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PubMed2004

Intestinal inflammation measured by fecal neopterin in Gambian children with enteropathy: association with growth failure, Giardia lamblia, and intestinal permeability.

OBJECTIVES: Investigate whether fecal neopterin concentration (a potential marker of gut inflammation) in Gambian children with enteropathy was associated with growth failure. Secondary outcome measures tested the associations between Giardia lamblia infestation, fecal neopterin and lactulose mannitol absorption ratio(L:M), a measure of intestinal permeability. METHODS: Seventy-two children had height and weight measured every 6 to 8 weeks until 15 months of age in a rural Gambian village. L:M ratio, a measure of small intestinal permeability and fecal neopterin were measured at these times. Stool was examined by immunofluorescence and light microscope for Giardia cysts. RESULTS: Long-term height and weight gains were negatively associated with mean subject fecal neopterin concentration (r = -0.29 and -0.36, respectively; P < 0.001). There was no correlation between fecal neopterin and intestinal permeability or history of diarrhea. Of 72 children studied, 19 had Giardia cysts in stool and 38 had negative stool examinations. Infected children had a mean of 0.7 days of diarrhea/week (95% confidence interval [CI], 0.31-1.03) versus 0.8 days/week (95% CI, 0.71-0.85) in uninfected children. No difference in growth was detected between those with positive or negative fecal smears. Mean L:M ratio was the same in both groups (0.31; 95% CI, 0.26-0.34). CONCLUSIONS: Consistent with the theory that intestinal inflammation in tropical infants may impair growth, fecal neopterin concentrations were inversely associated with growth. Factors other than Giardia are causing enteropathy and growth failure in Gambian infants.

Animals↗
PubMed1991

Cytokine induction of neopterin production.

The pteridine neopterin is a marker of immunological activation and has been shown to be a useful marker of graft-versus-host disease (GVHD) in bone marrow transplant patients. High levels of both neopterin and interferon-gamma (IFN-gamma) were produced in vitro during mixed lymphocyte responses, which may be considered to be a model of the primary events leading to GVHD. Neopterin was shown to be produced by monocytes in response to stimulation with IFN-gamma, but not other cytokines. However, the interleukins IL-1 alpha, IL-1 beta, IL-2, and tumour necrosis factor (TNF) alpha and beta, but not IL-6, stimulated neopterin production by unfractionated peripheral blood mononuclear cells (PBMC), and culture supernatants from PBMC stimulated with IL-1 alpha, IL-1 beta, IL-2 and IL-6, but not TNF-alpha or TNF-beta induced neopterin production following transfer to fresh monocyte cultures. It therefore appears that cytokines may generate neopterin by induction of IFN-gamma, by synergy with low levels of induced IFN-gamma, or by non-IFN-gamma-dependent mechanisms.

Biopterins↗
PubMed1992

Neopterin release from human endothelial cells is triggered by interferon-gamma.

Human umbilical vein endothelial cells (HUVEC) were investigated for their ability to produce neopterin, a biochemical marker for an activated immune system. Interferon-gamma (IFN-gamma), IL-1 alpha, IL-2, IL-6, tumour necrosis factor-alpha, granulocyte/macrophage colony stimulating factor, phytohaemagglutinin and concanavalin A were used to stimulate HUVEC. While IFN-gamma induced neopterin release from HUVEC in a time- and dose-dependent manner, all the other cytokines used had no effect on neopterin production. High neopterin levels are found in patients with rejection episodes or infections. Our results suggest that not only monocytes and macrophages, which are known to synthesize neopterin, but also endothelial cells are responsible for these high serum neopterin levels.

Biopterins↗
PubMed1992

Increased neopterin levels in brains of patients with human immunodeficiency virus type 1 infection.

Postmortem levels of native neopterin (D-erythro-neopterin) were measured in cerebral cortical samples from 44 human immunodeficiency virus type 1-infected and eight uninfected, nonneurological control patients. Cerebral cortical gray and white matter neopterin levels for the controls ranged from 0.5 to 7.2 pmol/mg of protein in contrast to neopterin levels in brains of the virus-infected patients, which frequently were more than threefold and occasionally more than 30-fold higher than mean control levels. Cortical neopterin levels did not correlate with severity of the acquired immunodeficiency syndrome dementia complex, but subcortical levels correlated with the presence of active human immunodeficiency virus type 1 infection, as reflected by pathological evidence of multinucleated giant cell encephalitis. Evidence of opportunistic cytomegalovirus infections in approximately 25% of the human immunodeficiency virus type 1-infected patients was associated with enhanced levels of neopterin in frontal cortex.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Increased serum neopterin concentration as indicator of disease severity and poor survival in multiple myeloma.

In this study we investigated serum neopterin levels in 73 multiple myeloma (MM) patients (63 determinations at diagnosis, 58 in remission, and 35 at relapse), in 56 monoclonal gammopathies of undetermined significance (MGUS), and in 70 normal controls. Median neopterin level was 5.3 nmol/l in normal controls, 6.8 nmol/l in MGUS, and 10.7 nmol/l in MM patients. In comparison to healthy subjects, significantly higher levels were observed in MM patients (p less than 0.0001). A statistical difference was observed between MGUS and MM patients at diagnosis (p less than 0.007). Compared to diagnosis, a further increase was noticed during relapse, suggesting a correlation between neopterin and disease activity. The prognostic significance of raised neopterin levels was confirmed by a survival analysis. Median survival for patients with high values was 20 months, whereas it was 63.9 months for those with low values (log-rank test p less than 0.003). Serum neopterin concentrations also correlated to beta 2 microglobulin levels and the percentage of CD38+ circulating lymphocytes, indicating a link between neopterin and other myeloma prognostic factors.

Biomarkers, Tumor↗
PubMed1989

Correlation between synovial neopterin and inflammatory activity in rheumatoid arthritis.

According to recent investigations neopterin (a pyrazinopyrimidine derivative) is a biochemical marker that reflects the activity of the proinflammatory immunocellular system of the synovial tissue in rheumatoid arthritis (RA). Interferon gamma, derived from antigen activated T lymphocytes, stimulates macrophages to synthesise and release neopterin into the culture supernatant in vitro. To extend this in vitro model to a clinical level a sensitive new radioimmunoassay technique was used to measure neopterin concentrations in the synovial fluid (SF) of 17 patients with active RA, nine with osteoarthritis, and six with acute gout, and in that of 12 controls undergoing meniscectomy. The SF neopterin concentrations were significantly higher in patients with RA than in the other groups of patients, particularly the controls. Multivariant analysis showed that SF neopterin concentrations correspond better with the systemic inflammatory activity of RA than with the local disease activity of the knee joints. Thus the study strengthens the hypothesis that neopterin reflects the essential role of the activated immunocellular reaction in the pathogenesis of RA.

Adult↗
PubMed1998

Neopterin-induced tumor necrosis factor-alpha synthesis in vascular smooth muscle cells in vitro.

Synthesis and secretion of proinflammatory mediators like tumor necrosis factor-alpha and neopterin are common events in severe systemic inflammatory disorders, e.g. sepsis and septic shock. Recent data suggest that both substances show similarities with respect to their bioactivities. In the present study we investigated the potential interactions of neopterin and tumor necrosis factor-alpha on inducible nitric oxide synthase gene expression and nitric oxide generation in rat vascular smooth muscle cells. In addition, we studied the influence of neopterin on tumor necrosis factor-alpha synthesis in this cell type. Single stimulation of smooth muscle cells with either neopterin or tumor necrosis factor-alpha caused inducible nitric oxide synthase gene expression and nitric oxide production. Coincubation of cells with both compounds resulted in at least additive effects on nitric oxide synthesis. Quantification of tumor necrosis factor-alpha cDNA revealed a dose-dependent effect of neopterin on tumor necrosis factor-alpha gene expression. Similar results were obtained concerning the detection of tumor necrosis factor-alpha protein and the assessment of tumor necrosis factor-alpha bioactivity. These data suggest that neopterin and tumor necrosis factor-alpha are closely associated with regard to synthesis and effects, respectively. The interactions of both inflammatory mediators in vascular smooth muscle cells might contribute to the excessive release of nitric oxide observed during sepsis, thus triggering cellular destruction and multiple organ failure.

Animals↗
PubMed1987

Monitoring of serum neopterin levels in renal transplant recipients: increased values during impaired renal function and cytomegalovirus infection.

In 92 renal transplant recipients, serum or plasma levels of neopterin were significantly elevated during pretransplant uremia, rejection, cyclosporin A induced nephrotoxicity and cytomegalovirus (CMV) infections. In patients with normal serum creatinine (less than 115 mumol/l) 71% had elevated serum neopterin levels. None of 19 cyclosporin A treated patients with stable renal function had a normal level of neopterin compared to 50% for patients treated with azathioprine (p less than 0.05). Due to the dependency on renal function the serum levels of neopterin could not distinguish between rejection and cyclosporin A induced nephrotoxicity. Marked increases in neopterin levels were seen during infections and especially during CMV infection. Determination of neopterin levels may be helpful in the diagnosis of CMV infection.

Adolescent↗
PubMed1989

Urinary neopterin as a new biochemical marker for the monitoring of disease activity and prognosis in membranous nephropathy associated with hepatitis B surface antigenemia.

In an attempt to find a parameter for the differentiation of membranous nephropathy with hepatitis B surface antigenemia (HBVMN) and other types of nephrotic syndrome (NS) in HBsAg (+) carriers, we measured the urinary neopterin in 20 HBVMN patients, other types of NS in HBsAg (+) carriers, asymptomatic HBsAg (+) carriers and HBsAg (-) controls, during the active nephrotic phase and in remission. The urinary neopterin excretion was found to be significantly elevated only in the HBVMN during NS or heavy proteinuria. It progressively decreased and corresponded with the amount of proteinuria. In patients with deteriorated renal function, initially, urinary neopterin excretion was significantly higher than in others and it remained significantly elevated during the follow-up period. In vitro when a patient's mononuclear cells were stimulated with lymphoblastoid cell line, the release of neopterin content in supernatant was increased during the acute phase. There was a significant correlation between supernatant and urinary neopterin level. These results suggest that urinary neopterin may be a new biochemical marker for the differential diagnosis of HBVMN and may be used to monitor the course of HBVMN and serve as a prognostic indicator. However, the specificity is not clear.

Biomarkers↗
PubMed1990

Close relationships between neopterin and beta-2-microglobulin levels in intravenous drug abusers.

Serum from 36 intravenous drug abusers without acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were tested for concentrations of neopterin and beta 2-microglobulin. The seroprevalence of human immunodeficiency virus (HIV) antibody in this group was 50%. Previous studies of this group showed that the HIV antibody positive patients had significant increases in HLA-DR expression on peripheral blood lymphocytes and increases in serum soluble CD8 antigen. Both neopterin and beta 2-microglobulin concentrations were significantly higher in the HIV antibody seropositive patients compared to the seronegative patients (p = 0.001 and p = 0.005, respectively). A highly significant positive correlation between neopterin and beta 2-microglobulin was found for the seropositive patients (r = 0.8879, p less than 0.0001) as well as for the entire group (r = 0.6054, p = 0.0002). Significant positive correlations were also found between neopterin or beta 2-microglobulin and the percent DR + T cells and CD8 antigen levels, although these correlations were not as significant as that observed between neopterin and beta 2-microglobulin. No relationships were found between neopterin or beta 2-microglobulin and total CD4 cell concentrations or CD4/CD8 ratios. These data demonstrate the significant interrelationships between various immune activation markers in a population at risk for developing AIDS.

Antibodies, Monoclonal↗
PubMed1993

Neopterin, biochemistry and clinical use as a marker for cellular immune reactions.

Large amounts of neopterin are produced and released from human macrophages on stimulation with interferon-gamma. Neopterin is biologically stable, and it can be easily quantified in human body fluids. Neopterin measurements are useful to monitor allograft recipients to detect immunological complications. In autoimmune diseases, neopterin concentrations reflect the extent and activity of the disease. In infectious syndromes and in patients with cancer, neopterin concentrations provide prognostic information. In addition to providing clinically useful information, neopterin monitoring allows insight into the immunopathogenesis of a variety of diseases.

Biomarkers↗
PubMed1989

Urinary neopterin in pulmonary sarcoidosis. Relationship to clinical and biologic assessment of the disease.

Neopterin is a metabolite of guanosine-triphosphate, released in vitro by macrophages under the control of gamma-interferon and described as a marker of T cell activation in vivo. We have compared the urinary neopterin/creatinine ratio (mumol/mol) in patients with pulmonary sarcoidosis (n = 66), interstitial lung diseases other than sarcoidosis (nonsarcoid ILD, n = 35), and 45 normal control subjects. For the sarcoid population as a whole, urinary neopterin was higher (496 +/- 52 mumol/mol [mean +/- SEM]) than in control subjects (126 +/- 5 mumol/mol) (p less than 0.001). In patients with nonsarcoid ILD, urinary neopterin was frequently higher in granulomatous and/or lymphoproliferative diseases (hypersensitivity pneumonitis, tuberculosis, primitive Sjögren's syndrome, and malignant lymphomas) (781 +/- 193 mumol/mol, n = 10) but remained normal in other types of nonsarcoid ILD [( 163 +/- 14 mumol/mol, n = 25]: histiocytosis X, idiopathic pulmonary fibrosis, lung collagen-vascular diseases, diffuse neoplasms, pneumoconiosis; p less than 0.001 compared with sarcoidosis). We have also evaluated the relationship between urinary neopterin and the clinical or biologic markers currently used to assess sarcoidosis: alveolar lymphocytosis in lavage fluid (ALY), 67-gallium scan semiquantitative index (67Ga), or serum angiotensin-converting enzyme (SACE). Sarcoid patients with the highest urinary neopterin were those in whom mean values of these markers were the highest (p less than 0.05, all comparisons). Patients with positive markers (i.e., either clinical expression of sarcoidosis-ALY greater than 30%-67Ga greater than 20-SACE greater than 60 U/ml) had significantly higher urinary neopterin levels than did other sarcoid patients (p less than 0.05, all comparisons).

Adult↗
PubMed1993

Comparison of urinary neopterin and pseudouridine in patients with malignant proliferative diseases.

The HPLC method for the simultaneous determination of urinary neopterin, pseudouridine, and creatinine allows a rapid evaluation of the activation state of cell-mediated immunity, and the stimulation of whole-body rRNA + tRNA turnover, associated with malignant growth. Urinary neopterin and pseudouridine concentrations in healthy subjects amounted to: 106.6 +/- 34.6 mumol/mol creatinine, and 19.6 +/- 5.2 mmol/mol creatinine (mean +/- SD), respectively. The increase of neopterin excretion in patients with haematological neoplasms ranged from 146% in Hodgkin's disease to 534% in non-Hodgkin's lymphoma, whereas the increase in cancer cases ranged from 95% in adenocarcinoma of the gaster to 741% in hepatocellular carcinoma. The changes in pseudouridine excretion were much less pronounced: 63% in non-Hodgkin's lymphoma and 120% in carcinoma of the urinary bladder. The correlation coefficient between neopterin and pseudouridine was relatively low (r = 0.43), although statistically significant (P < 0.01). In the case of several neoplasms e.g. Hodgkin's disease, polycythaemia vera, and adenocarcinoma of the gaster, neopterin was significantly elevated, whereas pseudouridine remained at a normal concentration. There was a positive relationship between the stage of the disease (primary focus, regional metastases, dissemination) and urinary concentration of pseudouridine in patients with adenocarcinoma of the large intestine. In the same patients the increase of neopterin excretion was noticed both in early and advanced stages, with the highest values in disseminated disease.

Analysis of Variance↗
PubMed1993

Neopterin in patients with choroidal melanoma.

Neopterin excretion in urine and the serum concentrations of neopterin were compared in 101 patients with a malignant melanoma of the choroid and in a matched group of healthy volunteers. The majority of cases (n = 99) presented an untreated (n = 20) or treated and either partially (n = 33) or completely regressed (n = 47) melanoma of stage I-III without signs of extraocular manifestation at the time of analyses. The incidence of elevated neopterin concentrations in all melanoma patients beyond the upper limit (mean + 2 S.D. of healthy controls) was 16% for both serum and urine. In patients with critical events, for example orbital infiltration or delayed metastatic disease during the subsequent follow-up period (at least 14 months), the neopterin concentrations were at the higher end of distribution. One patient with verified metastatic disease at the time of analysis presented extremely elevated neopterin concentrations in serum (82.3 nmol/l) and urine (1608 mumol/mol creatinine). It seems that the results of neopterin analyses are informative as a prognostic factor for the follow-up of patients with a malignant melanoma of the choroid.

Aged↗
PubMed1993

Soluble interleukin-2 receptor and urinary neopterin concentrations in malignant lymphoma.

The serum concentrations of soluble interleukin-2 receptors and urine neopterin were studied in 82 patients with malignant lymphomas (25 patients with Hodgkin's disease and 57 patients with non-Hodgkin's lymphoma. Increases in soluble interleukin-2 receptors and in urinary neopterin were significantly correlated with the clinical phase of the disease. The average values in both Hodgkin's disease and non-Hodgkin's lymphoma patients suffering from the disease in its active phase were significantly higher than those of patients in complete remission. Neopterin concentrations (but not soluble interleukin-2 receptor concentrations) were also elevated in clinical stages III-IV of each disease. Urinary neopterin correlated directly and significantly with the erythrocyte sedimentation rate and inversely with haemoglobin. Finally, a longitudinal analysis showed a general tendency for the markers to return to normal values, in accordance with the favourable outcome of therapy; this was more evident for urinary neopterin than for soluble interleukin-2 receptors. These findings seem to confirm that soluble interleukin-2 receptors and especially urinary neopterin can be useful markers for monitoring and prognosis of malignant lymphomas.

Adult↗
PubMed1998

Neopterin plasma concentrations predict the course of severe acute pancreatitis.

In a prospective, descriptive study in 25 patients with acute pancreatitis neopterin plasma concentrations were found to be associated with the severity of the disease, which was assessed using weights of the worst 17 physiological abnormalities of the APACHE-III score over a 24 h-period after hospital admission. Neopterin concentrations were higher in severe pancreatitis (n = 10) compared to mild disease, and there existed a positive exponential correlation between neopterin and the Acute Physiology Score (r = 0.66). Higher neopterin concentrations were associated with the development of multiple organ failure (p = 0.012) and death (p = 0.019). At a cut-off concentration of 12 nmol/l the sensitivity (80%) and specificity (100%) of neopterin for the discrimination between mild and severe clinical course of pancreatitis was more accurate than C-reactive protein at a risk threshold of 1.2 g/l (70% and 87%). Development of pancreatic necrosis was associated with higher neopterin concentrations than edematous pancreatitis (p < 0.001).

Adult↗
PubMed1999

Increased serum neopterin concentrations in patients with Alzheimer's disease.

We measured serum neopterin concentrations in 24 patients with Alzheimer's disease (8 males, 16 females; age: 73.1+/-6.2 years; free of any infectious process) and fourteen controls of similar age (4 males, 10 females; age: 69.7+/-8.8 years). Compared to controls, significantly higher concentrations of neopterin (p< 0.01) were found in patients with Alzheimer's disease. Among patients, concentrations of neopterin were higher in those with lower mini-mental-state (p < 0.05), and an inverse correlation existed between mini-mental-state and neopterin concentrations. No such association existed with the duration of the disease. There were also significant correlations between neopterin and serum concentrations of immune activation markers such as soluble tumor necrosis factor (TNF) receptor and soluble interleukin-2 receptor (all p<0.01). Thus, increased concentrations of neopterin in serum of patients with Alzheimer's disease correlate with the severity of dementia. The data imply a chronic state of peripheral immune activation in Alzheimer's disease.

Aged↗
PubMed1988

Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma.

Urinary neopterin levels were measured by high-performance liquid chromatography in 15 patients with liver cirrhosis, 18 patients with hepatocellular carcinoma and 20 normal subjects. The mean levels of urinary neopterin in patients with hepatocellular carcinoma were significantly elevated (p less than 0.01) compared to those in cirrhotics and normal subjects, but did not significantly differ between cirrhotics and normal subjects. Urinary neopterin levels correlated significantly with tumor size in patients with hepatocellular carcinoma but not with serum alpha-fetoprotein. Hepatocellular carcinoma patients with high urinary neopterin levels appeared to have more serious hepatic dysfunction than those with normal urinary neopterin levels, and moreover, there was a significant difference (p less than 0.05) in survival between the two groups. These findings suggest that urinary neopterin excretion may be a good biochemical marker to assess the progression of tumor and a useful prognostic indicator in patients with hepatocellular carcinoma.

Biomarkers, Tumor↗