The pivotal role of neutrophils and macrophages in smoking-related lung inflammation and COPD development is well-established.We aimed to assess whether sputum concentrations of Human Neutrophil Peptides (HNP), Neutrophil Elastase (NE), Interleukin-8 (IL-8), and Metalloproteinase-9 (MMP-9), major products of neutrophils and macrophages, could be used to trace airway inflammation and progression towards pulmonary functional impairment characteristic of COPD.Forty-two symptomatic smokers and 42 COPD patients underwent pulmonary function tests; sputum samples were collected at enrolment, and 6 months after smoking cessation.HNP, NE, IL-8, MMP-9 levels were increased in individuals with COPD (p &lt; 0.0001). HNP and NE concentrations were higher in patients with severe airways obstruction, as compared to patients with mild-to-moderate COPD (p = 0.002). A negative correlation was observed between FEV1 and HNP, NE and IL-8 levels (p &lt; 0.01), between FVC1/FVC and HNP, NE and IL-8 levels (p &lt; 0.01), and between NE enrolment levels and FEV1 decline after 2 years (p = 0.04).ROC analysis, to discriminate symptomatic smokers and COPD patients, showed the following AUCs: for HNP 0.92; for NE 0.81; for IL-8 0.89; for MMP-9 0.81; for HNP, IL-8 and MMP-9 considered together 0.981.The data suggest that the measurement of sputum markers may have an important role in clinical practice for monitoring COPD.

Gregorino Paone

Vittoria Conti

Annarita Vestri

Alvaro Leone

Giovanni Puglisi

Fulvio Benassi

Giuseppe Brunetti

Giovanni Schmid

Ilio Cammarella

Claudio Terzano

Analysis of Sputum Markers in the Evaluation of Lung Inflammation and Functional Impairment in Symptomatic Smokers and COPD Patients

We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.

Casey Sarapas

Guiqing Cai

Linda M. Bierer

Julia A. Golier

Sandro Galea

Marcus Ising

Theo Rein

James Schmeidler

Bertram M&#xfc;ller-Myhsok

Manfred Uhr

Florian Holsboer

Joseph D. Buxbaum

Rachel Yehuda

Genetic Markers for PTSD Risk and Resilience Among Survivors of the World Trade Center Attacks

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women.A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T&#x2192;C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted.Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR = 3.01; 95&#x25; CI = 1.74&#x2013;5.23; P = 2.9 &#xd7; 10&#x2212;4).Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker.

Lizbeth D&#xed;az-Olgu&#xed;n

Ram&#xf3;n Mauricio Coral-V&#xe1;zquez

Thelma Canto-Cetina

Samuel Canizales-Quinteros

Belem Ram&#xed;rez Regalado

Genny Fern&#xe1;ndez

Patricia Canto

Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Preeclampsia in Maya Mestizo Women

Introduction and Aims: Acute and chronic heart failure may manifest different degrees of endothelial damage and angiogenesis. Circulating endothelial cells (CEC) have been identified as marker of vascular damage. The aim of our study was to evaluate the evolution of the CEC at different stages of patients with heart failure. We also investigated a potential correlation between CEC and markers of vascular damage and angiogenesis.Methods: We studied 32 heart failure patients at hospital admission (acute phase) and at revision after 3 months (stable phase) and 32 controls. Circulating markers of endothelial damage (CEC; von Willebrand factor, vWF and soluble E-selectin, sEsel) and angiogenesis (vascular endothelial growth factor, VEGF and thrombospondin-1) were quantified.Results: Levels of CEC, vWF, sEsel and VEGF are significantly higher in heart failure patients than in controls. Levels of CEC (36.9 &#xb1; 15.3 vs. 21.5 &#xb1; 10.0 cells/ml; p &lt; 0.001), vWF (325 &#xb1; 101 vs. 231 &#xb1; 82&#x25;; p &lt; 0.001) and VEGF (26.3 &#xb1; 15.2 vs. 21.9 &#xb1; 11.9 ng/ml; p &lt; 0.001) are significantly higher in the acute phase than in the stable phase of heart failure. CEC levels correlate with vWF and VEGF. Results show than 100&#x25; of patients in acute phase and 37.5% in stable phase have levels of CEC higher than the 99th percentile of the distribution of controls (16 cells/ml). Therefore, increases in CEC represent a relative risk of 9.5 for heart failure patients suffering from acute phase.Conclusions: CEC, in addition to being elevated in heart failure, correlate with vWF levels, providing further support for CEC as markers of endothelial damage. Levels of CEC are associated with the acute phase of heart failure and could be used as a marker of the worsening in heart failure.

Vicenta Mart&#xed;nez-Sales

Ignacio S&#xe1;nchez-L&#xe1;zaro

Virtudes Vila

Luis Almenar

Teresa Contreras

Edelmiro Reganon

Circulating Endothelial Cells in Patients with Heart Failure and Left Ventricular Dysfunction

Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

Ananda B. Amstadter

Nicole R. Nugent

Bao-Zhu Yang

Alisa Miller

Richie Siburian

Priya Moorjani

Stephen Haddad

Aditi Basu

Jesen Fagerness

Glenn Saxe

Jordan W. Smoller

Karestan C. Koenen

Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1) Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients

Aims: To investigate the hypothesis that circulating resistin reflects the degree of pulmonary inflammation, this study explores putative roles of resistin in patients with acute and stable inflammatory obstructive airway diseases and cigarette smokers.Methods: We determined complements C3, C4, fasting resistin, insulin, glucose and lipid profile; calculated insulin resistance (homeostasis model assessment (HOMA-IR) in patients with acute asthma exacerbation (n = 34); stable asthma (n = 26) and stable chronic obstructive pulmonary disease (COPD; n = 26), cigarette smokers (n = 81), and healthy control subjects (n = 42). We determined the associations between these variables and pulmonary function tests.Results: Patients with COPD, acute and stable asthma had significantly higher resistin and insulin than control subjects. Resistin, insulin, HOMA-IR, FEV1&#x25; and FEV1/FVC were significantly (p &#x3c; 0.05) different between patients with acute asthma compared with stable asthma and COPD; smokers had similar levels of resistin, C3 and C4 as patients with asthma and COPD. In smokers,
patientswith asthma or COPD, resistin showed significant inverse correlations with FEV1&#x25;; FEV1/FVC&#x25; and positive significant correlations with BMI and HOMA-IR. Logistic regression showed that resistin is associated (p &#x3c; 0.05) with inflammatory obstructive airways disease &#x2212; odds ratio (OR) = 1.22 and smoking OR = 1.18.Conclusion: Resistin may be a disease activity marker and may contribute to insulin resistance in smokers, asthma and COPD.

Sana S. Al Mutairi

Olusegun A. Mojiminiyi

Aida Shihab-Eldeen

Tahani Al Rammah

Nabila Abdella

Putative Roles of Circulating Resistin in Patients with Asthma, COPD and Cigarette Smokers

A molecular diagnostic assay using easily accessible peripheral blood would greatly assist in the screening and diagnosis of ulcerative colitis (UC) and Crohn&#x2019;s disease (CD). Transcriptional profiles in blood/biopsy samples from 12 UC (6/12), 9 CD (5/9), 6 non-inflammatory bowel disease (non-IBD) colitis (6/0), and 11 healthy (11/11) patients were assessed by Affymetrix HGU133Plus2.0 microarrays. Prediction analysis of microarrays, discriminant and ROC analyses were performed, the results were validated by RT-PCR and immunohistochemistry using also an independent set of samples (15 blood samples, 45 biopsies). A set of 13 transcripts was differentially expressed in IBD, non-IBD controls and healthy blood samples (100&#x25; specificity and sensitivity). Validated difference was found in 16 transcripts between UC, non-IBD and normal blood, and 4 transcripts between CD, non-IBD and normal samples. UC and CD blood cases could be also distinguished by 5 genes with 100&#x25; specificity and sensitivity. Some disease associated alterations in blood transcripts were also detected in colonic tissue. IBD subtypes may be discriminated from non-IBD (diverticulitis, infective and ischemic colitis) in vitro from peripheral blood by screening for differential gene expression revealed in this study. Transcriptional profile alterations in peripheral blood can be located in diseased colon.

Ferenc Sipos

Orsolya Galamb

Barnab&#xe1;s Wichmann

Tibor Kren&#xe1;cs

Kinga T&#xf3;th

Katalin Leiszter

Gy&#xf6;rgyi M&#x26;udblac;zes

Tam&#xe1;s Z&#xe1;goni

Zsolt Tulassay

B&#xe9;la Moln&#xe1;r

Peripheral Blood Based Discrimination of Ulcerative Colitis and Crohn&#x2019;s Disease from Non-IBD Colitis by Genome-Wide Gene Expression Profiling

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

Disease Markers