Biomedical subjects

J G Harris

Publications and source records attributed to J G Harris.

At least 37 records · Page 2Linked to original sources

PubMed1996

Modulation of ICAM-1 levels on U-937 cells and mouse macrophages by interleukin-1 beta and dexamethasone.

Differentiation of U-937 cells with phorbol ester (10 nM) induced a time-dependent (24 h or 48 h) increase of adhesion molecules and lipocortin 1 expression on the cell surface. Stimulation with interleukin-1 beta for a further 16 h increased the levels of intercellular adhesion molecule-1, and this effect was inhibited by co-incubation with 0.1-1 microM dexamethasone. The effect of the glucocorticoid was not modified by addition of a specific anti-lipocortin 1 monoclonal antibody (mAb 1A, 5 micrograms/ml). This opposite modulatory role of interleukin-1 and dexamethasone on intercellular adhesion molecule-1 expression was also, for the first time, observed in vivo using mouse peritoneal macrophages: a four-fold increase in intercellular adhesion molecule-1 expression was measured after local administration of the cytokine (5 micrograms/kg) and this effect was greatly inhibited (> 70%) by co-injection with 1 microgram dexamethasone. In conclusion, modulation of intercellular adhesion molecule-1 expression by glucocorticoids is an effect independent endogenous lipocortin 1, and it is an in vivo feature of these potent anti-inflammatory drugs.

Animals↗

PubMed1996

Relative contribution of the selectins in the neutrophil recruitment caused by the chemokine cytokine-induced neutrophil chemoattractant (CINC).

Rat CINC induced a dose- and time-dependent accumulation of neurophils into murine air-pouches, a response which was inhibited by two selective H1-antagonists, mepyramine and triprolidine (approximately 60%). As pretreatment with fucoidin abolished CINC effect, the relative time-related contribution of selectins on this process was then investigated by using specific monoclonal antibodies (mAb). Anti-CD62L mAb gave a similar degree of inhibition of CINC-induced cell accumulation both at the 2h and 4h time-point (approximately 75%). Anti-CD62P mAb, but not the anti-CD62E mAb, inhibited PMN accumulation at 2h (65%), but only co-administration of these two mAbs inhibited the cell response to CINC at the 4h time-point (90%). Thus endogenous histamine, CD62L, CD62P, and CD62E, though to a different degree, are required for PMN extravasation observed in response to CINC administration.

Animals↗

PubMed1996

Acute inflammatory response in the mouse: exacerbation by immunoneutralization of lipocortin 1.

1. An immuno-neutralization strategy was employed to investigate the role of endogenous lipocortin 1 (LC1) in acute inflammation in the mouse. 2. Mice were treated subcutaneously with phosphate-buffered solution (PBS), non-immune sheep serum (NSS) or with one of two sheep antisera raised against LC1 (LCS3), or its N-terminal peptide (LCPS1), three times over a period of seven days. Twenty four hours after the last injection several parameters of acute inflammation were measured including zymosan-induced inflammation in 6-day-old air-pouches, zymosan-activated serum (ZAS)-induced oedema in the skin, platelet-activating factor (PAF)-induced neutrophilia and interleukin-1 beta (IL-1 beta)-induced corticosterone (CCS) release. 3. At the 4 h time-point of the zymosan inflamed air-pouch model, treatment with LCS3 did not modify the number of polymorphonuclear leucocytes (PMN) recruited: 7.84 +/- 1.01 and 7.00 +/- 0.77 x 10(6) PMN per mouse for NSS- and LCS3 group, n = 7. However, several other parameters of cell activation including myeloperoxidase (MPO) and elastase activities were increased (2.2 fold, P < 0.05, and 6.5 fold, P < 0.05, respectively) in the lavage fluids of these mice. Similarly, a significant increase in the amount of immunoreactive prostaglandin E2 (PGE2; 1.81 fold, P < 0.05) and IL-1 alpha (2.75 fold, P < 0.05), but not tumour necrosis factor-alpha (TNF-alpha), was also observed in LCS3-treated mice. 4. The recruitment of PMN into the zymosan inflamed air-pouches by 24 h had declined substantially (4.13 +/- 0.61 x 10(6) PMN per mouse, n = 12) in the NSS-treated mice, whereas high values were still measured in those treated with LCS3 (9.35 +/- 1.20 x 10(6) PMN per mouse, n = 12, P < 0.05). A similar effect was also found following sub-chronic treatment of mice with LCPS1: 6.48 +/- 0.10 x 10(6) PMN per mouse, vs. 2.77 +/- 1.20 and 2.64 +/- 0.49 x 10(6) PMN per mouse for PBS- and NSS-treated groups (n = 7, P < 0.05). Most markers of inflammation were also increased in the lavage fluids of LCS3-treated mice: MPO and elastase showed a 2.47 fold and 17 fold increase, respectively (P < 0.05 in both cases); TNF-alpha showed a 11.1 fold increase (P < 0.05) whereas the IL-1 alpha levels were not significantly modified. PGE2 was still detectable in most (5 out of 7) of the mice treated with LCS3 but only in 2 out of 7 of the NSS-treated mice. 5. Intradermal injection of 50% ZAS caused a significant increase in the 2 hoedema formation in the skin of LCS3-treated mice in comparison to PBS- and NSS-treated animals: 16.7 +/- 1.5 microliters vs. 10.8 +/- 1.2 microliters and 10.2 +/- 1.0 microliters, respectively (n = 14 mice per group, P < 0.05). ZAS-induced oedema had subsided by 24 h in control animals but a residual significant amount of extravasation was still detectable in LCS3-treated mice: 4.4 +/- 0.8 microliters (P < 0.05). 6. A recently described model driven by endogenous glucocorticoids is the blood neutrophilia observed following administration of PAF. In our experimental conditions, a single bolus of PAF (100 ng, i.v.) provoked a marked neutrophilia at 2 h (2.43 and 2.01 fold) in NSS- and PBS-treated mice (n = 11), respectively, which was significantly attenuated in the animals treated with LCS3: 1.26 fold increase in circulating PMN (n = 11, P < 0.01 vs. NSS- and PBS-groups). 7. Intraperitoneal injection of IL-1 beta (5 micrograms kg-1) caused a marked increase in circulating plasma CCS by 2 h, to a similar extent in all experimental groups. In contrast, measurement of CCS levels in the plasma of mice bearing air-pouches inflamed with zymosan revealed significant differences between LCS3 and NSS-treated mice at the 4 h time-point: 198 +/- 26 ng ml-1 vs. 110 +/- 31 ng ml-1 (n = 8, P < 0.05). 8. In conclusion, we found a remarkable exacerbation of the inflammatory process with respect to both humoral and cellular components in mice passively immunised agains

Animals↗

PubMed1995

Endogenous corticosteroids mediate the neutrophilia caused by platelet-activating factor in the mouse.

Platelet-activating factor (PAF; 100 ng i.v.) transiently modified the number of circulating neutrophils in the mouse, inducing a fast neutropenia (2 min) followed by a late onset neutrophilia (2 h). The potential involvement in PAF-induced neutrophilia of granulocytotic agents such as interleukin-1 and tumor necrosis factor-alpha could be excluded on the basis of the ineffectiveness of interleukin-1 receptor antagonist and of a specific monoclonal antibody anti-murine tumor necrosis factor-alpha. PAF granulocytosis was preceded by a significant rise in plasma corticosterone at 20 min. The involvement of endogenous corticosteroids was confirmed by the experiments with adrenalectomized mice and in animals pretreated with the steroid antagonist RU486 (11 beta-(4-dimethyl amino-phenyl) 17 beta-hydroxy, 17 alpha(prop-1-ynyl) estra 4,9-dien-3-one), where PAF-induced neutrophilia was greatly reduced (approximately 50%). Moreover, sustained increase in plasma corticosterone by administration of adrenocorticotropic hormone was paralleled by an intense neutrophilia. We show evidence that endogenous corticosterone acts through the glucocorticoid-inducible protein lipocortin 1.

Adrenal Cortex Hormones↗

PubMed1995

Alteration of neutrophil trafficking by a lipocortin 1 N-terminus peptide.

Sialidase, fucoidin and a peptide corresponding to most of lipocortin 1 N-terminus, termed LC1-(Ac2-26)-peptide, induced an intense 2 h neutrophilia whereas a monoclonal antibody to murine CD11b induced an effect by 1 h. The neutropenic response stimulated by platelet-activating factor (PAF) was significantly reduced in the presence of sialidase, fucoidin, LC1-(Ac2-26)-peptide and monoclonal antibody anti-CD11b. Neutrophil migration into a 6-day-old mouse air-pouch induced by interleukin-1 was inhibited by all the pharmacological agents. In vitro, PAF up-regulated CD11b expression on the neutrophil surface but neither human or mouse LC1-(Ac2-26)-peptide inhibited this response. CD11b up-regulation on neutrophils occurred after PAF administration in vivo and was maximal at 2 min. LC1-(Ac2-26)-peptide mimics the action of agents interfering with leucocyte rolling and adhesion in vivo, however, does not inhibit CD11b up-regulation in vitro suggesting other phenomena are important in the activity of this peptide.

Amino Acid Sequence↗

PubMed1995

Learning to ignore: psychophysics and computational modeling of fast learning of direction in noisy motion stimuli.

The effects of practice on the discrimination of direction of motion in briefly presented noisy dynamic random dot patterns are investigated in several forced-choice psychophysical tasks. We found that the percentage of correct responses on any specific task increases linearly with repetition of trials within roughly 200 trials from about chance to a performance of 90% or better. The level of performance remained constant or improved over several days, and in most instances it did not transfer when stimulus parameters changed. We used a modified Radial Basis Function (RBF) representation to model the psychophysical tasks. The performance of the model is functionally similar to the psychophysical results. We propose a Hebbian learning algorithm which deactivates the inputs from neurons responding to motion noise in the stimulus. Our computational model suggests that to solve this task in biological systems, neurons (perhaps in MT) improve their performance by 'learning to ignore' noise in the image.

Acoustic Stimulation↗

PubMed1995

Effects of bilingualism on verbal learning and memory in Hispanic adults.

The effect of bilingualism on qualitative aspects of verbal learning and memory was investigated. Equivalent list learning tests in English and Spanish were carefully constructed, and compared across two bilingual Hispanic groups of Mexican origin that differed in their level of English proficiency ("balanced" and "nonbalanced" bilinguals) and a group of monolingual English-speaking non-Hispanic subjects. Groups were matched for age, education, and gender composition. Nonbalanced bilinguals assessed in English utilized semantic clustering to the same extent as monolinguals, but learned fewer words overall, and demonstrated lower retention scores compared to monolinguals. Comparisons of groups assessed in their dominant languages, however, revealed no significant differences on any of the learning and memory indices examined. In addition to comparisons with standard clinical memory indices, assessment issues concerning bilingual individuals are addressed.

Adult↗

PubMed1994

A role for endogenous histamine in interleukin-8-induced neutrophil infiltration into mouse air-pouch: investigation of the modulatory action of systemic and local dexamethasone.

1. When injected into a 6-day-old mouse air-pouch, human recombinant interleukin-8 (IL-8; 0.03-3 micrograms) induced, in a dose-dependent fashion, an accumulation of neutrophils which could be reliably assessed 4 h after the injection. No protein extravasation was measured above the values obtained with the vehicle alone (carboxymethylcellulose, CMC, 0.5% w/v in phosphate-buffered solution, PBS). 2. The IL-8 effect (routinely evaluated at 1 microgram dose) was inhibited neither by local administration of actinomycin D (1 microgram) nor by systemic treatment with indomethacin (1 mg kg-1, i.v.), BWA4C (5 mg kg-1, p.o.), methysergide (6 mg kg-1, i.p.) and RP67580 (2 mg kg-1, i.p.). 3. Treatment of mice with the H1 antagonist, mepyramine (1-10 mg kg-1, i.p.) resulted in a dose-dependent inhibition of the cell accumulation elicited by the chemokine, with a maximal reduction of approximately 50-60%. The mepyramine effect was not due to a non specific reduction of neutrophil function, since treatment with this drug (6 mg kg-1, i.p.) did not modify the cell infiltration measured in response to a challenge with interleukin-1 beta (20 ng) or with the vehicle CMC to any extent. Moreover, treatment of mice with mepyramine did not modify cell counts in a peripheral blood film with respect to controls. Two other H1 antagonists, chemically unrelated to mepyramine, diphenhydramine (9 mg kg-1, i.p.) and triprolidine (0.5 mg kg-1, i.p.), inhibited IL-8-induced migration to a similar extent (approximately 50-60%), whereas the H2 antagonist, ranitidine (5 mg kg-1, i.p.) was without effect. 4. The concept that endogenous histamine could be involved in the IL-8 effect was strengthened in two ways: (i) addition of histamine (0.2-2 microg) to a small dose of IL-8 (0.3 microg) potentiated the cell elicitation induced by the chemokine without having any effect on its own; (ii) IL-8-induced neutrophil accumulation was greatly impaired in animals depleted of mast cell amines by sub-chronic (5 day) treatment with compound 48/80 according to an established protocol.5. The glucocorticoid dexamethasone (Dex; 1-50 microg per mouse, i.v., corresponding approximately to 0.03-1.5 mg kg-1, given i.v. 2 h prior to challenge with IL-8) potently inhibited neutrophil infiltration with an approximate ED50 of 5 microg per mouse (~ 0.3 mg kg-1 , i.v.). Passive immunisation of mice with a polyclonal sheep serum raised against the steroid-inducible anti-inflammatory protein lipocortin 1 (LCl)abolished the inhibitory action of Dex whereas a control serum was without effect.6. Local administration of Dex at a dose which was ineffective when given systemically (1 microg) also reduced neutrophil migration induced by IL-8, either alone or in combination with histamine. This local inhibition (~50%), also seen with hydrocortisone (30 microg), was prevented by the concomitant administration of the steroid antagonist RU38486 (10 microg) indicating the involvement of glucocorticoid receptor in the response.7. These findings characterize further the mechanisms underlying PMN recruitment induced by IL-8 in vivo, and point to a role for histamine. The anti-inflammatory action of the glucocorticoids, as in some other models, appears to be LCl-dependent when these drugs are given systemically and LCl independent when the steroids are given locally.

Adjuvants, Immunologic↗

PubMed1993

Lipocortin-1 fragments inhibit neutrophil accumulation and neutrophil-dependent edema in the mouse. A qualitative comparison with an anti-CD11b monoclonal antibody.

The activity of the steroid-inducible protein lipocortin-1 (LC1; with a primary sequence of 346 amino acids; also called annexin 1), a fragment corresponding to amino acids 1-188 and a short peptide from the N-terminus (amino acid 2-26) were tested for anti-inflammatory actions in three models of acute inflammation in the mouse in comparison with a mAb anti-CD11b (alpha CD11b). In the mouse air-pouch model LC1, fragment 1-188 and peptide Ac2-26 exhibited powerful inhibitory effects (ED50 approximately 5.2, 38 and 88 micrograms/mouse, respectively) on leukocyte migration elicited by IL-1. LC1 was approximately 200 times more potent than Ac2-26 on a molar basis although both gave maximal inhibitions, in contrast fragment 1-188 only produced a partial dose-response curve. LC1 was approximately 20 times more potent on a molar basis in this assay than the alpha CD11b mAb. Peptide Ac2-26 and the mAb alpha CD11b also blocked cell migration into the air-pouch induced by IL-8 with approximately the same potency. In the mouse skin edema and zymosan peritonitis assays Ac2-26 was inhibitory (ED50 of 200 micrograms/mouse) but less so than the alpha CD11b antibody (ED50 approximately 0.5 mg/mouse). Both LC1 (10 micrograms) and Ac2-26 (200 micrograms) completely blocked FMLP-induced neutropenia in the mouse. Studies using an inactivated LC1 preparation, which binds to the same high affinity binding sites as the biologically active material, indicated that the short peptide acts on the same sites as the native LC1. This study confirms the activity of LC1 in another model of experimental inflammation and suggests that it acts partly through inhibition of leukocyte activation with an overall effect qualitatively comparable to the blocking of CD11b portion of a beta 2-integrin complex. It also shows that peptides derived from the N-terminal domain of LC1 may mimic the activity of the full length molecule and points the way for a new family of anti-inflammatory substances that inhibit leukocyte trafficking.

Amino Acid Sequence↗

PubMed1993

Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia.

The behavior of the P50 wave of the auditory evoked potential in a paired stimulus or conditioning-testing paradigm has been used as a measure of sensory gating disturbance in schizophrenia. Schizophrenics fail to decrement the P50 response to the second stimulus of the pair, so that the ratio of the test to the conditioning amplitude is elevated over normal values. The aim of this study was to compare this neurophysiological measure to neuropsychological measures of attention and memory. As expected, schizophrenics performed worse than controls on most measures. The time to complete a digit cancellation test, a measure of sustained attention, was found to be particularly longer in schizophrenics than in control subjects. Furthermore, the increased time to complete this task correlated with the increased ratio of the amplitude of the test P50 response to the conditioning response in the schizophrenics. Thus, a neurophysiological defect in sensory gating may relate to a disorder in sustained attention in schizophrenia. Although the P50 wave may come from the hippocampus, neuropsychological measures of verbal learning and memory were not correlated with alterations in the P50 ratio.

Adult↗

PubMed1990

A two-dimensional analog VLSI circuit for detecting discontinuities in early vision.

A large number of computer vision algorithms for finding intensity edges, computing motion, depth, and color, and recovering the three-dimensional shape of objects have been developed within the framework of minimizing an associated "energy" or "cost" functional. Particularly successful has been the introduction of binary variables coding for discontinuities in intensity, optical flow field, depth, and other variables, allowing image segmentation to occur in these modalities. The associated nonconvex variational functionals can be mapped onto analog, resistive networks, such that the stationary voltage distribution in the network corresponds to a minimum of the functional. The performance of an experimental analog very-large-scale integration (VLSI) circuit implementing the nonlinear resistive network for the problem of two-dimensional surface interpolation in the presence of discontinuities is demonstrated; this circuit is implemented in complementary metal oxide semiconductor technology.

Algorithms↗

PubMed1990

DataVoice: a microcomputer-based general purpose voice-controlled data-collection system.

An integrated system of hardware and software has been developed to combine the input of coordinate data from a digitizing pad with voice input for object identification or classification. The menu and voice-controlled software generates a sequential ASCII file which contains an object identification section and a data section. Rules for data entry and analysis programs have been developed for several applications. These are being tested and include general stereological analyses, bone, kidney and skin histomorphometry, boundary analyses, neuron classification and malignancy grading.

Artificial Intelligence↗

PubMed1987