Plasma amino acids and neopterin in healthy persons with Down’s syndrome

Summary In persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism. In the present study, 48 older healthy DS persons without signs of dementia, psychiatric or somatic comorbidity and free of medication were analyzed for plasma levels of amino acids, neopterin and monoaminergic metabolites. Data were compared with those obtained from age and sex matched healthy controls. It was found that the spectrum of amino acids showed widespread differences in that levels of nearly all essential amino acids were lower in DS patients as compared to healthy controls. In addition, a significantly lower methionine and higher taurine concentration were observed which is in accordance with a disturbed homocysteine metabolism. With respect to the monoamine metabolites, the concentration of 5-hydroxyindoleacetic acid was not altered whereas that of homovanillic acid was significantly increased. Finally, the concentration of the immune activation marker neopterin was increased in persons with DS. It is concluded that healthy DS persons of older age show extensive biochemical abnormalities suggesting a compromised homocysteine metabolism, an activated cell-mediated immune response and an enhanced turnover of dopamine.     

Is there any relationship between serum and urine neopterin and serum interferon‐γ levels in the activity of Behcet's disease?

Background  Behcet's disease (BD) is a chronic, inflammatory, multisystem vasculitic disorder. There is no reliable laboratory marker that indicates disease activity. Neopterin is an immunological marker of cellular immune activation, which is secreted by monocytes/macrophages as a result of interferon-gamma (IFN-γ) secretion by activated T lymphocytes.
Objective  We aimed to investigate serum and urine neopterin levels in BD patients.
Methods  Forty-five patients who were diagnosed according to the criteria of the International Study Group for BD and 45 age- and sex-matched healthy controls were enrolled in the study. Disease activity was considered by clinical findings. Serum and urine neopterin levels and serum IFN-γ levels were measured.
Results  The mean values of serum and urine neopterin levels were 12.68 ± 4.87 nmol/L and 167.53 ± 148.73 µmol/mol creatinine, respectively, in BD patients ( P =  0.000 and P  = 0.008, respectively), which were statistically significantly different from the control group. However, there was no significant statistical difference between serum and urine neopterin levels of the clinically active and inactive patients. It was also found that the mean value of serum IFN-γ levels was higher in healthy controls than in BD patients ( P =  0.000).
Conclusions  We conclude that serum and urinary neopterin measurement can not be used as a reliable laboratory marker as the BD patients' serum and urinary neopterin levels do not increase in the active stage even though these levels increase when compared to healthy controls.     

Metastatic melanoma

Current treatment options in metastatic melanoma are of limited efficacy. Achievement of durable responses with biological agents, and the possibility to complement the higher response rate of chemotherapy and combined chemotherapy by prolonged duration of responses, led to development of biochemotherapy. Although a clear improvement in response rate (40–60% OR) resulted in some studies of the combined modality, several phase III studies had mixed results on the duration of survival. Various timeframes between the administration of chemotherapy and biologics have been tested, ranging between concurrent biochemotherapy, 1 d (immediately sequential), and up to 3 wk (long sequence or alternating). An analysis of the trend of responses and survival versus the duration of the chemobiotherapy sequence showed that, as the timeframe between chemo and bio components increases, the overall survival, survival of complete responders, and survival of partial responders appear to increase, but the effect is only present for the chemo-bio, and not for the bio-chemo sequence. Because there is no current explanation for this observation, it appears possible that the interaction between components of biochemotherapy results in a double effect: an increase in the immediate response reflected in the OR, CR, PR on one side, and an increase in survival on the other side. An analysis of mechanisms involved in the response leads us hypothesize that macrophage activation, as measured by the neopterin levels, may correlate with the survival of patients undergoing biochemotherapy, while the generation of nitric oxide, acting synergistically with chemotherapy in producing tumor cell killing, may be reflected in the overall response rate seen with the biochemotherapy combinations.     

Tryptophan degradation and immune activation in Alzheimer's disease

Summary. Alzheimer's disease (AD) is likely associated with systemic immune activation. During immune response, interferon-gamma stimu-lates indoleamine 2,3-dioxygenase (IDO) converting tryptophan to N-formylkynurenine followed by kynurenine in an ensuing step. Thus, IDO activity is estimated by the kynurenine per tryptophan quotient (Kyn/Trp). In 21 patients suffering from AD, in 20 controls of similar age, and in 49 blood donors we measured serum tryptophan and kynurenine concentrations by HPLC. Lower tryptophan concentrations were found in elderly control subjects compared to blood donors (62.1 vs. 73.0 μM, p < 0.005). Tryptophan concentrations tended to be still lower in AD patients (54.4 μM, p = 0.07) compared to elderly controls. Enhanced tryptophan degradation in patients was reflected by significantly increased Kyn/Trp (46.1 vs. 34.1 in elderly controls, p < 0.05). Correlations were found in patients between Kyn/Trp and concentrations of soluble immune markers in serum, i.e., neopterin, interleukin-2 receptor and tumor necrosis factor receptor (all p < 0.001). Increased Kyn/Trp was associated with reduced cognitive performance. Tryptophan degradation due to immune activation may exert impact on the pathogenesis of AD. Received May 15, 1999; accepted August 24, 1999     

Effects of interferon-alpha (IFN-α) administration on leucocytes in healthy humans

Plasma concentrations of IFN-α are increased in several inflammatory conditions. Several lines of evidence indicate that IFN-α has anti-inflammatory properties. To study the effects of IFN-α on leucocyte subsets and activation and on cytokines, we administered IFN-α (rhIFN-α2b; 5 × 10⁶ U/m²) to eight healthy human subjects in a randomized controlled cross-over study and analysed changes in circulating leucocytes and parameters for neutrophil and monocyte activation. After administration of IFN-α, neutrophil counts increased, monocyte counts decreased transiently, whereas the number of lymphocytes, basophils and eosinophils showed a sustained decrease. IFN-α administration was also associated with neutrophil activation, reflected in an increase in the plasma concentrations of elastase–α₁-antitrypsin complexes and lactoferrin. Serum neopterin, a marker for monocyte activation, was significantly increased 10 h after administration of IFN-α. IFN-α significantly increased plasma concentrations of IL-6, IL-8 and IL-10. Although IL-1 and tumour necrosis factor (TNF) remained undetectable, plasma concentrations of soluble TNF receptors p55 and p75 increased after IFN-α administration. We conclude that IFN-α induces multiple alterations in the distribution and functional properties of leucocytes. IFN-α exerts pro- as well as anti-inflammatory effects within the cytokine network.     

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.     

Homocysteine and serum markers of immune activation in primary dystonia.

The cause of primary dystonia remains unknown. Several reports point to immune system disturbances in primary dystonia and a recent study demonstrated hyperhomocysteinemia in cervical dystonia. Homocysteine (HCY) is an amino acid and elevated HCY concentrations were shown to be associated with immune system activation and increased neopterin serum concentrations. We examined HCY serum concentrations together with serum markers of immune activation in patients with different types of primary dystonia. Eighty-three patients with different types of primary dystonia were included and investigated at least 3 months following botulinum toxin treatment. Thirty-six healthy volunteers with similar age and sex distribution served as controls. Total serum HCY, kynurenine, and tryptophan concentrations were determined by high-performance liquid chromatography; neopterin, folate, and vitamin B12 concentrations were measured by immunoassays. Routine blood analysis, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood count (WBC), was performed. Patients with primary dystonia had significantly higher HCY concentrations compared to controls. Among the dystonia subtypes, no significant difference of HCY serum concentrations was observed. CRP and ESR were within the normal range in >90% of the patients and all had normal WBC. Neopterin, kynurenine, and tryptophan serum concentrations were similar in patients and controls and not correlated with HCY serum concentrations. The results provide evidence against enhanced cellular immune activation in patients with primary dystonia. However, hyperhomocysteinemia was present in all dystonia subtypes and unrelated to immune activation in this study. HCY is a neuronal excitotoxic amino acid and hyperhomocysteinemia is considered an independent vascular risk factor. Further studies are required to define the background of hyperhomocysteinemia in primary dystonia.     

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  > 0.05). 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  < 0.05–0.01). In addition, circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxaemia on day 14 ( r  = 0.368, P  < 0.05) and day 21 ( r  = 0.439, P  < 0.01) 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.     

Oral candidosis in HIV-infected patients. Prognostic value and correlation with immunological parameters

In a prospective study, 29 patients were observed over a period of 42 weeks for signs of oral candidosis (OC), immunological parameters and other typical AIDS-related events. Before the study started, no OC was observed in any of the patients. During the observation period, OC was diagnosed in 12 of the 29 patients (41%). 5 of these 12 patients (42%) developed full-blown AIDS during the 42 weeks. In contrast, a progression to AIDS was observed in only 1 of the 17 patients (5.9%) without OC. The laboratory findings for patients with and without OC showed statistically significant differences for neopterin (23.6 against 14.4 nmol l-1), CD4 counts (417 against 763/mm3) and CD4/CD8 ratios (0.45 against 0.85). Based on these results, it seems justifiable to consider prophylactic measures such as pentamidine inhalation and/or treatment with zidovudine in HIV-infected patients with immunodeficiency and occurrence of OC.     

原发性肾病综合征患儿血清血管内皮生长因子、新蝶呤的变化

目的检测原发性肾病综合征（PNS）患儿血清血管内皮生长因子（VEGF）、新蝶呤（NP）水平,评价其临床意义。方法PNS活动期患儿42例（A组）。其中对类固醇治疗反应敏感30例（A1组）;不敏感者12例（A2组）。缓解期PNS22例（B组）。健康对照组26例（C组）。酶联免疫吸附法（ELISA）测定其不同时期血清VEGF、NP水平。结果A组血清VEGF、NP较B及C组显著升高（Pa〈0.01）。B组血清VEGF、NP与C组比较无显著性差异（Pa〉0.05）。A1与A2组血清VEGF、NP水平无显著性差异（Pa〉0.05）。A组血清VEGF、NP分别与尿蛋白程度呈正相关（r=0.47,0.43Pa〈0.01）。结论血清VEGF、NP在PNS活动期升高,可能是反映PNS急性活动期指标,但不是区分激素敏感或耐药指标。血清VEGF、NP水平与PNS蛋白尿形成有一定关系。