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Biomedical subjects

M Mintz

Publications and source records attributed to M Mintz.

At least 19 recordsLinked to original sources
PubMed1995

Activation of the subthalamic nucleus and pedunculopontine tegmentum: does it affect dopamine levels in the substantia nigra, nucleus accumbens and striatum?

Parkinson's disease is a neurodegenerative disorder, of which the most prominent morphological feature is the progressive loss of dopaminergic nigrostriatal neurons. Increased glutamatergic transmission in the basal ganglia has been implicated in the pathophysiology of Parkinson's disease (PD). This study investigated whether death of substantia nigra (SN) dopaminergic neurons could be caused by the hyperactivity of afferent pathways resulting in the release of a toxic dose of excitatory amino acids in the SN. Twice-daily unilateral stimulation of the subthalamic nucleus (STN) for 21 days, using two different pulse frequencies and current strengths, significantly increased amphetamine-induced rotation, whereas sham stimulated rats showed significantly reduced rotation. Striatal and SN dopamine (DA) levels were unaffected when compared to naïve and sham stimulated rats. However, levels of the DA metabolite, homovanillic acid (HVA), were significantly higher in the ipsilateral anterior striata of rats that had been stimulated at high frequency (100 Hz) and low current (100 microA) as compared to sham treated animals. Stimulation of the pedunculopontine tegmentum (PPT), using a single kainic acid injection, did not affect DA concentration in the ipsilateral striatum and nucleus accumbens when compared to sham-treated rats. DA levels in the contralateral striatum and nucleus accumbens of lesioned rats were significantly higher than ipsilateral levels. DOPAC/DA ratios were lower in the contralateral striatum and nucleus accumbens, suggesting decreased DA turnover. Glutamic acid decarboxylase activity was significantly higher in the ipsilateral than the contralateral SN. The physical manifestations of PD require a large reduction in caudate and putamen DA levels and no such depletion was measured in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effect of amygdaloid kindling on [3H]dopamine and [14C]acetylcholine release from rat prefrontal cortex and striatal slices.

The involvement of the dopaminergic (DA) systems in the control of limbic kindled seizures is ill defined. The effects of kindling on DA activity may have been overlooked in the past, because of its subtle unilateral occurrence and/or the variance of the endogenous imbalance of DA activity in normal animals. In the present study rats were screened for their endogenous DA imbalance using amphetamine-induced rotational behaviour. Electrical or sham kindling was applied in the hemisphere with the higher endogenous DA activity. Sections of the bilateral prefrontal cortex and dorsal and ventral striatum were dissected either 2 hours or 21 days after the final seizure and the electrically stimulated release of [3H]DA and [14C]acetylcholine (ACh) determined. Release was also measured in the presence of quinpirole or sulpiride to assess the activity of pre- and postsynaptic DA D2-receptors. Long-term effects of kindling consisted of facilitation of ACh release in the ventral striatum contralateral to the kindled amygdala and bilateral depression of DA release in the prefrontal cortex. Kindling therefore produced area specific changes in neurotransmitter systems giving rise to increased pro-convulsive cholinergic activity in the ventral striatum and decreased anti-convulsive dopaminergic activity in the prefrontal cortex.

Acetylcholine↗
PubMed1992

HIV-1 sensitivity to zidovudine and clinical outcome in children.

In adults with the acquired immunodeficiency syndrome, long-term monotherapy with zidovudine selects for human immunodeficiency virus type 1 (HIV-1) strains with substantially reduced in-vitro susceptibility to the drug. We have assessed the relation between in-vitro resistance to zidovudine and clinical outcome in children, in whom disease progression is more rapid than in adults. We studied 23 children with symptoms of HIV-1 disease during extended monotherapy with zidovudine. An in-vitro assay was used to determine the concentration of zidovudine required to inhibit by 50% the replication of viral isolates (IC50) obtained after 9 to 39 months of treatment. Viral stocks of high enough titre to yield reproducible results were obtained from 19 of the children. During the following 6 months of therapy, 9 children were stable, 7 deteriorated, and 3 died. There was a highly significant relation between decreased zidovudine susceptibility and poor clinical outcome (p less than 0.001) but no relation between IC50 and age at start of therapy or length of time on treatment. Age-adjusted CD4 lymphocyte counts were lower at the start of treatment (p = 0.02) and at the time of sampling (p = 0.01) in children whose viral isolates had an increased zidovudine IC50. Initial serum p24 antigen levels were not predictive of subsequent emergence of resistant virus, but at the time of sampling for viral sensitivity higher p24 antigen levels were associated with raised IC50 (p = 0.004). The findings suggest that most children who become unresponsive to monotherapy with zidovudine, as judged by clinical criteria, will have changes in in-vitro sensitivity to the drug. In these children, an alternative antiretroviral therapy should be considered.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Idiopathic childhood stroke is associated with human leukocyte antigen (HLA)-B51.

We report four children with idiopathic stroke syndromes who were assayed for human leukocyte antigen (HLA) class I markers and found to have HLA-B51 in common. This finding suggests that there may be a genetic predisposition for "idiopathic" childhood stroke, and host factors, possibly in concert with environmental factors or viruses, may play a major role in the mechanism of unexplained occlusion of the cerebral vasculature in children.

Cerebrovascular Disorders↗
PubMed1992

Ornithine decarboxylase induction and polyamine synthesis in the kindling of seizures: the effect of alpha-difluoromethylornithine.

It has been suggested that the kindling of seizures may depend on the induction of genes encoding enzymes involved in neurotransmission. Experimental seizures are followed by an especially rapid and massive induction of brain ornithine decarboxylase (ODC), an enzyme which catalyses the rate-limiting step in the synthesis of polyamines. The latter compounds have been shown to act as positive allosteric modulators of the NMDA receptor, and also to play an important role in cell growth and differentiation. The induction of ODC by seizures has accordingly been suggested to play a pivotal role in the changes in synaptic structure and function that underlie kindling. In the present study we examined the progress of kindling during treatment with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. We found that progressive increase in the duration and severity of kindled seizures and in the duration of local afterdischarges was unaffected by daily injections of DFMO in doses previously shown to cause substantial depression of brain ODC activity. Treatment with DFMO also failed to produce significant anticonvulsant or proconvulsant effects. Progressive increase in seizure activity during kindling is therefore unlikely to depend to any appreciable extent on enhanced synthesis of polyamines by ODC.

Animals↗
PubMed1991

Event-related potentials in drug-naive schizophrenic patients.

Decreased amplitudes of late components of event-related potentials (ERPs) in schizophrenia were ascribed to either psychotic features or to neuroleptic treatment of the patients. To rule out the drug effect, ERPs to stroboscopic stimuli were recorded in drug-naive schizophrenics and control subjects during no-task and simple-task sessions. Patients had significantly lower amplitudes of the late ERP components during both sessions, thus confirming similar results with treated schizophrenics. On the other hand, drug-naive patients did not differ from controls in the task-related relative facilitation of late ERP components. These results differ from findings of minimal ERP facilitation to task in treated schizophrenics. This discrepancy is discussed in the context of the effects of neuroleptic treatment and task demands on ERPs.

Adult↗
PubMed1991

A steroid derivative (RU 5135) exhibits epileptogenicity in the presence of deficient blood-brain barrier.

A hypothesis was tested that epileptic spiking, induced by systemic administration of a steroid derivative (RU 5135), may be associated with surgery-related cortical damage rather than epileptogenicity of the agent. Cumulative doses of the drug were given to rats and rabbits. The lasting quasi-periodic seizure discharges were always seen initially only under an epicortical electrode implant. Brain damage in inflicted by such an electrode was confirmed anatomically (by assessing the area of lesion) and noninvasively (by showing contrast-induced enhancement of CT brain images in the hemisphere homolateral to epicortical electrodes). The threshold of epileptic spiking varied inversely with the area of cortical damage inflicted by the electrode. In a number of cases no spiking was obtained from the hemisphere with nonpenetrating (intraosteal) electrodes. We caution that a breach of the BBB caused by conventional surgery in rodents can make a benign drug appear as excessively toxic thereby discrediting potentially useful compounds.

Androstanes↗
PubMed1990

The effect of the NMDA receptor antagonist, MK-801, on the course and outcome of kindling.

A rapid kindling procedure was used to distinguish between the anticonvulsant activity of drugs and their ability to retard the kindling process. MK-801 is a specific ligand at the phencyclidine (PCP) recognition site, and acts as a noncompetitive antagonist of NMDA-type glutamate/aspartate receptors. Intraperitoneal injections of MK-801 (0.5-4.0 mg/kg IP) significantly reduced the cumulated effect of 12 2-hr kindling stimulations, as determined from behavioral measures of seizure activity in immediately ensuing 24-hr drug-free kindling sessions; however, the corresponding electrographic effects did not reach significance. MK-801 also showed significant anticonvulsant activity when injected in fully kindled rats. Higher doses tested were accompanied by locomotor and postural effects. The anticonvulsant benzodiazepine, clonazepam, formulated with a proprietary diluent (as Rivotril, Roche), injected in anticonvulsant doses during the first 12 kindling sessions (0.64 mg/kg IP, repeated after 9 hr) did not significantly affect the course of subsequent sessions of drug-free kindling. Systemic injections of kynurenic acid (300-600 mg/kg IP 4 hours), a nonspecific antagonist of glutamate receptors in vitro, were without significant anticonvulsant or antikindling activity. Activity of NMDA-sensitive glutamate/aspartate receptors associated with the PCP recognition site may induce lasting facilitation of neural transmission; this facilitation may be responsible for the remote propagation and progressive enhancement of seizure activity kindled in the amygdala. The facilitatory process appears to be antagonised by MK-801.

Animals↗
PubMed1990

Skin conductance responding in schizophrenic patients with abnormal involuntary movements.

The present study tested the hypothesis that neuroleptic treatment modifies the skin conductance response (SCR) to loud tones. Schizophrenic patients with and without drug-induced abnormal involuntary movements were tested before and after drug withdrawal. During the on-drugs session, habituation of SCR correlated with the daily neuroleptic dose, and patients with tardive dyskinesia (TD) showed the fastest habituation of SCR. These findings were interpreted as indicating that SCR is attenuated by neuroleptics present during the examination and that TD patients demonstrate a preferential susceptibility to this effect. Withdrawal of medication resulted in slowing of SCR habituation only in TD patients, following which the entire sample showed a similar rate of habituation. These findings suggest that accelerated SCR habituation is not a stable trait of TD patients.

Adult↗
PubMed1989

Elevated serum levels of tumor necrosis factor are associated with progressive encephalopathy in children with acquired immunodeficiency syndrome.

The cytokine tumor necrosis factor (TNF) was assayed in the sera (n = 31) and cerebrospinal fluid (n = 26) of children with acquired immunodeficiency syndrome, using a competitive radioimmunoassay. Elevated serum levels of TNF were found in 15 (79%) of 19 patients with progressive encephalopathy (PE), compared with 1 (8%) of 12 patients without neurologic involvement. There was a significant association of PE with elevated serum TNF levels. Conversely, of 16 patients with elevated serum TNF levels, 15 (94%) were found to have PE, and of 8 patients with serum TNF levels greater than 100 pg/ml, all 8 (100%) had PE. No association was found between cerebrospinal fluid levels of TNF and PE. Neither serum nor cerebrospinal fluid TNF levels correlated with the degree of cachexia. These data suggest that circulating TNF may be responsible for the myelin damage that occurs in human immunodeficiency virus type 1-associated PE.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Psychopathology and plasma cortisol responses to dexamethasone in prepubertal psychiatric inpatients.

This study of 51 prepubertal psychiatric inpatients evaluates plasma cortisol measurements at 8 AM, 4 PM, and 11 PM before and after dexamethasone was administered in counterbalanced order at doses of 0.5 mg and 1.0 mg. Approximately 76.5% of the children had an affective disorder. Major depressive disorder was associated with higher plasma cortisol levels than other disorders. Pre- and postdexamethasone plasma cortisol levels using 0.5 mg dexamethasone exhibited a circadian variation. The optimal criterion for cortisol nonsuppression was 5 micrograms/dl measured at 8 AM after administration of 0.5 mg dexamethasone.

Child↗
PubMed1989

Changes in suicidal behavior in child psychiatric inpatients.

This study of 49 preadolescent psychiatric inpatients, aged 6-12 years, evaluated changes from the time of admission to 7 weeks later in ratings of suicidal behavior, assaultive behavior, depression, hopelessness, and global functioning. Standard research instruments were used to measure these variables. There were significant decreases in suicidal behavior, assaultiveness, and depression and a significant increase in global assessment during the 7 weeks of hospitalization. Severity of suicidal behavior and severity of assaultive behavior at admission predicted a subsequent change in level of suicidal behavior. Furthermore, severity of suicidal behavior at admission was the best indicator of a change in severity of suicidal behavior.

Anxiety, Separation↗
PubMed1988

Chronic l-dopa fails to lessen rebound enhancement of self-stimulation after chronic haloperidol.

Chronic treatment with haloperidol (approximately 4.8 mg/rat/day PO for 18 days) severely impaired variable-interval hypothalamic self-stimulation. Cessation of treatment was followed by a strong rebound increase in response rates at submaximal currents, to well above pretreatment rates. The rebound increase in responding was not prevented (and at submaximal currents was actually enhanced) by treatment with l-dopa plus benserazide (respectively 240 and 60 mg/kg/day PO) for 6 days after withdrawal of haloperidol. This result is at variance with previously reported findings.

Animals↗
PubMed1987

The crossed nigrostriatal projection decussates in the ventral tegmental decussation.

Horseradish peroxidase (HRP) tract-tracing techniques were used in 44 rats in order to establish the site of decussation of the crossed nigrostriatal projection. Somata in both the ipsilateral and the contralateral ventromedial mesencephalon were labelled after injection of HRP into the caudate nucleus. In agreement with previous studies, contralateral labelling constituted about 3% of the ipsilateral labelling. Midsagittal transection of the mesodiencephalic junction did not prevent the contralateral labelling. However, mid-sagittal transection of the ventral mesencephalon, or selective 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental decussation did prevent the contralateral labelling. Moreover, 6-OHDA lesions of the substantia nigra ipsilateral to the horseradish peroxidase injection also prevented contralateral labelling. We conclude that the crossed nigrostriatal projection decussates in the ventral tegmental decussation, and that this projection is susceptible to damage by standard 6-OHDA lesions located on the opposite side to the origin of the crossed pathway.

Animals↗
PubMed1987

Amygdala kindling modifies interhemispheric dopaminergic asymmetry.

Brain dopamine is known to retard the development of kindled seizures, but it is uncertain whether kindling affects dopamine function. In the present study, rats were screened for cerebral dominance by recording their preferred direction of rotation when injected with d-amphetamine. Bipolar stimulating electrodes were then implanted in the amygdaloid complex of either the dominant or nondominant hemisphere (i.e., respectively, contra- and ipsilateral to the preferred direction of rotation; the dominant hemisphere identified in this way has been shown to contain higher concentrations of dopamine than the nondominant hemisphere). Kindling stimulation (or sham-kindling, in control rats) was applied through the electrodes two or three times daily for 21 days, and the rats were reassessed for amphetamine- and apomorphine-induced rotation, during and after the course of treatment. Kindling of the originally dominant hemisphere caused a diminution of rotational asymmetry as measured in tests 2 to 3 h after stimulation sessions, and in some rats led to a reversal in the preferred direction of amphetamine-induced rotation. Kindling of the nondominant hemisphere tended to accentuate the original amphetamine-induced asymmetry. The direction of rotation induced by a direct postsynaptic DA-receptor agonist (apomorphine) was not significantly affected by kindling of either hemisphere. It appears that kindling stimulation brings about a relatively inferior level of DA function on the stimulated vs. the nonstimulated side of the brain, and that this process depends mainly on changes occurring at a presynaptic level.

Amygdala↗
PubMed1987

Lateralized neuroleptic-induced side effects are associated with asymmetric visual evoked potentials.

Recent studies suggest that neuroleptic drugs may have an asymmetric effect on the two cerebral hemispheres. This effect is reflected by emergence of drug-induced lateralized extrapyramidal side effects and by dose-related alterations in electrophysiological asymmetries. The present study examined the hypothesis that asymmetry of visual evoked potentials (VEPs) is associated with lateralized appearance of neuroleptic-induced parkinsonism or tardive dyskinesia (TD). The asymmetry of the amplitudes of later VEP components was significantly higher in patients with lateralized side effects (n = 8) than in patients with symmetrical side effects (n = 6) or free of extrapyramidal side effects (n = 11). The possibility that VEP asymmetry reflects the differential degree to which the two hemispheres are affected by medication is discussed.

Adult↗
PubMed1986

Transient contralateral rotation following unilateral substantia nigra lesion reflects susceptibility of the nigrostriatal system to exhaustion by amphetamine.

Following unilateral 6-OHDA induced SN lesion, a transient period of contralateral rotation has been reported to precede the predominant ipsilateral circling. In order to clarify the nature of this initial contralateral rotation we examined the effect of the duration of recovery period after the lesion, on amphetamine-induced rotational behavior. Three days post lesion, most rats circled predominantly contralaterally to the lesion. Such contralateral rotation may result from either degeneration-induced breakdown of the DA pool, or lesion-induced increase of DA turnover in the spared neurons. A substantial degree of contralateral preference was still evident when amphetamine was administered for the first time 24 days after lesioning, indicating involvement of spared cells in the contralateral rotation. However, regardless of the duration of recovery (and irrespective of either lesion volume, amphetamine dose, or post-lesion motor exercise), amphetamine-induced rotation tended to become gradually more ipsilateral as the observation session progressed, and all rats circled ipsilaterally to the lesion in response to further amphetamine injections. These findings suggest that amphetamine has an irreversible effect on the post-lesion DA pool contributing to contralateral rotation.

Amphetamine↗