Increased neopterin levels in brains of patients with human immunodeficiency virus type 1 infection.

Postmortem levels of native neopterin (D-erythro-neopterin) were measured in cerebral cortical samples from 44 human immunodeficiency virus type 1-infected and eight uninfected, nonneurological control patients. Cerebral cortical gray and white matter neopterin levels for the controls ranged from 0.5 to 7.2 pmol/mg of protein in contrast to neopterin levels in brains of the virus-infected patients, which frequently were more than threefold and occasionally more than 30-fold higher than mean control levels. Cortical neopterin levels did not correlate with severity of the acquired immunodeficiency syndrome dementia complex, but subcortical levels correlated with the presence of active human immunodeficiency virus type 1 infection, as reflected by pathological evidence of multinucleated giant cell encephalitis. Evidence of opportunistic cytomegalovirus infections in approximately 25% of the human immunodeficiency virus type 1-infected patients was associated with enhanced levels of neopterin in frontal cortex.

Activated microglia mediate neuronal cell injury via a nitric oxide mechanism.

Activated microglial have been proposed to play a pathogenetic role in immune-mediated neurodegenerative diseases. To test this hypothesis, purified murine neonatal microglial were cocultured with neuronal cells derived from fetal brain. Activation with IFN-gamma and LPS of these cocultures brought about a sharp decrease in uptake of gamma-amino butyric acid and a marked reduction in neuronal cell survival. These effects varied with the density of microglia, the concentrations of the activation signals (IFN-gamma and LPS), and the duration of coculture. Inasmuch as addition of NG-monomethyl-L-arginine blocked these effects, a L-arginine-dependent neurocytotoxic mechanism was implicated. Abundant nitrite, a metabolite of the free radical nitric oxide (NO) derived from L-arginine, was detected in activated microglial/neuronal cell cocultures and in purified microglial cell cultures but not in purified astrocyte or neuronal cell cultures, suggesting that microglial were the principal source of the NO. These findings support the hypothesis that microglia are the source of a neurocytotoxic-free radical, and shed light on an additional mechanism of immune-mediated brain injury.

Differential induction of indoleamine-2,3-dioxygenase (IDO) by interferon-gamma in human gynecologic cancer cells.

Induction of indoleamine-2,3-dioxygenase (IDO) by interferon-gamma (IFN-gamma) is thought to be one mechanism underlying IFN-gamma's antineoplastic properties. Since clinical trials with IFN-gamma have yielded variable efficacy in treating cancers of gynecological origin, we tested the effects of IFN-gamma on cell growth and IDO activity in cell lines from seven gynecologic and five breast cancers. At a dose of 250 IU/ml, IFN-gamma suppressed cell growth and induced IDO activity in one cervical (C41), one vulva (A431), one breast (HS578T) and two ovarian (OVCAR-3, CAOV-3) cancer cell lines. Differing inhibition of cell growth, but with no induction of IDO activity, was found with IFN-gamma treatment of the other cell lines.

Glioblastoma, transforming growth factor-beta, and Candida meningitis: a potential link.

The development of Candida meningitis in a patient following partial resection of a glioblastoma raised suspicion that transforming growth factor (TGF-beta), an immunosuppressive cytokine known to be produced by this tumor, would be elevated in his cerebrospinal fluid (CSF). By using a highly specific bioassay, the concentration of TGF-beta was found to be 609 pg/mL, which was 10-fold greater than the mean CSF TGF-beta value in control subjects with no neurologic disease. Increased CSF TGF-beta levels were also detected in patients with other central nervous system (CNS) diseases: malignancies and AIDS dementia complex. These findings suggest that TGF-beta may play an immunopathogenetic role in the CNS.

Endogenous breath acetaldehyde levels among alcoholic and non-alcoholic probands: effect of alcohol use and smoking.

The effects of possible confounding factors on endogenous breath acetaldehyde levels were examined in alcoholic and non-alcoholic subjects. Demographic characteristics, family history for alcoholism, smoking and drinking history, and breath acetaldehyde levels were assessed. Differences in endogenous breath acetaldehyde levels could not be attributed to age, sex, or having a family history positive for alcoholism. Individuals who smoke or abuse alcohol had higher endogenous breath acetaldehyde levels than persons who did not.

Elevated endogenous breath acetaldehyde levels among abusers of alcohol and cigarettes.

Endogenous (fasting) breath acetaldehyde levels were assessed as a discriminator between alcoholic and non-alcoholic subjects. The influence of smoking as a potential confounding variable on breath acetaldehyde was determined. Individuals with a history of smoking and/or drinking had higher endogenous breath acetaldehyde levels as compared to controls. Mean acetaldehyde levels revealed an additive (noninteractive) pattern associated with combined abuse of these substances. The similarity in acetaldehyde levels between alcoholic non-smokers and non-alcoholic smokers limits the usefulness of endogenous breath acetaldehyde for the purpose of early diagnosis of alcoholism. Results support hypotheses that elevations in acetaldehyde could be a common factor in disease associated with alcohol and cigarette abuse.

Basic aspects of blood platelet monoamine oxidase activity in hospitalized men alcoholics.

Platelet MAO activity (tryptamine as substrate) was assessed in 44 hospitalized men alcoholics to examine the relationships between MAO levels and variables related to alcohol misuse and physiological status. Mean MAO levels were lower in this population than in normal controls and hospitalized psychiatric patients. MAO activity correlated with age but was independent of variables derived from self-reported drinking histories and scales of alcohol dependence. Similarly, platelet MAO activity was not related to the misuse of other drugs. Of the variance in MAO activity, 38% could be accounted for by age, and the values of Mg++, low density lipoproteins and eosinophil combined. The significance of low platelet MAO activity in alcoholics is discussed.

Dietary ascorbic acid deficiency in guinea pigs: no effect on ethanol preference, spiroperidol binding, or monoamine oxidase activity.

Ascorbic acid levels are commonly reported to be decreased in alcoholics. Although this deficiency could be due to dietary factors, there is evidence that ascorbic acid may be involved in the metabolism and acute effects of ethanol, possibly related to the pathogenesis of alcoholism. Therefore, we examined ethanol preference in guinea pigs receiving an ascorbate deficient vs a normal diet. Brain and spleen ascorbic acid levels were dramatically decreased, but ethanol preference was not altered by the acute dietary deficiency of this vitamin. In addition, an acute stressor (cold water swim), alone or in combination with ascorbate deficiency, had no effect on ethanol preference. At termination of the experiment, two measures of brain aminergic function (MAO activity and 3H-spiroperidol binding), purportedly altered by ethanol or ascorbic acid or both, were not associated with tissue ascorbate levels.

Spiroperidol binding sites on mouse lymphoid cells. Effects of ascorbic acid and psychotropic drugs.

Since highly differentiated cells of mammalian immune systems reportedly have binding sites for a variety of neurohumoral agents, we investigated parameters related to possible existence of dopamine receptors on murine lymphoid cells. Using a dopamine antagonist, [3H]spiroperidol, we found evidence for displaceable binding on mouse spleen cells. Total and displaceable (10 microM haloperidol) binding of spiroperidol was markedly enhanced by the absence of ascorbic acid in the incubation medium. Displaceable binding of a dopamine receptor agonist [( 3H]ADTN) could not be found on lymphoid cells either in the presence or absence of ascorbic acid. In the absence of ascorbate, displaceable spiroperidol binding to mouse spleen cells revealed partially saturable, but complex, kinetics and we calculated positive cooperativity at low ligand concentrations.

Platelet monoamine oxidase (MAO) activity: evidence for a single major locus.

Monoamine oxidase (MAO), a mitochondrial enzyme involved in the degradation of biogenic amines, has been associated with psychiatric morbidity. Although twin and family studies have indicated that MAO activity is familial, the exact mode of transmission is unclear. We performed segregation analysis on 154 nuclear families containing 419 individuals using the mixed model, which allows for a single major locus with a polygenic background. We were able to reject a dominant and additive locus with or without a heritable background and a recessive locus without background. The acceptable models were: (1) a codominant model without background where the mean of the heterozygote distribution was 30% of the distance from the low to the high homozygote distributions, and (2) a recessive locus with heritable background. In both cases, the gene frequency for the high-MAO allele is approximately .25--at odds with suggestions that low-MAO represents a genetic marker for a disorder such as schizophrenia with a lifetime risk of only 0.85%. To ensure that results were not artifacts from a familial, skewed distribution, the data were also analyzed after power transformation. In addition, hypotheses were tested using both the joint and conditional likelihoods to examine for possible misspecification of the model with respect to intergenerational differences. Finally, we allowed for non-Mendelian transmission probabilities to provide another class of alternatives against which to test the hypothesis of a major locus. All these approaches provided additional confirmation for the presence of a major locus segregating within these families.

A commingling analysis of platelet monoamine oxidase activity.

The distribution of platelet monoamine oxidase (MAO) activity is examined in a large cohort of 18-year-olds from a college setting. A mixture of three distributions is needed to describe the data, even when a power transformation is used to remove skewness in the distribution. This is compatible with MAO activity being controlled by a single major locus with a gene frequency of 0.02 for high-MAO activity. Accordingly, it is unlikely that such a locus could serve as a genetic marker for a disorder which is associated with low activity. However, this finding does not rule out the possibility that MAO activity is an associated risk factor in disease.

Elevation of serum prostaglandin E levels following electrical stimulation of the midbrain.

Serum prostaglandin E (PGE) levels were measured in rats immediately following electrical stimulation of the mesencephalic periaqueductal gray (PAG) region and the nucleus raphe magnus (NRM) and compared to controls. An additional group received aspirin prior to PAG stimulation. A significant increase in serum PGE levels was found after stimulation of the PAG, but not the NRM. Aspirin inhibited the stimulation-induced increases in PGE.

Influence of blood sampling methods on dopamine-receptor-blocking activities as determined by a radioreceptor assay.

The influence of blood collection methods on dopamine-receptor-blocking activities as determined by a radioreceptor assay kit was investigated. Thirty-one patients treated with one of six neuroleptic drugs (thioridazine, trifluoperazine, haloperidol, chlorpromazine, thiothixene, or fluphenazine) participated in this study. Blood samples were drawn from each patient into five different evacuated blood collection tubes made by the same manufacturer (red-stoppered tube containing no additives, lavender-stoppered tube containing EDTA, green-stoppered tube containing heparin, dark blue-stoppered tube containing no additives, and dark blue-stoppered tube containing heparin). The results show that for five drugs (chlorpromazine, fluphenazine, haloperidol, thiothixene, and trifluoperazine), the dark blue-stoppered tubes without additives resulted in significantly higher dopamine-receptor-blocking activities than the red-, lavender-, or green-stoppered tubes. For thioridazine, the green-stoppered tubes resulted in significantly higher blocking activities than the blue- and red-stoppered tubes. The possible effect of tris(2-butoxyethyl) phosphate, a plasticizer, on dopamine-receptor-blocking activities by neuroleptic drugs is discussed.

Studies of platelet monoamine oxidase activity in Epstein-Barr and dengue virus infections.

As part of a prospective, psychosocial, and biochemical study of infectious mononucleosis, platelet monoamine oxidase (MAO) activity has been evaluated as a host factor. It was found that platelet MAO activity may be a possible predisposing host factor but not a precipitating factor. The results on infectious mononucleosis, a viral disease which involves the host's cell-mediated immune system, are compared with an evaluation of platelet MAO activity in dengue, a viral disorder involving the host's humoral immune system. The platelet MAO activity in these disorders has been compared to that in schizophrenia, a disease for which low platelet MAO activity has been postulated, from retrospective and twin studies, to be a risk factor. One hypothesis suggests that low platelet MAO activity predisposes to development of schizophrenia, but also increases cell-mediated immune system responses.

Platelet monoamine oxidase activity in schizophrenic patients.

The authors studied platelet monoamine oxidase (MAO) activity in 29 schizophrenic inpatients and 26 schizophrenic outpatients during a 4-week double-blind trial of chlorpromazine with imipramine or thiothixene with placebo. The found that significantly more schizophrenic patients than normal control subjects had low platelet MAO activity after 4 weeks. Outpatients with low MAO activity were distinguished by increased behavioral activity and reduced social apathy. Inpatients with low MAO activity were distinguished by severity of illness and symptoms. Hallucinations were significantly more frequent among patients with low MAO activity. The authors suggest that platelet MAO activity might decline in some actively schizophrenic patients as part of the psychotic process.

Blood platelet monoamine oxidase activity in anergic schizophrenics.

Blood platelet monoamine oxidase (MAO) activity was evaluated in twenty-four anergic, schizophrenic outpatients during a double-blind study comparing a chlorpromazine-imipramine combination to thio-thixeneplacebo. Platelet MAO activity was determined on blood samples drawn after a two-week drug-free washout and once weekly over a four-week on-drug period. Schizophrenic patients could be classified according to their blood platelet MAO activity into either a low-MAO or a high-MAO group. In neither group of this population of schizophrenics did blood platelet MAO activity correlate with any of the primary or secondary symptoms of schizophrenia. Ten alcoholics and seven volunteer non-patients could similarly be divided into low- and high-MAO groups. Mean blood platelet MAO activity for these groups was not significantly different from the mean values of the low and high-MAO groups of the schizophrenics. These findings do not support published reports of low blood platelet activity as a genetic marker for schizophrenia. Discriminate function analysis of symptomatology ratings at baseline was used to characterize the low- and high-MAO schizophrenic patient groups. Individuals in the low-MAO group were distinguished by hyperactivity, anergia and sleep disturbance.