Elevated Serum Neopterin Levels Research Articles

ATAXIA AS A PRESENTING SYMPTOM OF IMMUNE DYSREGULATION DISORDER IN THE SETTING OF EBV INFECTION

Introduction Epstein-Barr virus usually leads to mild, self-limiting infection in immunocompetent host. However, patients with defective cell-mediated cytotoxicity can get life-threatening infection with Hemophagocytic Lymphohistiocytosis features. Case Description 2-year-old Hispanic girl presented with acute onset of ataxia and slurry speech. No fever or lymphadenopathy were noted. CSF EBV PCR was positive and her MRI was consistent with viral encephalitis. She was treated with IVIG, steroids, and Acyclovir for 2 weeks. Over the next few months, her symptoms started to worsen again to the point that she could not sit up. Her MRI showed worsening of the inflammation with new hemorrhagic lesions. Brain biopsy was positive EBV DNA in situ hybridization and showed T cell and histiocytic infiltration. Her immunological evaluation revealed a mild reduction in T and NK cells number, normal B cells count, and normal immunoglobulin levels. HIV PCR was negative. SAP expression was normal; however, NK cell function was absent. HLH evaluation was unremarkable except for elevated serum and CSF neopterin levels. She was treated with steroid in addition to rituximab (IV and then intrathecally) to decrease the EBV viral load (fig1). Few weeks later, the Genetic test revealed a missense homozygotic mutation of perforin gene (c.1337A>C) which is validated by flow cytometry. With a diagnosis of primary HLH confirmed, the patient was treated with etoposide waiting for matched donor bone marrow transplant. Discussion NK cells disorders should be considered in pediatric patients with severe or unusual EBV infection. Rituximab is effective in decreasing EBV viral load.

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.

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.

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.

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.

Usefulness of serum neopterin levels in acute decompensated heart failure to predict renal dysfunction

Context: Neopterin serum concentration increases in the presence of renal dysfunction.Objective: We sought to determine the relationship between admission serum neopterin levels and worsening renal function (WRF) in patients with heart failure (HF).Methods: We prospectively measured serum neopterin levels in patients with HF and the patients were subdivided into two groups: with and without WRF during hospital admission.Results: Logistic regression analysis showed that high serum neopterin levels at admission were associated with a greater likelihood of developing WRF.Conclusions: Patients admitted to hospital with HF, elevated serum neopterin levels are associated with an increased risk of developing WRF.

IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults

neopterin is a monocyte/macrophage-derived immune activation marker and its levels increase with age. Frailty is an important clinical syndrome of old age. Previous studies have shown significant association between elevated interleukin-6 (IL-6) levels and frailty. The objective of this study was to evaluate IL-6-independent association of serum neopterin levels with prevalent frailty. this is a cross-sectional study in community-dwelling older adults recruited from residential and retirement communities in Baltimore, MD, USA. Frailty was determined using validated screening criteria. Serum neopterin and IL-6 levels were measured using standard enzyme-linked immunosorbent assay. Pearson correlation and multivariate linear regression analysis was performed to assess the relationship between log(neopterin) and log(IL-6). Odds ratios (ORs) for frailty were calculated using log(neopterin) and log(IL-6) as continuous measures and across tertiles of neopterin and IL-6 levels, adjusting for age, race, sex, education and body mass index. one hundred and thirty-three individuals with a mean age of 84 years (range 72-97) completed the study. Neopterin levels were significantly higher in frail older adults than those in non-frail controls [median: 8.94 versus 8.35 nM, respectively, P < 0.001 t-test on log(neopterin)]. Log(neopterin) was significantly associated with prevalent frailty, adjusting for log(IL-6). Participants in the top tertile of neopterin had OR of 3.80 [95% confidence interval (CI) = 1.36-10.6, P < 0.01] for frailty. As expected, participants in the top tertile of IL-6 had OR of 3.29 (95% CI = 1.21-7.86, P < 0.05) for frailty. Log(neopterin) correlated with log(IL-6) (correlation coefficient = 0.19, P < 0.05). Moreover, OR for participants in the top neopterin tertile remained significant after adjusting for IL-6 (OR = 3.97, 95% CI = 1.15-13.72, P < 0.05). elevated neopterin levels had IL-6-independent association with prevalent frailty, suggesting potential monocyte/macrophage-mediated immune activation in the frail elderly.

Elevated serum neopterin levels in acetaminophen-induced liver injury

Neopterin is synthesized in macrophage/Kupffer cells by interferon-gamma and other cytokines. This study aimed to evaluate the utility of using neopterin as a biomarker of acetaminophen (APAP)-induced liver injury. Wistar rats, randomly divided into two groups (APAP and normal), received APAP (1.0 g/kg) and distilled water, respectively, by gastric tube. The APAP group had a higher degree of liver necrosis than the control group. The APAP group also had significantly higher serum neopterin levels than the normal group. Serum neopterin levels correlated with serum AST, ALT activities, and degree of necrosis. This study demonstrates the preclinical utility of neopterin as a biomarker for the animal model of APAP-induced liver injury. Further research studies are required to determine the preclinical opportunities of using neopterin as a marker of APAP-induced liver injury.

The association between neopterin and acetaminophen-induced nephrotoxicity

Introduction: In large dosages, acetaminophen (APAP) produces acute kidney necrosis in most mammalian species. High neopterin levels have been accepted as strong indicators for the clinical severity of some diseases. In this study, we aimed to evaluate whether neopterin is a biomarker in the identification of APAP-induced nephrotoxicity. Materials and Methods: Thirty adult male Wistar rats were randomly divided into three groups: control, APAP-1, and APAP-2 groups. APAP-1 and APAP-2 group rats were given a single dose of 1 and 2 g/kg body weight of APAP by gastric tube, respectively. Kidney tissues and blood samples were obtained for biochemical and histopathological analyses. Biochemical parameters, serum and kidney neopterin levels, and the grade of tubular injury were compared in the control, APAP-1, and APAP-2 group animals. Results: APAP treatments caused tubular necrosis in the kidney and increase in serum creatinine concentrations accompanied by elevated serum and kidney neopterin levels. In the rats of groups APAP-1 and APAP-2 when compared with that of the control group (109.1 pmol/mg protein), median kidney neopterin concentrations were 162.1 (p = 0.089) and 222.2 (p < 0.001) pmol/mg protein, respectively. The grade of tubular injury of the APAP-1 and APAP-2 groups was higher than the group of control (both p < 0.001). Conclusions: Serum and kidney neopterin levels could be sensible alternative to evaluate the risk to have nephrotoxicity because of APAP overdose. The elevated serum and kidney neopterin in the APAP-induced tubular necrosis might be a marker of acute histological kidney injury.

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Comparative evaluation of postmortem serum concentrations of neopterin and C-reactive protein

The cellular immune response is accompanied by the release of neopterin. The level of neopterin in serum is increased in patients suffering from viral infections, autoimmune diseases, systemic inflammation, allograft rejection and malignant diseases, while that of C-reactive protein (CRP) is known to rise during inflammatory diseases and traumas. To investigate postmortem neopterin and CRP concentrations with regard to the cause of death, we examined cardiac and peripheral blood samples in 474 autopsy cases without advanced decomposition (0–96 years of age, 343 males and 131 females), 2.8 h to 3 days (median, 18.0 h) after death. Survival time was 0.1 h to 5 months (median, 3.0 h) for traumatic death, and 0.1–1, 440 h (median, 2.5 h) for natural death. In autopsied subjects, neopterin concentrations were higher than the clinical reference, independent of the time after death, and depended on the survival time. In cases of acute and subacute death due to trauma, the neopterin level in right heart blood was mildly to moderately elevated (about 50–200 nmol/l) except for sharp instrument injury, whereas the CRP concentration usually remained low (<1 mg/dl). However, a moderate rise in the CRP level (around 1–10 mg/dl) was observed in fatal cases of hypothermia (cold exposure). Markedly elevated serum CRP and neopterin levels (>10 mg/dl and >500 nmol/l, respectively) were detected in cases of delayed death due to trauma involving systemic inflammatory response syndrome (SIRS) and of fatal bacterial infections. For sepsis, the serum CRP level was markedly elevated but the neopterin level was low in some cases. Fatal viral infections usually resulted in a marked elevation in the serum neopterin level (>500 nmol/l) with a mild to moderate rise in the CRP level. Combined analyses of neopterin and CRP may be useful to investigate viral infections and delayed traumatic death involving SIRS to support pathological findings.

High serum levels of neopterin in patients with Crimean–Congo hemorrhagic fever and its relation with mortality

ObjectiveNeopterin is generated and released in increased amounts by macrophages upon activation by interferon-gamma during cellular immune response. In this study, we aimed to investigate serum neopterin levels in patients with Crimean–Congo hemorrhagic fever (CCHF) and its clinical significance as a predictor factor of mortality.MethodsNeopterin concentrations on the first day of hospitalization were measured in serum samples from 51 CCHF patients. Serum neopterin levels and other clinical–laboratory parameters for fatal and nonfatal CCHF patients were compared.ResultsSerum neopterin levels (73.22 ± 54.30 nmol/L) were highly elevated in all CCHF patients (p < 0.0001) with higher levels in fatal group (153.66 ± 81.34 nmol/L, p = 0.0001) compared to nonfatal disease (55.99 ± 24.09 nmol/L). In univariate analysis, the level of neopterin on the first day of hospitalization, bleeding, platelet count, aspartate transferase and lactate dehydrogenase were associated with mortality. In multivariate analysis, only the serum level of neopterin was associated with mortality. As a mortality risk factor, area under the curve was 0.939 (p = 0.0001, 95% confidence interval: 0.85–1.00).ConclusionsIn this first study of serum neopterin levels for CCHF, elevated serum neopterin level showing strong activation of monocytes/macrophages was a risk factor for CCHF.

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.

Abstract 2602: Elevated Serum Neopterin Levels and Adverse Cardiac Events in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome

Objectives: We sought to assess whether plasma neopterin predicts adverse clinical outcomes in patients with NSTEACS. Background: Circulating C reactive protein (CRP), a marker of inflammation, correlates with events in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). High neopterin levels - a marker of macrophage activation - predict cardiovascular events in stable angina patients but their prognostic role in NSTEACS has not been systematically evaluated. Methods: We prospectively assessed 397 patients (74 % men) admitted with NSTEACS: 169 (42.5%) had unstable angina and 228 (57.5%) non-ST-segment elevation myocardial infarction (NSTEMI). Blood samples for neopterin and CRP assessment were obtained at admission. TIMI risk score was also assessed among other clinical and biochemical variables. The study end point was the composite of cardiac death, acute myocardial infarction and recurrent angina at 180-days. Results: Baseline neopterin concentrations (nmol/L) were similar in unstable angina and NSTEMI patients (8.3 [6.5–10.6] vs 8.0 [6.2–11.1], p = 0.54). Fifty-nine patients (14.9 %) had events during follow-up (highest third (%) 21.5 vs 1 st and 2 nd thirds 11.5, log rank 7.341, p = 0.007). On multivariable hazard Cox regression, only neopterin (highest vs 1 st and 2 nd thirds, HR 2.15, 95 % CI [1.21–3.81]) was independently associated with the combined endpoint.CRP levels, however, were not significantly different in patients with events compared to those without events (adjusted HR = 0.98, p = 0.89, 95% CI 0.80 –1.21). Conclusion: Increased neopterin levels are an independent predictor of 180-day adverse cardiac events in patients with NSTEACS.

Decreased Serum Tryptophan Concentration Predicts Poor Prognosis in Malignant Melanoma Patients

Background: Indoleamine (2,3)-dioxygenase (IDO) catalyses the initial, rate-limiting step in the degradation of the essential amino acid tryptophan. Via tryptophan deprivation, IDO activity suppresses T cell proliferation and differentiation and is thought to be a fundamental immune escape mechanism for tumor cells. Objective and Methods: To investigate the potential role of tryptophan degradation as a prognostic marker, serum tryptophan and kynurenine concentrations and the kynurenine-to-tryptophan ratio (kyn/trp) in 87 patients with malignant melanoma were compared to the course of the disease and to concentrations of the immune activation marker neopterin. Results: Compared to 49 healthy volunteers, the melanoma patients presented with lower tryptophan levels due to accelerated degradation. This was especially true for the subgroups of patients with distant metastases (p = 0.01), though not in patients with lymph node metastases or in patients who had not yet progressed. There existed a positive correlation between kyn/trp and neopterin concentrations (r_s = 0.587, p <0.001). In patients who died due to dissemination of the tumor, median tryptophan concentrations were significantly decreased (p = 0.006) and kyn/trp (p = 0.03) and neopterin concentrations (p = 0.002) were higher compared to survivors. In addition, lower tryptophan concentrations as well as higher kyn/trp and neopterin concentrations predicted a shorter survival. Conclusion: Decreased serum tryptophan concentrations and elevated serum neopterin levels can be used as predictive markers for the future course in melanoma patients. Moreover, our data support previous speculations that a higher degree of IDO expression could play a crucial role for tumor progression.

Tetrahydrobiopterin: Mediator of Endothelial Protection

During the past twenty years, the essential role of endothelial cells in preservation of vascular homeostasis has been well established.1,2⇓ Protection of the vascular endothelium against harmful influences of circulating substances including excessive levels of lipids has been a major therapeutic approach in prevention of atherosclerosis. While endothelial dysfunction, defined as a loss of biologically active nitric oxide (NO) produced in the endothelium, has been recognized as a prime target for prevention and reversal of atherosclerotic process, identification of exact molecular mechanisms responsible for the loss of endothelial NO have been more difficult to determine. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Alp et al3 report a series of elegant studies on genetically modified mice supporting the concept that NO synthase cofactor, tetrahydrobiopterin (Figure 1), is an important vascular protective molecule. The beneficial effect of tetrahydrobiopterin in apolipoprotein E (ApoE)-deficient mice appears to be mediated by preservation of endothelial nitric oxide synthase (eNOS) activity and production of nitric oxide in endothelial cells. The major steps of tetrahydrobiopterin biosynthesis. GTP=guanosine 5′-triphosphate. See page 445 In the early 1990s it was recognized that in the presence of suboptimal concentrations of tetrahydrobiopterin, activation of purified neuronal nitric oxide synthase (nNOS) causes “uncoupling of NOS” with subsequent increase …

Elevated serum neopterin level: its relation to endotoxaemia and sepsis in patients with major burns.

The present study was conducted to determine the relationship between levels of neopterin and endotoxin in the circulation, and whether the neopterin level was related to the development of severe sepsis after extensive burns. This prospective study included 35 patients with burn size greater than 30% (30-98%), and 22 healthy volunteers who served as a comparison group. Neopterin levels increased in most patients on day 3 post-burn, but they were not significantly correlated with the extent of the burn surface (P > 0 center dot 05). A high serum neopterin level was found in patients with sepsis (n = 15), and a marked elevation persisted throughout the observation period. The difference between septic and non-septic patients (n = 20) became significant on 14 and 28 days post-burn. Although the presence of early endotoxaemia did not influence the alterations in serum neopterin, patients with endotoxaemia had much higher neopterin values than those who showed no endotoxaemia from the second week onward (P < 0 center dot 05-0 center dot 01). In addition, circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxaemia on day 14 (r = 0 center dot 368, P < 0 center dot 05) and day 21 (r = 0 center dot 439, P < 0 center dot 01) after major burns. These results suggest that thermal injury can lead to an elevation of serum neopterin independent of the burn surface area. The initial increase in the neopterin level may be a part of the acute-phase response to tissue injury itself, whereas the endotoxin release in the circulation may be responsible for the continuous induction of neopterin during the late stage. In addition, the presence of a constant high neopterin level is associated with a critical event in the development of severe burn sepsis.