Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.

NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

Dementia and brain atrophy are established features of a large proportion of patients with acquired immune deficiency syndrome (AIDS). To investigate a potential mechanism for atrophy in AIDS, we measured the concentration of the endogenous neurotoxin quinolinic acid in the cerebrospinal fluid of 10 patients with AIDS and found that they had 3-fold higher quinolinic acid concentrations than 9 age-matched control subjects: 53. As a preliminary investigation to determine whether there is evidence of increased levels of QUIN in the brains of AIDS patients, the concentration of QUIN was measured in samples of cerebrospinal fluid (CSF) from 10 AIDS patients without systemic bacterial infection or neurological deficits at the time of study. It was then compared to that of 9 age-matched control subject volunteers wthout neurological deficits or infection. MethodsCerebrospinal fluid was collected from 10 male AIDS patients and 9 normal paid volunteers (5 men, 4 women) by lumbar puncture with the subject in the lateral decubitus position after an overnight fast. Some patients were receiving 3 '-azido-2',3'-dideoxythymidine in a blind study at the time of CSF collection. The blood T4 cell count, a measure of disease duration, was quantified in all AIDS patients and expressed as a percentage of the value in noninfected subjects. Mean ages of AIDS patients and control subjects were 37.5 ? 1.8 years and 29.2 ? 2.6 years, respectively. Samples were stored at -70°C until analysis. All procedures were conducted under protocols approved by the National Institutes of Health.Q U I N was quantified by electron capture negative chemical ionization gas chromatographyimass spectrometry {7, 81.Briefly, a weighed volume of CSF (0.4-1.1 ml) and Q U I N standards (1.5-90 pmol) dissolved in water were heated in a water bath at 60°C for 30 minutes to deactivate any HIV present. After cooling, the standards and CSF were mixed with 1 ml perchloric acid (PCA), 1 moUL containing 12 pmoUml { '80]-QUIN as internal standard [8], and were then centrifuged. The PCA was neutralized with 10 moliL potassium hydroxide and Q U I N and [180}-QUIN isolated by ion exchange chromatography, and the eluate was freeze dried. Q U I N and ['80)-QUIN were converted to their dihexafluoroisopropanol esters, extracted into 250 pI hexane over 300 p1 water, and Q U I N was quantified by selected ion monitoring of peak heights at a mass charge ratio of 467 (QUIN): 471 ({*80}-QUIN).Results were analyzed by unpaxed Student's t tests, and regression analysis was performed using the method of least squares. Values presented are mean 2 1 standard error of the mean. 275

In this randomised, double-blind, placebo-controlled, 2-year multicentre study intrathecally administered natural human fibroblast interferon (IFN-B) was effective in reducing exacerbations of multiple sclerosis (MS) in patients with exacerbating/remitting disease. The mean reduction in exacerbation rate of 34 patients who received IFN-B (recipients) was significantly greater during the study than that of 35 patients who received placebo (p less than 0.04). The prestudy exacerbation rates were comparable in recipients and controls, but the rate at the end of the study was significantly lower in recipients than in controls (p less than 0.001). IFN-B was given by nine or ten lumbar punctures over the first 6 months of the study, and patient observations continued for 2 years. IFN-B was well tolerated in 95% of the recipients, and the side-effects experienced were clearly acceptable for the benefits achieved. Low doses of indomethacin reduced the toxicity of IFN-B and played an important role in successful double-blinding.

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