Stephen I. Deutsch

Increased alkaline phophatase activity in HeLa cells mediated by aliphatic monocarboxylates and inhibitors of DNA synthesis

Abstract Alkaline phosphatese activity of HeLa cells is increased from 3- to 8-fold during growth in medium with certain aliphatic monocarboxylates. The four-carbon fatty acid salt, sodium butyrate, is the most effective “inducer” with propionate (C3), pentanoate (C5) and hexanoate (C6) having lesser effects. Other straight-chain aliphatic monocarboxylates, branched-chain analogues of inducers, hydroxylated derivatives, and metabolytes structurally related to butyrate are ineffective in mediating an increase in enzyme activity, indicating stringent structural requirements for inducers. The kinetics of increase in alkaline phosphatase activity in HeLa cells shows a 20–30 h lag period after adding the aliphatic acid followed by a rapid linear increase of enzyme activity. Protein synthesis is required for “induction”. The isozyme of HeLa alkaline phosphatase induced by monocarboxylates is the carcinoplacental form of the enzyme as determined by stereospecific inhibition by the l -enantiomorphs of phenylalanine and tryptophan, heat stability, and immunoreactivity with antibody against the human placental enzyme. Monocarboxylates that mediate increased alkaline phosphatase activity inhibit HeLa cell multiplication. Inhibition of HeLa cell growth may be necessary for induction and this hypothesis is supported by the findings that three different inhibitors of DNA synthesis, i.e. hydroxyurea, 1-β- d -arabinfuranosyl cytosine and methotrexate, also increase alkaline phosphatase activity. These inhibitors are synergistic with butyrate in causing HeLa cells to assume a more spindle-like shape and in producing an up-to 25-fold increase of enzyme activity. Studies on the modulation of carcinoplacental alkaline phosphatase by monocarboxylates commonly used as antimicrobial food additives and by anti-neoplastic agents may provide methods to evoke “tumor markers” of human occult malignancies. These drug-induced elevations of fetal isozyme activity may further our understanding of gene expression in human cells.

Plasma growth hormone response to oral l-dopa in infantile autism.

In order to assess further the occurrence of hypothalamic dysfunction in infantile autism and its possible relationship to dopaminergic abnormalities, the 1-dopa provocative test was performed in 22 patients fulfilling DSM-III criteria for this disorder. The results indicate a high incidence (at least 30%) of blunted plasma growth hormone (GH) responses following oral administration of 1-dopa in this sample. These data suggest an alteration of hypothalamic dopamine receptor sensitivity in the patients with blunted responses. Thus, a subgroup of autistic patients within a descriptively homogeneous diagnostic category shows evidence of hypothalamic dysregulation and dopaminergic abnormalities.

Status of cholinesterase activities in blood in neuropsychiatric disorders

The availability of easily accessible biochemical trait markers of central cholinergic activity would assist in the identification of homogeneous subgroups of neuropsychiatric patients within specific diagnostic categories. In addition to a refinement of nosology, these measures could also help to design specific treatment interventions. The activities of cholinesterase isoenzymes in blood have been reported to be abnormal in neuropsychiatric disorders with proven or hypothesized abnormalities of central cholinergic transmission. However, the relevance of these peripheral cholinesterase abnormalities to disordered central cholinergic transmission remains uncertain. Future studies examining specific cholinesterase isoenzymes in homogeneous diagnostic groups are needed to determine the potential utility of these measures as peripheral trait markers of central cholinergic activity.

Relative Affinities for Different Classes of Neurotransmitter Receptors Predict Neuroleptic Efficacy in Infantile Autism: a Hypothesis

In this report, the clinical efficacy of specific neuroleptics in infantile autism was related to the degree to which they bind to different classes of neurotransmitter receptors and calcium channels in brain. Based upon available receptor-binding data, predictions were made regarding the efficacy of neuroleptics which have not yet been studied in this disorder. Future selection of potentially effective agents should be based upon a pharmacological rationale.

Effects of prednisolone and butyrate on agglutinability of HeLa cells by concanavalin A

Agglutinability by concanavalin A was measured with HeLa65 cells grown with prednisolone or sodium butyrate, 2 compounds that increase the activity of the carcinoplacental form of alkaline phosphatase, an enzyme localized in membranes. Prednisolone enhanced concanavalin A agglutination approximately 3-fold while sodium butyrate had no effect.

Effect of chronic haloperidol and quinacrine coadministration on striatal HVA levels and stereotypic behaviors in response to apomorphine in the rat.

The effects of chronic administration of quinacrine, a phospholipase A2 inhibitor, on striatal homovanillic acid (HVA) levels and behavioral sensitivity to challenge with a dopamine agonist were examined in rats. Moreover, the ability of chronic phospholipase A2 inhibition to modulate the behavioral supersensitivity and striatal HVA reduction induced by chronic haloperidol administration was also examined. Daily intraperitoneal injection of quinacrine resulted in a significant reduction of striatal HVA levels. Coadministration of haloperidol with quinacrine in this paradigm caused a more profound reduction of striatal HVA levels than either drug administered alone. That this effect of combined administration is not simply due to postsynaptic effects of quinacrine on dopamine receptor sensitivity is suggested by the fact that behavioral supersensitivity was not induced by quinacrine alone nor was the behavioral supersensitivity induced by the quinacrinehaloperidol combination greater than that induced by chronic haloperidol administration alone. There were no effects of any treatment condition on striatal levels of serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). These data implicate phospholipase A2 activity in the regulation of dopaminergic transmission.

Adenosine deaminase activity in livers of congenitally athymic nude mice

Une forme de maladie humaine dimmunoinsuffisance grave combinée est associée à une insuffisance dadénosine-déaminase dans les cellules de lymphe et dans dautres tissus comprenant le foie, la rate et les érythrocytes des cultures de fibroblastes de la peau. Un modèle animal dimmuno-insuffisance combinée a été récememt créé dans une race de souris sans poils. Nous avons montré que chez ces souris immunologiquement déficientes lactivité de ladénosine-déaminase est normale.