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Biomedical subjects

S M Cooper

Publications and source records attributed to S M Cooper.

At least 19 recordsLinked to original sources
PubMed1992

CD2 expression correlates with proliferative capacity of alpha beta + or gamma delta + CD4-CD8- T cells in lpr mice.

The T lymphocytes that accumulate in vast numbers in the lymphoid tissues of lpr/lpr (lpr) mice express a TCR-alpha beta that is polyclonally rearranged, and yet is devoid of surface CD4 or CD8 (CD4-8-) as well as CD2. lpr CD2- alpha beta + CD4-8- T cells exhibit an apparent block in signal transduction, in that when activated they produce little or no IL-2 and proliferate minimally in the absence of exogenous IL-2. In contrast to the predominant hyporesponsive alpha beta + CD4-8- T cells, we observe that a minor subset (1 to 2%) of lpr lymph node CD4-8- cells expresses a TCR-gamma delta and can proliferate upon activation with PMA and ionomycin in the absence of exogenous IL-2. Furthermore, these responsive gamma delta T cells express surface CD2. The functional and phenotypic distinctions of lpr gamma delta T cells led us to identify an analogous minor (4 to 10%) subset of alpha beta + CD4-8- cells in lpr thymus and lymph nodes that does express CD2. Similar to the gamma delta subset, these CD2+ alpha beta + CD4-8- cells are also capable of proliferation and IL-2 production. Thus the capacity for IL-2 production and proliferation by a small proportion of lpr CD4-8- T cells, either alpha beta + or gamma delta +, correlates with their expression of surface CD2. This correlation is supported by the observation that the lpr liver contains actively cycling alpha beta + CD4-8- lymphocytes that are strikingly enriched for CD2 expression. Consequently, unlike the vast proportion of abnormal lpr CD2- CD3+ CD4-8- cells, the CD2+ CD3+ CD4-8- T cells may not express the basic lpr defect, or else are not affected by its presence. These studies suggest that expression of the lpr abnormality may be restricted to a particular T cell lineage. This functional correlation with CD2 expression may be more broadly applicable to phenotypically similar subsets of normal thymocytes, and possibly peripheral tolerized T lymphocytes.

Animals↗
PubMed1992

The relationship between paroxetine and the sparteine oxidation polymorphism.

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol.hr/L), whereas at steady state the median AUCss tau interphenotype difference was only twofold (4410 versus 2550 nmol.hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/dehydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

Adult↗
PubMed1991

Diversity of rheumatoid synovial tissue T cells by T cell receptor analysis. Oligoclonal expansion in interleukin-2-responsive cells.

The synovitis of rheumatoid arthritis (RA) is characterized by infiltrates of CD4+ T lymphocytes. To determine the clonal diversity of these cells, we cloned T cells with interleukin-2 (IL-2), alone or with phytohemagglutinin (PHA), directly from actively inflamed synovial tissue obtained at synovectomy. A total of 205 clones from 4 specimens was analyzed for T cell receptor (TCR) gene rearrangements using Hind III and Eco RI digests with beta chain and gamma chain complementary DNA probes. A comparison of the TCR rearrangements enabled us to determine if the T cell clones arose from the same or different precursor cells. Most of the T cell clones (92%) had distinct TCR gene rearrangement patterns, indicating a unique clonal origin. However, a few clones (1 quadruplicate and 6 pairs) with identical TCR rearrangements were identified, and these clonal multiples were most commonly found in clones selected with IL-2 alone. Mass cultures were propagated with IL-2, alone or with PHA, and at each passage, cells were removed for TCR analysis. The later passages of the lines selected with IL-2 had oligoclonal TCR rearrangements, whereas no oligoclonal rearrangements were found in the PHA + IL-2-selected cell lines. The TCR rearrangements in the later passages of the IL-2 mass cultures were often identical to the TCR rearrangements that were found in the IL-2-derived clonal multiples. These findings indicate that while the majority of CD4+ T cells within the actively inflamed rheumatoid joint have diverse clonal origins, small numbers of clonal multiples and oligoclonal populations are present, and these cells may be enriched in an IL-2-responsive T cell subset.

Adult↗
PubMed1991

Screening for lupus anticoagulant and anticardiolipin antibodies in women with fetal loss.

Sixty six women with first or second trimester fetal loss were investigated for the presence of lupus anticoagulant by routine coagulation tests and the dilute Russell's viper venom time with a platelet neutralisation procedure, and for raised anticardiolipin antibodies by an enzyme linked immunosorbent assay. Of 35 women with recurrent fetal loss, seven were positive for lupus anticoagulant and six had increased IgG anticardiolipin antibodies, while of 31 women with only one or two episodes of fetal loss, one had lupus anticoagulant and none increased IgG anticardiolipin antibodies. These findings were significantly different. There was no difference in the incidence of increased IgM anticardiolipin antibodies between the two groups (three and two cases, respectively). A further 11 women with intrauterine death in the third trimester were studied and lupus anticoagulant and raised IgM anticardiolipin antibodies were found in one case. No woman was known to have systemic lupus erythematosus. It is concluded that lupus anticoagulant and increased IgG anticardiolipin antibodies are independently associated with recurrent first and second trimester fetal loss and that such cases should be investigated, even in the presence of otherwise good health, by a comprehensive methodological approach.

Abortion, Habitual↗
PubMed1990

A morphometric, electron microscopic analysis of tissue channels shown by ionic tracer in normal and tensioned rat molar apical periodontal ligament.

A 1.0 newton continuous, extrusive load was applied to the right maxillary molar for 30 min to determine the presence of channels as shown by the distribution of tracer across the interstitial compartment of normal and tensioned PDL. Sodium ferrocyanide (1% w/v), perfused via the common carotid arteries, was the tracer probe and tris(ethylenediamine) cobalt III chloride (1% w/v) the precipitating ion. Left molar control PDL had an overall mean of 0.43 +/- 0.05/microns2 tissue channels at 0.2 microns from the vascular endothelium, and 0.15 +/- 0.04/microns2 at 7-8 microns. On the experimental side, the overall mean number of tissue channels was 0.65 +/- 0.13/microns2 at 0-2 microns and 0.19 +/- 0.07/microns2 at 7-8 microns. A significant depth effect (P less than 0.01) was present in the control and experimental interstitial tissues for tissue channels adjacent to the endothelium of different categories of vessel. Extrusion increased the tissue channel density adjacent to arterial capillaries (P less than 0.01), venous capillaries (P less than 0.01) and postcapillary-sized venules (P less than 0.01). These findings implicate these three types of vessel as being functionally important in fluid exchange across endothelial boundaries in the PDL.

Animals↗
PubMed1990

Altered distribution of excitatory amino acid receptors in temporal lobe epilepsy.

In temporal lobe epilepsy, excitatory amino acid receptors in the hippocampus and temporal lobe may contribute to both increased excitability and vulnerability to excitotoxic damage. We used receptor autoradiography to examine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors in the hippocampus and parahippocampal gyrus obtained from five patients who had undergone anterior temporal lobectomy for the treatment of intractable seizures and from six control individuals, in which the hippocampus was obtained postmortem. Within the hippocampal formation, loss of [3H]KA and NMDA-sensitive L-[3H]glutamate binding was apparent in the sclerotic regions CA3, hilus, and CA1. In the subiculum and molecular layer of the denate gyrus, binding densities were maintained or even increased in some of the epileptic patients. A two-fold increase in L-[3H]glutamate binding, along with an increase in [3H]KA binding, was observed in the parahippocampal gyrus obtained from the epileptic patients. The results suggest that the vulnerability of the hippocampus in temporal lobe epilepsy may result, at least in part, from the presence of aberrant excitatory circuits in the parahippocampal gyrus.

Adult↗
PubMed1990

A comparison of the central nervous system effects of haloperidol, chlorpromazine and sulpiride in normal volunteers.

1. Twelve healthy male volunteers participated in four experimental occasions during each of which they were dosed with one of the following anti-psychotic drugs: chlorpromazine (50 mg), haloperidol (3 mg), sulpiride (400 mg) and placebo. Drugs were allocated to subjects in a double-blind, crossover fashion. 2. The subject's mood state, psychometric performance and electroencephalogram (EEG) were assessed pre-dose, and at 2, 4, 6, 8, 24 and 48 h post-dose. Mood states were assessed using 16 visual analogue scales and psychomotor performance was measured using the following tests: elapsed time estimation, tapping rate, choice reaction times, a rapid information processing task, flash fusion threshold, a manipulative motor task, digit span, body sway and tremor. 3. Chlorpromazine and haloperidol significantly reduced subjective ratings of 'alertness' and 'contentedness', and haloperidol significantly reduced feelings of 'calmness'. Sulpiride did not significantly affect any of the visual analogue scales. 4. All three anti-psychotic drugs had similar EEG effects with peak effect 2 to 4 h postdose. The profile was characterised by an increase in the proportion of slow wave activity (delta and theta) as well as decreased alpha (8-14 Hz) and faster (beta) wave activity. 5. Chlorpromazine reduced tapping rate and increased choice reaction movement times. Haloperidol reduced the flash fusion threshold frequency at 6 h post-dose. Sulpiride prolonged the duration of the manipulative motor task, particularly at 48 h post-dose. 6. All three anti-psychotic drugs impaired performance on the rapid information processing task. Chlorpromazine significantly reduced the number of correct letter pair identifications at 2, 4 and 6 h post-dose, haloperidol at 4, 6, 8, 24 and 48 h post-dose, and sulpiride at 24 h post-dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis.

Folinic acid (leucovorin) supplementation has been suggested as a possible means of treating the short term side effects that occur with low dose methotrexate (MTX). However, it has not been established whether leucovorin will abrogate the antiarthritic effect of MTX. We entered 20 patients with rheumatoid arthritis treated with MTX into a 48 week randomized, double blind, crossover trial of folinic acid vs placebo. The dose of folinic acid was equal to the dose of MTX and it was given orally 4 h following the single, weekly MTX administration. Under these conditions, leucovorin did not decrease the therapeutic effect of MTX. While the incidence of stomatitis and gastrointestinal toxicity were lower during leucovorin treatment, our study lacked sufficient power to establish a statistically significant difference.

Administration, Oral↗
PubMed1990

Educational and psychosocial needs of patients with chronic disease. A survey of preferences of patients with rheumatoid arthritis.

There is increasing interest in better defining and meeting the nonmedical needs of patients with chronic diseases, such as rheumatoid arthritis (RA). We surveyed patients with RA about the importance of eight psychosocial and eight educational issues, and asked patients from what source they preferred to get help with these issues and which sources they would not use. We also looked at individual variables, including sex, age, disease duration, and disease severity, to see if they affected patients' choices. The issues rated most important by patients included communicating with the doctor, understanding medication, dealing with pain, and the effects of arthritis on energy level, the future, and work. Most patients preferred to seek help from their physicians, although up to 75% were willing to attend groups, and 68% were willing to see individual counselors for some issues.

Adaptation, Psychological↗
PubMed1989

Ovine ceroid lipofuscinosis. The major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence.

Previous studies on lipopigment isolated from sheep affected with ceroid lipofuscinosis (Batten's disease) showed that the disease is a lysosomal proteinosis, involving specific storage of peptide(s) that migrate in dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent Mr of 3500. This band is the dominant contributor to the lipopigment mass. When purified total lipopigment proteins were loaded onto a protein sequencer, a dominant sequence was found, identical to the NH2 terminus of the lipid-binding subunit of protein translocating mitochondrial ATP synthase. This sequence was determined to 40 residues and a minimum estimate of 40% made for its contribution to the lipopigment protein mass. The full lipid-binding subunit has physical and chemical properties similar to those of the specifically stored low Mr peptide, which may be the full protein or a large NH2-terminal fragment of it. Lipopigments in the human ceroid lipofuscinoses also contain a major component with similar physical and chemical properties. These and previous results indicate that the genetic lesion in ovine ceroid lipofuscinosis causes an abnormal accumulation of this peptide in lysosomes, i.e. the disease is a proteolipid proteinosis, specifically a lysosomal mitochondrial ATP synthase lipid-binding subunit proteinosis. The analogous human diseases are likely to reflect storage of the same or similar peptides.

Animals↗
PubMed1989

N-methyl-D-aspartate receptors in the cortex and hippocampus of baboon (Papio anubis and Papio papio).

In vitro autoradiography was used to examine the N-methyl-D-aspartate receptor in the brain of a baboon species, Papio anubis, and compared to that of Papio papio which exhibits a photosensitive epilepsy. The epilepsy originates in the frontal cortex and is accompanied by an enhanced sensitivity to N-methyl-D-aspartate. In both Papio anubis and Papio papio, the density of N-methyl-D-aspartate receptors was greatest in the hippocampus, followed by associational areas including frontal cortex, and low in primary sensory areas such as the visual cortex. The receptors were concentrated in the outer cortical layers I-III, very low in layer IV except in primary visual cortex, and of intermediate density in layer V. The density of binding sites was approximately two-fold lower than previously observed in the rodent brain, whereas the affinity of the receptor for [3H]L-glutamate was greater in the primate versus the rodent brain. Glycine potentiated the binding of [3H]L-glutamate in both cortex and hippocampus. No significant differences in the properties of N-methyl-D-aspartate receptors were observed between the two baboon species, suggesting that the photosensitivity of Papio papio is not due to alterations in the binding of L-glutamate to the N-methyl-D-aspartate receptor complex.

Animals↗
PubMed1989

A double-blind dose ranging study of BRL 24924 and metoclopramide on lower oesophageal sphincter pressure in healthy volunteers.

1. A double-blind placebo controlled dose ranging study of the effect of single oral doses of 1 and 2 mg BRL 24924 and 10 mg metoclopramide on lower oesophageal sphincter pressure has been performed in 20 healthy volunteers. 2. The 2 mg dose of BRL 24924 caused a statistically significant increase in mean lower oesophageal sphincter pressure (P less than 0.05) at 30-45 min post-dose (20.8 +/- 7.1 cm H2O BRL 24924; 16.4 +/- 5.7 cm H2O placebo). BRL 24924 1 mg and metoclopramide 10 mg failed to increase lower oesophageal sphincter pressure at any time. However, eight volunteers with a hypotensive resting lower oesophageal sphincter pressure (less than 15 cm H2O) showed a statistically significant rise in pressure at 120 min for both 1 mg, 2 mg (P less than 0.01; P less than 0.001) BRL 24924 and 10 mg metoclopramide (P less than 0.01). No other significant effect was detected on oesophageal manometry. 3. BRL 24924 (2 mg) has statistically significant effects on lower oesophageal sphincter pressure. However, further studies in patients with gastro-oesophageal reflux disease and oesophagitis are needed to evaluate its clinical efficacy, especially where a hypotensive lower oesophageal sphincter pressure predominates.

Adult↗
PubMed1989

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+.

1. The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2. In normal Krebs solution, cromakalim (1 microM) produced a 39.1% reduction in area under the curve (AUC) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 microM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3. LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (EC90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 microM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4. Pinacidil (3 microM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3 microM) plus LaCl3 (1 mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%). 5. In both normal and Ca2+-free Krebs solution, cromakalim (0.1, 1.0 and 10 microM) produced concentration-related inhibition of the contraction to caffeine (10 mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3 microM). Similarly, pinacidil (0.3, 3.0 and 30 microM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.O microM) and sodium nitroprusside (0.03, 0.3 and 3.0 microM) had no significant effect on caffeine contractions. 6. The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.

Animals↗
PubMed1989

Evidence of acute inflammation in the periodontal ligament subsequent to orthodontic tooth movement in rats.

Experimental orthodontic tooth extrusion can result in red cell diapedesis through the PDL vascular wall. Diapedesis is an early sign of acute inflammation. At the ultrastructural level, red cell migration is demonstrated occurring through the endothelial junction of a postcapillary-sized venule. This phenomenon is considered to be indicative of unphysiological tooth loading.

Animals↗
PubMed1988

Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma.

Collagen-induced arthritis (CIA) is an experimental model in which a specific immune response to type II collagen (CII) is associated with the development of inflammatory arthritis. In this study, we evaluated the effects of early and delayed treatments with anti-Ia mAb and IFN-gamma on murine CIA. Administration of anti-Ia mAb at the time of immunization with CII decreased the incidence and delayed the onset of arthritis, whereas anti-Ia treatments begun 2 wk after immunization had no effect upon either arthritis incidence or onset. Neither treatment protocol resulted in a significant decrease in antibody titer or proliferative response to CII. Because IFN-gamma increases Ia expression in a variety of cells, we determined its effect on arthritis incidence and onset. When IFN-gamma treatments were begun at the time of immunization the incidence of arthritis was increased and arthritis onset was more rapid. Treatment with IFN-gamma did not result in an increase in anti-CII antibody levels. These results support the importance of Ia expression in the induction of murine collagen-induced arthritis, and suggest that suppression with anti-Ia antibodies and augmentation with IFN-gamma are not the result of changes in the humoral response to CII, but may be due to local effects within the target organ.

Adjuvants, Immunologic↗