Serotonergic interhemispheric asymmetry: Neurochemical and pharmaco-EEG evidence

1. Postmortem neurochemical investigations revealed interhemispheric asymmetry in the mediofrontal region of human brain. Significantly higher right hemisphere serotonin metabolite (5HIAA) content as well as increased maximal imipramine binding (IB) were found in the right hemisphere than in the left side.

2. IB did not show a gender difference in the mediofrontal area. However, women had higher IB in the right orbital frontal cortex than did men.

3. In vivo pharmaco-EEG results tend to support the postmortem neurochemical data. Intravenous chlorimipramine resulted in an asymmetric topographic distribution of the P300 auditory evoked potential, peak amplitudes were shifted to the right hemisphere.     

Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu _b )on steady state total (C _b )and unbound (Cu _b )blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL _int ).For a substance of very low CL _int ,if fu _b changes, C _t will change and Cu _b will remain constant, whereas if CL _int isvery high, Cu _b will change and C _b will remain constant.The present study defines the effects of a change in fu _b on C _b and Cu _b over the whole CL _int range. Computer simulations were undertaken which predicted that, for a given change in fu _b ,absolute and relative changes in C _b would decreasenonlinearly with increasing CL _{int, twhile the relative change in} Cu _{b would} increasewith CL _int .The absolute change in Cu_b would be independent of CL _int .Significant changes in C_b and Cu _{b would be observed at intermediate values of} CL _{int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in} fu _{b of sodium taurocholate a substance with intermediate} CL _int (such that at fu _b =0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24- ¹⁴ C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu _{b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate} C _{b of 22.7% and a relative decrease in} Cu _{b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance}.This study was supported by the National Health and Medical Research Council of Australia.     

Tardive dyskinesia on Hungarian psychiatric wards

The authors found tardive dyskinesia (TD) in 23.5% of 200 hospitalized schizophrenic patients, most of whom had received neuroleptic treatment for at least two years. The frequency and severity of TD increased with age, and the more advanced the age at which the patient started taking neuroleptics, the more likely it was that TD would develop. Severe TD was more common in men than in women. Prolonged treatment with neuroleptics or the use of antiparkinsonism drugs increased the risk of TD.     

Effect of vinpocetine on retrograde axoplasmic transport

Vinpocetine, a derivate of vincamine, is widely used in the clinical pharmacotherapy of cerebral circulatory diseases. Herewith we report on a novel effect of vinpocetine: inhibition of retrograde axoplasmic transport of nerve growth factor (NGF) in the peripheral nerve. Blockade of retrograde transport of NGF results in transganglionic degenerative atrophy (TDA) in the segmentally related ipsilateral superficial spinal dorsal horn, which is characterized by depletion of the marker enzymes fluoride-resistant acid phosphatase (FRAP) and thiamine monophosphatase (TMP). At the same time, pain-related neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), are depleted from lamina I-III from the segmentally related, ipsitateral Rolando substance of the spinal cord. On the basis of these experiments it is suggested that vinpocetine may result in a locally restricted decrease of nociception, that might be useful in clinical treatment of intractable pain. Pilot self-experiments support this assumption.     

Dexamethasone suppression and multiple hormonal responses (TSH,prolactin and growth hormone) to TRH in some psychiatric disorders

Summary Baseline and TRH-induced changes of thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) were measured in 15 healthy control subjects and 63 psychiatric inpatients with DSM-III diagnoses of major depression (n = 19), schizophrenic disorder (n = 20), alcohol dependence (n = 10), and adjustment disorder (n = 14); baseline and postdexamethasone cortisol (CS) were also determined 3–6 days after the TRH-challenge. All patients and controls were women of similar mean age, weight, height, and they were free from interfering illness or drugs.Baseline TSH and PRL were lower in depression, TRH-induced TSH and PRL responses were lower in the whole patient group, but most markedly in depression and alcohol dependence. Postdexamethasone CS was significantly higher in depression, schizophrenia and alcohol dependence. Basal GH did not differentiate the subgroups; TRH-induced pathological GH responses were sometimes found in the patient groups. The differences were most marked quantitatively in major depression: a multivariate analysis of variance showed that TSH, postdexamethasone CS and PRL were the most important variables in separating patients from controls. A discriminant function derived from these variables classified all controls and 18 of 19 depressed patients correctly; however, 25 of the 44 other patients were also classified with depression.It was confirmed that psychiatric patients show significantly more endocrine disturbances than controls, and this was seen not only in major depression but also in at least three other conditions. Further work is needed to identify other neuroendocrine patterns more specific to depressive disorder.     

A ventral approach to stereotaxy of the guinea pig brain

For skeletal muscles, a well-known match exists between the properties of motoneurones and those of their muscle fibres. Hence, the intramuscular distribution of different kinds of motoneuronal nerve endings (e.g. ‘slow’ versus ‘fast’) can be mapped by determining the distribution of the corresponding types of muscle fibre. As a background for further studies of motoneuronal plasticity, we needed precise measures of such distributions. Simple quantitative methods were developed for defining the position and extent of sub-populations of cells within a structure (e.g. the regional distribution of slow versus fast muscle fibres within a muscle cross-section): (a) The ‘mass vector method’ defined the relative position of the target cell cloud. A line was drawn between the calculated centre of mass for the target cells and that for the whole structure. The direction (a1) and length (a2) of this line gave a measure of the direction and degree of target cell eccentricity within the structure. (b) The ‘sector method’ delineated the region containing the target fibres. A circle around the centre of mass for the target fibres was subdivided into a number of equal sectors (standard setting: 20). The most remote point was found within each sector and a line joining these points defined the region of the target fibres. When applied to the ‘slow’ type I fibres of cross-sections from rat hindlimb muscles, the regional area estimates obtained by the sector method were highly correlated with, but 10% lower than those achieved by the well-established ‘convex hull’ method. Highly significant inter-muscular differences were observed for each one of the three new parameters described in this paper (a1, a2, b).     

Xenograft of Microencapsulated Sertoli Cells for the Cell Therapy of Type 2 Diabetes Mellitus in Spontaneously Diabetic Nonhuman Primates: Preliminary Data

Insulin resistance in type 2 diabetes mellitus (T2DM) may be due to a chronic inflammation of the visceral adipose tissue (VAT) leading to local and systemic increases in proinflammatory cytokines. Microencapsulated porcine Sertoli cells (MC-pSC), by provision of immunomodulatory and trophic factors, have been successfully used to reduce such inflammation in rodent animal models of type 1 diabetes with no complications or deleterious side effects. Herein, we have begun to investigate this novel and safe therapeutic approach in the spontaneously obese nonhuman primate with spontaneous, insulin-dependent T2DM. After MC-pSC intraperitoneal injection we have evaluated, throughout a 6-month follow-up period, daily ad libitum fed glucose levels, daily exogenous insulin supplementation, biweekly body weight measurements, periodic fasting blood glucose concentrations, glycated hemoglobin (HbA1c) levels, glucose tolerance tests (GTT), and fluorescence-activated cell sorting cytometry (FACS) assessment of peripheral blood mononuclear cells. Very preliminarily, we have observed a slight reduction in fasting (FPG) and mean nonfasting (NF) plasma glucose levels. We found minimal changes, only in 1 animal, in daily exogenous insulin requirements and HbA1c levels. Flow cytometric analysis was associated with decrease in CD8⁺ cells only in 1 recipient with a reduction in mean regulatory T Cells (Treg), whereas interestingly, decrease of B lymphocytes was observed in both animals. These results may suggest that this novel MC-SC–based transplantation protocol might possibly impact the metabolic status of T2DM in higher mammals that are close to humans.     

IgG3 and IgG4 cells are increased in active ulcerative colitis

Cells containing various subclasses of IgG and IgA were counted in the rectal and colonic mucosae from 14 pediatric patients with ulcerative colitis (UC) and in rectal biopsy specimens from 10 control subjects using monoclonal antibodies and the peroxidase-staining method. In both the patients and controls, the IgG1 cells predominated. The numbers of IgG1, IgG2, IgG3 and IgG4 cells were highest in the colonic specimens of patients with UC. The numbers of IgG3- and IgG4-containing cells were increased in the rectal mucosa of untreated UC patients compared to controls. In the rectal mucosa of patients with UC, the percentage of IgG2 cells was decreased compared to the controls (20 vs. 28%; p less than 0.05). In the great majority (37 out of 40) of specimens the number of IgA1 cells was higher than that of IgA2. The median number of IgA1 cells in the rectal specimens of untreated patients was slightly higher than that in the rectal specimens of the controls, for IgA2 the numbers were similar. Accentuation of colorectal IgG3 and IgG4 responses may be characteristic early changes in UC.