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Biomedical subjects

A J Mandell

Publications and source records attributed to A J Mandell.

At least 19 recordsLinked to original sources
PubMed1990

Dystonia musculorum deformans: a 'critical phenomenon' model involving nigral dopaminergic and caudate pathways.

In physical systems, a 'critical phenomenon' is a macroscopic occurrence which arises from a change in the relative magnitudes of two or more physical influences whose action is expressed purely in microscopic terms. This concept is potentially valuable in describing the clinical symptomatology of dystonia musculorum deformans (DMD) and other movement disorders. The lateral inhibitory network of Spiny I caudate cells and the profuse neostriatal projection of dopaminergic neurons from the substantia nigra are proposed as anatomic substrates for two short-range neostriatal influences whose interaction contributes to the onset and progression of global dystonic spasm in DMD. Such spasm may be explainable as a critical phenomenon, suggesting new directions for research into the etiology and treatment of this disorder.

Caudate Nucleus↗
PubMed1990

Application of entropy measures derived from the ergodic theory of dynamical systems to rat locomotor behavior.

Measures of complexity derived from ergodic theory of dynamical systems were developed and applied to an exemplary data set describing locomotor movements of rats in a bounded space. A symbolic dynamical system was obtained by partitioning the event space into equally probable partition elements, using a k-dimensional tree. The measures calculated from the symbolic sequences included the topological entropy (ht)--i.e., the rate of increase of all possible sequences with increasing sequence length--and the metric entropy (hm)--i.e., the rate of increase of all likely sequences with increasing sequence length. These measures were used to assess changes in rat locomotor behavior as recorded in the behavioral pattern monitor (BPM) that were induced by amphetamine (0.25, 0.50, 1.0, or 2.0 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA; 1.25, 2.5, 5.0, or 10.0 mg/kg). Amphetamine increased the mean activity, ht, and hm. MDMA resulted in a monotonic dose-response curve for activity but exhibited a biphasic dose response in ht and hm. In particular, some animals in the higher dose groups showed a ht in the range of the saline controls, whereas other animals exhibited a significantly reduced ht and a greater decrease in hm, suggesting that two different behavioral reactions coexist within the same higher dose range of MDMA. An important implication of our method is that, in applied ergodic measure-theoretic approaches, the partition that determines the elements of the symbolic dynamical system should not be specified a priori on abstract mathematical grounds but should be chosen relative to its significance with respect to the data set in question. Here, the animal constructs its own spatiotemporal partition in behavioral phase space.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Induction of c-fos, calcitonin gene expression, and acidic fibroblast growth factor production in a multipeptide-secreting neuroendocrine cell line.

The multipeptide-secreting 44-2C cell line maintains differentiated function when grown in a serum-free, growth factor- and hormone-deprived milieu. The cells continue to synthesize and secrete calcitonin (CT), CT gene-related peptide, neurotensin, and somatostatin and respond to cellular secretagogues such as GRF and acidic and basic fibroblast growth factor. We designed experiments to ascertain the functional role(s) of cellular factors involved in the maintenance of the differentiated state in 44-2C cells. We report here the phenotypic transformation that occurs in these cells in the course of adjustment to the serum-free state. We also show the differential increase in CT-specific mRNA, the transient induction of c-fos, and the characterization of biologically active acidic fibroblast growth factor.

Animals↗
PubMed1988

Fibroblast growth factor stabilizes ribonucleic acid and regulates differentiated functions in a multipeptide-secreting neuroendocrine cell line.

A clonal cell line (44-2C) which synthesizes and secretes somatostatin, neurotensin, calcitonin (CT), and CT gene-related peptide and transiently expresses c-fos was used to characterize the mechanism of action of basic fibroblast growth factor (bFGF). bFGF had two modes of action: 1) short term incubation of 44-2C cells with bFGF increased the cellular content of neurotensin, somatostatin, and CT; and 2) bFGF enhanced the response of the cells to rat hypothalamic GRF-mediated cAMP efflux. The long term action of bFGF was manifested by the permissive effect of the molecule. bFGF had a sustained effect on RNA synthesis, and pretreatment with bFGF for 24 h altered the time course of response of the cells to rat GRF. In this cell line the cellular action of bFGF was not mediated via protein kinase-C action. bFGF was not mitogenic in 44-2C cells. bFGF stimulated uridine incorporation without affecting thymidine incorporation. Results obtained with actinomycin-D and alpha-amanitin suggest that the above effects of bFGF can be correlated with increased RNA stability produced by bFGF.

Amanitins↗
PubMed1986

P300 latency reflects the degree of cognitive decline in dementing illness.

An auditory discrimination paradigm was employed to elicit the P3 component of the event-related brain potential (ERP) from 39 demented patients (mean age = 71 years). Component latency was longer in patients who were diagnosed as having primary degenerative dementia and other cognitive impairment disorders compared to age-matched controls. Neurologist ratings of cognitive impairment were significantly correlated with P3 latency values, although no differences in mean latency were obtained between the various categories of dementia. ERP measurement techniques and the interpretation of P3 latency as in index of dementing illness are discussed.

Aged↗
PubMed1986

Arousal and stability: the effects of five new sympathomimetic drugs suggest a new principle for the prevention of space motion sickness.

Sympathomimetic agents are frequent components in antimotion-sickness drug combinations because of their usefulness in counteracting the sedation caused by stressful motion or resulting from the administration of other antimotion-sickness drugs. The noradrenergic neurochemistry of the brain's arousal-attentional systems prompted us to evaluate the efficacy of five new sympathomimetic drugs and to further define the role of arousal in susceptibility to motion. Subjects were orally administered methamphetamine (20 mg), phenmetrazine (25 mg), phentermine (37.5 mg), methylphenidate (20 mg), or pemoline (75 mg) 2 h prior to taking a Staircase Profile Test. All of the drugs increased resistance to stressful coriolis stimulation by 80-120%. Methylphenidate and pemoline showed fewer side effects. These findings, interpreted in conjunction with the documented inefficacy of most anticholinergic and antihistaminergic drugs tested to date, suggest that sympathomimetic drugs or a generalized state of arousal can inhibit the development of motion sickness.

Clinical Trials as Topic↗
PubMed1985

On a mechanism of cardiac electrical stability. The fractal hypothesis.

Electrical activation of the ventricles via the His-Purkinje system is represented on the body surface by a waveform with a broad range of frequency components. We speculate that this process is mediated by current flow through a fractal-like conduction network and therefore that the broadband spectrum of the depolarization waveform should be scaled as a power-law distribution. The prediction is confirmed by Fourier analysis of electrocardiographic data from healthy men. This observation suggests a new dynamical link between nonlinear (fractal) structure and nonlinear function in a stable physiologic system.

Adult↗
PubMed1985

Relationships between drug-induced changes in tetrahydrobiopterin and biogenic amine concentrations in rat brain.

In vitro studies of rat brain tyrosine hydroxylase and tryptophan hydroxylase activities have demonstrated nonlinearities in both time course and substrate velocity curves that were sensitive to small changes in tetrahydrobiopterin (BH4) concentrations when studied within a range speculated to approximate the in vivo condition. High-performance liquid chromatographic determinations of rat striatal BH4 levels reported here are consistent with such a nonlinear relationship of BH4 and brain monoamine synthesis under four in vivo conditions: 1-day s.c. amphetamine infusion, L-tryptophan loads, i.v.t. administration of corticotropin releasing factor and the diurnal rhythms of the dopaminergic nigrostriatal and serotonergic raphe hippocampal systems. Only the results of continuous 10-day amphetamine infusion were consistent with a simple stoichiometric relationship between the (postulated) rate limiting concentrations of BH4 and regional levels of brain monoamines. Although some of the statistically significant changes in regional brain BH4 levels are small, previous reports of the failure of biopterin to change in response to more than 30 other central nervous system drugs, including such stimulants as methylphenidate and cocaine, makes them noteworthy.

Animals↗
PubMed1979

Conformational influences on brain tryptophan hydroxylase by submicromolar calcium: opposite effects of equimolar lithium.

Tryptophan hydroxylase from rat midbrain, EGTA-pretreated and dialyzed, manifested allosteric properties with respect to its substrate tryptophan, cofactor tetrahydrobiopterin, and the calcium ion. Kinetic studies suggest two preferred enzyme conformations in the presence of low concentrations of the cosubstrates: a higher affinity form manifesting hyperbolic substrate kinetics, induced by submicromolar (0.4--0.8 microM) calcium in vitro and cocaine in vivo, and a lower affinity form exaggerating cooperativity with respect to substrate, induced by submicromolar (0.4 to 0.8 microM) lithium in vitro and lithium in vivo. Lithium's effect on serotonin biosynthesis may be due to its antagonism of the positive effector influence of calcium on tryptophan hydroxylase, either as a negative effector or by blocking the calcium site.

Animals↗
PubMed1978

Fading: a new cytofluorimetric measure quantifying serotonin in the presence of catecholamines at the cellular level in brain.

A new histopharmacological approach to the study of serotonergic neurons is described. Using a computerized microspectrofluorimeter, we demonstrated that a measure of fluorescence fading reliably detects changes in serotonin even in the presence of catecholamines. This "fading measure" was validated with model droplets containing serotonin, norepinephrine or mixtures of the two, and with in vivo studies using pargyline to increase brain serotonin. After various doses of pargyline, a correlation of 0.927 was found between our intraperikaryal fading measure and a standard florimetric measure of serotonin in dissected samples of the raphe. Further experiments were designed to test the feasibility of the cytofluorimetric fading measure for quantifying differential changes in serotonin in intraperikaryal and extraperikaryal regions. Both LSD (75 and 150 microgram/kg) and a low dose of the monoamine oxidase inhibitor pargyline (25 mg/kg) increased intraperikaryal serotonin without affecting extraperikaryal fluorescence. Conversely, the serotonin reuptake inhibitor fluoxetine produced the opposite effect of selectively increasing extraperikaryal serotonin. Another inhibitor of serotonin reuptake, chlorimipramine, which also blocks reuptake of norepinephrine in vivo, markedly increased both intraperikaryal and extraperikaryal serotonin. These results confirm the utility of cytofluorimetric measures of serotonin within raphe cell bodies from untreated rats, and indicate that changes in the intracellular and extracellular concentrations of serotonin can be differentiated.

Animals↗
PubMed1978

Regional and subcellular distribution and some factors in the regulation of reduced pterins in rat brain.

We have studied the regional and subcellular distribution, functional role, and pharmacology of quinoid dihydropterin reductase (QDPR) and endogenous reduced pterins (PH4) subserving tyrosin hydroxylase (TOH) and tryptophan hydroxylase in the rat brain. There is a significant correlation between the regional distribution of PH4 and TOH but not between PH4 and tryptophan hydroxylase or between either TOH or tryptophan hydroxylase and QDPR. This suggests that a major portion of PH4 is associated with the biosynthetic activity of brain catecholaminergic systems. The regional and subcellular distribution of QDPR was inconsistent with a regulatory function for QDPR in monoamine synthesis. In vitro measures of PH4, TOH, and synaptosomal dopamine (DA) and serotonin synthesis in the striate cortex of untreated animals and animals subjected to neurotoxin or electrolytic lesions of the dorsal raphe or substantia nigra exhibit significant covariation of PH4 with synaptosomal DA but not serotonin synthesis and a significant partial correlation of PH4 with DA synthesis. The subcellular distribution of PH4 in the striatum demonstrates an association of PH4 with the biosynthetic function of dopaminergic nerve terminals. Reserpine and d-amphetamine in vivo elicited an increase and decrease, respectively, in striatal PH4 paralleling induced changes in synaptosomal DA synthesis. Other drugs altering central catecholaminergic function did not alter striatal PH4 levels significantly. The data suggest that 1) a major portion of total PH4 (as much as 90% in the striatum) is related to the function of catecholaminergic rather than serotonergic systems, 2) PH4 levels is a determinant of the velocity of DA synthesis and 3) PH4 levels are altered by some psychoactive drugs in association with changes in synaptosomal catecholamine biosynthetic rates.

Animals↗