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Biomedical subjects

S M Cooper

Publications and source records attributed to S M Cooper.

At least 73 records · Page 4Linked to original sources
PubMed1995

Effects of low dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis.

OBJECTIVE: To assess the effect of low doses of corticosteriods on the bone mineral density (BMD) of patients with rheumatoid arthritis (RA). METHODS: A cross sectional study of BMD as measured by dual photon x-ray of the femoral neck and lumbar spine (lateral view) in 139 patients with RA followed in a university setting. RESULTS: The mean daily dose of prednisone taken by the study group was 4.15 mg/day. Patients receiving daily doses of prednisone between 1 to 4 mg/day had similar BMD to patients who were not receiving corticosteroids, but patients taking 5-9 mg/day and those taking > 10 mg/day had significantly lower BMD of the lumbar spine (84.28 and 80.51% of controls, respectively) than patients who received 1-4 mg/day (99.16% of controls). The effect of corticosteroids remained significant when other risk factors such as disease severity, disease duration, functional class, and activity level were controlled for. No significant relationship between prednisone dose and BMD of the femoral neck was seen at the low doses studied. CONCLUSION: Low dose corticosteroid use has a significant effect on BMD of the lumbar spine.

Absorptiometry, Photon↗
PubMed1994

Increased usage of V beta 2 and V beta 6 in rheumatoid synovial fluid T cells.

OBJECTIVE: To determine if the T cell antigen receptor V beta usage of unstimulated rheumatoid arthritis (RA) synovial fluid (SF) T cells is biased compared with those in peripheral blood (PB). METHODS: Freshly isolated, matched synovial fluid and peripheral blood T cells were analyzed for V beta gene expression using quantitative polymerase chain reaction (PCR) methods. Ten synovial fluid samples from the knees of 7 patients with RA were studied. The PCR assay used 26 V beta primers with a constant region C beta primer, and 2 C alpha primers that co-amplified a product that served as an internal standard. Cycle number and complementary DNA content were controlled to ensure the linear accumulation of PCR products. Labeled products were separated on 10% polyacrylamide gels and counted with a Betascope blot analyzer. RESULTS: There were consistent differences between the V beta gene usage of SF and PB T cells directly isolated from patients with RA, regardless of HLA-DR haplotype. In all synovial specimens, V beta 2 was increased relative to the peripheral blood, while V beta 13.1 and V beta 13.2 were decreased. V beta 6 and V beta 21 were increased in 9 of the 10 synovial samples. Analyses of bilateral SF specimens from 2 subjects and serial specimens from the same knee of 1 subject revealed virtually identical patterns in each patient. The SF V beta bias was not solely due to differences in the proportion of CD4+ and CD8+ cells, because the CD4:CD8 ratios in SF and PB were similar. However, V beta gene usage of separated CD4+ and CD8+ synovial T cells showed that V beta 2 and V beta 6 were more highly expressed on CD4 cells. CONCLUSION: Freshly isolated synovial T cells from inflamed (not end-stage) knees of patients with RA have a remarkably consistent biased V beta gene usage compared with PB T cells. V beta 2 and V beta 6 are uniformly increased, and this increase is primarily in CD4+ T cells. The same V beta bias in the SF T cells of several RA patients suggests that shared antigens may be stimulating the T cell response.

Adult↗
PubMed1994

Prominent T lymphocyte response to Borrelia burgdorferi from peripheral blood of unexposed donors.

The proliferative response of peripheral blood T cells to the spirochete, Borrelia burgdorferi, can be as pronounced in unexposed normal individuals as it is in Lyme disease patients. This finding was observed using three geographically distinct isolates of B. burgdorferi. The response is not due to a lipopolysaccharide effect of the spirochete, is sensitive to Proteinase K, and requires antigen processing. It does not result from cross-reactivity of memory T cells that may be reactive to another antigen; the proliferative response to B. burgdorferi is equally distributed between naive (CD29-, CD45RO-) and memory (CD29+, CD45RO+) T cells, whereas the tetanus response is confined to the memory subset. In support of this notion, cord blood specimens that contain almost entirely naive T cells, respond as vigorously to B. burgdorferi as T cells from normal adult peripheral blood. A large panel of CD4+ T cell clones has been derived that are specific for B. burgdorferi. The majority of these clones are reactive to B. burgdorferi in the presence only of autologous HLA-DR molecules. Collectively, these data suggest that the T cell response from normal individuals is more likely due to multiple antigenic epitopes within Borrelial proteins than a superantigen response.

Antigen-Presenting Cells↗
PubMed1994

Reversal of hyporesponsiveness in lpr CD4-CD8- T cells is achieved by induction of cell cycling and normalization of CD2 and p59fyn expression.

T cells freshly isolated from the peripheral lymph nodes of autoimmune MRL lpr/lpr (lpr) mice contain a large proportion of functionally non-mature T cell receptor (TcR)-alpha beta+CD3+CD2-CD4-CD8- T cells displaying the B cell isoform of CD45, B220. These cells are hyporesponsive as defined by minimal interleukin-2 (IL-2) production and proliferation in response to stimulation. However, increased levels of inositol phosphates and a rapid mobilization of Ca2+ do occur upon stimulation of the TcR/CD3 complex. Furthermore, lpr CD4-CD8-T cells contain high levels of transcripts for the src-family tyrosine kinase p59fyn, and express a constitutively tyrosine-phosphorylated CD3-zeta chain. These features bear a certain resemblance to anergized T cells. These similarities are extended to show that culturing of lpr CD4-CD8- T cells in the presence of IL-2 in combination with phorbol 12-myristate 13-acetate and ionomycin initiates cell cycling and results in the gain of function; re-stimulation now yields IL-2-dependent proliferation in the absence of exogenous IL-2. In parallel with this gain in function, the population of cells obtained after 1 week in culture retains the TcR-alpha beta + CD4-CD8- phenotype, yet displays increased levels of CD2, decreased surface B220, and normal amounts of p59fyn-specific transcripts. These findings show that cell cycling is associated with the recovery of functional capabilities by lprCD4-CD8-T cells and is closely allied with surface CD2 expression. Thus, the hyporesponsiveness of lpr T cells is not a fixed state.

Aged↗
PubMed1994

Physiological changes arising from a training programme in under-21 international netball players.

Physiological and anthropometric measurements were taken on 21 members of an under-21 international squad of mean age 18.9 years. The aims of the investigation were (i) to examine the physiological status of players according to playing unit; and (ii) to quantify the changes arising from a four-month training programme. Maximal/peak oxygen uptake was assessed using an incremental test to exhaustion during treadmill running. Anaerobic performance was measured using the 30s Wingate test. Significant differences occurred between playing units in height (p < 0.001), body mass and FVC (p < 0.05), but not in skinfolds or any of the expressions of aerobic or anaerobic performance (p > 0.05). As a consequence of the training programme significant differences were evident in height (169.7 v 170.1 cm, p < 0.01), body mass (62 v 64 kg, p < 0.05), FVC (4.3 v 4.51, p < 0.01), and anaerobic performance (p < 0.01). Increases in VO2 max (3.3 v 3.51.min-1) were not significant (p > 0.05). Standard deviation scores illustrated that aerobic and anaerobic performances were of roughly the same magnitude before training (-0.35 v -0.29, p > 0.05), but that after training the dominant performance was anaerobic (+0.11 v +1.48, p < 0.01).

Adolescent↗
PubMed1993

Co-stimulation via CD28 induces activation of a refractory subset of MRL-lpr/lpr T lymphocytes.

Peripheral lymphoid tissues of lpr mice contain a large proportion of TCR alpha beta/CD3+CD4-CD8- T cells that lack surface CD2 and express the B cell isoform of CD45, B220. This subset of T cells does not proliferate or produce IL-2 in response to mitogenic signals or TCR-CD3 ligation. At the same time, these abnormal T cells display several characteristics of an activated phenotype. Collectively, these properties of lpr CD4-CD8- T cells have functional parallels with anergic T cells. A critical co-stimulatory molecule implicated in the prevention of or recovery from anergy is CD28, which binds the ligand BB1/B7 on certain accessory cells. lpr CD4-CD8- T cells express normal levels of CD28 which is capable of transducing a strong proliferative signal to these cells in co-stimulation with mitogens. However, proliferation of lpr CD4-CD8- T cells in response to CD28 co-stimulation does not reach the levels observed in normal T cells stimulated under similar conditions. Stimulation with anti-CD28 mAb in conjunction with phorbol myristate acetate and ionomycin promotes cell cycling in the CD2- subset of CD4-CD8- T cells, and results in a slight induction of CD2 levels during the course of the culture period. However, the majority of cells obtained at the end of the culture period remain TCR alpha beta+ CD4-CD8-, CD2low/- and B220high, similar to freshly isolated CD4-CD8- lpr T cells. In contrast, if IL-2 is included in the cultures, a strong shift toward a CD2+ phenotype is observed by a majority of the lpr T cells. Upon repeat stimulation, these lpr CD4-CD8- T cells can now proliferate in an IL-2-dependent manner when stimulated with only anti-CD3 mAb or mitogens, in the absence of exogenous IL-2 or anti-CD28 mAb. These data show that the hyporesponsiveness of lpr CD4-CD8- T cells does not result from a lack of CD28 expression, that it is not a fixed state, and that it can be reversed by the induction of cell cycling in the presence of IL-2. These observations extend the parallels between lpr CD4-CD8- T cells and anergic T cells.

Animals↗
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↗