Cytokine-induced activation of indoleamine 2,3 dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during IFN-alpha treatment has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ~12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 (sTNFR2) and monocyte chemoattractant protein (MCP)-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN, QUIN, KA, and ultimately depressive symptoms.

Context Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. Objectives To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. Design Cross-sectional and longitudinal studies. Setting Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. Patients Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. Main Outcome Measures Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa–induced depression, anhedonia, fatigue, and neurotoxicity. Results Patients with HCV receiving interferon alfa for 4 to 6 weeks (n=14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n=14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n=12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. Conclusions These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

The natural history of cytomegalovirus (CMV) disease associated with solid organ transplantation has been modified as a result of the widespread use of antiviral prophylaxis. Anecdotal reports have indicated a reduction of CMV disease at the expense of its later occurrence after completion of ganciclovir prophylaxis. The present study investigated the occurrence of CMV disease and its risk factors among 37 liver and kidney transplant recipients with CMV D+/R- status who received oral ganciclovir during the first 100 days posttransplantation. CMV disease occurred in 9 patients (24.3%) at a median of 144 days posttransplantation (range, 95-190 days). Allograft rejection was found to be strongly associated with the occurrence of late-onset CMV disease (risk ratio, 6.6; 95% confidence interval, 1.4-32.1; P=.02). Thus, CMV D+/R- solid organ transplant recipients receiving 3 months of oral ganciclovir who develop allograft rejection during the period of antiviral prophylaxis may benefit from extended and/or enhanced antiviral prophylaxis to prevent late-onset CMV disease.

Chenodeoxycholate is toxic to hepatocytes, and accumulation of chenodeoxycholate in the liver during cholestasis may potentiate hepatocellular injury. However, the mechanism of hepatocellular injury by chenodeoxycholate remains obscure. Our aim was to determine the mechanism of cytotoxicity by chenode- (Ca,2.) was observed. Removal of extracellular Ca2" abolished the rise in Ca,2., decreased cellular proteolysis, and protected against cell killing by glycochenodeoxycholate. The results suggest that glycochenodeoxycholate cytotoxicity results from ATP depletion followed by a subsequent rise in Ca,". The rise in Ca,2. leads to an increase in calcium-dependent degradative proteolysis and, ultimately, cell death. We conclude that glycochenodeoxycholate causes a bioenergetic form of lethal cell injury dependent on ATP depletion analogous to the lethal cell injury of anoxia. (J. Clin. Invest. 1993. 92:17-24.)