the association between YKL-40 levels and survival., Results: Serum and BALF YKL-40 levels were significantly higher in patients than in healthy controls (p < 0.001). The - 329 A/G polymorphism had a significant influence on BALF YKL-40 levels and the influence on serum YKL-40 levels showed a trend towards significance in IPF patients. IPF patients with high (> 79 ng/ml) serum or high BALF YKL-40 (> 17 ng/ml) levels had significantly shorter survival than those with low YKL-40 levels in serum or BALF. In patients with both low serum and low BALF YKL-40 levels no IPF related mortality was observed. Cox regression modelling showed that there were no confounding factors., Conclusions: The - 329 polymorphism was associated with serum and BALF YKL-40 levels in IPF patients. High serum and BALF YKL-40 levels are associated with poor survival in IPF patients and could be useful prognostic markers for survival in IPF., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Activation of the immune system is suggested to prevent transplant tolerance and to promote the development of bronchiolitis obliterans syndrome (BOS). The innate immune system is activated by the interaction of pathogen-associated molecular patterns of microorganisms with Toll-like receptors (TLRs). Activation of innate immunity via TLRs was shown to be a barrier to the induction of transplantation tolerance after lung transplantation. We hypothesized that polymorphisms in 10 genes coding for TLR1 to TLR10 might contribute to an altered immune response and the subsequent development of BOS., Methods: DNA was collected from 110 lung transplant recipients. Twenty patients developed BOS. The control group comprised 422 individuals. Sixty-four single-nucleotide polymorphisms (SNPs) in 10 genes coding for TLR1 to TLR10 were genotyped., Results: The genotype distribution of TLR2 (rs1898830 and rs7656411), TLR4 (rs1927911) and TLR9 (rs352162 and rs187084) was significantly different between BOS(pos) patients and BOS(neg) patients and controls. The BOS(pos) group had significantly more patients with 3 or 4 of these risk alleles compared with the BOS(neg) and control groups., Conclusions: Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: CA 15-3 is a widely used tumor marker for breast cancer. We have investigated whether the MUC1 568 A/G polymorphism can influence CA 15-3 levels in healthy women and patients with breast tumors., Design and Methods: CA 15-3 was measured in 208 healthy women, in 67 with benign disease, and in 162 women with breast cancer. All subjects were genotyped for the MUC1 568 A/G polymorphism., Results: Significant differences were observed between mean CA 15-3 levels of control subjects grouped according to the MUC1 568 genotype (mean+/-SD): AA (10.3+/-3.8), AG (15.9+/-5.0) and GG (19.0+/-5.6) U/mL, p<0.0001. Similar (median) results were observed in women with benign breast disease: AA (10.2), AG (14.2) and GG (16.6) U/mL, p<0.0001, and those with breast cancer: AA (10.4), AG (17.1) and GG (23.9) U/mL, p<0.0001., Conclusions: The MUC1 568 A/G polymorphism strongly influences CA 15-3 levels in healthy women and women with either benign or malignant breast tumors.

Nonparametric approaches have been developed that are able to analyze large numbers of single nucleotide polymorphisms (SNPs) in modest sample sizes. These approaches have different selection features and may not provide similar results when applied to the same dataset. Therefore, we compared the results of three approaches (set association, random forests and multifactor dimensionality reduction [MDR]) to select from a total of 93 candidate SNPs a subset of SNPs that are important in determining high-density lipoprotein (HDL)-cholesterol levels. The study population consisted of a random sample from a Dutch monitoring project for cardiovascular disease risk factors and was dichotomized into cases (low HDL-cholesterol, n = 533) and non-cases (high HDL-cholesterol, n = 545) based on gender-specific median values for HDL cholesterol. Clearly, all three approaches prioritized three SNPs as important (CETP Taq1B, CETP-629 C/A and LPL Ser447X). Two SNPs with weaker main effects were additionally prioritized by random forests (APOC3 3175 G/C and CCR2 Val62Ile), whereas MTHFR 677 C/T was selected in combination with CETP Taq1B as best model by MDR. Obtained p-values for the selected models were significant for the set association approach (p =.0019), random forests (p<.01) and MDR (p<.02). In conclusion, the application of a combination of multi-locus methods is a useful approach in genetic association studies to select a well-defined set of important SNPs for further statistical and epidemiological interpretation, providing increased confidence and more information compared with the application of only one method., ((c) 2007 Wiley-Liss, Inc.)

Background: YKL-40, a chitinase-like cartilage glycoprotein, has recently shown its potential as a marker for sarcoidosis., Methods: This study aimed to assess whether YKL-40 at presentation may predict the course of sarcoidosis over a 4-year follow-up period and to investigate whether polymorphisms in the chitinase 3-like 1 (CHI3L1) gene might influence serum YKL-40 levels in sarcoidosis patients (n=63) and controls (n=333)., Results: Patients had significantly higher (mean, 95% CI) serum YKL-40 levels (181.3 ng/ml, 50.7-648.1) compared to controls (36.6 ng/ml, p<0.0001. Serum YKL-40 was elevated in 79% of the patients and was inversely correlated with DLco at presentation (r(2)=-0.27, p=0.03), but not after 2-4 years of follow-up (r(2)=-0.16, p=0.27). Serum YKL-40 levels in controls were dependent on the CHI3L1 -329 G/A polymorphism (mean, 95% CI): GG (n=213) 48.3 ng/ml, 41.7-56.0; GA (n=101) 31.2 ng/ml, 26.6-36.3; AA (n=17) 17.8 ng/ml, 13.6-23.4, p<0.0001. In patients, this effect was not observed., Conclusions: YKL-40 may be used as a sarcoidosis disease marker, but it is unsuitable as a marker to predict the course of the disease. The CHI3L1 -329 G/A polymorphism contributes to inter-individual variations of YKL-40 levels, but does not influence sarcoidosis disease susceptibility or severity.

Background: The value of elevated serum angiotensin-converting enzyme (ACE) activity in the diagnosis and follow-up in sarcoidosis is a matter of ongoing debate. This may be at least related to the insertion (I)/deletion (D) polymorphism in the ACE gene (ACE I/D). ACE activity is influenced by the ACE I/D polymorphism. As a consequence, the use of one reference interval instead of three genotype-specific reference intervals for ACE activity may lead to a less precise interpretation of ACE activity., Methods: In order to assess whether determination of ACE activity indeed requires the ACE I/D genotype to be taken into account, we established ACE I/D-corrected reference intervals in healthy, Caucasian volunteers (n=200). In addition, ACE activities in ACE I/D genotyped patients suspected of or having sarcoidosis (n=129) were expressed as the Z-score related to ACE I/D-corrected reference intervals., Results: Comparison of the Z-score with ACE activity in which ACE I/D is ignored rendered 8.5% misclassification of 'elevated' versus 'normal' ACE or vice versa., Conclusions: Our data demonstrate a convenient way to circumvent the use of three reference intervals by introducing a Z-score for ACE activity. It also illustrates the need to re-investigating the possible clinical value of serum ACE activity in sarcoidosis by considering ACE I/D.

Background and Aim of the Study: Angiotensin II (Ang II) formation by angiotensin-converting enzyme (ACE) or other enzymes has shown to exhibit profibrotic properties in a variety of fibrotic diseases. A homologue of ACE called ACE2 has been shown to counteract the formation of Ang II. Genetic variation in the components involved in Ang II formation may underlie the progression of pulmonary sarcoidosis., Method: Seven ACE2 SNPs, located on the X-chromosome, were investigated using SSP-PCR and haplotypes were constructed. Gender-matched analyses of sarcoidosis patients (80 males/64 females) and controls (110 males/218 females) were performed to correlate disease susceptibility and pulmonary disease phenotypes with ACE2 genotypes and haplotypes., Results: ACE2 SNPs or haplotypes were not associated with susceptibility for sarcoidosis. Haplotype 4 was only present in sarcoid males without parenchymal involvement (frequency: 0.19) and absent in males with parenchymal involvement (p = 0.006; pcorr. = 0.05; degrees of freedom (df) = 1; OR = 0). No significant difference was observed between haplotype 4 frequencies in females with (0.08) or without (0.13) parenchymal involvement (p = 0.5). Although not significant after correction, analysis of the patient group with fibrosis showed that males with haplotype 5 (0.27) were predominant over those with haplotype 5 of the groups without fibrosis (0.03); p = 0.01; pc = 0.08; df = 1; OR = 11.4. Females with fibrosis vs. no fibrosis revealed no difference between haplotype 5 frequencies: 0.05 vs. 0.03; p = 0.37; pc = 1; df = 1., Conclusion: These results suggest that ACE2 might be involved in the progression of pulmonary sarcoidosis which may depend on gender. Subsequent studies using larger groups are needed to confirm these findings.

The variation in cystic fibrosis (CF) lung disease and development of CF related complications correlates poorly with the genotype of the CF transmembrane regulator (CFTR) and with environmental factors. Increasing evidence suggests that phenotypic variation in CF can be attributed to genetic variation in genes other than the CFTR gene, so-called modifier genes. In recent years, multiple candidate modifier genes have been investigated in CF, especially genes that are involved in the control of infection, immunity and inflammation. Some of these genes have been rather conclusively identified as modifiers of the CF phenotype, whereas associations found in other genes have not been confirmed or are conflicting. Identification of genetic variation in modifier genes, obtained by genotype-phenotype studies in well-defined patient populations, may be used as an aid to prognosis and may provide the possibility of new therapeutic interventions.

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.