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.     

Microbiome and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.     

Influenza vaccination in the elderly: improved antibody response with Imuthiol (Na diethyldithiocarbamate) adjuvant therapy

To improve influenza vaccine efficacy in hospitalized elderly, we compared the evolution of antibody level after vaccination in three patient groups. A sample of apparently primo vaccinated elderly were randomized to receive either Imuthiol (Na diethyldithiocarbamate: group 1) or a placebo (group P). They were compared to patients who had been vaccinated annually for several years (group C). All patients were immunized in the same week. Antibody responses increase within 15 days to reach a plateau in group P and C, while they continue to increase in the Imuthiol treated group, reaching higher antibody levels 30 days after vaccination. This higher antibody rise in group I is essentially due to higher antibody responses in patients with initially low antibody levels and who exhibited at least a four-fold antibody rise. This effect of Imuthiol on influenza antibody responses was observed in spite of a lower nutritional status in this group, a condition that induces lower antibody responses. The higher antibody responses observed in the Imuthiol treated group allow longer protection against influenza.     

High-Throughput Analysis of Antimalarial Susceptibility Data by the WorldWide Antimalarial Resistance Network (WWARN) In Vitro Analysis and Reporting Tool

Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC₅₀s) were determined by a modified sigmoid E_max model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC₅₀s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs.     

Legume grains enhance ileal losses of specific endogenous serine-protease proteins in weaned pigs

Feeding legume grains to pigs usually increases losses of endogenous proteins at the terminal ileum. However, the identity of such proteins is largely unknown. This study was undertaken to determine the ileal flow and identity of soluble proteins present in large concentrations in ileal digesta of young pigs fed soybean meal (SBM), peas (P), faba beans (FB), or blue lupin (L) in expt. 1, and white (WPC) or black (BPC) chickpeas in expt. 2. Protein in the control diet (C) was provided by casein. Ileal digesta proteins were analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis, Coomassie blue staining, densitometry and N-terminal amino acid sequencing. Three protein bands at molecular masses of 25, 27, and 30 kDa had a higher ileal flow (P < 0.05) in the pigs fed the legume-based diets compared to those fed the control diet in expt. 2. This was true for the 25- and 30-kDa proteins (P < 0.05) and the 27-kDa protein (P < 0.10) in pigs fed the legume-containing diets in expt. 1. These proteins shared N-terminal amino acid sequences with enzymes of the serine protease family including pig trypsin (25 kDa) and blood coagulation factor IX or chymotrypsin (27 and 30 kDa).