Elevated Neopterin Levels Research Articles

185 (PB-086) - Clinical value of serum neopterin in breast cancer

Background: The immune marker neopterin may have a prognostic role in different cancers including breast cancer. Aim: To assess the relation between pre-chemotherapy serum level of neopterin and the clinical and pathological features of breast cancer patients. Methods:Sixty-three patients with histologically confirmed breast cancer and 20 healthy females matched for age and sex as controls were included. All patients were subjected to full history taking, thorough medical examination and complete investigation. Venous blood samples were collected from all participants to measure serum neopterin level. Serum neopterin level more than 10 nMolL was considered elevated. Results: The mean serum neopterin level among patients was 8 ± 7.43. Twenty-two patients (34.9%) had elevated serum neopterin level. Neopterin was found to be significantly elevated in patients with advanced stages and grade III tumors. Metastatic disease was associated with significantly higher levels of neopterin (p = 0.04). There was no significant association between high neopterin level and mean time to progression or overall survival. Conclusion:Among breast cancer patients, the immune marker neopterin was significantly related to metastatic disease and it could be considered a potential marker for systemic spread of the tumor.

Elevated serum neopterin levels in children with functional constipation: association with systemic proinflammatory cytokines.

Functional constipation is a clinical problem with an incompletely understood etiology. Functional bowel diseases have been shown to be related to inflammation in many studies in adults. In this study, we aimed to evaluate leukocytes, C-reactive protein, proinflammatory and anti-inflammatory cytokines, and neopterin levels in children with functional constipation. Seventy-six children with constipation and 71 healthy controls (mean age 7.12±3.46years and 7.32±4.33years, respectively, P=0.991) were included in the study. Leukocytes, C-reactive protein, interleukin (IL)-1β, IL-6, IL-10, IL-12, tumor necrosis factor-alpha (TNF-α) and neopterin levels were assessed in patients and healthy controls. Parameters were measured in the serum using enzyme-linked immunosorbent assay methods. Mean IL-6 (20.31±12.05 vs. 16.2±10.25pg/mL, respectively, P=0.003), IL-12 (181.42±133.45 vs. 135.6±83.67pg/mL, respectively, P=0.018) and neopterin levels (2.08±1.12 vs. 1.52±1.02pg/mL, respectively, P=0.001) were significantly higher in constipated children than healthy controls. Leukocyte and thrombocyte counts, C-reactive protein, and IL-1β, IL-10 and TNF-α levels did not show any difference between the two groups. In this study, IL-6, IL-12 and neopterin levels of constipated patients were found to be higher than those of controls. These results indicate the presence of subclinical inflammation in children with functional constipation.

Neopteryna jako wskaźnik stanu zapalnego i rozrostu nowotworowego w ostrych białaczkach

Introduction. Neopterin (NPT) is a sensitive marker for cellular immune responses. It is a pteridine group compound as a dye substance in insects, lower vertebrata and mammals. Neopterin is released from human monocytes, macrophages and dendritic cells upon stimulation by interferon gamma produced by T-lymphocytes. High neopterin concentrations in serum and urine were shown to be a reliable indicator for the severity of bacterial, viral infections including autoimmune diseases, allograft rejections and various malignant disorders. Aim. The aim of the study was the concentration of the neopterin in acute leukemias may be an endogenous marker of unfavorable processes in acute leukemia for which the growth of the tumor, the coexistence of inflammation. Material and methods. The studies involved 80 patients suffering from acute leukemias including 53 patients with acute myeloid leukemia, 21 patients with acute lymphoblastic leukemia and 6 patients with mixed phenotype acute leukemia. The patients with acute leukemia was analyzed as a group with inflammatory condition and a group without inflammatory condition. The quantitative assessment of serum neopterin level was performed by means of immunoenzymatic test ELISA. Results. Patients with all types of leukemia showed elevated serum neopterin levels in comparison to the control group and significantly elevated neopterin levels in patients with coexisting inflammation compared to the values of these parameters in patients without inflammation. The neopterin concentration was highest in the group of patients diagnosed with acute M4 and M5 leukemia, both without inflammation (32.8 ± 13.6 nmol/l) and with co-existing inflammation (116.57 ± 97.0 nmol/l) (p = 0.00024). Conclusions. Neopterin as a marker of malignant hyperplasia may be used only in cases where inflammation does not occur.

Elevated Neopterin Levels Are Associated with Increased Tuberculosis Risk in Rheumatoid Arthritis Patients with QuantiFERON Conversion during Biologic Therapy.

QuantiFERON-TB-Gold (QFT-G) conversion is frequently observed in rheumatoid arthritis (RA) patients receiving biologic therapy. However, there have not been any known biomarkers available for detecting tuberculosis (TB) in QFT-G converters. We aimed to evaluate clinical utility of cytokines/chemokines for detecting TB in patients with QFT-G conversion. Among a total of 227 RA patients who underwent QFT-G assay, 187 QFT-G-negative patients received biologic therapy without isoniazid prophylaxis. QFT-G assay was repeated at week 52 of biologic therapy or at the time of TB diagnosis. Levels of cytokines/chemokines were determined by magnetic bead array or ELISA in QFT-G converters and 12 non-RA patients with TB (non-RA TB). QFT-G conversion was found in 54 (28.9%) of 187 baseline QFT-G-negative patients, of which 7 (13.0%) developed active TB during the one-year follow-up period. Among the examined cytokines/chemokines, non-stimulated and TB-antigen-stimulated neopterin levels were significantly higher in RA patients who developed TB (RA-TB) (median, 24.5pg/ml and 23053pg/ml, respectively) and non-RA TB patients (12.2pg/ml and 9633pg/ml, respectively) compared with QFT-G converters without TB (3.0pg/ml and 2720pg/ml, respectively, both p<0.001). Rising levels of neopterin relative to baseline (non-stimulated levels, 4.4pg/ml vs. 24.5pg/ml; TB-antigen-stimulated levels, 1801pg/ml vs. 23053pg/ml) were observed in QFT-G converters who developed TB. A high proportion (85.7%) of QFT-G converters with high plasma neopterin levels developed TB during the one-year follow-up period. In conclusion, RA patients with QFT-G conversion during the period of biologic therapy should be carefully monitored for elevation of neopterin levels, which is associated with TB risk in QFT-G converters, particularly in TB-endemic areas.

Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO)

Neopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves. In a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed. Elevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004). In ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.

No relationship between lipoprotein-associated phospholipase A2, proinflammatory cytokines, and neopterin in Alzheimer's disease

ObjectiveLipoprotein-associated phospholipase A2 (Lp-PLA2) is a reported risk factor for dementia. However, the relationship between Alzheimer's disease (AD) and Lp-PLA2 is still debatable and, to the best of our knowledge, no study has evaluated the associations between levels of Lp-PLA2, proinflammatory cytokines, and neopterin in AD. MethodsIn total, 59 patients with AD and 38 non-demented individuals were included in the case–control study. Fasting serum concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), neopterin, and Lp-PLA2 were determined using ELISA. The associations between AD and each of the variables were analyzed by logistic regression. ResultsThe median Lp-PLA2 levels in AD and controls were similar (P=0.29, not significant). Median serum neopterin and IL-6 levels were significantly higher in patients with AD than in controls (P=0.0001 and P=0.03, respectively). In regression analyses, median neopterin levels, a lower level of education, and female gender were significantly associated with AD when compared with controls (OR, 31.44, 95% CI 3.59–275.28, P=0.002; OR, 4.35, 95% CI 1.13–16.61, P=0.032; OR, 7.25, 95% CI 1.88–28.00, P=0.004, respectively). ConclusionIn contrast to previous evidence suggesting its role in dementia and AD, Lp-PLA2 enzyme levels were higher in the controls, and no relationship between Lp-PLA2 and either proinflammatory cytokines or neopterin was identified in AD. Elevated neopterin levels may be considered inflammatory markers of AD.

Patients with idiopathic recurrent miscarriage show higher levels of DR+ activated T-cells that are less responsive to mitogens

In 50% of recurrent miscarriages (RM) the cause remains unknown and standardized immunological diagnosis and treatment of idiopathic RM (iRM) is yet not established. In this prospective case-control study, out of 220 RM patients screened, 97 iRM patients were identified and compared to 26 healthy controls without a previous pregnancy or blood transfusion in order to identify deregulated immunological parameters. Blood levels of lymphocyte subpopulations, cytokines and neopterin were determined by FACS, ELISA, and Luminex technique. Lymphocyte function was studied by in-vitro lympocyte proliferation tests. As compared to controls, patients had significantly higher proportions of activated CD3+DR+, CD4+DR+ and CD8+DR+ lymphocytes, elevated levels of neopterin and a lower in-vitro proliferation of lymphocytes (all p<0.05). Within the iRM patients higher proportions of CD3+DR+ T-lymphocytes correlated with higher proportions and absolute numbers of CD4+DR+ and CD8+DR+ T-lymphocytes and lower CD16+CD56+ NK-cells. Further, it was associated with lower absolute numbers of CD19+ B-lymphocytes, CD3+CD25+ T-lymphocytes and CD45+ total lymphocytes (all p<0.05). In addition we found decreased in-vitro lymphocyte proliferation in iRM patients with high CD3+DR+ T-lymphocytes (p<0.05). In summary patients with iRM showed increased activated T-cells that are less responsive to mitogens in-vitro. The inverse relationship of increased DR but decreased CD25 expression on CD3+ T-cells and the decreased in-vitro proliferation characterize an immunological disorder with similarities to T-cell exhaustion in patients with HIV and cancer. These abnormalities potentially contribute to the pathogenesis of iRM and might be a target for future immunomodulatory therapies.

Elevated Serum Levels of Neopterin at Admission Predicts Depression After Acute Ischemic Stroke: a 6-Month Follow-Up Study.

Inflammation and cell-mediated immune activation are attributed to the pathogenesis and pathophysiology in depression. Our aim was to test the possible association between serum levels of neopterin and the development of post-stroke depression (PSD) in Chinese patients. The subjects were first-ever acute ischemic stroke patients who were hospitalized at the First Affiliated Hospital of Xinxiang Medical University during the period from December 2012 to December 2013. Clinical information and stroke severity were collected at admission. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum neopterin levels were measured using fluorometry and a high performance liquid chromatography (HPLC) method. Multivariate analyses were performed using logistic regression models. During the study period, 226 patients were included and finished the 6-month follow-up. Sixty-nine patients (30.5%) were diagnosed as having major depression at 6months. Patients with major depression showed higher levels of serum neopterin (21.6[IQR, 18.9-25.7]nmol/L vs. 14.6[IQR, 12.2-18.4]nmol/L, P < 0.0001) at admission. In multivariate analyses, serum neopterin was an independent predictor of PSD at 6months [odds ratio (OR): 1.952 (95% CI, 1.358-2.805), P < 0.0001]. With an AUC of 0.850 (95% CI, 0.797-0.902), neopterin showed a significantly greater discriminatory ability as compared with high-sensitivity C-reactive protein, age, body mass index, and National Institutes of Health and Stroke Scale score. Neopterin is a novel, independent predictor of the development of depression 6months after stroke. This indicated that the elevated neopterin levels may play a significant role in the pathology of depression and that the pathways leading to inflammation and cell-mediated immune activation warrant further exploration.

High plasma neopterin levels in Chinese children with autism spectrum disorders

BackgroundNeopterin, a pteridine mainly synthesized by activated macrophages, is a marker of inflammation, immune system activation and an active participant in Autism spectrum disorders (ASD). The aim of this study was to assess the clinical significance of plasma neopterin levels in ASD. MethodsEighty patients diagnosed with ASD and 80 sex and age matched typically developing children were assessed for plasma levels of neopterin at admission. Plasma neopterin levels were measured using a human ELISA kit and severity of ASD were evaluated with the Childhood Autism Rating Scale (CARS) score. ResultsWe found that the mean plasma neopterin level was significantly (P<0.0001) higher in children with ASD as compared to controls. Plasma neopterin increased with increasing severity of ASD as defined by the CARS score. Based on the ROC curve, the optimal cutoff value of plasma neopterin level as an indicator for auxiliary diagnosis of ASD was projected to be 8.5nmol/L, which yielded a sensitivity of 84.2% and a specificity of 80.1%, with the area under the curve at 0.876 (95% CI, 0.825–0.928). Elevated neopterin (≥8.5nmol/L) was an independent diagnosis indicator of ASD with an adjusted OR of 12.11 (95% CI: 5.48–28.11; P<0.0001). ConclusionsThese results indicated that autistic children had higher plasma levels of neopterin, and elevated plasma neopterin levels may be associated with severity of ASD among Chinese children.

Abstract 12851: Clinical Significance of Myeloperoxidase, Neopterin, and High Sensitivity C-Reactive Protein as Independent Predictors of Cardiovascular Events

Background: We previously demonstrated that inflammatory biomarkers such as myeloperoxidase (MPO), a member of the heme peroxidase superfamily, and neopterin (produced by activated macrophages after interferon-γ stimulation by T-lymphocytes) are important in the pathogenesis of coronary plaque instability. Additional evidence supports high sensitivity C-reactive protein (hs-CRP) as an independent predictor of increased coronary risk. We assessed the prognostic significance of plasma MPO and neopterin levels, and serum hs-CRP levels in patients with stable angina pectoris (SAP) and unstable angina pectoris (UAP). Methods: Plasma MPO, neopterin, and serum hs-CRP levels were measured in 219 SAP patients and 144 UAP patients at admission. Cardiovascular (CV) events were defined as sudden cardiac death, fatal or non-fatal myocardial infarction and other non-fatal events including unstable angina pectoris or coronary revascularization. Results: Over a mean follow-up of 27±14 months, 56 SAP patients (26%) had CV events. When SAP patients were stratified based on the median neopterin level (15.0 nmol/L), Kaplan-Meier analysis showed that the high-neopterin group (&gt;15.0 nmol/L) had significantly worse outcomes (P=0.015) than the low-neopterin group. Multivariate analysis showed that elevated neopterin was the only independent factor associated with CV events (OR, 2.19; 95% CI, 1.18-4.09; P=0.014). In contrast, over a mean follow-up of 30±24 months, 33 UAP patients (23%) had CV events. When UAP patients were divided based on the median MPO level (16.0 ng/mL), Kaplan-Meier analysis showed that the high-MPO group (&gt;16.0 ng/mL) had significantly worse outcomes (P=0.012) than the low-MPO group. Multivariate analysis showed that elevated MPO was the only independent factor associated with CV events (OR, 2.58; 95% CI, 1.07-6.23; P=0.035). With regard to hs-CRP levels, there were no significant differences in CV events between the two groups according to the median hs-CRP in both SAP and UAP patients. Conclusions: The clinical significance of elevated MPO and neopterin levels as independent predictors of CV events differs depending on the clinical condition of SAP and UAP patients, because of different production mechanisms of these biomarkers.

The relation between oxidative stress, inflammation, and neopterin in the paraquat-induced lung toxicity.

Paraquat (PQ) is a well-known quaternary nitrogen herbicide. The major target organ in PQ poisoning is the lung. Reactive oxygen species (ROS) and inflammation play a crucial role in the development of PQ-induced pulmonary injury. Neopterin is synthesized in macrophage by interferon γ and other cytokines. We aimed to evaluate the utility of neopterin as a diagnostic marker in PQ-induced lung toxicity. Sprague Dawley rats were randomly divided into two groups (sham and PQ), administered intraperitoneally 1 mL saline and PQ (15 mg/kg/mL) respectively. Blood samples and lungs were collected for analyses. Lung injury and fibrosis were seen in the PQ group. Serum total antioxidant capacity, lactate dehydrogenase (LDH), and lung transforming growth factor-1β (TGF-1β) levels were significantly higher than the sham group (in all, p < 0.001). In addition, in the PQ group, serum neopterin and lung malondialdehyde (MDA) levels were also significantly higher than the sham group (in all, p = 0.001). Serum neopterin levels were correlated with LDH activities, lung MDA, lung TGF-1β levels, and the degree of lung injury. These findings demonstrated that oxidative stress, reduction of antioxidant capacity, and inflammation play a crucial role in the PQ-induced lung injury. Elevated serum neopterin levels may be a prognostic parameter to determine extends of PQ-induced lung toxicity. Further studies may be performed to clarify the role of neopterin by different doses of PQ.

Usefulness of Elevated Urine Neopterin Levels in Assessing Cardiac Dysfunction and Exercise Ventilation Inefficiency in Patients With Chronic Systolic Heart Failure

Neopterin is synthesized by macrophages upon stimulation with gamma-interferon, and high neopterin production is associated with cellular immune activation and increased production of reactive oxygen species (oxidant stress), but the clinical utility of urine neopterin levels in patients with heart failure (HF) has not been explored. Fifty-three ambulatory patients with chronic systolic HF (left ventricular [LV] ejection fraction ≤40%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise testing. Urine neopterin levels were quantified by liquid chromatography with tandem mass spectrometric analyses and corrected to urine creatinine (Cr) levels. In our study cohort, median urine neopterin level was 60 μmol/mol Cr (interquartile range 40 to 86). There were modest correlations between urine neopterin levels and abnormalities in cardiac structure and function by echocardiography: LV ejection fraction (r = -0.33, p = 0.017), indexed LV end-diastolic volume (r = 0.31, p = 0.029), indexed LV end-systolic volume (r = 0.32, p = 0.024), and E/septal Ea (r = 0.28, p = 0.041). Although there was no significant correlation between urine neopterin and maximal oxygen uptake (peak VO2: r = -0.25, p = 0.07), there was a modest correlation between urine neopterin and maximal ventilation/carbon dioxide production ratio (VE/VCO2 max: r = 0.38, p = 0.005). In conclusion, increase in urine neopterin levels tracks with disease severity in patients with chronic systolic HF.

Prenatal immunologic predictors of postpartum depressive symptoms: a prospective study for potential diagnostic markers

In postpartum depression (PPD), immunologic changes have been proposed to be involved in the disease pathology. The study evaluates the regulation of the innate and adaptive immune response over the course of late pregnancy and postpartum period and their association with the development of postpartum depressive symptoms. Furthermore, prenatal immunologic markers for a PPD were investigated. Hundred pregnant women were included. At 34th and 38th week of pregnancy as well as 2 days, 7 weeks and 6 months postpartum, immune parameters (neopterin, regulatory T cells, CXCR1, CCR2, MNP1 and CD11a) were measured by flow cytometry/ELISA, and the psychopathology was evaluated. We found that regulatory T cells were significantly increased prenatal (p=0.011) and postnatal (p=0.01) in mothers with postnatal depressive symptoms. The decrease in CXCR 1 after delivery was significantly higher in mother with postnatal depressive symptoms (p=0.032). Mothers with postnatal depressive symptoms showed already prenatal significantly elevated neopterin levels (p=0.049). Finally, regulatory T cells in pregnancy strongly predict postnatal depressive symptoms (p=0.004). The present study revealed that prenatal and postnatal immunologic parameters are associated with postpartum depressive symptoms in mothers. In addition, we found immune markers that could eventually be the base for a biomarker set that predicts postnatal depressive symptoms already during pregnancy.

Neopterin in Diagnosis and Monitoring of Infectious Diseases.

Neopterin is produced by activated monocytes, macrophages, and dendritic cells upon stimulation by interferon gamma produced by T-lymphocytes. Quantification of neopterin in body fluids has been achieved by standard high-performance liquid chromatography, radioimmunoassays, and enzyme-linked immunosorbent assays. Neopterin levels predict HIV-related mortality more efficiently than clinical manifestations. Successful highly active antiretroviral therapy is associated with a decrease in neopterin levels. Elevated neopterin levels were associated with hepatitis by hepatitis A, B, and C viruses. Serum neopterin levels were found to be a predictor of response to treatment of chronic HCV infection with pegylated interferon combined with ribavirin. Neopterin levels of patients with pulmonary tuberculosis were found to be higher in patients with more extensive radiological changes. Elimination of blood donors with elevated neopterin levels to reduce risk of transmission of infections with known and unknown viral pathogens has been undertaken. Neopterin measurement is hereby more cost effective but less sensitive than screening using polymerase chain reaction based assays. In conclusion neopterin is a nonspecific marker of activated T-helper cell 1 dominated immune response. It may be a useful marker for monitoring of infectious disease activity during treatment and for more accurate estimation of extent of disease and prognosis.

Levels of Circulating Neopterin in Patients with Severe Carotid Artery Stenosis Undergoing Carotid Stenting

The association between an elevated serum neopterin level and the development of coronary artery complex lesions has been extensively assessed; however, the correlation between the serum neopterin level and the development of carotid artery stenosis has seldom been reported. This study tested whether this biomarker is increased in patients with severe carotid artery stenosis(≥70%) undergoing carotid artery(CA) stenting and investigated independent predictors of an increased circulating neopterin level. Fifty patients with severe CA stenosis(CAS) undergoing CA stenting were consecutively enrolled in this study from January 2009 through December 2011. The serum neopterin levels of age- and gender-matched acute ischemic stroke(AIS) patients(n=120) and control subjects(CS)(n=33) were also measured. A blood sample was prospectively collected from each patient in the catheterization room. The serum levels of neopterin were significantly higher in the CAS patients than in the AIS patients or CS and significantly higher in the AIS patients than in the CS(all p＜0.001). An analysis of the variables of 170 patients(CAS＋AIS) demonstrated that age, a previous history of stroke and severe CAS were significantly correlated with an increased serum level of neopterin(all p＜0.005). A multivariate binary logistic regression analysis of the severe CAS patients(n=50) demonstrated that age and the creatinine level were independent predictors of a high neopterin level(neopterin level ≥16.52 ng/dL, i.e., according to the median value of neopterin)(all p＜0.05). The circulating neopterin levels are significantly higher in patients with severe CAS than in those with AIS. The presence of CAS, age and the creatinine level were significantly correlated with an increased serum neopterin level.

Pulmonary Function Tests in Idiopathic Inflammatory Myopathy: Association With Clinical Parameters in Children

To determine the association of decreased lung function in children with idiopathic inflammatory myopathies (IIMs) with specific clinical parameters. This study of 38 children ages 6-23 years diagnosed with definite/probable IIM evaluated the association of myositis-specific/-associated antibodies (MSAs/MAAs), duration of untreated disease at diagnosis, Disease Activity Score for muscle (DAS-M), muscle-derived enzymes (aldolase, lactate dehydrogenase [LDH], aspartate transaminase, and creatine phosphokinase [CPK]), neopterin and von Willebrand factor antigen, and the Childhood Myositis Assessment Scale (CMAS) scores with data from pulmonary function testing (PFT). Impaired PFTs were defined as total lung capacity (TLC) or diffusing capacity for carbon monoxide (DLCO) of <80% predicted. The PFTs documented that 37% of the children (14 of 38) had either decreased TLC or decreased DLCO; 5% (2 of 38) had both. Children with decreased TLC alone (7 [18%] of 38) were older both at the time of PFT and diagnosis, had anti-Jo-1 and anti-Scl-70 antibody, and had elevated levels of CPK and neopterin. Children with decreased DLCO alone (5 [13%] of 38) had a shorter duration of untreated disease at diagnosis, had higher DAS-M and total DAS, were positive for anti-Ro and anti-PL-12, had increased LDH, and had elevated levels of neopterin and aldolase, with low CMAS scores for items 1, 3, 10, 11, and 14. Assessment of PFTs in children with IIMs should be considered, since more than one-third of patients were found to be impaired. The presence of MSAs/MAAs, an elevated serum neopterin level (mean ± SD 12.4 ± 9.6 nmoles/liter, normal value <10.5), older age at diagnosis, and shorter duration of untreated disease at diagnosis suggest the presence of potential lung pathology.

Prognostic Utility of Serum Neopterin in Obstructive Jaundice Secondary to Malignant Lesions Treated by Percutaneous Transhepatic Biliary Drainage

PurposeTo perform biochemical profiles before and after percutaneous transhepatic biliary drainage (PTBD) and investigate the potential utility of measuring C-reactive protein (CRP), circulating cytokines, and neopterin, a marker of cell-mediated immunity, to predict outcomes of patients with obstructive jaundice. Materıals and MethodsIn a prospective study, 47 patients with obstructive jaundice secondary to malignant lesions were evaluated before, at the fifth hour after, and on the fifth day after PTBD for neopterin, nitrate, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, CRP levels, and liver function. ResultsNeopterin levels on day 5 after PTBD were significantly higher than the levels before treatment and at the fifth hour. However, nitrate, cytokine, white blood cell, albumin, and creatinine levels were not significantly different. On the fifth day after PTBD, CRP levels were significantly higher and total bilirubin, direct bilirubin, alkaline phosphatase, aspartate transaminase, and alanine transaminase values were lower than the before-treatment values. Seven patients (15%) died within 30 days after drainage. On the fifth day after PTBD, neopterin, IL-6, IL-10, and creatinine levels were significantly higher and albumin levels were lower in the early mortality group. The performance characteristics of neopterin and creatinine were statistically significant in predicting mortality. ConclusionsNeopterin levels increased after PTBD, indicating cellular immune activation. The nonsignificant change in cytokine levels may be related to low enduring release in malignancy. The extremely elevated levels of neopterin and creatinine after PTBD might serve as harbingers of early death in patients with cholestasis secondary to malignant lesions.

Alveolar neopterin, procalcitonin, and IL-6 in relation to serum levels and severity of lung injury in ARDS

To the Editor,Tsantes et al. evaluated plasma and bronchoalveolar lavage fluid (BALF) procalcitonin (PCT) and interleukin-6 (IL-6) in discriminating septic from non-septic causes of acute respiratory distress syndrome (ARDS) [1]. They concluded that early plasma, but not BALF-PCT concen-trations, can help distinguish between septic and non-septic ARDS causes and are associated with the severity of multiple organ dysfunction syndrome in septic ARDS patients. In addition to PCT and IL-6 we want to point out the role of alveolar and serum neopterin and PCT in the early phase of ARDS and acute lung injury (ALI) as a valu -able marker of increased activity of the cellular immune system [2]. Elevated levels of neopterin in serum and BALF in various lung diseases, e.g., sarcoidosis and interstitial lung disease, have been reported [3]. Pneumonia was associated with significantly elevated neopterin levels in BALF compared to controls [4]. Serum PCT determination in early ARDS was used to discriminate between septic and non-septic underlying disease [5]. PCT was detectable in BALF of patients with severe lung contusion, however, it failed to be a reliable parameter in the assessment of lung contusion severity [6]. IL-6 concentrations are high in the BALF of patients at risk for ARDS and remain elevated throughout the course of ARDS [7].We would like to contribute the so far unpublished results of a previous study concerning alveolar and serum neopterin, PCT and IL-6 in the early phase of ARDS and ALI. In our study, we measured neopterin, PCT, granulo-cyte colony-stimulating factor (G-CSF), TNF-α, IL-6, IL-8, epithelial neutrophil-activating peptide (ENA)-78, soluble TNF-α receptor type I (sTNF-RI), soluble TNF-α receptor type II (sTNF-RII), IL-1 receptor antagonist (IL-1RA), and IL-10 in BALF and serum within 12 and 24 h after onset of ARDS/ALI. Alveolar G-CSF, IL-8, and ENA-78 in relation to serum levels, pulmonary neutrophilia, and severity of lung injury in ARDS, and the association of endogenous G-CSF with anti-inflammatory mediators in patients with ARDS have been published previously [8, 9]. Addition-ally, we determined the concentration of neopterin, PCT, IL-6 in lung epithelial lining fluid (ELF) by using the urea dilution method for estimating the volume of ELF in the lavaged lung segment [10].We evaluated levels of neopterin, PCT, and IL-6 in BALF, ELF and serum for comparison of the concentra-tions of these compounds between the blood circulating compartment and the alveolar space. Furthermore, we evaluated whether there is a difference between ARDS and ALI, septic and non-septic ARDS/ALI, survivors and non-survivors or a correlation to lung injury expressed as PaO

Neopterin levels are independently associated with cardiac remodeling in patients with chronic heart failure

ObjectivesNeopterin, a marker of inflammation and monocyte activation, is found increased in patients with heart failure (HF). This study investigates whether neopterin levels correlate with left ventricular (LV) remodeling and brain natriuretic peptide (BNP), a marker of cardiac stress, in chronic HF (CHF) patients with different severity of disease. Design and methodsThe relationship between neopterin and LV dimensions, NT-proBNP, and pro-inflammatory cytokines were studied in 98 CHF patients, while nineteen healthy subjects were enrolled as controls. Nineteen (19%) patients were in NYHA class I, 38 (39%) in NYHA class II, 27 (28%) in NYHA class III, and 14 (14%) in NYHA class IV. ResultsNeopterin levels were higher in CHF patients than in age- and gender-matched healthy controls, and related with indexed LV end-diastolic volume (LVEDVi). Prospectively CHF patients were separated into tertiles of low, medium and high neopterin levels. Among patients, male gender, LVEDVi, diuretic treatment, NYHA class I, NT-proBNP and IL-8 levels were significant determinants of urine neopterin levels by bivariate analysis. Neopterin levels were associated only to LV remodeling, as assessed by LVEDVi, and IL-8 levels, a crucial monocyte chemoattractant, by multivariate ordinal regression analysis. ConclusionsThe relationship between elevated neopterin levels and LV enlargement in CHF patients suggests a crucial role of monocyte activation in the development of cardiac dysfunction in CHF patients. Assessment of neopterin levels is a potential biomarker to evaluate the progression of LV remodeling in CHF patients.

An immunosuppressive subtype of neutrophils identified in patients with hepatocellular carcinoma.

Functional disorders of various immune cells have been reported in hepatocellular carcinoma (HCC) patients. Recently, distinct subsets of neutrophils (polymorphonuclear leukocytes, PMN) have been identified in hosts with enhanced or impaired cell-mediated immunity. In this study, therefore, plasma factors and PMN from HCC patients were immunobiologically investigated. Plasma neopterin and CCL17 levels were measured by ELISA in 95 HCC patients. Peripheral PMN were isolated from each HCC patient and tested for CCL2 or CCL3 production by ELISA and flow cytometry. The results showed elevated plasma neopterin levels in HCC patients, while CCL17 levels decreased in correlation with tumor size. PMN from HCC patients produced CCL2, while PMN from healthy subjects did not. Moreover, CCL2 production by PMN was significantly increased in proportion to tumor load. When HCC patients were divided into two groups based on CCL2 produced by PMN, the survival rate of the CCL2 high group was significantly lower than that for other patients. While CCL3 production by PMN was also significantly increased in HCC patients, their CCL3 production did not correlate with tumor load and survival. The CCL2/CCL3 ratio in culture fluids of each PMN was also increased in proportion to tumor size. These results suggest that cell-mediated immunity may be impaired in advanced HCC patients. Moreover, distinct PMN subsets may exist in the peripheral blood of HCC patients. These PMN subsets, especially CCL2-producing PMN, may be involved in tumor extension and the survival outcomes for HCC patients.