Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity. T-cell proliferation and differentiation to effector cells require increased glucose consumption, aerobic glycolysis and glutaminolysis. The effect of IDO on the above metabolic pathways was evaluated in alloreactive T-cells. Mixed lymphocyte reaction (MLR) in the presence or not of the IDO inhibitor, 1-methyl-dl-tryptophan (1-MT), was used. In MLRs, 1-MT decreased tryptophan consumption, increased cell proliferation, glucose influx and lactate production, whereas it decreased tricarboxylic acid cycle activity. In T-cells, from the two pathways that could sense tryptophan depletion, i.e. general control nonrepressed 2 (GCN2) kinase and mammalian target of rapamycin complex 1, 1-MT reduced only the activity of the GCN2 kinase. Additionally 1-MT treatment of MLRs altered the expression and/or the phosphorylation state of glucose transporter-1 and of key enzymes involved in glucose metabolism and glutaminolysis in alloreactive T-cells in a way that favors glucose influx, aerobic glycolysis and glutaminolysis. Thus in alloreactive T-cells, IDO through activation of the GCN2 kinase, decreases glucose influx and alters key enzymes involved in metabolism, decreasing aerobic glycolysis and glutaminolysis. Acting in such a way, IDO could be considered as a constraining factor for alloreactive T-cell proliferation and differentiation to effector T-cell subtypes.     

Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C

OBJECTIVES: Hepatic steatosis is a common feature of chronic hepatitis C. The purpose of this study was to determine factors related to the presence of steatosis and to define the role of steatosis in the response to antiviral treatment in chronic hepatitis C patients. METHODS: We retrospectively analysed all patients with chronic hepatitis C treated in a 5 year period in our department. Patients were included in the study only if a pretreatment liver biopsy specimen was available for evaluation. All patients treated either with interferon in combination with ribavirin, or with pegylated interferon in combination with ribavirin were included irrespectively of their response (early, end of treatment and/or sustained) to antiviral therapy. RESULTS: A total of 116 patients with chronic hepatitis C were included in the study with a mean age of 45.5 +/- 14.1 years. Steatosis was present in 52 patients (44.8%). On univariate analysis age, P = 0.04 and body mass index > or = 25, P = 0.004 were correlated with the presence of steatosis and on multivariate analysis only body mass index > or = 25, P = 0.032. Advanced fibrosis was not found associated with steatosis. Sixty patients out of 116 (51.7%) had sustained virological response (SVR). In particular 42 out of 64 patients with no steatosis (65.6%) had SVR compared to 20 out of 52 patients (38.4%) with any degree of steatosis (P = 0.009). Patients with genotype 2 or 3 had a more favourable outcome compared to patients with 1 or 4 genotypes, 63.2% vs 49.2%, P = 0.032. Also increased age (P = 0.0001), gamma glutamyltransferase (GGT) (P = 0.029), no history of intravenous drugs use (P = 0.001) and advanced fibrosis on pretreatment biopsy (P = 0.046) were correlated with treatment failure. On multivariate analysis significant independent association with SVR was found with the presence of steatosis on pretreatment biopsy (P = 0.004), increased GGT (P = 0.005) and genotype (P = 0.017). CONCLUSION: Steatosis in the liver biopsy performed before the beginning of antiviral treatment was found to be associated only to the body mass index of the patients and to be a strong independent factor for treatment failure.     

Ultrasound-guided injection of botulinum toxin A into the submandibular gland in children and young adults with sialorrhoea

Hypersalivation is a common and distressing complaint in children with neuromuscular disorders such as cerebral palsy. Complications associated with severe drooling include daily changes of clothing, perioral dermatitis, dental problems, dehydration, and aspiration pneumonia, which potentially have a detrimental effect on the quality of life of the patient and carer. In this paper we update our previous work to show the potential benefits of ultrasound-guided injection of botulinum toxin A (BTX-A) into the submandibular gland and report on new patients and follow-up data on the existing group.     

Learning and switching between stimulus-saccade associations in Parkinson’s disease

Making flexible associations between what we see and what we do is important for many everyday tasks. Previous work in patients with focal lesions has shown that the control of saccadic eye movements in such contexts relies on a network of areas in the frontal cerebral cortex. These regions are reciprocally connected with structures in the basal ganglia although the contribution of these sub-cortical structures to oculomotor control in complex tasks is not well understood. We report the performance of patients with idiopathic Parkinsons disease (PDs) in a test which required learning and switching between arbitrary cue-saccade rules. In Experiment 1 feedback was given following each response which reliably indicated which of the two possible rules was correct. PDs were slower to learn the first cue-saccade association presented, but did not show increased error or reaction time switch costs when switching between two rules within blocks. In a follow up experiment the feedback given by the computer was adjusted to be probabilistic such that executing a response based upon the “correct” rule only resulted in positive feedback on 80% of trials. Under these conditions patients were impaired in terms of response latencies and number of errors. In all conditions PDs showed multi-stepping/hypometria of saccades consistent with a motoric deficit in executing actions based on cognitive cues. The findings are consistent with a role for the nigrostriatal dopamine system in the reinforcement of saccade-response-outcome associations. Intact performance of PDs when associations are not stochastically reinforced suggests that striatal learning systems are complemented by cognitive representations of task rules which are unaffected in the early stages of PD.