Antibodies to a novel antigen in acute hepatitis C virus infections.

BACKGROUND: Conformational viral proteins potentially play an important role in the immunobiology of acute hepatitis C virus (HCV) infection and may enable earlier antibody detection. MATERIALS AND METHODS: HCV RNA was detected using nucleic acid testing. Early antibody production was evaluated using three enzyme immunoassays (EIAs) containing antigenic proteins not present in licensed EIAs. Respectively, these contained: (1) multiple-epitope fusion antigen (MEFA) 7.1-NS3/4a, (2) F and Core, and (3) E1/E2 proteins. NS3/4a is a conformational antigen retaining protease and helicase enzymatic activities. MEFA 7.1 contains the linear epitopes used in licenced EIAs, including the latest EIA-3.0, in combination with genotype 1-3 specific epitopes. Forty-two RNA positive, EIA-3.0 negative samples, including two persistently serosilent cases, were used to evaluate these research EIAs. As controls, 54 EIA-3.0 negative/RNA negative and three HCV RNA+/antibody positive specimens were included. RESULTS: Only the MEFA 7.1-NS3/4a EIA was positive in seven (17%) of the 42 HCV RNA + specimens, in all three EIA-3.0 positive controls but in none of 54 EIA-3.0 negative/HCV RNA negative controls. Notably, six of the seven (86%) specimens had evidence of active hepatitis (ALT > 210 IU/l). The two serosilent cases were research EIA negative. CONCLUSION: A novel EIA with conformational and linear epitopes detected HCV antibodies in 17% of viraemic specimens missed by the standard reference EIA-3.0. Our research EIA appears to detect HCV antibodies closer to the initiation of acute hepatitis. Given that the average RNA-positive, antibody-negative window period is 56.4 days, this 17% yield would translate into a 10-day earlier detection of antibodies.

A comprehensive study of chronic schizophrenic patients. II: Biological, neuropsychological, and clinical correlates of CT abnormality.

There are numerous reports of lateral cerebral ventricle enlargement on computed tomography (CT) in schizophrenics, but the significance and its relationship to traditional notions of organicity remain unclear. Therefore we studied a subgroup of chronic schizophrenics who had lateral ventriculomegaly (and also cortical hyperdensity) on a battery of relevant biological, neuro-psychological, and clinical parameters such as electroencephalogram (EEG), platelet monoamine oxidase (MAO) and serum dopamine-beta-hydroxylase (DBH) activity, the Halstead Reitan Neuropsychological Battery (HRB), premorbid personality adjustment, drug response, positive and negative symptoms, employment history, and family history. Our findings support the notion that there is an "organic" subgroup of schizophrenia that has 1) CT structural abnormalities such as lateral ventricle enlargement and cortical hyperdensity; and cerebral dysfunction or deficits as evidenced by 2) an increased incidence of abnormal EEGs and also 3) greater impairment on neuropsychological tests. The biochemical measures, platelet MAO and serum DBH activity, nor any of the clinical measures could differentiate between the subgroups. The implications of these findings for the subtyping of schizophrenia are discussed.

Inhibition of neuroleptic binding by human brain extracts--an effect of endogenous dopamine?

Extracts of autopsied human brain tissue exhibited a specific inhibition of [3H]spiroperidol binding, in support of previous reports. The extent of binding inhibition varied depending upon the brain region from which the tissue was taken. We observed two peaks of inhibition binding from extracts of caudate or putamen placed on a Sephadex G10 column. Results of experiments to characterize the extract in the second peak indicate a correlation between inhibition of spiroperidol binding and dopamine content of the tissue. The content of the first peak could not be definitively identified but indirect evidence indicates that it may be a high molecular weight conjugate of dopamine that is formed at low concentrations. No evidence was obtained to suggest the existence of previously undetected neuroleptic-like material in human brain.

Platelet monoamine oxidase activity: demographic characteristics contribute to enzyme activity variability.

In a large (n = 459) sample of adults free of psychiatric, neurologic, and endocrinologic disease, platelet monoamine oxidase activity was analyzed by multiple regression of the demographic variables age, race, and gender on enzyme activity. Reported here are variations for all three demographic variables such that significantly greater enzyme activity is seen in female, older, and white subjects relative to male, younger, and black subjects. For each demographic group the data demonstrated a curvilinear relationship of age and enzyme activity with a nadir of activity at age 30. For this sample enzyme activity nearly doubled between subjects at age 30 and at age 80. We believe this study to be the first to report racial differences in this enzyme activity and to analyze normative data for this enzyme by multiple regression techniques.

Possible interference by the reduced haloperidol metabolite with the radioimmunoassay and radioreceptor assay of blood haloperidol.

Serum or plasma samples from haloperidol-treated patients were analyzed by high performance liquid chromatography (HPLC) with electrochemical detection, radioimmunoassay (RIA), and radioreceptor assay (RRA). The HPLC assay allows simultaneous quantitation of the reduced alcohol metabolite of haloperidol. The HPLC and RIA haloperidol results correlated fairly well (r = 0.63), while the HPLC reduced haloperidol and the RIA haloperidol had a weak correlation (r = 0.28). The RRA haloperidol results had a fair correlation with those of the HPLC (r = 0.55), but their correlation with the HPLC reduced haloperidol was almost as good (r = 0.52). The RIA tended to give lower and the RRA higher apparent haloperidol concentrations than the HPLC assay. The results indicate that the reduced haloperidol does not interfere with the RIA procedure used in this study, but it may partially account for higher concentrations obtained with the RRA.

The Genain Quadruplets 25 years later: a diagnostic and biochemical followup.

A biological and clinical followup of the Genain Quadruplets was initiated as a multilaboratory collaborative effort at the National Institute of Mental Health (NIMH). The quadruplets are 51-year-old monozygotic women previously studied with a battery of psychological and physiological tests 25 years ago at the NIMH. The present article (the first of a series of three) details the clinical history and course of the schizophrenic illness in each of the quadruplets and describes the biochemical measures determined. The findings of elevated urinary phenylethylamine excretion, decreased plasma dopamine-beta-hydroxylase activity, and increased alpha-adrenergic receptor concentrations in all quadruplets warrant further genetic studies.

Haloperidol concentrations elevated in Chinese patients.

After 6 weeks of fixed dose oral haloperidol treatment. Chinese schizophrenic patients (in the People's Republic of China) had 52% higher plasma haloperidol concentrations than U.S. non-Asian schizophrenic patients. Chinese and U.S. patients were matched for sex and body weight. The difference in plasma drug concentrations may explain why Asians are reported to require smaller dosages of neuroleptic drugs than non-Asians, and why they may be more sensitive to neuroleptic-induced side effects. When prescribing haloperidol to persons of Asian ancestry, physicians should consider that higher than expected plasma haloperidol concentrations and an increased sensitivity to haloperidol may occur.

Peripheral catecholamine enzyme function and cognitive impairment of elderly schizophrenics and controls.

Alterations of peripheral and central catecholamine systems are found in both schizophrenic and demented subjects. Reported here are the results of bivariate and multivariate analyses of cognitive function and peripheral catecholamine enzyme activities in a group of elderly schizophrenic patients and controls. The entire sample shows an inverse relationship of platelet monoamine oxidase (MAO) activity with cognitive impairment after controlling for the effects of age, race, and gender. Schizophrenic subjects also demonstrated an inverse relationship of plasma dopamine beta hydroxylase (DBH) activity with cognitive impairment. Demented subjects were characterized in both groups as having increments in platelet MAO activity. Demented schizophrenic subjects also were characterized by increments in plasma DBH activity. Results from this sample are discussed with respect to findings from other studies and future research.

Schizophrenic outcome in late life: symptom state and platelet monoamine oxidase activity.

Reported here are the results of a study of symptom state, platelet monoamine oxidase (MAO) activity, and demographic variables in a group of elderly neuroleptic-free schizophrenics. Analyzed by both bivariate and multivariate techniques, the data from this sample indicate that after the effects of demographic variables upon the variance of enzyme activity have been controlled for, the patients most likely to continue to manifest schizophrenic symptomatology in the senium are those with low platelet MAO activity. The results are discussed with respect to other studies of platelet MAO and prognosis in schizophrenia and with respect to future studies.

Simultaneous determination of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection.

We describe a liquid-chromatographic method for simultaneous quantification of haloperidol and its reduced metabolite in plasma and serum. Haloperidol and reduced haloperidol are concentrated from blood samples by liquid/liquid extraction into a hexane/isoamyl alcohol mixture, with chlorohaloperidol as the internal standard. For chromatographic separation we used a reversed-phase cyano-bonded column and a mobile phase of pH 6.8 phosphate buffer/acetonitrile (55/45 by vol). Haloperidol and its reduced metabolite are detected electrochemically at +0.90 V potential between the working and reference electrodes. As little as 0.5 ng per injection is detectable. Within- and between-day CVs for determinations of haloperidol and reduced haloperidol ranged from 4 to 7% each at a concentration of 10 micrograms/L. Haloperidol concentrations measured by this method correlated well with those by gas-chromatography with nitrogen-sensitive detector and by radioimmunoassay. The present method can be used to study the effects of haloperidol on the central nervous system. It is simple enough for use in clinical laboratories that are monitoring haloperidol concentrations in the blood of psychiatric patients.

An inverse correlation between spontaneous eye-blink rate and platelet monoamine oxidase activity.

An inverse correlation between platelet monoamine oxidase activity and spontaneous eye-blink rate, a putative measure of central dopaminergic activity, was found in medication-free chronic schizophrenic patients without tardive dyskinesia (n = 20, rs = -.47, P less than .025). A similar correlation was found when patients with tardive dyskinesia were included but was weaker (n = 27, rs = -.35, P less than .05). Normal controls and patients with tardive dyskinesia did not demonstrate this relationship. This report confirms a previous finding of a significant platelet monoamine oxidase-blink rate correlation in chronic schizophrenic patients. Insofar as this relationship is mediated by dopamine, it suggests that dopaminergic relations are more readily demonstrated in schizophrenic subjects than normals. Moreover, tardive dyskinesia appears to obscure this dopaminergic relationship.

Enzyme studies in tardive dyskinesia. I. One-year biochemical follow-up.

Over a 1-year period we followed 12 female in-patients with and 13 without persistent tardive dyskinesia. Clinical signs of tardive dyskinesia as well as plasma dopamine-beta-hydroxylase and platelet monoamine oxidase activities remained stable over time in spite of medication changes. Tardive dyskinesia was associated with higher plasma dopamine-beta-hydroxylase and lower monoamine oxidase activities, both initially and at follow-up. In two patients, an apparent elevation in dopamine-beta-hydroxylase activity preceded the onset of clinical dyskinesia, suggesting that elevated plasma dopamine-beta-hydroxylase activity might be a potential risk marker for the development of tardive dyskinesia.

Enzyme studies in tardive dyskinesia. II. Familial aspects.

Two peripheral enzymes, dopamine-beta-hydroxylase (DBH) and monoamine oxidase (MAO), have previously been found to be altered in patients with tardive dyskinesia (TD). In order to examine whether these changes relate to the inherited component of enzyme activity or environmental factors, we assayed DBH and MAO activities in families of six TD probands and six matched non-TD probands. Five of six TD probands had DBH activity at least 50% greater than that of the family mean, whereas two of six non-TD probands had the same trend. No deviation from family means was suggested for MAO activity in the TD group. A study of chronic schizophrenic quadruplets with a history of prolonged neuroleptic treatment showed that only one quadruplet had TD. This quadruplet had plasma DBH activity four standard deviations above the means for her three siblings and three other family members. Our data do not support inheritance of predisposition to develop TD. The enzymatic alterations in TD patients do not seem to have been determined genetically, but they are probably a result of abnormal biochemical effects of prolonged neuroleptic treatment in those patients.

Enzyme studies in tardive dyskinesia. III. Noradrenergic hyperactivity in a subgroup of dyskinetic patients.

This study was undertaken to test a hypothesis that tardive dyskinesia (TD) patients with high plasma dopamine-beta-hydroxylase (DBH) activity would also have other enzymatic alterations suggestive of noradrenergic hyperactivity. Plasma renin activity was chosen as a peripheral indicator of noradrenergic function. We measured plasma renin activity in three groups of female psychiatric inpatients over the age of 50: a TD group with high plasma DBH activity, a TD group with low plasma DBH activity, and a non-TD group. The high-DBH TD group had significantly greater plasma renin activity than the other two groups. Our results are consistent with the hypothesis that a subgroup of TD patients has relative noradrenergic hyperactivity.

A biochemical study of tardive dyskinesia in young male patients.

Based on specific criteria, tardive dyskinesia was diagnosed in 6 out of 29 young schizophrenic male inpatients. We compared several biochemical parameters in these six dyskinesia patients with those in six matched controls. The patients with dyskinesia had significantly lower platelet monoamine oxidase activity and significantly higher plasma dopamine-beta-hydroxylase activity as compared with the controls, thus confirming our previous findings in a population of elderly female inpatients. The dyskinetic and nondyskinetic groups did not differ from each other in mean whole blood serotonin concentration and mean serum neuroleptic concentration as measured with a radioreceptor binding assay. Possible significance of our results is discussed.

Dopamine-beta-hydroxylase, monoamine oxidase, and schizophrenia.

Plasma dopamine-beta-hydroxylase (DBH) activity was studied in two different populations of chronic schizophrenic patients and assayed by two independent laboratories. No significant difference between schizophrenic patients and normal controls was found although in both groups chronic undifferentiated schizophrenics with paranoid features had a trend towards lower DBH activity than the other patients and controls. In addition, DBH and monoamine oxidase (MAO) activities were studied in 13 schizophrenic patients and available first degree-relatives. There was no association of low MAO and low DBH activities within the schizophrenic families.

Monoamine oxidase in schizophrenia: an overview.

A brief history and summary of studies designed to elucidate the role of monoamine oxidase (MAO) in schizophrenia are presented. The majority of these studies have reported a decrease in the platelet enzyme activity of chronic schizophrenic patients when compared to controls. Difficulties encountered when comparing MAO activity measured in different patient populations are also considered. Finally, the significance of decreased platelet MAO activity is discussed with respect to its possible etiological role in some forms of schizophrenia.