Biomedical subjects

E E Brown

Publications and source records attributed to E E Brown.

At least 19 recordsLinked to original sources

PubMed1999

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy.

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.

Adult↗

PubMed1998

The significance of hypersialylation of dipeptidyl peptidase IV (CD26) in the inhibition of its activity by Tat and other cationic peptides. CD26: a subverted adhesion molecule for HIV peptide binding.

The functionality of DPP-IV, purified from human placenta and isolated from CD4+/CD26+ T cells of noninfected and HIV-1-infected individuals, was investigated as to its ability to bind certain specific peptides. Using isoelectric focusing and the specificity of substrate-impregnated overlay membranes, we found that DPP-IV from term placenta and from T cells of HIV-infected individuals was significantly more sialylated compared with enzyme isozyme patterns of other tissues. We report here that (1) the number of isoforms of DPP-IV and extent of sialylation are critical to function and peptide binding; (2) the number of sialylated isoforms isolated from PBMCs increases significantly with age greater than 40 years; (3) hypersialylation by extreme anionic isoforms is highly associated with HIV infection and pathognomonic to remaining CD4+ cells in overt AIDS; and (4) highly sialylated DPP-IV is more significantly inhibited by Tat and cationic peptides. We conclude that hypersialylation of DPP-IV modifies surface charge of the CD26 antigen, promoting binding of HIV peptides through their cationic domains to the sialic acid residues of DPP-IV, and that certain HIV moieties are likely to engage this phenomenon as an auxiliary adhesion mechanism to fuse with cells. Furthermore, as a consequence of this occurrence, DPP-IV enzymatic activity can be significantly reduced, competitively.

Adolescent↗

PubMed1998

Requirement for microtubules in new membrane formation during cytokinesis of Xenopus embryos.

In cleaving Xenopus eggs, exposure to nocodazole or cold shock prevents the addition of new plasma membrane to the cleavage plane and causes furrows to recede, suggesting a specific role for microtubules in cytokinesis. Whole-mount confocal immunocytochemistry reveals a ring of radially arranged, acetylated microtubule bundles at the base of all advancing cleavage furrows, from the first cleavage through the midblastula stage. We hypothesize that this novel microtubular structure is involved in transporting maternal stores of membrane in the subcortex to a site of membrane addition near the leading edge of the furrow.

Acetylation↗

PubMed1994

Provisional bilateral symmetry in Xenopus eggs is established during maturation.

Dorsal-ventral patterning in the Xenopus egg becomes established midway through the first cell cycle during a 30 degree rotation of the subcortical yolk mass relative to the egg cortex. This 'rotation of symmetrisation' is microtubule dependent, and its direction is thought to be cued by the usually eccentric sperm centrosome. The fact that parthenogenetically activated eggs also undergo a directed rotation, despite the absence of a sperm centrosome, suggests that an endogenous asymmetry in the unfertilised egg supports the directed polymerisation of microtubules in the vegetal cortex, in the way that an eccentric sperm centrosome would in fertilised eggs. Consistent with this idea, we noticed that the maturation spot is usually located an average of more than 15 degrees from the geometric centre of the pigmented animal hemisphere. In parthenogenetically activated eggs, this eccentric maturation spot can be used to predict the direction of rotation. Although in most fertilised eggs the yolk mass rotates toward the sperm entry point (SEP) meridian, occasionally this relationship is perturbed significantly; in such eggs, the maturation spot is never on the same side of the egg as the SEP. In oocytes tilted 90 degrees from upright during maturation in vitro, the maturation spot developed 15 degrees or more from the centre of the pigmented hemisphere, always displaced towards the point on the equator that was up during maturation. This experimentally demonstrated lability is consistent with an off-axis oocyte orientation during oogenesis determining its eccentric maturation spot position, and, in turn, its endogenous rotational bias.

Animals↗

PubMed1993

ECS-induced dopamine release: effects of electrode placement, anticonvulsant treatment, and stimulus intensity.

Although electroconvulsive therapy (ECT) remains an important therapy for severe depression, its mechanism of action remains elusive. We previously demonstrated that there is a significant increase of interstitial dopamine of neuronal origin in the rat striatum after electroconvulsive shock (ECS) but not after chemically (flurothyl) induced seizures. The present studies examined how electrode placement, stimulus intensity, and the administration of an anticonvulsant affect ECS-induced dopamine release in the rat striatum. Bilateral electrode placement resulted in greater dopamine release than that produced by a unilaterally applied stimulus. Pretreatment with sodium pentobarbital markedly decreased seizure duration but had no effect on the magnitude of the increase in interstitial dopamine. Finally, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase in seizure duration. These data suggest that the passage of current may be directly responsible for certain ECS-induced chemical changes. These findings are discussed in the context of clinical observations that challenge the traditional view that the production of generalized seizures of adequate duration is both necessary and sufficient for a therapeutic response to ECT.

Animals↗

PubMed1993

Deep cytoplasmic rearrangements in ventralized Xenopus embryos.

Following fertilization in Xenopus, dramatic rearrangements of the egg cytoplasm relocalize maternally synthesized egg components. During the first cell cycle the vegetal yolk mass rotates relative to the egg surface, toward the sperm entry point (SEP) (J. P. Vincent, G. F. Oster, and J. C. Gerhart, 1986, Dev. Biol. 113, 484-500), while concomitant deep cytoplasmic rearrangements occur in the animal hemisphere (M. V. Danilchik and J. M. Denegre, 1991, Development 111, 845-856). In this paper we examine the role of vegetal yolk mass rotation in producing the animal cytoplasmic rearrangements. We inhibited rotation by uv-irradiating embryos during the first cell cycle, a treatment that yields an extremely ventralized phenotype. Both uv-irradiated embryos and unirradiated control embryos show cytoplasmic rearrangements in the animal hemisphere during the first cell cycle. Cytoplasmic rearrangements on the SEP side of the embryo associated with the path of the sperm pronucleus, plus a swirl on the anti-SEP (dorsal) side, are seen, whether or not yolk mass rotation has occurred. This result suggests a role for the expanding sperm aster in directing animal hemisphere cytoplasmic movements. In unirradiated control embryos the anti-SEP (dorsal) swirl is larger than that in uv-irradiated embryos and often extends into the vegetal hemisphere, consistent with the animal cytoplasm having been pulled dorsally and vegetally by the sliding vegetal yolk mass. Thus the yolk mass rotation may normally enhance the dorsalward cytoplasmic movement, begun by the sperm aster, enough to induce normal axis formation. We extended our observations of unirradiated control and uv-irradiated embryos through early cleavages. The vegetal extent of the anti-SEP (dorsal) swirl pattern seen in control embryos persists through the early cleavage period, such that labeled animal cytoplasm extends deep into dorsal third-tier blastomeres at the 32-cell stage. Significantly, in uv-irradiated embryos, which have not undergone vegetal rotation, most of this labeled material remains more equatorial.

Animals↗

PubMed1993

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference.

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.

Amygdala↗

PubMed1992

The neurobiology of cocaine-induced reinforcement.

Cocaine has potent pharmacological actions on a number of monoaminergic systems in the brain, including those that use noradrenaline, dopamine and serotonin as neurotransmitters. There is growing evidence that cocaine's effects on dopaminergic neurons, particularly those that make up the mesolimbic system, are closely associated with its rewarding properties. For example, low doses of dopamine receptor antagonists reliably influence cocaine self-administration, whereas noradrenaline and serotonin receptor antagonists are without consistent effects. Similarly, selective lesions of dopaminergic terminals in the nucleus accumbens, a major target of the mesolimbic dopamine projection, disrupt cocaine self-administration in a manner that is consistent with loss of cocaine-induced reward. The introduction of in vivo brain microdialysis as a tool with which to investigate the neurochemical correlates of motivated behaviour has provided new opportunities for investigating the role of dopamine in the nucleus accumbens in the acquisition and maintenance of cocaine self-administration. Although the body of literature that has been generated by this approach appears to contain some important inconsistencies, these probably reflect the use of inappropriate microdialysis conditions by some investigators. A critical review of the literature suggests that microdialysis results are generally consistent with a role for mesolimbic dopamine in cocaine-induced reward, although it does not seem to be the case that animals will work to maintain consistent increases in extracellular concentrations of dopamine in the nucleus accumbens in all experimental conditions. Elucidation of the complete neural circuitry of cocaine-induced reward remains an important priority for future research.

Animals↗

PubMed1992

Cocaine self-administration differentially alters mRNA expression of striatal peptides.

The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, enkephalin and substance P was analyzed in the rat striatum with in situ hybridization histochemistry. Cocaine, an indirect dopamine agonist, was found to differentially affect the levels of mRNA encoding these neuropeptides in different subregions of the striatum. Following a 7 day period of variable free access to cocaine, dynorphin and substance P mRNA levels were elevated throughout the striatum, but the increases were substantially greater in the dorsal striatum than in the nucleus accumbens. Enkephalin mRNA was not significantly altered in the dorsal striatum but was slightly elevated in the nucleus accumbens. These results suggest that cocaine self-administration has differential effects on striatonigral and striatopallidal projection neurons, and that these effects vary in subregions of the striatum.

Animals↗

PubMed1992

Cocaine-induced conditioned locomotion: absence of associated increases in dopamine release.

The potent reinforcing effects of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This phenomenon is of considerable significance as intense craving can be evoked by stimuli previously associated with the effects of cocaine. It has been proposed that the reinforcing properties of these conditional stimuli are due to their ability to elicit neural events that are similar to those produced by the drug itself. Given the large body of evidence that implicates the mesolimbic dopaminergic projection in the unconditioned behavioural properties of cocaine, the present study used in vivo microdialysis to determine whether stimuli paired with cocaine elicit increases in interstitial dopamine in the nucleus accumbens that are similar to the unconditioned effects of this drug. When administered acutely, cocaine (10 mg/kg, i.p.) produced a potent unconditioned increase in interstitial dopamine concentrations (300% of basal values) in the nucleus accumbens. The results from two separate experiments indicate that the administration of cocaine (10 mg/kg for seven days) in association with a specific environment produced significant locomotion in that environment. Compared to subjects that received saline in both settings, rats that received cocaine in their home cage (pseudoconditioned group) did not exhibit increased locomotion on the test day. Although repeated pairing of cocaine with a specific environment produced conditioned locomotion, there was no concomitant conditional increase in dopamine release. Specifically, the modest increase in dopamine (10-15% above basal values) observed after exposure to the conditional environment was equal in the conditioned and pseudoconditioned groups.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy.

The authors investigated early human focal ischemia with phosphorus-31 nuclear magnetic resonance spectroscopy at 1.89 T to characterize the temporal evolution and relationship of brain pH and phosphate energy metabolism. Data from 65 symptomatic patients were prospectively studied; none of the patients had had ischemic stroke in the internal carotid artery territory before. Twenty-eight neurologically normal individuals served as control subjects. Serial ischemic brain pH levels indicated a progression from early acidosis to subacute alkalosis. When acidosis was present there was a significant elevation in the relative signal intensity of inorganic phosphate (Pi) and significant reductions in signal intensities of alpha-adenosine triphosphate (ATP) and gamma-ATP compared with those of control subjects. Ischemic brain pH values directly correlated with the relative signal intensity of phosphocreatine (PCr) and the PCr index and inversely correlated with the signal intensity of Pi. There was a general lack of correlation between either ischemic brain pH or phosphate energy metabolism and the initial clinical stroke severity. The data suggest a link between high-energy phosphate metabolism and brain pH, especially during the period of ischemic brain acidosis, and the authors propose that effective acute stroke therapy should be instituted during this period.

Acidosis↗

PubMed1992

Neurochemical effects of electrically and chemically induced seizures: an in vivo microdialysis study in the rat hippocampus.

This study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), acetylcholine and choline, and the dopamine metabolite homovanillic acid (HVA) in the hippocampus of freely moving rats using online brain microdialysis. The effects of ECS on 5-HT, 5-HIAA, and HVA were compared to the effects of seizures induced by the convulsant agent flurothyl. Interstitial concentrations of 5-HT increased several fold in response to ECS and this increase was accompanied by a significant increase in the concentration of HVA. Acetylcholine and choline concentrations were also increased significantly by ECS. The ECS-induced increase in interstitial 5-HT was markedly reduced when the voltage-dependent sodium channel blocker tetrodotoxin (1 mumol/L) was added in the perfusion solution, indicating that the observed increase was of neuronal origin. Interstitial concentrations of 5-HT also increased in response to flurothyl-induced seizures and this increase was accompanied by a significant increase in the concentration of HVA. These results provide direct in vivo evidence that interstitial concentrations of 5-HT increase several fold in response to both ECS- and flurothyl-induced seizures. These observations are discussed in relation to the hypothesized role of 5-HT in ECS-induced memory deficits.

Acetylcholine↗

PubMed1992

Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures.

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This form of classical conditioning is of considerable clinical relevance as intense craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. To understand better the neurobiology of cocaine-induced environment-specific conditioning, Fos expression was examined in the forebrain of rats exposed to an environment in which they had previously received cocaine. These results were compared to those observed following an acute injection of cocaine. Consistent with its stimulant actions, cocaine produced an increase in locomotion that was accompanied by an increase in Fos expression within specific limbic regions (cingulate cortex, claustrum, piriform cortex, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and amygdala) as well as the basal ganglia (dorsomedial striatum and nucleus accumbens). Exposure of rats to the cocaine-paired environment also produced an increase in locomotion, as compared to various control groups. In addition to this behavioral effect, conditioned subjects exhibited a significant increase in Fos expression within the cingulate cortex, claustrum, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and the amygdala, suggesting increased neuronal activity within these regions. In contrast to the dramatic effects observed within these structures, no conditional activation was observed within the piriform cortex, nucleus accumbens, or dorsal striatum, suggesting that these brain areas are not involved in the conditioned response. The present findings indicate that specific limbic regions exhibit increased neuronal activation during the presentation of cocaine-paired cues and may be involved in the formation of associations between cocaine's stimulant actions and the environment in which the drug administration occurred. Although the nucleus accumbens is necessary for the reinforcing and locomotor effects of cocaine, it does not exhibit a conditional Fos response, suggesting that different neural circuits are involved in the unconditioned and conditioned effects of cocaine.

Amygdala↗

PubMed1991

Chronic desipramine enhances the effect of locally applied amphetamine on interstitial concentrations of dopamine in the nucleus accumbens.

In vivo microdialysis was used to study the effect of chronic desipramine (DMI, 5 mg/kg, twice daily for 21 days) on increases in interstitial dopamine (DA) produced by local administration of d-amphetamine (1.0, 3.3 and 10.0 microM) in the nucleus accumbens. Locally applied amphetamine increased interstitial DA in a dose-dependent manner. The amphetamine-induced increase was significantly greater in the DMI treated animals. These data suggest that chronic DMI may directly influence the functional status of the DA terminals in the nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Interstitial 3-methoxytyramine reflects striatal dopamine release: an in vivo microdialysis study.

Previous ex vivo studies have provided indirect evidence that the dopamine (DA) metabolite 3-methoxytyramine (3-MT) may be a useful index of DA release in vivo. In the present study, in vivo microdialysis was utilized to assess directly the relationship between extracellular DA and 3-MT in the striatum of rats following a variety of pharmacological manipulations. Apomorphine, a DA receptor agonist, produced a rapid, transient decrease in both DA and 3-MT. Conversely, the DA receptor antagonist haloperidol produced a concomitant increase in extracellular DA and 3-MT. Increases in DA and 3-MT were also noted following the administration of the DA uptake inhibitor, bupropion. Local application of tetrodotoxin resulted in the complete elimination of measurable amounts of DA and 3-MT in the dialysate, gamma-Butyrolactone also greatly decreased DA and 3-MT. Finally, d-amphetamine produced a large increase in DA and 3-MT in animals that had been treated previously with gamma-butyrolactone. The Pearson correlation coefficients for DA and 3-MT following these manipulations ranged from 0.87 to 0.97. These data indicate that interstitial 3-MT is an accurate index of DA release. However, when compared with previous ex vivo findings, the present results also suggest that changes in tissue concentrations of 3-MT may not reliably reflect DA release following certain pharmacological manipulations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse.

Intravenous self-administration studies in nonhuman primates suggest that the opioid receptor agonist-antagonist buprenorphine may be useful in the pharmacotherapy of cocaine abuse. In the present studies, behavioral and neurochemical interactions between cocaine and buprenorphine were examined using a conditioned place preference (CPP) procedure and in vivo microdialysis. Cocaine-induced CPP was linearly related to the dose administered (0-5.0 mg/kg). Buprenorphine (0-0.9 mg/kg) also elicited CPP in a dose-related manner; an inverted U-shaped function was obtained. Subthreshold doses of cocaine (1.5 mg/kg) and buprenorphine (0.01 mg/kg), themselves incapable of eliciting CPP, produced a significant CPP when given together. Moderate doses of cocaine (5.0 mg/kg) and buprenorphine (0.075 mg/kg), which were individually capable of eliciting CPP, produced a significantly larger CPP when given in combination. In the in vivo microdialysis studies, a low dose of buprenorphine (0.01 mg/kg) produced a progressive increase in extracellular dopamine in the nucleus accumbens, reaching approximately 200% of basal levels after 5 hr. Cocaine (5.0 mg/kg) rapidly increased extracellular dopamine concentrations (180% of basal values within 20 min), which returned to baseline in 2 to 3 hr. This effect of cocaine was significantly potentiated by coadministering buprenorphine (0.01 mg/kg); under this condition the peak increase in extracellular dopamine reached 260% of baseline values. These neurochemical findings are consistent with the CPP results and indicate that buprenorphine can interact with cocaine in a synergistic manner. In contrast to previous speculations, these results suggest that buprenorphine may enhance rather than attenuate the rewarding properties of cocaine.

Animals↗

PubMed1989

Regulation of larval cuticle protein gene expression in Drosophila melanogaster.

Genes that encode 3rd instar larval cuticle proteins (LCP's) of Drosophila melanogaster are located in at least two chromosomal sites. The genes encoding four of the five predominant LCP's are located in a cluster at the chromosomal region 44D. They are organized in pairs that are transcribed divergently, and expressed with different timing during the third larval instar. Towards understanding the basis of gene regulation within the 44D cluster, we have analyzed genetic variants, including the 2-3 variant, which has an insertion of a copia-like transposable element, H.M.S. Beagle, within the 44D cluster. The Beagle element appears to inactivate the LCP-3 gene by inserting into its TATA box, but also may cause the precocious expression of two other LCP genes, LCP-1 and LCP-f2, in the cluster. The long terminal repeat (LTR) of the Beagle element apparently contains a sequence, perhaps an enhancer-like element, which causes altered expression of these genes. We have also investigated the cis-regulatory elements involved in expression of the LCP-2 gene in wild-type larvae. We have identified two upstream regions that may contain separate cis-regulatory elements. The region between -252 bp and -515 bp may be essential for any expression of LCP-2. Additionally, the region between -515 bp and -795 bp appears to be required for the normal level of expression of the LCP-2 gene.

Animals↗

PubMed1988

Prepupal differentiation of Drosophila imaginal discs: identification of four genes whose transcripts accumulate in response to a pulse of 20-hydroxyecdysone.

We have isolated and initially characterized a novel set of four genes expressed during the prepupal differentiation of imaginal discs of Drosophila melanogaster. These four ecdysone-dependent genes are named EDG-42A, EDG-64CD, EDG-78E and EDG-84A-1 based on their respective chromosomal locations. Their expression is like that expected for genes encoding proteins that participate in the formation of the pupal cuticle. Transcripts complementary to these genes accumulate in imaginal discs during an 18-hr in vitro culture period that begins with a 6-hr pulse of 20-hydroxyecdysone (20-HE). Transcripts for three of these genes were not detected in imaginal discs following culture in the absence or the continuous presence of 20-HE (1 microgram/ml). Transcripts corresponding to EDG-64CD exhibit delayed accumulation in the continuous presence of 20-HE. Transcripts corresponding to three of the genes are only detected in the prepupal stage of development. Only EDG-64CD is complementary to transcripts present at other stages of development. One of the genes, EDG-78E, encodes a pupal cuticle protein. This is the first reported isolation of a set of steroid hormone-responsive genes that require first the presence, then removal of hormone for transcript accumulation.

Animals↗