Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment.

BACKGROUND: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy. METHODS: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. RESULTS: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-alpha therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients. CONCLUSIONS: The results suggest that reduced TRP availability plays a role in IFN-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated TRP depletion.     

Cytokines and psychopathology: lessons from interferon-alpha.

Interferon-alpha is a potent inducer of the cytokine network and is notorious for causing behavioral alterations. Studies on interferon-alpha-treated patients reveal at least two distinct syndromes: 1) a mood/cognitive syndrome that appears late during interferon-alpha therapy is responsive to antidepressants and is associated with activation of neuroendocrine pathways and altered serotonin metabolism; and 2) a neurovegetative syndrome characterized by psychomotor slowing, and fatigue that appears early during interferon-alpha treatment is antidepressant nonresponsive and may be mediated by alterations in basal ganglia dopamine metabolism. Findings from interferon-alpha may provide important clues regarding the pathophysiology and treatment of cytokine-induced behavioral changes in medically ill patients, while also potentially modeling the development of neuropsychiatric symptoms in patients without medical disorders.     

Plasma homocysteine and immune activation in patients with malignant melanoma undergoing treatment with IFN-alpha.

Immune activation and cell proliferation may contribute to the development of increased homocysteine concentrations in patients with malignant diseases. In this study, we investigated the effect of interferon-alpha (IFN-alpha) on plasma homocysteine concentrations in patients being treated for malignant melanoma. In parallel, neopterin formation and tryptophan degradation were monitored to assess the capacity of IFN-alpha to activate macrophages. Plasma concentrations of homocysteine, folate, and vitamin B(12) were determined in 15 patients with malignant melanoma during 12 weeks of high-dose IFN-alpha therapy. Concurrently, concentrations of neopterin, tryptophan, and kynurenine were measured, and the kynurenine/tryptophan ratio (kyn/trp) was calculated. Homocysteine and folate concentrations during treatment with IFN-alpha did not differ from baseline. In contrast, significant increases in neopterin formation and tryptophan degradation were apparent during IFN-alpha therapy. Plasma concentrations of vitamin B(12) and cysteine also increased. These results indicate that IFN-alpha directly activates macrophages to release neopterin and to degrade tryptophan, but obviously treatment with INF-alpha did not affect homocysteine metabolism.     

Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.     

A Feasibility Study of Smoking Cessation Utilizing an Exercise Intervention among Black Women: ‘Quit and Fit’

BackgroundWomen who engage in higher levels of exercise while trying to quit smoking have been shown to be less likely to relapse and to sustain their smoking abstinence longer. This study sought to examine the benefits of exercise for improving smoking cessation among Black women.MethodsWe evaluated the feasibility of a 12-week smoking and exercise intervention, Quit and Fit, tailored for Black women. All participants (intervention and control) received 12 weeks of smoking cessation counseling via telephone and 9 weeks of nicotine lozenges. Participants who were randomly assigned to the intervention condition were also assigned to a 12-week exercise group.ResultsThirty-eight women were enrolled and 27 completed a 12-week follow-up assessment. Women from the intervention group were more likely to complete the 12-week follow-up assessment compared to participants in the control group (80% vs. 61%). Overall, 7 of the 38 participants (18%) were abstinent at 12 weeks (biochemically verified by expired carbon monoxide). Among the 25 women who completed the 12-week follow-up, abstinence was reported in 33% of the intervention group and 20% of the control group. Using an intent-to-treat approach, 25% of women in the intervention group were abstinent at 12 weeks (n = 5), compared to 11.1% for the control group (n = 2). These differences were not statistically significant.ConclusionsThe overall retention rate was 71% (27/38) at 12 weeks with higher among the intervention group (16/20; 80%) compared to the control group (11/18; 61%). The study demonstrates that it is feasible to retain African-American women in a short-term study of smoking cessation and exercise.     

Early steps of a thymic tumor in SV40 transgenic mice: hyperplasia of medullary epithelial cells and increased mature thymocyte numbers disturb thymic export

Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4+ and CD8+ thymocytes in adult mice (39 +/- 10 x 10(6) in transgenic mice and 12 +/- 5 x 10(6) in age-matched controls). Furthermore, thymocyte export was disturbed.