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Biomedical subjects

R A Armstrong

Publications and source records attributed to R A Armstrong.

At least 91 records · Page 5Linked to original sources
PubMed1995

What determines the size frequency distribution of beta-amyloid (A beta) deposits in Alzheimer's disease patients?

The factors determining the size of individual beta-amyloid (A beta) deposits and their size frequency distribution in tissue from Alzheimer's disease (AD) patients have not been established. In 23/25 cortical tissues from 10 AD patients, the frequency of A beta deposits declined exponentially with increasing size. In a random sample of 400 A beta deposits, 88% were closely associated with one or more neuronal cell bodies. The frequency distribution of A beta deposits which were associated with 0,1,2,...,n neuronal cell bodies deviated significantly from a Poisson distribution, suggesting a degree of clustering of the neuronal cell bodies. In addition, the frequency of A beta deposits declined exponentially as the number of associated neuronal cell bodies increased. A beta deposit area was positively correlated with the frequency of associated neuronal cell bodies, the degree of correlation being greater for pyramidal cells than smaller neurons. These data suggested: (1) the number of closely adjacent neuronal cell bodies which simultaneously secrete A beta was an important factor determining the size of an A beta deposit and (2) the exponential decline in larger A beta deposits reflects the low probability that larger numbers of adjacent neurons will secrete A beta simultaneously to form a deposit.

Aged↗
PubMed1995

Hypothesis: is Alzheimer's disease a metal-induced immune disorder?

A hypothesis that a metal-induced immune disorder may be involved in the pathogenesis of some forms of Alzheimer's disease (AD) is presented. The classical complement pathway is activated in AD and T cells and reactive microglia appear in the brain. Studies of metal induced autoimmunity and the use of compounds containing aluminium as vaccine adjuvants suggest that metals can activate complement and can be taken up by antigen presenting cells. The consequent immune response could contribute to neuronal damage, beta-amyloid deposition and cell death. The strengths and weaknesses of this hypothesis are discussed and tests of some aspects are proposed.

Alzheimer Disease↗
PubMed1995

Factors determining the morphology of beta-amyloid (A beta) deposits in Down's syndrome.

Immunostained preparations of the medial temporal lobe from patients with Down's syndrome (DS) were counterstained with cresyl violet to reveal the beta-amyloid (A beta) deposits and their associated cell populations. A beta deposits in the cornu Ammonis (CA) of the hippocampus were, on average, more strongly stained, less often directly associated with neurons and more often associated with glial cells than the adjacent areas of cortex. Cored deposits were more frequently recorded in sulci rather than gyri and were associated with more glial cells than the uncored deposits. Multiple regression analyses suggested there was a positive correlation in the cortex between A beta deposit size and the frequency of closely associated neurons, the correlation being most significant with larger (> 25 microns) neurons. The morphology of A beta deposit was also correlated with the location of deposits in the cortex, CA and dentate gyrus but this factor was of lesser importance. No significant variation in the morphology of the A beta deposits was associated with the presence of blood vessels within or adjacent to the deposit. The data suggest that neuronal cell bodies are important in the initial formation of A beta deposits and glial cells with the development of more mature amyloid deposits.

Adult↗
PubMed1995

Characterization of the EP-receptor mediating dilatation and potentiation of inflammation in rabbit skin.

The interactions of bradykinin (BK) and FMLP (a leukocyte-dependent mediator of inflammation) with thirteen prostaglandin E analogs have been investigated in a rabbit skin model of inflammation. The PGE analogs were chosen with a view to defining the EP-receptor subtypes involved. Five analogs, PGE2, misoprostol, 16,16-dimethyl PGE2, nocloprost, and enisoprost, were potent vasodilators (133Xe clearance method) and potent potentiators of both BK and FMLP exudation ([125I]albumin method). A further four analogs, butaprost, 11-deoxy PGE1, mexiprostil, and AH 13205, were weaker vasodilators and weaker potentiators of exudation. The remaining four analogs, 11-deoxy PGE2-1-alcohol, MB 28767, sulprostone, and GR 63779X did not induce vasodilatation and did not potentiate FMLP exudation. However, the latter three prostanoids (which are all potent and moderately selective EP3 agonists) produced a modest potentiation of BK exudation at low doses (1 and 10 ng), with no greater effect at higher doses (100 and 1000 ng). Statistical correlation of vasodilator responses with potentiation of FMLP exudation responses was highly significant. A similar correlation for vasodilation/BK exudation, although statistically significant, was not as convincing. The analyses suggested that vasodilatation is a major mechanism of PGE-induced potentiation of plasma exudation and that an EP2-receptor subtype is involved. However, the possibility of a second non-dilator mechanism could not be ruled out.

16,16-Dimethylprostaglandin E2↗
PubMed1995

Comparison of the EP receptor subtypes mediating relaxation of the rabbit jugular and pig saphenous veins.

A fourth PGE receptor subtype, the EP4 receptor, has recently been described in the pig saphenous vein (PSV). Similar to the EP2 receptor, it mediates relaxation and is linked to stimulation of adenylate cyclase. The aim of this study was to determine whether or not the EP receptor present in the rabbit jugular vein (RJV), currently classified as an atypical EP2 receptor, is of the EP4 subtype. The relaxant activities of four EP2 agonists, 11-deoxy PGE1, 16,16-dimethyl PGE2, butaprost, and AH 13205, on the RJV and PSV have been examined, and the effect of the EP4 receptor antagonist AH 23,848B studied. The EP2 agonists showed a similar order of potency on the two preparations. 11-Deoxy PGE1 and 16,16-dimethyl PGE2 were potent agonists on the EP4 receptors of the PSV and on the RJV giving approximately equi-effective concentration ratios (EECs) of 2.0-6.6 and 2.8-9.9, respectively, compared to PGE2 (EEC = 1), and so do not discriminate between EP2 and EP4 receptors. Butaprost was less active on these preparations (EEC 42-43) than on classical EP2 receptors, and AH 13205 was much less active (EEC 3100-2780). While these results suggest that the EP receptors on the RJV are of the EP4 subtype, this was not confirmed using the EP4 receptors antagonist AH 23,848B.

16,16-Dimethylprostaglandin E2↗
PubMed1995

Aspects of the thromboxane receptor system.

1. The aim of this review is to establish what is known about the thromboxane (TP) receptor, and to identify where future research is headed. In addition, the impact of the recent advances at the molecular level on resolving pharmacological controversies, such as possible subtypes of the TP receptor, is discussed and what molecular information is known about the TP receptor presented. 2. The clinical status of TP receptor antagonists is considered particularly in relation to the potential role of epi prostaglandins. 3. Basic information about TP agonists, antagonists and signal transduction pathways is also given.

Animals↗
PubMed1995

Characterization of the PGE receptor subtype mediating inhibition of superoxide production in human neutrophils.

1. The aims of this study were to characterize the EP receptor subtype mediating the inhibition of superoxide anion generation by formyl methionyl leucine phenylalanine (FMLP)-stimulated human neutrophils, and to test the hypothesis that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is the second messenger mediating the inhibition of the neutrophil by prostaglandin (PG)E2. 2. PGE2 (0.001-10 microM) inhibited FMLP (100 nM)-induced O2-generation from human peripheral blood neutrophils in a concentration-dependent manner, with an EC50 of 0.15 +/- 0.03 microM, and a maximum effect ranging from 36-84% (mean inhibition of 68.7 +/- 2.5%, n = 32). 3. The EP2-receptor agonists, misoprostol, 11-deoxy PGE1, AH13205 and butaprost, all at 10 microM, inhibited O2- generation, causing 95.5 +/- 2.9%, 56.8 +/- 5.2%, 37.1 +/- 6.6% and 18.9 +/- 4.4% inhibition respectively, the latter two being much less effective than PGE2. Similarly, the EP1-receptor agonist, 17-phenyl PGE2 (10 microM), and the EP3/EP1-receptor agonist, sulprostone (10 microM), also inhibited O2- generation, causing 32.2 +/- 7.0% and 15.3 +/- 3.4% inhibition respectively. 4. The non-selective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX, 0.25 mM) inhibited the FMLP response by 54.5 +/- 5.0%. In addition, IBMX shifted concentration-effect curves for PGE2, misoprostol, 11-deoxy PGE1, butaprost, and AH 13205 to the left, to give EC50s of 0.04 +/- 0.03 (n = 13), 0.07 +/- 0.03 (n = 4), 0.08 +/- 0.03 (n = 4), 0.33 +/- 0.13 (n = 4) and 0.41 +/- 0.2 microM (n = 3) respectively, allowing equieffective concentration-ratios (EECs, PGE2 = 1) of 11.5, 5.3, 50.7 and 12.7 to be calculated. This agrees well with the relative potencies of these agonists at EP2 receptors.5. By contrast, even in the presence of IBMX (0.25 mM), sulprostone and 17-phenyl PGE2 were only effective at the highest concentration (10 microM), and gave EECs of > 700 and 486 respectively, suggesting that EP1 or EP3 receptors are not involved.6. The selective type IV phosphodiesterase inhibitor, rolipram at 2 and 10 nM did not inhibit the FMLP response, but at the higher concentration of 50 nM, it decreased the FMLP response by 46.6 +/-7.3%.However, rolipram shifted concentration-effect curves for PGE2 to the left to give EC50s of 0.06 +/-0.022,0.015 +/- 0.0, 0.012 +/- 0.006 microM at 2, 10 and 50 nM respectively, compared to the control EC50 of0.27+/- 0.09 microM for PGE2.7. The EP4/TP receptor blocking drug, AH 23848B (10 microM, 10 min) did not inhibit 02- generation by PGE2, but was found to potentiate significantly the effect of PGE2 at the lower concentrations of PGE2 tested (0.001-0.1 microM).8. The adenylate cyclase inhibitor, SQ 22,536 (0.1 mM, 2 min) reduced PGE2-induced inhibition of 02-production, giving an EC50 in the absence of SQ 22,536 of 0.24 +/- 0.1, and 1.9 +/- 1.1 AM in its presence.9. These results suggest that inhibition of superoxide generation by PGE2 is mediated by stimulation ofEP2 receptors and activation of adenylate cyclase, leading to the elevation of intracellular levels of cyclic AMP.

Adenine↗
PubMed1995

Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils.

1. The aims of this study were to investigate the inhibitory effects of prostaglandin E2 (PGE2) on chemotaxis of N-formyl-methionyl-leucine-phenylalanine (FMLP)-stimulated human neutrophils, and to test the hypothesis that cyclic AMP is the second messenger involved. For this purpose, the inhibitory effect of selective EP agonists, and the modulatory effects of the adenylate cyclase inhibitor, SQ 22536, the protein kinase A (PKA) inhibitors H-89 and Rp-cAMPs, and the type IV phosphodiesterase (PDE) inhibitors, rolipram and Ro20-1724 have been examined. 2. Chemotaxis has been measured using blindwell chambers. When human neutrophils were stimulated with FMLP (100 nM), PGE2 inhibited chemotaxis in a concentration-dependent manner (0.01-10 microM), with an EC50 of 90 +/- 24.5 nM, a maximum effect ranging from 45-75% and a mean inhibition of 64.5 +/- 2.4%. 3. The EP2-receptor agonists, 11-deoxy PGE1, butaprost and AH 13205 also inhibited chemotaxis. The order of potency of these agonists was PGE2 > butaprost (EC50 = 106.4 +/- 63 nM) > 11-deoxy PGE1 (EC50 = 140.9 +/- 64.7 nM) > AH 13205 (EC50 = 1.58 +/- 0.73 microM). Correlation of the ability of EP2 agonists to increase cyclic AMP and to inhibit chemotaxis was poor (r = 0.38). 4. The IP agonist, cicaprost gave similar increases in cyclic AMP to those achieved with PGE2, yet produced 50% of the maximum inhibition of chemotaxis observed with PGE2. 5. Slight potentiation of the inhibitory effects of PGE2 after type IV PDE block was observed with rolipram (EC50 for PGE2 = 57.2 +/- 5.9; 35.2 +/- 6.8 nM) but not Ro20-1724 (EC50 for PGE2 = 216.0 +/- 59.7; 97.8 +/- 50.6 nM). Type IV PDE inhibitors are themselves potent inhibitors of chemotaxis with EC50 values of 23.0 +/- 2.3 and 73.6 +/- 10.3 nM for rolipram and Ro20-1724, respectively. 6. Inhibition of cyclic AMP production with the adenylate cyclase inhibitor SQ 22,536 (0.1 mM) failed to antagonize inhibition of chemotaxis by PGE2 (EC50s for PGE2 of 57.2 +/- 5.9 and 56.8 +/- 27.3 nM, in the absence and presence of SQ 22,536, respectively) despite a reduction in the increase in cyclic AMP induced by PGE2. 7. Inhibition of PKA with either H-89 (10 microM) or Rp cyclic AMPS (10 microM) similarly failed to antagonize inhibition of chemotaxis by PGE2; EC50 for PGE2 of 90 +/- 40 and PGE2 + H-89 60 +/- 17 nM; PGE2 216.0 +/- 58.7 and PGE2 + Rp cyclic AMP 76.9 +/- 14.7 nM. 8. Of the two PKA inhibitors tested, H-89 (10 microM) and Rp cyclic AMPS (10 microM), the more effective inhibitor of PGE2-induced inhibition of neutrophil superoxide anion generation was H-89 (EC50s for PGE2 were 0.36 +/- 0.1 and > 10 microM, respectively). We have previously shown this to be a cyclic AMP-dependent effect of PGE2. 9. Confirmation of block of PKA by H-89 was suggested by the finding that H-89 blocked inhibition of superoxide anion generation observed with the type IV PDE inhibitors rolipram and Ro20-1724; EC50s of 12.9 +/- 8.9 nM for rolipram alone and rolipram+H-89 > 1 microM; Ro20-1724 alone 59.5 +/- 28.1 nM and Ro20-1724 + H-89 > 1 microM. 10. The results suggest that inhibition of chemotaxis by PGE2 and EP2 agonists is not mediated by increased neutrophil cyclic AMP levels.

Adenylyl Cyclase Inhibitors↗
PubMed1995

Healthy decision making: a new approach in health promotion using health state utilities.

Empowerment of the individual is the central tenet of health promotion philosophy. Application of health state utility methodology to clinical decisions will facilitate this process. The study reported here used health state utilities to examine the preferences of young adults concerning third molar care. Respondents were asked to indicate the strength of their preferences for various outcomes consequent to removing, or not removing these teeth by using standardised visual analogue scales. The results demonstrated that health state utilities for most complications of surgery were lower than, and therefore reduced health more than, those associated with the complications of leaving teeth in place. Therefore dental surgeons should be more circumspect about surgical intervention: this group of potential patients believed that the 'cure' is often worse than the 'disease'. This study illustrates the use of health state utilities, a methodology which allows patients' perspectives to be incorporated into the planning of rational health care.

Adult↗
PubMed1994

beta-Amyloid (A beta) deposition in elderly non-demented patients and patients with Alzheimer's disease.

beta-amyloid (A beta) deposition in the medial temporal lobe (MTL) was studied in elderly non-demented (ND) cases and in patients with Alzheimer's disease (AD). In AD, A beta deposits were present throughout the MTL although density was less in the hippocampus than the adjacent cortical regions. In the ND cases, no A beta deposits were recorded in 6 cases and in the remaining 8 cases, A beta deposits were confined to the cortical regions adjacent to the hippocampus. The mean density of A beta deposits in the cortical regions examined was greater in AD than in the ND cases but there was a significant overlap between the two groups. The ratio of mature to diffuse A beta deposits was greater in the ND than the AD cases. In both patient groups, A beta deposits formed clusters in the cortex and many tissues exhibited a regular distribution of clusters along the cortex parallel to the pia. The mean dimension of the A beta clusters was greater in AD than in the ND cases. Hence, few aspects of A beta deposition appeared to consistently separate AD from ND cases. However, the spread of A beta pathology between modular units of the cortex and into regions of the hippocampus could be factors in the development of AD.

Aged↗
PubMed1994

Differences in beta-amyloid (beta/A4) deposition in human patients with Down's syndrome and sporadic Alzheimer's disease.

The density of diffuse, primitive, classic and compact beta-amyloid (beta/A4) deposits was estimated in the hippocampus and adjacent gyri in human patients with Down's syndrome (DS) and sporadic Alzheimer's disease (AD). The objective of the study was to determine whether there were differences in beta/A4 deposition in DS and sporadic AD and whether these differences could be attributed to overexpression of the amyloid precursor gene (APP) in DS. Total beta/A4 deposit density was greater in DS than AD in all brain regions studied but the DS/AD density ratios varied between brain regions. In the majority of brain regions, the ratio of primitive to diffuse beta/A4 deposits was greater in DS but the ratio of classic to diffuse deposits was greater in AD. The data were consistent with the hypothesis that overexpression of the APP gene in DS may lead to increased beta/A4 deposition. However, local brain factors also appear to be important in beta/A4 deposition in DS. Overexpression of the APP gene may also be responsible for increased production of paired helical filaments (PHF) and result in enhanced formation of primitive beta/A4 deposits in DS. In addition, increased formation of classic deposits in AD suggests that factors necessary for the production of a compact amyloid core are enhanced in AD compared with DS.

Adult↗
PubMed1994

Beta-amyloid (beta/A4) deposition in the medial temporal lobe in Down's syndrome: effects of brain region and patient age.

The density of diffuse, primitive, classic and compact beta-amyloid (beta/A4) deposits was studied in the medial temporal lobe in 12 cases of Down's syndrome (DS) from 38 to 67 years of age. Total beta/A4 deposit density was greater in the adjacent cortex compared with regions of the hippocampus, and these differences were similar within each age group of patients. The ratio of the primitive to diffuse deposits was greater in the hippocampus than in the adjacent cortex. Total beta/A4 density did not vary significantly with patient age. However, the density of the diffuse deposits exhibited a parabolic, and the primitive, classic and compact deposits an inverted parabolic, response with age. Hence, in DS, (1) beta/A4 density remains relatively constant with age, (2) differences in beta/A4 density between the hippocampus and adjacent cortex are established at an early age, and (3) mature beta/A4 subtype formation depends on brain region and patient age.

Adult↗
PubMed1994

The identification of pathological subtypes of Alzheimer's disease using cluster analysis.

A cluster analysis was performed on 78 cases of Alzheimer's disease (AD) to identify possible pathological subtypes of the disease. Data on 47 neuropathological variables, including features of the gross brain and the density and distribution of senile plaques (SP) and neurofibrillary tangles (NFT) were used to describe each case. Cluster analysis is a multivariate statistical method which combines together in groups, AD cases with the most similar neuropathological characteristics. The majority of cases (83%) were clustered into five such groups. The analysis suggested that an initial division of the 78 cases could be made into two major groups: (1) a large group (68%) in which the distribution of SP and NFT was restricted to a relatively small number of brain regions, and (2) a smaller group (15%) in which the lesions were more widely disseminated throughout the neocortex. Each of these groups could be subdivided on the degree of capillary amyloid angiopathy (CAA) present. In addition, those cases with a restricted development of SP/NFT and CAA could be divided further into an early and a late onset form. Familial AD cases did not cluster as a separate group but were either distributed between four of the five groups or were cases with unique combinations of pathological features not closely related to any of the groups. It was concluded that multivariate statistical methods may be of value in the classification of AD into subtypes.

Aged↗
PubMed1994

Comparison of the prostaglandin E (EP) receptor of human neutrophils and HL-60 cells differentiated with DMSO.

Human promyelocytic leukaemic HL-60 cells can be differentiated with DMSO to become neutrophil-like. In this study, the prostanoid receptors linked to adenylate cyclase have been compared in human neutrophils and in differentiated HL-60 cells. Both cell types appear to express EP2 receptors as recognised by the ability of EP2 agonists and not EP1 or EP3 agonists to increase cell cyclic AMP levels, and the finding that the increase in cyclic AMP induced by PGE2 was not blocked by the EP4 receptor antagonist AH 23,848 (30 microM). Neither cell type appears to express receptors for PGI2, but human neutrophils and not differentiated HL-60 cells express receptors for PGD2. In addition, human neutrophils may contain EP3 receptors linked to a reduction in cyclic AMP levels. The lack of other prostanoid receptors coupled to adenylate cyclase in HL-60 cells suggests that these cells may provide a useful starting point for the cloning of the EP2 receptor.

Adenylyl Cyclases↗
PubMed1993

Is the clustering of neurofibrillary tangles in Alzheimer's patients related to the cells of origin of specific cortico-cortical projections?

The spatial pattern of cellular neurofibrillary tangles (NFT) was studied in the supra- and infragranular layers of various cortical regions in cases of Alzheimer's disease (AD). The objective was to test the hypothesis that NFT formation was associated with the cells of origin of specific cortico-cortical projections. The novel feature of the study was that pattern analysis enabled the dimension and spacing of NFT clusters along the cortical ribbon to be estimated. In the majority of brain regions studied, NFT occurred in clusters of neurons which were regularly spaced along the cortical strip. This pattern is consistent with the predicted distribution of the cells of origin of specific cortico-cortico projections. Mean NFT cluster size varied from 250 to > 12800 microns in different cortical tissues suggesting either variation in the size of the cell clusters or a dynamic process in the development of NFT in relation to these cell clusters. The formation of NFT in cell clusters which may give rise to the feed-forward and feed-back cortico-cortical projections suggests a possible route of spread of NFT pathology in AD between cortical regions and from the cortex to subcortical areas.

Alzheimer Disease↗
PubMed1993

The spatial patterns of beta/A4 deposit subtypes in Alzheimer's disease.

The spatial patterns of diffuse, primitive, classic (cored) and compact (burnt-out) subtypes of beta/A4 deposits were studied in coronal sections of the frontal lobe and hippocampus, including the adjacent gyri, in nine cases of Alzheimer's disease (AD). If the more mature deposits were derived from the diffuse deposits then there should be a close association between their spatial patterns in a brain region. In the majority of tissues examined, all deposit subtypes occurred in clusters which varied in dimension from 200 to 6400 microns. In many tissues, the clusters appeared to be regularly spaced parallel to the pia or alveus. The mean dimension of the primitive deposit clusters was greater than those of the diffuse, classic and compact types. In about 60% of cortical tissues examined, the clusters of primitive and diffuse deposits were not in phase, i.e. they alternated along the cortical strip. Clusters of classic deposits appeared to be distributed independently of the diffuse deposit clusters. Cluster size of the primitive deposits was positively correlated with the density of the primitive deposits in a tissue but no such relationship could be detected for the diffuse deposits. This study suggested that there was a complex relationship between the clusters of the different subtypes of beta/A4 deposits. If the diffuse deposits do give rise to the primitive and classic varieties then factors unrelated to the initial deposition of beta/A4 in the form of diffuse plaques were important in the formation of the mature deposits.

Aged↗
PubMed1993

Chronotopographical analysis of the pattern onset visual evoked magnetic response (VEMR): implications for waveform peak identification.

The topography of the visual evoked magnetic response (VEMR) to a pattern onset stimulus was studied in five normal subjects using a single channel BTi magnetometer. Topographic distributions were analysed at regular intervals following stimulus onset (chronotopography). Two distinct field distributions were observed with half field stimulation: (1) activity corresponding to the C11 m which remains stable for an average of 34 msec and (2) activity corresponding to the C111 m which remains stable for about 50 msec. However, the full field topography of the largest peak within the first 130 msec does not have a predictable latency or topography in different subjects. The data suggest that the appearance of this peak is dependent on the amplitude, latency and duration of the half field C11 m peaks and the efficiency of half field summation. Hence, topographic mapping is essential to correctly identify the C11 m peak in a full field response as waveform morphology, peak latency and polarity are not reliable indicators.

Adult↗