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Biomedical subjects

A M White

Publications and source records attributed to A M White.

At least 19 recordsLinked to original sources
PubMed2005

Decreasing endogenous glucocorticoids alters the ability of bone marrow cells to produce nitric oxide in response to stimulating agents.

Glucocorticoids (GC) are essential for the body to maintain homeostasis. Patients with adrenal insufficiencies suffer from numerous health related problems including increased mortality due to sepsis. Here, we examine bone marrow (BM) cells from mice with adrenal insufficiency for their ability to produce nitric oxide (NO). Mice were injected with metyrapone (MR), an agent that selectively blocks glucocorticoid synthesis. BM cells were removed and tested for NO production. The stimulating agents LPS, TNF-alpha, IL-1beta, and IL-4 were all able to synergize with IFN-gamma, stimulating large concentrations of NO compared to normal mice. An important finding is that BM from injected mice produces NO in response to LPS alone, while normal BM cells do not. Experiments with anti IFN-gamma antibody demonstrate that, in MR injected mice, LPS alone stimulated sufficient quantities of IFN-gamma necessary for NO production. Our results demonstrate that reducing GCs alters regulation of NO production by BM cells at several levels.

Animals↗
PubMed2005

Increased prevalence of activated CD70+CD4+ T cells in the periphery of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by loss of immune tolerance. A hallmark of SLE is the presence of autoantibodies resulting from B cell hyperactivity. Previous studies have shown that the presence of abnormal B cell subsets in the periphery, such as CD27highCD20- B cells, correlate with disease activity. We examined the relationship between the expression of CD70, the ligand for CD27 expressed by activated T cells, and indicators of disease activity. A significant increase in median CD70+CD4+ T cell frequencies and memory CD45RA-CD4+ T cell frequencies was observed in SLE samples as compared to healthy controls. The frequencies of CD70+CD4+ T cells correlated with disease duration but not age, treatment, or disease activity. Although a majority of CD70+CD4+ T cells appeared to be effector memory cells, mitogen-stimulated CD70+CD4+ T cells were capable of secreting a full repertoire of effector cytokines. Despite the presence of activated CD4+ T cells, no increase in immunosenescent CD4+ T cells, as defined by the loss of CD28 and/or the acquisition of CD57 was observed in samples from SLE patients. These studies indicate that increased CD70 expression might serve as a useful marker of abnormal T cell activity in SLE.

Adult↗
PubMed2002

Activation of bovine peripheral blood gammadelta T cells for cell division and IFN-gamma production.

Bovine peripheral blood gammadelta T cells have been evaluated for effector function (IFN-gamma production) and clonal expansion in a variety of systems including following activation by mitogens, IL-12, and stimulation, through the T cell receptor (TCR) with anti-CD3 monoclonal antibody (mAb), a cell-bound molecule and a soluble antigenic extract. To evaluate cell division, carboxyfluorescein succinimidyl ester (CFSE) loading of cells and flow cytometric analysis were used, while IFN-gamma production was evaluated by intracytoplasmic staining. It was found that bovine gammadelta T cells produced IFN-gamma and clonally expanded when stimulated through the TCR/CD3 complex by a cell-associated autologous molecule on monocyte, by bacterial components following in vivo sensitization of gammadelta T cells with a leptospira vaccine or by anti-CD3 mAb. In addition, gammadelta T cells were activated efficiently for effector function but not clonal expansion by culturing with IL-12. In contrast, stimulation by Con A or PMA/ionomycin induced efficient replication but only low level IFN-gamma production which was not enhanced by the presence of IL-12. In several systems the amount of IFN-gamma produced per cell by gammadelta T cells was less than that produced by CD4 T cells in the same cultures.

Animals↗
PubMed2001

Ionic mechanisms of GABA-induced long-term potentiation in the rat superior colliculus.

GABA-induced excitation and long-term potentiation (LTPG) have been demonstrated recently in the superficial layers of the superior colliculus (SC). In other regions of the nervous system, GABA elicits excitatory responses via ionotropic GABA receptors under certain conditions. This excitation is proposed to be due to either a high neuronal chloride concentration favouring a depolarising chloride efflux, or to a bicarbonate efflux coupled to a chloride influx. The aim of this study was to characterise the mechanisms underlying excitation and prolonged increase in synaptic transmission induced by GABA in the SC. Extracellular field potentials were recorded from 1-month-old rat SC slices, and LTPG of these responses was evoked by application of 3 mM GABA. GABA-induced excitation and LTPG were significantly reduced by lowering the extracellular calcium concentration, but not by a decreased potassium concentration. Replacing the extracellular bicarbonate-buffered perfusion medium with a HEPES-buffered solution had no effect on LTPG but blocking the bicarbonate-generating enzyme carbonic anhydrase both intra- and extracellularly with ethoxyzolamide (50 microM) prevented LTPG. The chloride transport inhibitor bumetanide (50 microM) reduced but did not block LTPG. We therefore suggest that the contribution of the chloride equilibrium to LTPG is only of minor importance. The intracellular bicarbonate pool and related efflux provides the basis for the excitatory action of GABA, leading to a subsequent depolarisation and calcium influx through voltage-dependent calcium channels, thus causing long-lasting changes in synaptic transmission.

Acid-Base Equilibrium↗
PubMed2001

Spatial processing in the brain: the activity of hippocampal place cells.

The startling discovery by O'Keefe & Dostrovsky (Brain Res. 1971; 34: 171-75) that hippocampal neurons fire selectively in different regions or "place fields" of an environment and the subsequent development of the comprehensive theory by O'Keefe & Nadel (The Hippocampus as a Cognitive Map. Oxford, UK: Clarendon, 1978) that the hippocampus serves as a cognitive map have stimulated a substantial body of literature on the characteristics of hippocampal "place cells" and their relevance for our understanding of the mechanisms by which the brain processes spatial information. This paper reviews the major dimensions of the empirical research on place-cell activity and the development of computational models to explain various characteristics of place fields.

Animals↗
PubMed2000

Prenatal choline exposure alters hippocampal responsiveness to cholinergic stimulation in adulthood.

Manipulation of dietary choline levels during gestation results in enduring neurobehavioral changes in offspring that last into adulthood. Alterations of hippocampal function and memory are among the most striking changes. Depending upon the measures assessed, prenatal choline supplementation tends to promote excitatory synaptic efficacy in hippocampal circuits while prenatal choline deficiency diminishes it. However, the mechanisms underlying these changes remain unclear. Transverse hippocampal slices were prepared from adult offspring of dams fed choline supplemented, choline deficient, or control diets. We assessed paired-pulse inhibition, and excitatory synaptic responsiveness before and after activation of cholinergic receptors with Carbachol. Prenatally choline deficient animals yielded significantly fewer electrophysiological viable hippocampal slices than did animals from either of the other two treatment groups. Among the slices tested, there were no differences in paired pulse inhibition between the treatment groups. However, transient cholinergic activation resulted in a prolonged enhancement of the amplitude of the population EPSP (pEPSP) response in slices from prenatally choline supplemented animals. These results suggest that GABA receptor-mediated inhibition remains intact after prenatal choline manipulations, and that enhancement of the excitatory responsiveness of hippocampal circuits in slices from prenatally choline supplemented rats may be related in part to an increase in cholinergic tone within the CA1 circuit.

Animals↗
PubMed2000

Effects of ethanol on hippocampal place-cell and interneuron activity.

Mounting evidence suggests that ethanol exerts effects on learning and memory by altering cellular activity in the hippocampus and related structures. However, little is actually known regarding ethanol's effects on hippocampal function in awake, freely-behaving animals. The present study examines the effects of ethanol on hippocampal place-cell and interneuron activity in freely-behaving rats. Signals from individual hippocampal neurons were isolated while subjects traversed a symmetric Y-maze for food reward. Following 15 min of baseline recording, subjects were injected with one of four doses of ethanol (0.0, 0.5, 1.0 and 1.5 g/kg), and cellular activity was monitored for a 1-h time period. Following sufficient time for recovery (minimum of 3 h post injection), cellular activity was monitored for an additional 15-min period. Both 1.0 and 1.5 g/kg ethanol potently suppressed the firing of hippocampal place-cells without altering place-field locations. Ethanol did not significantly suppress out-of-field firing rates, leading to a decrease in spatial specificity (i.e. the ratio of in-field/out-of-field firing rates). Interneuron activity was not altered by 1.0 g/kg ethanol, but was occasionally suppressed by 1.5 g/kg ethanol. Results are interpreted in light of recent behavioral and electrophysiological studies examining the effects of ethanol on hippocampal function.

Animals↗
PubMed2000

Ges, A human GTPase of the Rad/Gem/Kir family, promotes endothelial cell sprouting and cytoskeleton reorganization.

Rad, Gem/Kir, and mRem (RGK) represent a unique GTPase family with largely unknown functions (Reynet, C., and C.R. Kahn. 1993. Science. 262:1441-1444; Cohen, L., R. Mohr, Y. Chen, M. Huang, R. Kato, D. Dorin, F. Tamanoi, A. Goga, D. Afar, N. Rosenberg, and O. Witte. Proc. Natl. Acad. Sci. USA. 1994. 91:12448-12452; Maguire, J., T. Santoro, P. Jensen, U. Siebenlist, J. Yewdell, and K. Kelly. 1994. Science. 265:241-244; Finlin, B.S., and D.A. Andres. 1997. J. Biol. Chem. 272:21982-21988). We report that Ges (GTPase regulating endothelial cell sprouting), a human RGK protein expressed in the endothelium, functions as a potent morphogenic switch in endothelial cells (ECs). Ges function is sufficient to substitute for angiogenic growth factor/extracellular matrix (ECM) signals in promoting EC sprouting, since overexpression of Ges in ECs cultured on glass leads to the development of long cytoplasmic extensions and reorganization of the actin cytoskeleton. Ges function is also necessary for Matrigel-induced EC sprouting, since this event is blocked by its dominant negative mutant, Ges(T94N), predicted to prevent the activation of endogenous Ges through sequestration of its guanine nucleotide exchange factor. Thus, Ges appears to be a key transducer linking extracellular signals to cytoskeleton/morphology changes in ECs.

Actins↗
PubMed2000

Ethanol, memory, and hippocampal function: a review of recent findings.

For well over a century, ethanol was believed to exert its effects on cognition and behavior by producing a ubiquitous depression of central nervous system activity. A general disruption in brain function was consistent with the belief that ethanol's effects on cognition and behavior were also quite general. Substantial evidence now indicates that ethanol produces a host of selective effects on neural activity, resulting in regional differences in ethanol's effects in the brain. Consistent with such evidence, recent research suggests that ethanol's effects on cognition and behavior are not as global as previously assumed. The present paper discusses evidence that many of ethanol's effects on learning and memory stem from altered cellular activity in the hippocampus and related structures. Potential mechanisms for ethanol's disruption of hippocampal function are reviewed. Evidence suggests that ethanol disrupts activity in the hippocampus by interacting directly with hippocampal neurons and by interacting with critical hippocampal afferents.

Animals↗
PubMed2000

Islet hormones from the African bullfrog Pyxicephalus adspersus (Anura:Ranidae): structural characterization and phylogenetic implications.

The African bullfrog Pyxicephalus adspersus is generally classified along with frogs of the genus Rana in the subfamily Raninae of the family Ranidae but precise phylogenetic relationships between species are unclear. Pancreatic polypeptide (PP), insulin, and glucagon-like peptide (GLP-1) were isolated from an extract of P. adspersus pancreas and characterized structurally. A comparison of the amino acid sequence of Pyxicephalus PP (APSEPQHPGG(10)QATPEQLAQY(20)YSDLYQYITF(30)ITRPRF++ +. NH(2)) with those of the known amphibian PP molecules in a maximum parsimony analysis generates a single phylogenetic tree in which Pyxicephalus is the sister to the clade comprising the members of the genus Rana. The three orders of living amphibians form discrete clades with the representative of the Gymnophiona appearing as sister to the Caudata-Anura. In contrast, Pyxicephalus insulin (A chain, GIVEQCCHSA(10)CSLYDLENYC(20)N; B-chain, LANQHLCGSH(10)LVEALYMVCG(20)ERGFFYYPKS(30)) and and GLP-1 (HAEGTFTSDM(10)TSYLEEKAAK(20)EFVDWLIKGR(30)PK) resemble more closely the corresponding peptides from the cane toad Bufo marinus than the peptides from any species of Rana. Cladistic analysis based upon the amino acid sequences of insulin produced a polyphyletic assemblage with the Gymnophiona nesting within an unresolved clade containing the non-ranid frogs. The data support the assertion that the amino acid sequence of PP, but not those of the other islet hormones, is of value as a molecular marker for inferring phylogenetic relationships between early tetrapod species.

Amino Acid Sequence↗
PubMed2000

Age- and species-dependent maturation of synaptic transmission in the superficial superior colliculus.

Both neonatal maturity and postnatal maturation are known to be species dependent. For instance, guinea pigs are born with their eyes open, while eye opening takes place 2 weeks after birth in rats. Moreover, several abnormalities have been observed in albino compared to pigmented species. The pigment melanin is proposed to play a protective role and its absence is thought to contribute to neuronal deficits. In the present study, we aimed to investigate functional differences in synaptic transmission in the visual, superficial layers of the superior colliculus (SC) of albino and pigmented rats and pigmented guinea pigs, at eye opening and 1 month after birth. This was achieved by analysing evoked field excitatory postsynaptic potentials (fEPSPs) in vitro, and by investigating the ability of these responses to express gamma-aminobutyric acid (GABA)-induced long-term potentiation (LTPG), an enduring increase in synaptic efficacy resulting from bath application of GABA. Guinea pigs did not show any obvious differences with respect to overall fEPSP characteristics and synaptic plasticity at both ages studied, indicating that maturation must have occurred prenatally. Rats, however, underwent synaptic maturation and refinement to produce stronger fEPSPs and a more robust level of synaptic plasticity 1 month after birth compared to the conditions at eye opening. The state of pigmentation was found to have a crucial influence, with albino rats showing less enhancement of the strength of synaptic transmission in the SC. It can therefore be concluded that profound developmental differences in pre- and postnatal maturation of the superficial SC exist between guinea pigs and rats, and that the state of pigmentation is a crucial factor in this process.

Age Factors↗
PubMed2000

Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol.

BACKGROUND: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge-pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge. METHODS: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight-arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms. RESULTS: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups. CONCLUSIONS: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.

Aging↗
PubMed1999

Placing hippocampal single-unit studies in a historical context.

A profound increase in the study of the role of the hippocampus in behavior and cognitive processing resulted from the startling discovery by O'Keefe and Dostrovsky in 1971 that hippocampal neurons fire selectively in different regions or "place fields" of an environment. That discovery spawned a comprehensive theory of hippocampal function that was elucidated in the publication, The Hippocampus as a Cognitive Map by O'Keefe and Nadel in 1978. According to the theory, the hippocampus serves as the neural substrate for maps of allocentric space. The goal of this paper is to revisit the historical background for the development of the cognitive map theory and to examine the context in which the theory and the phenomenon of place field activity began to gain acceptance by the scientific community. While subsequent research has led some to question if the theory can adequately account for all consequences of hippocampal lesions and all the correlates of hippocampal cellular activity, it is clear the theory has stood the test of time and has been successful in generating an enormous amount of fruitful research.

Animals↗
PubMed1999

Insulin and proglucagon-derived peptides from the horned frog, Ceratophrys ornata (Anura:Leptodactylidae).

Insulin and peptides derived from the processing of proglucagon have been isolated from an extract of the pancreas of the South American horned frog, Ceratophrys ornata (Leptodactylidae). Ceratophrys insulin is identical to the insulin previously isolated from the toad, Bufo marinus (Bufonidae). Ceratophrys glucagon was isolated in two molecular forms with 29- and 36-amino acid residues in approximately equal amounts. Glucagon-29 is identical to glucagon from B. marinus and from the bullfrog, Rana catesbeiana (Ranidae) and contains only 1 amino acid substitution (Thr29 --> Ser) compared with glucagon from Xenopus laevis (Pipidae). Glucagon-36 comprises glucagon-29 extended from its C-terminus by Lys-Arg-Ser-Gly-Gly-Met-Ser. This extension is structurally dissimilar to the C-terminal octapeptide of mammalian oxyntomodulin and resembles more closely that found in C-terminally extended glucagons isolated from fish pancreata. Ceratophrys glucagon-like peptide-1 (GLP-1) (His-Ala-Asp-Gly-Thr-Tyr-Gln-Asn-Asp-Val10-Gln-Gln-Phe-Leu-Glu- Glu-Lys-Ala-Ala-Lys20-Glu-Phe-Ile-Asp-Trp-Leu-Ile-Lys-Gly- Lys30-Pro-Lys-Lys-Gln-Arg-Leu-Ser) contains 3 amino acid substitutions compared with the corresponding peptide from B. marinus, 8 substitutions compared with GLP-1 from R. catesbeiana, and between 4 and 11 substitutions compared with the three GLP-1 peptides identified in X. laevis proglucagon. GLP-2 was not identified in the extract of Ceratophrys pancreas. The data indicate that, despite its importance in the regulation of glucose metabolism, the primary structure of GLP-1 has been very poorly conserved during evolution, even among a single order such as the Anura.

Amino Acid Sequence↗
PubMed1999

Acute ethanol administration impairs spatial performance while facilitating nonspatial performance in rats.

Acute ethanol administration produces learning and memory impairments similar to those found following lesions to the hippocampal system in rats. For example, both ethanol and hippocampal lesions impair performance on spatial learning and memory tasks while sparing performance on many nonspatial learning and memory tasks. Lesions to the hippocampal system can also alter the nature of the information that the animal uses to guide its behavior, from using spatial information to using individual cues. In the present experiment, rats were trained, while sober, to navigate on an eight-arm radial arm maze to a specific arm for food reward. During training, the rewarded arm was always in the same specific location and contained well-defined cues. After the rat learned the task, a memory test was conducted under different doses of ethanol (0.0 g/kg [saline control], 1.0, 1.5, or 2.0 g/kg, intraperitoneal). On the test day the maze was rotated so that the cued arm was 90 degrees to the right of its original position. During testing, intact rats showed a significant bias to approach the place where they had been previously rewarded, even though the cue was no longer located there. Acute ethanol administration dose dependently reduced approaches to the rewarded place. However, ethanol administration did not result in increases in random choices; rather, it resulted in a dose-dependent increase in approaches to the cued arm, now in a new location. These results extend previous research showing that acute ethanol administration and lesions to the hippocampal system produce similar effects on learning and memory in rats.

Animals↗
PubMed1999

Anti-inflammatory actions of interleukin-13: suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung.

The Th2 cytokine interleukin (IL)-13 is believed to play an important role in the development of allergy, although it has also been ascribed anti-inflammatory roles in several experimental models. In this study, we have examined the effects of human recombinant IL-13 on eosinophilic lung inflammation in the guinea pig. IL-13 (1 to 100 ng, given by intratracheal instillation) did not elicit airway eosinophil recruitment. A pronounced accumulation of eosinophils, as well as monocyte/macrophages, was elicited by intratracheal instillation of guinea pig tumor necrosis factor alpha (gpTNF-alpha). Intratracheal administration of IL-13 (1 to 100 ng) given immediately prior to exposure to gpTNF-alpha resulted in a dose-related suppression of eosinophil and monocyte/macrophage accumulation in the airways, as assessed by bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in whole-lung homogenates. IL-13 treatment also reduced BAL fluid (BALF) leukocyte accumulation induced by subsequent aerosol antigen challenge of sensitized guinea pigs. Antigen challenge also resulted in elevated levels of immunoreactive eotaxin and eosinophil-stimulating activity in BALF, although only the latter was reduced significantly by IL-13 instillation prior to challenge. In contrast to the suppressive effects of IL-13, instillation of human recombinant IL-4 (100 ng) alone elicited an increase in BALF monocyte/macrophage numbers, and IL-4 was unable to inhibit gpTNF-alpha-induced leukocyte accumulation. Hence, IL-13 (but not human IL-4) exhibits an anti-inflammatory action in the airways of gpTNF-alpha- or antigen-challenged guinea pigs, by mechanisms that may involve the decreased generation of eosinophil-stimulating activity in the airways.

Animals↗
PubMed1998

The effects of MK-801 on spatial working memory and within-session spatial learning.

The present study investigated the effects of the NMDA channel blocker MK-801 (0.05, 0.10, and 0.15 mg/kg) on a task that allows for the assessment of both spatial working memory and within-session spatial learning. During the first trial of each day, subjects were shown the spatial location of a food reward on a six-arm radial-arm maze. During nine subsequent free-choice trials, subjects were reinforced for returning to that same spatial location. The location of the food reward varied across days. Thus, choosing correctly on any given trial required subjects to remember where food had been received during the previous trials of that day. The effects of MK-801 on working memory were assessed by analyzing the overall number of errors committed during the nine free-choice trials of each day. The effects of MK-801 on within-session learning were assessed by comparing the number of errors committed during the first three trials of each day to the number of errors committed during the last three trials of each day. Only the highest dose of MK-801 tested (0.15 mg/kg) impaired spatial working memory. No dose of MK-801 impaired the ability of subjects to acquire spatial information within a given session. The failure of MK-801 to impair within-session spatial learning stands in contrast to the well-known effects of MK-801 on spatial learning measured across days. Thus, when coupled with previous research, the findings of the present study further suggest that the NMDA receptor plays a role in the long-term, but not short-term, storage of spatial information.

Adaptation, Psychological↗