Plasma Neopterin Levels Research Articles

Pulmonary Administration of Interferon Beta-1a-Fc Fusion Protein in Non-Human Primates Using an Immunoglobulin Transport Pathway

Currently, products containing interferon beta (IFNβ) are injected either intramuscularly or subcutaneously. To avoid the necessity of injection, we developed a novel monomeric Fc fusion protein of IFNβ (IFNβFc) that is absorbed via an immunoglobulin transport system present in the upper and central airways upon administration of the drug as an inhaled aerosol. The systemic absorption of IFNβFc through the lung in non-human primates, at deposited doses of 1, 3, and 10 μg/kg, was compared to the absorption of a single 3 μg/kg dose of IFNβ-1a (Avonex®) subcutaneously administered. IFNβFc was well absorbed through the lung, displaying dose proportional increases in serum concentrations, and was biologically active, as shown by increases in plasma neopterin levels. The circulating half-life of IFNβFc was ∼3 times longer (∼30 h) than that of IFNβ-1a, (8-9 h). At approximately equimolar doses of IFNβFc (10 μg/kg) and IFNβ-1a (3 μg/kg), the stimulation of neopterin over background levels was approximately equivalent, demonstrating that the longer half-life of IFNβFc compensated for the lower relative specific antiviral activity of IFNβFc measured in vitro. In conclusion, IFNβFc was efficiently absorbed after pulmonary delivery in non-human primates, retained its biological activity, and may offer a convenient alternative to injectable IFNβ.

Plasma neopterin levels in a MCI and Alzheimer's disease

Plasma neopterin levels in a MCI and Alzheimer's disease

Preparation of Branched Dextran Microspheres of Soluble Interferon Interferon-alpha and its Activity In Vitro and In Vivo

The study objective was to prepare biodegradable branched dextran microspheres encapsulated with His-tagged interferon-alpha (BDM-hIFN-alpha) and evaluate its activity in vitro and in vivo. The glycidyl methacrylate derivatized dextrans (Dex-GMA) as precursor was primarily synthesized by substituting hydroxyl groups of either the branched or linear type of dextran with GMA. Dex-GMA microspheres loaded with hIFN-alpha was then prepared by the water-in-water emulsion technique. In vitro release and Western blotting experiments demonstrated the retained activity of hIFN-alpha released from branched dextran microspheres at 24 h by inducing phosphorylation of signal transducer and activator transcription-1 (STAT-1), a down-stream effector of IFN-alpha, in HepG2 cells. Animal data further revealed a peak of plasma levels of IFN-alpha in rats injected intravenously with BDM-hIFN-alpha at 10 min post-injection, but a sharp decline at 2 h. High plasma levels of neopterin, a plasma protein induced by IFN-alpha, were also detected in rats injected with BDM-hIFN-alpha at 10 min post-injection. Notably, plasma levels of neopterin remained high at 4 h, but largely declined thereafter.

Oxidant Production, oxLDL Uptake, and CD36 Levels in Human Monocyte–Derived Macrophages Are Downregulated by the Macrophage-Generated Antioxidant 7,8-Dihydroneopterin

The severity of atheroma burden in patients strongly correlates to increasing levels of plasma neopterin, the oxidation product of 7,8-dihydroneopterin. Interferon-γ stimulation of macrophages causes the synthesis of 7,8-dihydroneopterin, a potent antioxidant that inhibits oxidative damage to cells, and the cytotoxicity of oxidized low-density lipoprotein (oxLDL) to monocyte-like U937 cells but not THP-1 cells. With human monocyte-derived macrophages (HMDMs), oxLDL triggered a large oxidative stress, causing the rapid loss of cellular glutathione, glyceradehyde-3-phosphate dehydrogenase (GAPDH) inhibition, and eventual loss of viability without caspase-3 activation. Inhibition of oxLDL cytotoxicity to HMDMs occurred at 7,8-dihydroneopterin concentrations >100 μM. The oxLDL-mediated glutathione loss and GAPDH inactivation was inhibited by 7,8-dihydroneopterin. 7,8-Dihydroneopterin rapidly entered the HMDMs, suggesting that much of the protective effect was scavenging of intracellular oxidants generated in response to oxLDL. OxLDL uptake by HMDMs was reduced by 30% by 7,8-dihydroneopterin. Immunoblot analysis suggests that this decrease in oxLDL uptake was due to a significant downregulation in the levels of CD36. These results imply that 7,8-dihydroneopterin protects human macrophages both by scavenging oxidants generated in response to oxLDL and by decreasing CD36-mediated uptake of oxLDL.

Decreasing plasma soluble IL‐1 receptor antagonist and increasing monocyte activation early post‐transplant may be involved in pathogenesis of delayed graft function in renal transplant recipients

Delayed graft function (DGF) increases the risk of acute allograft rejection and may affect long-term graft survival. We compared pre-transplant, early post-transplant, and late post-transplant serum creatinine (Cr) and plasma levels of neopterin, cytokines, and cytokine receptors/antagonists in patients with DGF (n = 39), slow graft function (SGF) (n = 43), or immediate graft function (IGF) (n = 30). Three and eight days post-transplant, plasma neopterin (p < 0.001; p < 0.001), Soluble Interleukin-6 (IL-6) receptor (R) (p = 0.002; p = 0.001), and IL-10 (p = 0.003; p = 0.001) were higher in DGF than IGF patients. One month post-transplant, plasma neopterin (p < 0.001) and IL-10 (p < 0.001) were higher in DGF than IGF patients. Three days post-transplant, the results indicated reduced sIL-1 receptor antognist (RA) production in DGF patients (p = 0.001). Simultaneously, plasma sIL-6R and IL-10 increased in DGF (p < 0.001; p = 0.003) and SGF (p = 0.007; p = 0.030) patients, indicating increased production of sIL-6R and IL-10. Lower sIL-1 production in DGF than IGF patients early post-transplant might promote the increased production of monocyte-derived neopterin, sIL-6R, and IL-10. This monocyte/macrophage activation might induce inflammation in the graft and subsequently cause an impairment of graft function. Blocking of monocyte activity after renal transplantation may be considered a potential approach for improving graft outcome.

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Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris

ObjectiveNeopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP). MethodsWe measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells. ResultsPlasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2–39.3]nmol/L vs. 19.4 [11.9–25.1]nmol/L; P=0.01) or without any plaques (18.8 [14.9–23.6]nmol/L; P=0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13–4.33, P=0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions. ConclusionThese findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.

Association of Pretransplant Soluble Glycoprotein 130 (sgp130) Plasma Levels and Posttransplant Acute Tubular Necrosis in Renal Transplant Recipients

Previously, we reported that high pretransplant sIL-6R plasma levels are associated with posttransplant acute tubular necrosis (ATN). In this study, we examined associations of pretransplant plasma levels of sgp130 with ATN. Pretransplant serum creatinine (Cr), plasma neopterin, and sgp130 levels were studied in 105 first renal transplant recipients who received grafts from deceased donors. Although 57 patients had immediate and sustained graft function, ATN was diagnosed in 30 patients within the first 11.3+/-7.8 posttransplant days and acute rejection in 18 patients during the first 27.1+/-27.6 days. Pretransplant serum Cr and plasma neopterin were similar in the three patient groups. Pretransplant sgp130 plasma levels, however, were significantly lower in patients with ATN than in patients with immediate graft function (P=0.004) or acute rejection (P=0.009). Multivariable logistic regression analysis for ATN showed an odds ratio of 4.3 of patients with pretransplant sgp130 less than or equal to 250 pg/mL with posttransplant ATN (P=0.006). Patients at risk of ATN showed immediately before transplantation low anti-inflammatory sgp130, suggesting a contribution of the IL-6 cytokine family to the development of ATN. It might be useful to measure IL-6 family plasma levels pretransplant to identify patients who are at an increased risk of developing ATN.

Neopterin and the risk of dementia in persons with Down syndrome

Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimer's disease. In a prospective study, we examined whether the plasma neopterin level, a marker for cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly ( p = 0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04–3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome.

Elevated systemic IL-18 and neopterin levels are associated with posttraumatic complications among patients with multiple injuries: A prospective cohort study

Posttraumatic systemic inflammatory response syndrome (SIRS), sepsis and their subsequent complication, the multiple-organ dysfunction syndrome (MODS), remain major complications following polytrauma. This prospective clinical study aimed at evaluating the association between these and plasma interleukin-18 (IL-18) and neopterin levels. Inclusion in the series required an Injury Severity Score (ISS) >16, age 16-65 years, admission within 6 h of the accident and survival >48 h; 55 patients were enrolled. Over 14 days, plasma neopterin and IL-18 levels and the clinical course regarding MODS, SIRS and sepsis were recorded daily using the Marshall Score for MODS and the ACCP/SCCM criteria for SIRS and sepsis. Neopterin and IL-18 plasma levels were increased in +MODS cases as compared with -MODS cases over almost the entire observation period. IL-18 concentrations over days 3-6 were significantly increased among participants with sepsis. These increases were all apparent 2-3 days before the clinical diagnosis of sepsis or MODS was made. In contrast, no significant differences in neopterin and IL-18 plasma levels were observed between participants with and without SIRS. Determinations of neopterin and IL-18 concentrations might represent early markers for posttraumatic complications such as MODS and sepsis. They might help to differentiate between SIRS and sepsis and thereby guide the timing of the surgery for polytrauma. Neopterin and IL-18 levels should be used together with the clinical status and other inflammatory markers (IL-6, IL-8, etc.) for prediction of posttraumatic complications.

Abstract 957: Elevated Levels of Neopterin are Associated with Carotid Complex Plaques in Patients with Stable Angina Pectoris

Background: Neopterin is produced by activated macrophages and serves as an activation marker for monocytes/macrophages. Serum levels of neopterin have been shown to be associated with the presence of complex coronary lesions in unstable angina pectoris. However, the relationship between neopterin levels and complex carotid lesions is still unknown. We investigated the association between plasma neopterin levels and the characteristics of carotid plaques in patients with stable angina pectoris (SAP). Moreover, we immunohistochemically studied the presence of neopterin in carotid endarterectomy specimens. Methods: We studied 65 SAP patients who were scheduled coronary angiography. In all patients, plasma neopterin levels were measured and carotid ultrasound was performed for evaluation of carotid artery plaque score (PS) defined by the sum of plaque thickness, plaque number (PN) and plaque surface irregularity. Frozen tissue of 40 endarterectomy specimens for extracranial high-grade carotid stenosis were immunohistochemically examed with antibodies against macrophages and neopterin. Results: There was no significant correlation between plasma neopterin levels and PS (P=0.38) or PN (P=0.49). On the other hand, plasma neopterin levels were significantly higher in patients with carotid plaque surface irregularity compared with patients without it (25.4 ± 13.5 nmol/L vs.16.9 ± 6.5 nmol/L, P=0.0015). Carotid plaque irregularity was detected more frequently in patients with higher neopterin levels (&gt;=18.5 nmol/L median) compared with those with lower neopterin levels (41.9% vs. 16.1%, P=0.025). Using multivariate analyses, nepopterin levels (OR, 1.11; 95%CI, 1.01 to 1.21; P=0.023) and the number of diseased coronary vessels (OR, 2.51; 95%CI, 1.01 to 6.22; P=0.047) are independently associated with carotid plaque irregularity. Immunohistochemical staining showed abundant neopterin-positive macrophages in the unstable carotid plaques. Conclusions: Neopterin levels are associated with carotid complex plaques rather than the severity of carotid atherosclerotic change. Neopterin can be considered as one of the significant markers of plaque destabilization in not only coronary artery but carotid artery atherosclerotic lesions.

Association of T cell and macrophage dysfunction with surface gp 120-immunoglobulin-complement complexes in HIV-infected patients.

The mechanism of CD4+ cell depletion and functional T helper cell inhibition in HIV-infected individuals is poorly understood. The present study demonstrates that immune complex-covered CD4+ cells are associated with T cell inhibition and macrophage stimulation. We studied 30 patients with ARC/AIDS and 35 asymptomatic HIV+ haemophilia patients. Overall, 20 +/- 3% of peripheral CD4+ lymphocytes were covered with gp120 (range 0-94%). gp120+ cells also exhibited surface-bound IgG (P = 0.0001), IgM (P = 0.0001), and complement (P = 0.0001). Decreased in vitro lymphocyte proliferation was associated with the immune complex load of CD4+ cells. The higher the percentage of CD4+ gp 120+ cells in the blood, the lower the T cell response in vitro (P = 0.001). Moreover, an association was found between immune complex-positive cells and plasma neopterin (P = 0.01). Patients with increased plasma neopterin levels had decreased in vitro responses to pokeweed mitogen (PWM) (P = 0.006), phytohaemagglutinin (PHA) (P = 0.004), concanavalin A (Con A) (P = 0.09), and anti-CD3 MoAb (P = 0.03), and decreased CD4+ cell counts in the blood (P = 0.006). Since maximally 1% of CD4+ lymphocytes are infected with HIV, T cell dysfunction and T cell depletion in HIV-infected patients may also be caused by the release of free gp120 that binds to uninfected CD4+ cells. Our data suggest that the functional inhibition and subsequent elimination of uninfected CD4+ lymphocytes with surface gp120-immunoglobulin-complement complexes may be a pathomechanism in the manifestation of AIDS.

Comparison of Neopterin Levels in Patients with Coronary Artery Ectasia Versus Patients with Obstructive Coronary Artery Disease

Inflammation has been reported as an important component of vascular aneurysm formation, as found in obstructive vascular disorder. Neopterin is produced by activated macrophages and is thought to represent a marker of immune activation and macrophage activity. The plasma neopterin levels were investigated in coronary artery ectasia (CAE) patients to investigate the role of inflammation. The study population consisted of three groups: the first consisted of 28 patients with isolated CAE without stenotic lesion; the second of 27 patients with obstructive coronary artery disease (O-CAD) without CAE; and the third group of 15 control subjects with normal coronary arteries (NCA). Plasma soluble neopterin levels were measured in all patients and control subjects using commercially available enzyme-linked immunosorbent assay kits. Plasma neopterin levels were found to be significantly higher in patients with isolated CAE compared with control subjects with angiographically NCA (18.5 +/- 8.8 versus 8.7 +/- 2.6 nmol/L, respectively, P = 0.006). Although neopterin levels were higher in patients with CAE than in patients with O-CAD, they did not reach the statistically significant levels (18.5 +/- 8.8 versus 16.8 +/- 8.2 nmol/L, respectively, P = 0.77). Patients with O-CAD had significantly higher levels of neopterin compared with subjects with angiographically NCA (16.8 +/- 8.2 versus 8.7 +/- 2.6 nmol/L, respectively, P = 0.03). The mean serum neopterin levels in patients with single-vessel, two-vessel, and diffuse ectasia were as follows: 17.4 +/- 9.9 nmol/L, 19.5 +/- 8.9 nmol/L, and 20 +/- 5.5 nmol/L, respectively (P = 0.4). Patients with isolated CAE have raised levels of neopterin compared with patients with NCA, showing the possible role of inflammatory processes (monocyte/macrophage activity) in the higher levels of neopterin in patients with O-CAD.

Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome

Background Little information exists regarding the prognostic role of biomarkers of inflammation in Mediterranean patients. High C-reactive protein and neopterin levels – a marker of macrophage activation – predict cardiovascular events in stable angina patients and patients with acute coronary syndromes (ACS). We sought to assess whether plasma neopterin levels predict adverse clinical outcomes in Mediterranean patients with non-ST elevation (NSTE) ACS, i.e. unstable angina (UA) and NSTE myocardial infarction (MI). Methods We prospectively assessed 397 patients (74% men) admitted with NSTEACS, 147 (37%) had unstable angina and 250 (63%) NSTEMI. Blood samples for neopterin and CRP assessment were obtained at admission. The study endpoint was the composite of cardiac death, acute myocardial infarction and unstable angina at 180 days. Results Baseline neopterin concentrations (nmol/L) were similar in unstable angina and NSTEMI patients (8.3 [6.6–10.7] vs. 7.9 [6.2–10.9]; p = 0.4). Fifty-nine patients (14.9%) had events during follow-up. Twenty-nine (21.5%) patients with neopterin levels in the highest third experienced the combined endpoint, compared to 30 (11.5%) patients with neopterin levels in the second and the lowest thirds (log-rank 7.435, p = 0.024). On multivariable hazard Cox regression, neopterin (highest vs. 1st and 2nd thirds, HR 1.762, 95% CI [1.023–3.036]) was independently associated with the combined endpoint. Conclusion Increased neopterin levels are an independent predictor of 180-day adverse cardiac events in Mediterranean patients with NSTEACS.

Time-course of neopterin levels in patients suffering from severe sepsis treated with and without Drotrecogin-alpha (activated)

Neopterin is secreted by activated monocytes/macrophages upon stimulation with interferon-gamma. The release of this pro-inflammatory mediator permits the activation status of cell-mediated immune system to be examined. We assayed neopterin plasma concentrations in septic patients under treatment with (n=10) and without Drotrecogin-alpha (activated) (n=10) on d 1 and 6 of severe sepsis. In septic patients treated with Drotrecogin-alpha (activated), neopterin levels decreased significantly (p=0.027) from d 1 (baseline) (mean 140.8 nmol/l, +/-standard error of mean (SEM) 106.2) to d 6 (mean 68.9 nmol/l, +/-SEM 46.4). In patients not treated with Drotrecogin-alpha (activated) there was no significant (p=0.96) decrease of neopterin levels from d 1 (mean 147.8 nmol/l, +/-SEM 58.4) to d 6 (mean 139.7 nmol/l, +/-SEM 52.6). Furthermore, neopterin levels showed significant correlations with bilirubin in all patient groups on d 1 of severe sepsis (range of correlation coefficient, r: 0.69-0.88; p<0.05). Neopterin levels correlated significantly with creatinine with regard to all patient groups (range of correlation coefficient, r: 0.73-0.92; p<0.05). In conclusion, Drotrecogin- alpha (activated) was associated with a significant decrease of neopterin plasma levels in septic patients. Neopterin concentrations appear to depend on renal function and enterohepatic circulation.

Long-Term Prognostic Value of Neopterin

Monocyte activation is believed to play an important role in the pathogenesis of acute coronary syndromes (ACS). Neopterin is a soluble marker of monocyte activation, and elevated levels are of prognostic value in patients with stable coronary artery disease. Neopterin levels were measured on average at 7 days (in 3946 patients) and at 4 months (in 3369 patients) after ACS in the PRavastatin Or atorVastatin Evaluation Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI 22) trial. We assessed the relationship between plasma neopterin levels and the risk of death and death or acute coronary events (nonfatal myocardial infarction or unstable angina) over 2 years. Seven days after an ACS event, neopterin levels > or = 12.11 nmol/L (upper quartile, derived from a post hoc analysis) were associated with an increased risk of death and an increased risk of death or acute coronary events after adjustment for age, gender, history of diabetes mellitus, history of hypertension, history of smoking, type of ACS presentation, use of percutaneous coronary intervention for the index event, statin regimen, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hazard ratio, 1.86 [95% CI, 1.24 to 2.77], P=0.003; and hazard ratio, 1.33 [95% CI, 1.09 to 1.63] P=0.006, respectively). Neopterin levels > or = 12.11 nmol/L at 4 months remained a predictor of death alone and of death or acute coronary events after multivariable adjustment that included adjustment for month 4 low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and statin regimen (hazard ratio, 2.39 [95% CI, 1.43 to 3.99], P=0.001; and hazard ratio, 1.60 [95% CI, 1.21 to 2.11], P=0.001). High-dose atorvastatin significantly attenuated the risk among subjects with neopterin levels > or = 12.11 nmol/L at baseline (interaction P for death or acute coronary event, 0.018). Increased monocyte activation detected by an elevated plasma neopterin level identifies patients at long-term risk of death or recurrent acute coronary events after ACS. Intensive statin therapy significantly attenuates the risk of recurrent events among patients with an elevated neopterin level.

Increased Amyloid β Protein Levels in Children with Down Syndrome (129.47)

Abstract Objective: To quantitate plasma amyloid β protein (Aβ)40, Aβ42, and neopterin levels in Down Syndrome (DS) children and controls. Background: DS persons (&amp;gt;40 years) have neuropathological changes characteristic of Alzheimer disease (AD). Soluble forms of Aβ generated from amyloid precursor protein (APP) end at C-terminal residues 40 and 42. Neopterin is an immune activation marker for the cell-mediated immune response. Design/Methods: Blood was collected from DS (N = 35; 7 ± 3.8 years old) and their siblings (N = 34; 10 ± 4.5). Plasma Aβ40, Aβ42, and neopterin levels were quantitated by ELISA. Results: Aβ40 (Mean ± SD; 277 ± 70 pg/ml) and Aβ42 (31 ± 8 pg/ml) levels were higher in DS children than controls (Aβ40 155 ± 35 pg/ml, Aβ42 22 ± 5 pg/ml) (p&amp;lt;.0001). There were significant negative correlations between age and Aβ40 in DS (r=.47, p&amp;lt;.004) or controls (r=.38, p&amp;lt;.026) and Aβ42 levels in DS (r=.61, p&amp;lt;.001) but not in controls. Neopterin levels were higher in DS (3.01 ± 1.37 ng/ml) than controls (1.57 ± 0.65 ng/ml) (p&amp;lt;.0001). There was no correlation between neopterin levels and age, and Aβ40 or Aβ42 levels in DS or controls. Conclusion: The overexpression of APP gene in DS leads to increases in plasma Aβ40 and Aβ42 levels before plaque formation in DS brain. A lack of correlation between neopterin and Aβ levels suggests that higher neopterin concentrations in DS reflect inflammatory cell activation rather than AD neuropathology.

P1751 DARC and MBL2 polymorphisms in Kenya

Posttraumatic systemic inflammatory response syndrome (SIRS), sepsis and their subsequent complication, the multiple-organ dysfunction syndrome (MODS), remain major complications following polytrauma. This prospective clinical study aimed at evaluating the association between these and plasma interleukin-18 (IL-18) and neopterin levels.Inclusion in the series required an Injury Severity Score (ISS) >16, age 16–65 years, admission within 6 h of the accident and survival >48 h; 55 patients were enrolled. Over 14 days, plasma neopterin and IL-18 levels and the clinical course regarding MODS, SIRS and sepsis were recorded daily using the Marshall Score for MODS and the ACCP/SCCM criteria for SIRS and sepsis.Neopterin and IL-18 plasma levels were increased in +MODS cases as compared with −MODS cases over almost the entire observation period. IL-18 concentrations over days 3–6 were significantly increased among participants with sepsis. These increases were all apparent 2–3 days before the clinical diagnosis of sepsis or MODS was made. In contrast, no significant differences in neopterin and IL-18 plasma levels were observed between participants with and without SIRS.Determinations of neopterin and IL-18 concentrations might represent early markers for posttraumatic complications such as MODS and sepsis. They might help to differentiate between SIRS and sepsis and thereby guide the timing of the surgery for polytrauma. Neopterin and IL-18 levels should be used together with the clinical status and other inflammatory markers (IL-6, IL-8, etc.) for prediction of posttraumatic complications.

Increased amyloid β protein levels in children and adolescents with Down syndrome

Background Persons with Down syndrome (DS) (40 years and older) have neuropathological changes characteristic of Alzheimer disease (AD). Soluble forms of amyloid β (Aβ) peptide generated from amyloid precursor protein (APP) end at C-terminal residues 40 and 42. The presence of the apolipoprotein E (ApoE) ε4 allele is a significant risk factor for the development of sporadic AD. Although preliminary studies have shown an association of plasma Aβ42 and ApoE ε4 allele in older persons with DS who have dementia, the relationship between plasma Aβ40 and Aβ42 levels and ApoE phenotypes in children with DS has not been examined. Inflammation might play a role in the growth of DS brains. Neopterin is an immune activation marker for the cell-mediated immune response. Objective To examine the levels of plasma Aβ40, Aβ42, and neopterin in children or adolescents with DS or controls. Materials and methods Blood was collected from DS ( N = 35; 7 ± 3.8 years old) and their siblings ( N = 34; 10 ± 4.5). Plasma Aβ40 and Aβ42, and neopterin levels were quantitated by sandwich ELISA. Results Aβ40 and Aβ42 levels were higher in DS than controls. The ratio of Aβ42/Aβ40 was lower in DS than in controls. There were significant negative correlations between age and Aβ40 in DS and controls, and between age and Aβ42 levels in DS but not in controls. There was no association of Aβ40 or Aβ42 levels with Apo E in either group. Neopterin levels were higher in DS than controls, and the levels were not correlated with Aβ40 and Aβ42 levels in DS or controls. Conclusions The over expression of APP gene in DS leads to increases in plasma Aβ40 and Aβ42 levels before plaque formation in DS brain. Higher neopterin concentrations in DS reflect inflammatory cell activation. Further studies are needed to determine whether DS children with lower plasma Aβ42/Aβ40 ratios are at increased risk of developing AD during aging than those with higher ratios.

Association of High Pretransplant sIL-6R Plasma Levels with Acute Tubular Necrosis in Kidney Graft Recipients

Delayed graft function is primarily caused by acute tubular necrosis (ATN). We studied in renal transplant recipients with posttransplant graft biopsy whether an up-regulated immune system in the recipient immediately before transplantation affects the risk of developing ATN and might be relevant for the pathogenesis of ATN. In a retrospective study, we analyzed pretransplant and early posttransplant soluble interleukin (sIL)-1RA, interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta2, interferon (IFN)-gamma, and neopterin plasma levels in patients with ATN (n=26). Matched patients with acute rejection (AR) (n=26) or normal posttransplant biopsy (n=26) served as controls. Pretransplant sIL-6R was higher (P=0.0004) and pretransplant TGF-beta2 lower (P=0.002) in patients with ATN than in patients with normal biopsy. ROC curves showed that high pretransplant sIL-6R has a high sensitivity (77%) and high specificity (64%) for ATN (P=0.002). Posttransplant plasma sIL-6R continued to be higher in ATN patients than in patients with normal biopsy (P=0.001). Patients with acute rejection showed pre- and posttransplant sIL-6R and TGF-beta2 plasma levels similar to those of patients with normal biopsy (P=NS). High pretransplant sIL-6R plasma levels are associated with an increased risk of ATN and might contribute to the development of ATN early posttransplant. Our data suggest that preactivation of the recipient's immune system increases the risk of ATN.