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Biomedical subjects

Dietmar Fuchs

Publications and source records attributed to Dietmar Fuchs.

At least 91 records · Page 5Linked to original sources
PubMed2003

Tryptophan and quality of life in colorectal cancer.

We tested the hypothesis that reduced tryptophan availability due to immunological stimulation in colorectal cancer impairs quality of life (QoL) by measuring serum tryptophan levels, and correlating them with serum immunological markers and with QoL indices. Serum tryptophan level was significantly reduced in cancer patients compared with healthy controls. Serum tryptophan/kynurenine ratio and neopterin level were significantly increased in cancer, with a significant correlation between the two variables. Reduced serum tryptophan correlated significantly with worse QoL scores. The results support the hypothesis that in colorectal cancer, QoL impairment may be due to serum tryptophan depletion mediated by immunological activation.

Case-Control Studies↗
PubMed2003

Kynurenine and neopterin in the aqueous humor of the anterior chamber of the eye and in serum of cataract patients.

Serum kynurenine, neopterin, selenium concentrations; neopterin concentrations in aqueous humour from anterior chamber of eye and selenium content in lenses were determined in 40 catarat patients with and in 51--without pseudoexfoliation (PES). Significantly increased kynurenine and neopterin levels in serum and neopterin concentration in aqueous humour were observed in mature cataract patients with PES compared to whose without. These patients also presented with the lowest content of selenium in serum and lens, compared with cataract patients without PES. Increased concentrations of neopterin in serum and aqueous humour of anterior chamber of eyes suggest an increased degree of oxidative stress in patients with PES. Thus, the results support the role of oxidative stress in the development of PES in cataract patients. The decreased content of selenium may elicit immune system activation via an increased oxidative stress as it is indicated by the increased formation of kynurenine and neopterin.

Aged↗
PubMed2003

Tryptophan degradation during and after gestation.

In mice, activation of indoleamine-(2,3)-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, is required to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. On the other hand, postpartum blues and depression appear to be related to reduced availability of tryptophan and serotonin. In healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy and postpartum. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor, two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy. The data confirm earlier results and suggest significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were found, correlating significantly to the kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation has ceased. By contrast, still increased kynurenine concentrations and also increased kyn/trp suggest continuing turnover of tryptophan. Because also ALT was increased postpartum, abnormal activity of hepatic tryptophan pyrrolase and possibly other enzymes could be involved. We conclude that the decrease of tryptophan during pregnancy might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process, rather it seems related to abnormal activity of liver enzymes.

Adult↗
PubMed2003

Moderate hyperhomocysteinaemia and immune activation in patients with rheumatoid arthritis.

BACKGROUND: Moderate hyperhomocysteinaemia related to folate deficiency has been described in patients with cardiovascular risk and also in patients with autoimmune diseases including rheumatoid arthritis (RA). METHODS: In 33 patients with RA, serum concentrations of homocysteine and cysteine, of B-vitamins folate and vitamin B(12), and of immune activation markers neopterin and soluble 75-kDa TNF-receptor (sTNF-R75) were measured. RESULTS: A significant proportion of patients presented with elevated homocysteine and cysteine concentrations in comparison to reference ranges of healthy control persons. Moderate hyperhomocysteinaemia coincided with decreased serum folate and with higher concentrations of sTNF-R75 and neopterin, but it was rather independent from methotrexate (MTX) therapy. CONCLUSIONS: The coincidence of higher homocysteine and lower folate concentrations with increased concentrations of immune activation markers in patients with RA suggests that immune activation could be involved in the development of hyperhomocysteinaemia.

Adult↗
PubMed2003

Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway.

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.

Animals↗
PubMed2003

Rapid measurement of total plasma homocysteine by HPLC.

BACKGROUND: Determination of plasma homocysteine has gained increasing interest during the past few years. Several HPLC methods for determination of homocysteine are available. Based on these methods, we developed a new HPLC assay for rapid and sensitive measurement of total plasma homocysteine. METHODS: As a reducing reagent tris-(2-carboxylethyl)-phosphine is used, ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate serves as the derivatization agent. Separation is performed by reversed-phase HPLC using a precolumn and a 55-mm RP(18) cartridge; mobile phase: 0.1 mol/l KH(2)PO(4) with 5% methanol, adjusted to pH 2.7 with ortho-phosphoric acid, flow-rate 1.1 ml/min. RESULTS: Homocysteine is clearly separated from other thiols, the retention time being 2.2 min, total analysis time is 6 min. Tests for linearity, recovery and precision are satisfactory, as well as the comparison with a commercial available assay method. Detection limit of the method is 0.5 micro mol/l, it could be further enhanced for measurements of even lower homocysteine concentrations in, e.g., cell culture supernatants. CONCLUSIONS: The described method is well suited for analysis of thiols in blood specimens. It is more convenient and more rapid than methods described earlier.

Chromatography, High Pressure Liquid↗
PubMed2003

Association of increased neopterin production with decreased humoral immunity in the elderly.

Tetanus toxoid (TT) antibodies of 447 adult persons aged 27-69 years were investigated and analyzed in relationship with the time span since the last vaccination against tetanus as well as the serum concentration of neopterin. Neopterin is a pteridine, which is produced by monocytes/macrophages upon stimulation with the type 1 T cell-derived cytokine interferon-gamma. There was an inverse correlation between serum neopterin and TT antibody concentrations (Spearman's rank correlation coefficient: r(s)=-0.259; p<0.0001) which was even stronger when persons with neopterin concentrations and TT antibodies below the third quartile of the study population were excluded (residual group: n=210; r(s)=-0.718; p<0.0001). The study demonstrates that an immunoregulatory shift towards type 1 immunity as indicated by higher neopterin concentrations coincides with lower TT antibody concentrations in the elderly.

Adult↗
PubMed2003

Induction of apoptosis in human blood T cells by 7,8-dihydroneopterin: the difference between healthy controls and patients with systemic lupus erythematosus.

Neopterin (Neo) and 7,8-dihydroneopterin (H(2)Neo) are produced by human monocyte-derived macrophages upon stimulation with IFN-gamma. Increased amounts of Neo and H(2)Neo in human body fluids are found in many disorders, including viral infections and autoimmune diseases. Recent data suggest that neopterin derivatives may exhibit distinct biochemical functions activating redox-sensitive transcription factors and inducing apoptosis in various cell lines. In this study we investigated the effect of H(2)Neo on human peripheral blood T cells (PBT) from healthy blood donors in comparison with PBT isolated from patients with systemic lupus erythematosus (SLE). H(2)Neo induced apoptosis in healthy PBT in a concentration-dependent manner. In short time culture, a significantly lower ability of PBT isolated from patients with SLE to undergo apoptosis in response to H(2)Neo compared to healthy controls was detected. Our results suggest a possible role of the neopterin derivative H(2)Neo in T cell apoptosis mediated by stimulated monocytes/macrophages.

Adult↗
PubMed2003

Increase of haemoglobin levels by anti-retroviral therapy is associated with a decrease in immune activation.

DESIGN: We evaluated whether an increase in haemoglobin levels in the first 6 months of effective anti-retroviral therapy (ART) is associated with a decrease in immune activation. To reduce confounding factors only men (n = 35) and patients not receiving agents known to enhance haematopoiesis or patients without diseases that might suppress haematopoiesis were included. Simultaneously parameters of iron metabolism and cofactors for haematopoiesis were analysed. RESULTS: A median baseline haemoglobin level of 139 g L-1 increased to 149 g L-1 at month 6 of ART (P < 0.001). At baseline low haemoglobin levels were strongly associated with high neopterin concentrations (r = - 0.64, P < 0.001), and much less correlated to high HIV-1 RNA levels (r = - 0.41, P < 0.05) and to a lower CD4+ cell count (r = 0.33, P < 0.05). The change of neopterin levels during the study period correlated with the relative change in haemoglobin levels, r = - 0.35, P = 0.03, whereas no such correlations were found for the change of HIV-1 RNA levels and the CD4 cell count. A logistic regression analysis revealed that the change of neopterin and soluble transferrin receptors concentrations are independently associated with an increase of haemoglobin levels of more than 15 g L-1. CONCLUSION: Our study supports a cause-effect relationship between immune activation and anaemia in HIV-infected patients. Treatment of patients with ART decreases virus load, which may thereby result in silencing of immune effector activity thus ameliorating anaemia by reversing the anti-proliferative effects of cytokines towards erythroid progenitors and the iron withdrawal strategy of the immune system.

Adult↗
PubMed2003

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN).

BACKGROUND: Balkan endemic nephropathy (BEN) is of great clinical importance in restricted areas of Bulgaria, Serbia, Croatia, Bosnia, Herzegovina, and Romania, since the etiology of BEN is still unknown. METHODS: In urine samples from 48 patients (41 females and 7 males, aged 65.6 +/- 6.87 years) with BEN living in an endemic area of Vratza district, Bulgaria, neopterin concentrations were measured by high-pressure liquid chromatography (HPLC) and compared with other clinical and laboratory investigations, including creatinine, hemoglobin, and erythrocyte sedimentation rates (ESRs). RESULTS: Urinary neopterin concentrations were 263 +/- 128 (mean +/- SD; range, 78 to 786 micromol/mol creatinine), 24 (50%) of BEN patients presented with increased concentrations as compared to the established normal ranges. Average ESRs were increased (1 hour, 29.0 +/- 14.7 mm/hour) and hemoglobin was decreased (109.3 +/- 16.4 g/L). Hemoglobin correlated inversely with ESRs (rs = -0.787 and -0.780) and creatinine concentrations (r = -0.690, all P < 0.001), but not with neopterin concentrations. Neopterin concentrations also did not correlate with serum creatinine levels. There existed an age relationship of ESR, creatinine, and hemoglobin, but not of neopterin. Neopterin concentrations were slightly lower in five females with low titers of antibodies against local B1 hantavirus strain (P < 0.05). CONCLUSION: The findings can support an immune-mediated inflammatory process in the pathogenesis of BEN only in a subgroup of patients.

Aged↗
PubMed2003

Association of endogenous G-CSF with anti-inflammatory mediators in patients with acute respiratory distress syndrome.

Upregulation of the anti-inflammatory mediators, soluble tumor necrosis factor-alpha receptors I and II (sTNFRI/RII) and interleukin-1 receptor antagonist (IL-1RA), by granulocyte colony-stimulating factor (G-CSF) may contribute to the pathophysiology of lung injury. We determined the relation of endogenous G-CSF to proinflammatory and anti-inflammatory mediators in bronchoalveolar lavage fluid (BALF) and serum of patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Nineteen patients with ARDS and 10 with ALI were included in this prospective investigation. BAL was performed within 12 h and 24 h after onset of lung injury. Concentrations of G-CSF, TNF-alpha, IL-6, sTNFRI and sTNFRII, IL-1RA and IL-10 in BALF as well as in serum were determined by ELISA. G-CSF was associated with alveolar neutrophilia. Results in patients with ARDS and ALI exhibited significant positive correlations in BALF of G-CSF levels with that of IL-6, sTNFRII, and IL-1RA and of G-CSF levels in serum with that of serum IL-6, IL-1RA, and IL-10. Given the potential of G-CSF to directly induce anti-inflammatory cytokines in vitro, significant associations of endogenous G-CSF levels with these mediators early in the development of severe lung injury suggest an endogenous anti-inflammatory role of G-CSF in vivo.

Adolescent↗
PubMed2003

Antifungal properties of 5-hydroxytryptamine (serotonin) against Candida species in vitro.

In this study the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of 5-hydroxytryptamine (5 HT, serotonin) against clinical isolates of Candida albicans (n = 11), Candida glabrata (n = 9), Candida tropicalis (n = 10) and Candida parapsilosis (ATCC 22019) using a broth microdilution test were investigated. In addition, it was examined whether delayed regrowth as a post-antifungal effect results following short exposure to 5 HT. 5 HT showed antifungal activity towards all isolates of Candida spp. The isolates yielded comparable MIC and MFC values of 5 HT in the range 0.91-7.34 mM and 1.83-14.68 mM, respectively. A lag in regrowth was dependent on the concentration tested. Treatment for 3 h at concentrations of 5 HT below and equipotent to the MFC resulted in a delayed regrowth of 8-12 h for isolates of Candida spp. In conclusion, these in vitro studies clearly demonstrate antifungal effects of 5 HT. Identifying the mode of action could be of great help in developing and researching new antifungal drugs.

Antifungal Agents↗
PubMed2003

Association between increased serum cholesterol and signs of depressive mood.

Hypercholesterolemia is associated with an increased risk of atherosclerosis and coronary heart disease. Therefore, therapeutic lowering of cholesterol is an important preventive measure of cardiac morbidity and death. As one side effect, cholesterol-lowering drugs appear to increase the mortality due to suicides or violence, and low lipid concentrations were found to be associated with trait measures of depression. We compared serum cholesterol concentrations and the Beck Depression Rating Scale (Beck's score) in 604 otherwise healthy outpatients who visited the physician's office for a medical health check-up; 65.4% of individuals presented with serum cholesterol concentrations > or = 5.2 mmol/l (> 200 mg/dl) and 5.3% had elevated Beck's score (> 19), indicative for depression. Beck's score was higher in patients with cholesterol concentrations above the 75th percentile (= 6.2 mmol/l; U = 31221, p < 0.02, Mann-Whitney U-test), and Beck's score correlated with cholesterol concentrations and with age. Thus, in contrast to the widely accepted view, in our study, higher cholesterol concentrations were associated with signs of depressive mood. Hypercholesterolemia may not necessarily increase the risk of depressive mood, conversely, increased intake of fat and carbohydrates by individuals with depressive mood may increase cholesterol levels.

Adolescent↗
PubMed2003

HMG-CoA reductase inhibitors are associated with decreased serum neopterin levels in stable coronary artery disease.

Neopterin, a marker of stimulated cellular immune response, is increased in unstable angina, acute myocardial infarction and possibly stable coronary artery disease. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have anti-inflammatory properties, but their effect on neopterin is largely unknown. Neopterin was measured in 232 patients undergoing elective coronary angiography and compared to the degree of atherosclerosis, use of concomitant medications and demographics. Neopterin was lower in subjects using statins (n = 66) compared to those not taking statins (median (range): 6.65 (4.1-18.3) vs. 7.70 (3.6-29.1) nmol/l, p < 0.0001). This association was also found in the subgroup of patients with coronary artery disease (1-3-vessel disease, n = 164; 6.60 (4.1-18.3) vs. 7.80 (3.6-29.1) nmol/l, p = 0.0012), whereas only a slight tendency toward lower neopterin levels was found in the group without atherosclerosis (6.90 (5.1-16.0) vs. 7.60 (4.0-18.5) nmol/l, p = 0.17). In patients with coronary atherosclerosis, neopterin concentrations were lower in smokers (n = 105) compared to non-smokers (7.20 (3.6-29.1) vs. 7.90 (4.4-18.6) nmol/l, p < 0.02), confirming previous observations. However, use of statins was associated with lower neopterin levels in both non-smokers and smokers (6.70 (4.1-18.3) vs. 7.60 (3.6-29.1) nmol/l, p < 0.05, and 6.20 (5.2-16.0) vs. 7.80 (4.4-18.6) nmol/l, p < 0.05, respectively). Overall, similar serum neopterin concentrations were found in patients with coronary atherosclerosis and those without. In accordance with their anti-inflammatory effects, the use of statins is associated with lower neopterin levels in patients undergoing elective coronary angiography.

Adult↗
PubMed2003

Hyperhomocysteinemia and immune activation.

Hyperhomocysteinemia is an established risk factor for atherosclerosis, thrombosis and other vascular diseases. Homocysteine auto-oxidation is considered to be crucially involved in the pathogenesis of these diseases. However, the question remains to be elucidated whether vitamin deficiency and homocysteine accumulation are causal for disease development or rather comprise a secondary phenomenon. Most diseases accompanied by hyperhomocysteinemia are also associated with ongoing activation of the immune system. In vitro experiments show homocysteine to accumulate in stimulated peripheral blood mononuclear cells. In patients with coronary heart disease, with rheumatoid arthritis and in patients with dementia, an association between cellular immune activation and homocysteine metabolism is found. Homocysteine concentrations not only correlate inversely with folate concentrations, they also show a positive relationship with concentrations of immune activation markers like neopterin. Moreover, in patients with various kinds of dementia, increased concentrations of serum peroxides, homocysteine and neopterin correlate with each other. Studies support a role of immune system activation in the development of hyperhomocysteinemia. Stimulation and proliferation of immune cells may lead to the production of reactive oxygen species that may oxidize antioxidants and oxidation-sensitive B-vitamins. An enhanced demand for antioxidants as well as folate and vitamin B12 may develop, together with hyperhomocysteinemia, despite sufficient dietary intake.

Cytokines↗
PubMed2003

Increased degradation of tryptophan in blood of patients with rheumatoid arthritis.

OBJECTIVE: Activation of the enzyme indoleamine-(2,3)-dioxygenase (IDO) by interferon (IFN)-g leads to enhanced tryptophan conversion to kynurenine. In consequence of chronic immune activation, tryptophan availability is reduced, leading to inhibition of cell proliferation as protein synthesis is affected. Tryptophan deprivation due to IDO activation could therefore be effective in abrogating processes with high metabolic turnover, thus modulating cellular immune response. METHODS: Concentrations of tryptophan, kynurenine, and neopterin were measured by HPLC in the sera of 38 patients with rheumatoid arthritis (RA). The kynurenine:tryptophan ratios (kyn/trp) were calculated to estimate IDO activity. RESULTS: Tryptophan concentrations were lower in patients with RA (median, interquartile range: 44.95 microM, 40.31-49.95 microM) compared to healthy blood donors (62.62 microM, 57.27-74.61 microM; p < 0.001). Kynurenine in patients (1.86 microM, 1.54-2.31 microM) did not differ from controls (2.06 microM, 1.58-2.65 microM; NS). The kyn/trp ratio was higher in patients (42.39 mM/M, 37.02-48.60 mM/M) than in controls (31.72 mM/M; 27.95-35.03 mM/M; p < 0.001). Kynurenine concentrations (rs = 0.611; p < 0.001) and kyn/trp ratios (rs = 0.621; p < 0.001) correlated with neopterin concentrations, which indicate stimulated cellular immune response in patients with RA. CONCLUSIONS: The data point to a role of immune activation and Th1-type cytokine INF-g to induce elevated tryptophan degradation in patients with RA.

Arthritis, Rheumatoid↗