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Biomedical subjects

A Bond

Publications and source records attributed to A Bond.

At least 19 recordsLinked to original sources
PubMed2001

A survey of frequent attenders at a gastroenterology clinic.

OBJECTIVE: To examine a group of patients satisfying criteria for "frequent attending" as part of an audit of an outpatient gastroenterology service, and to note the prevalence of those with no conspicuous organic disease to account for their symptomatology. METHODS: We used the hospital computer (Oxford Patient Administration System, OXPAS) to identify 2530 consecutive patients who were given an appointment to attend the gastroenterology clinic during an 11-month period. Patients designated "frequent attenders" had their notes flagged before the clinic attendance and were examined in more detail. A frequent attender was defined as a patient who had attended any hospital outpatient clinic in the three Oxford general hospitals on four or more occasions in the previous 12 months. The gastroenterologist then interviewed the patients satisfying these criteria and indicated whether he/she was satisfied that there was no relevant organic disease to account for the symptoms. RESULTS: Of the total 2530 patients, 762 (30%) satisfied our criteria for frequent attendance (FA). Of these, 452 (59%) had organic disease, 128 (17%) either did not attend or cancelled and 159 (21%) had no relevant organic disease. The diagnosis was uncertain in 23 patients (3%). Of patients satisfying our criteria for frequent attending, approximately 20-25% had no established gastroenterological disease. CONCLUSIONS: Frequent attenders present formidable management problems for the gastroenterologist. If they can be identified by computer before the outpatient visit then assessment and management might be more appropriately supervised in designated clinics by more experienced gastroenterology staff.

Adolescent↗
PubMed2001

Potentiation of responses to AMPA on central neurones by LY392098 and LY404187 in vivo.

Enhancement of AMPA receptor mediated synaptic excitation has the potential to aid in the treatment of several psychiatric conditions. To test such claims there is a need to develop more potent compounds than those presently available and to demonstrate that they cross the blood-brain barrier to affect responses at central AMPA receptors. We have now completed in vivo tests with two such compounds, the newly discovered biarylpropylsulfonamides, LY392098 and LY404187, on spinal and hippocampal neurones in anaesthetised rats. In the initial study on spinal neurones, LY392098 (30-1000 microg/kg i.v.) dose-dependently increased responses to iontophoretically administered AMPA but not those to NMDA. Subsequently in a more detailed follow-up study on hippocampal neurones, LY392098 (1-100 microg/kg i.v.) and LY404187 (1-100 microg/kg i.v.) enhanced in a dose-dependent manner responses to AMPA. Responses to NMDA were also enhanced but to a less extent. Such enhanced responses to NMDA, but not those to AMPA, were reduced by the NMDA antagonist, ketamine (0.5-1 mg/kg i.v.) whereas the selective AMPA antagonist, LY300168 (GYKI53655; 1 mg/kg i.v.), reduced responses to both NMDA and AMPA. LY392098 also potentiated the synaptic excitation of dentate granule cells following perforant path stimulation. These combined data show that, at doses not dissimilar to those affecting behavioural responses (1-1000 microg/kg; see accompanying papers), the two new drugs cross the blood-brain barrier to affect directly the sensitivity of central AMPA receptors and enhance synaptic excitation in vivo.

Action Potentials↗
PubMed2001

Thiazolidinediones and glucocorticoids synergistically induce differentiation of human adipose tissue stromal cells: biochemical, cellular, and molecular analysis.

While adipocyte differentiation has been studied extensively in murine cultures, the lack of a readily available preadipocyte model has hindered equivalent studies in man. We describe methods for the isolation and culture of primary human stromal cells from surgical adipose tissue specimens. In vitro, the stromal cells rapidly differentiate in response to a combination of adipogenic agents. Among these, glucocorticoids and thiazolidinediones act together to induce the formation of lipid vacuoles within the cells. These morphologic changes accompany the increased expression of 2 characteristic adipocyte proteins, the cytoplasmic enzyme glycerol phosphate dehydrogenase (GPDH) and the secreted cytokine leptin. Likewise, stromal cell differentiation results in elevated mRNA levels for the fatty acid binding protein aP2 and the adipogenic regulatory transcription factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) in addition to leptin. The in vitro differentiated stromal cells exhibit a lipolytic response to beta-adrenergic agonists, comparable to that reported with primary human adipocytes. These studies demonstrate the validity of human adipose tissue-derived stromal cells as a reliable in vitro model for investigations of adipocyte metabolism in humans.

Adipose Tissue↗
PubMed2000

LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia.

We have evaluated the neuroprotective effects of the decahydroisoquinoline LY377770, a novel iGlu5 kainate receptor antagonist, in two models of cerebral ischaemia. Global ischaemia, induced in gerbils by bilateral carotid artery occlusion (BCAO) for 5 min, produced a large increase in locomotor activity at 96 hr post-occlusion and a severe loss of CA1 cells in the hippocampus histologically at 120 hr post-occlusion. LY377770 (80 mg/kg i.p. 30 min before or 30 min after BCAO followed by 40 mg/kg i.p. administered at 3 and 6 hr after the initial dose) attenuated the ischaemia-induced hyperactivity and provided (92%) and (29%) protection in the CA1 cells respectively. This protection was greater than that seen with maximally tolerated doses of other glutamate receptor antagonists (CGS19755, CPP, MK-801, ifenprodil, eliprodil, HA-966, ACEA1021, L701,324, NBQX, LY293558, GYKI52466 and LY300164). Focal ischaemia was induced by infusing 200 pmol of endothelin-1 (Et-1) adjacent to the middle cerebral artery and LY377770 was administered at 80 mg/kg i.p. immediately, 1 or 2 hr post-occlusion followed by 40 mg/kg i.p. 3 and 6 hr after the first dose. The infarct volume, measured 72 hr later, was reduced by LY377770 when given immediately (P<0.01), at 1 hr (P<0.05) but not significantly at 2 hr post-occlusion. Reference compounds, LY293558 (20 mg/kg i.p. and then 10 mg/kg as above) and MK-801 (2.5 mg/kg i.p. ), both administered immediately post-occlusion produced significant (P<0.05) but somewhat less neuroprotection. In parallel microdialysis studies, LY377770 (75 mg/kg i.p.) attenuated ischaemia-induced increases in extracellular levels of glutamate, but not of dopamine. In conclusion, these results indicated that iGlu5 kainate receptors play a central role in ischaemic brain damage following global and focal cerebral ischaemia. LY377770 is a novel, soluble, systemically active iGlu5 antagonist with efficacy in global and focal ischaemia, even when administered post-occlusion. LY377770 may therefore be useful as a neuroprotectant in man.

Animals↗
PubMed2000

Deliberate self-harm in adolescents in Oxford, 1985-1995.

Deliberate self-harm (DSH) has been one of the major health problems of adolescents in the U.K. for many years. Any changes in rates of DSH or the demographic characteristics of the patient population are likely to have important implications for clinical services and for future suicidal behaviour. Following a decline in rates in the late 1970s and mid 1980s, there were signs in the late 1980s that rates were beginning to increase again. We have used data collected by the Oxford Monitoring System for Attempted Suicide on the basis of patients presenting to the general hospital in Oxford to review trends in DSH in under 20-year-olds between 1985 and 1995. There was a substantial increase in the numbers of teenage DSH patients during the 11-year study period, with an increase between 1985-1986 and 1994-1995 of 27.7% in males, 28.3% in females, and 28.1% overall. There were no demographic changes within the catchment area to explain a change of this size. As rates of repetition of DSH also increased in both sexes during the study period the overall number of episodes of DSH rose even more between 1985-1986 and 1994-1995 (+56.9% in males, +46.3% in females, and +49.4% overall). As in previous studies the majority of adolescents had interpersonal problems and/or difficulties with studying or employment. Self-poisoning with paracetamol and paracetamol compounds became increasingly common such that by 1995 these were used in almost two-thirds of overdoses. The recent increase in DSH in adolescents has important implications for general hospital and adolescent psychiatric services. The greater frequency of repetition of DSH may herald increased future suicide rates. The case for restricting the amount of paracetamol available is overwhelming. Evaluative trials of specific interventions following adolescent DSH are urgently required.

Adolescent↗
PubMed2000

Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: investigations into possible mechanism of action in vivo.

The mechanisms underlying the neuroprotective effects of the group II metabotropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min after 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-induced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P <.001) when histological analysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pretreatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced (P <.001 and P <.05, respectively) the damage to CA1 hippocampal neurons. This result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotective factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (10 mg/kg i.p.) failed to alter the expression of transforming growth factor-beta, brain-derived neurotrophic factor, nerve growth factor, and basic fibroblast growth factor in the hippocampal regions of brains taken from gerbils sacrificed at 6, 24, 72, and 120 h postinjection. The new group II mGlu antagonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuroprotective effect of LY379268 administered 24 h before 5-min BCAO. Complementary pharmacokinetic studies showed that a significant receptor-active concentration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conclude that group II mGluR occupancy, rather than induction of neuroprotective factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia.

Amino Acids↗
PubMed1999

LY379268, a potent and selective Group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia.

The neuroprotective effects of a selective Group II metabotropic glutamate receptor (mGluR) agonist, LY379268, have been evaluated against global and focal cerebral ischaemia. Loss of CA1 hippocampal neurones following 5 min bilateral occlusion of the carotid artery (BCAO) in the gerbil was almost completely prevented by LY379268 (10 mg/kg, i.p.) given 30 min post-occlusion (P < 0.001); 10 mg/kg 1 h after and 20 mg/kg 2 h after BCAO also produced significant neuroprotection (P < 0.05). Similarly the BCAO-induced increase in TUNEL positive cells at 5 days post-occlusion was reduced by LY379268. By contrast the size of the infarct following middle cerebral artery occlusion (MCAO) induced by endothelin-1 infusion in the rat was unaffected by either 10 or 20 mg/kg i.p. of LY379268. This contrast between the results from these two animal models with LY379268, agrees with previous data on a less potent but similarly selective mGluR2/3 agonist, LY354740. It further suggests that mGluR Group II agonists are likely to have more utility in global, than in focal, cerebral ischaemia.

Amino Acids↗
PubMed1999

NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus.

Recent studies have shown that a brief 'pre-conditioning' ischaemic insult reduces the hippocampal cell death caused by a subsequent more severe test insult. In the present studies, we have examined the effects of the non-competitive NMDA receptor antagonist ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine, MK-801) a competitive NMDA receptor antagonist, LY202157, AMPA receptor antagonist ((3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroiso quinoline-3-carboxylic acid, LY293558), a non-competitive AMPA receptor antagonist ((-)-1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-acetyl -2,3-benzodiazepine, LY300164), and a mixed NMDA/AMPA receptor antagonist, LY246492, in a gerbil model of ischaemic tolerance. Ischaemic tolerance was induced by subjecting gerbils to a 2-min 'pre-conditioning' ischaemia (bilateral carotid occlusion) 2 days prior to a 3-min test ischaemia. The effects of MK-801 (2 mg/kg i.p.), LY293558 (20 mg/kg i.p., followed by 4 x 10 mg/kg at 3 h intervals), LY300164 (4 x 10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4 x 20 mg/kg i.p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4 x 15 mg/kg i.p. at 2 h intervals) were then examined in this model. Initial dosing commenced 30 min prior to the 2-min 'pre-conditioning' ischaemia. Results indicated that a 2-min 'pre-conditioning' ischaemia produced ischaemic tolerance in all cases. The non-competitive NMDA receptor antagonist, MK-801, produced a significant (P < 0.01) reduction in the induced tolerance, while the competitive NMDA receptor antagonist, LY202157, also attenuated (P < 0.05) the induction of tolerance. In contrast, two AMPA receptor antagonists (LY293558 and LY300164) and a mixed NMDA/AMPA receptor antagonist (LY246492) had no effect on the induction of tolerance. These results suggest that NMDA receptor activation, but not AMPA receptor activation is involved in the phenomenon of ischaemic tolerance.

Animals↗
PubMed1999

Early-onset myasthenia gravis: a recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a.

No immunodominant T-cell epitopes have yet been reported in the human acetylcholine receptor (AChR), the target of the pathogenic autoantibodies in myasthenia gravis (MG). We have selected and characterized T cells from MG patients by restimulation in culture with recombinant human AChR to alpha, gamma and epsilon subunits; the gamma and epsilon distinguish the fetal and adult AChR isoforms, respectively. We obtained clones specific for the epsilon, rather than the alpha or gamma, subunit in 3 of the first 4 early-onset MG cases tested. They all responded to peptide epsilon201-219 and to low concentrations of adult but not fetal AChR. Moreover, although using different T-cell receptor genes, they were all restricted to HLA-DR52a (DRB3*0101), a member of the strongly predisposing HLA-A1-B8-DR3 haplotype. This apparently immunodominant epsilon201-219 epitope (plus DR52a) was also recognized by clones from an elderly patient whose MG had recently been provoked by the drug D-penicillamine. In all 4 cases, however, the serum antibodies reacted better with fetal than adult AChR and may thus be end products of determinant spreading initiated by adult AChR-specific T cell responses. Furthermore, as these T cells had a pathogenic Th1 phenotype, with the potential to induce complement-activating antibodies, they should be important targets for selective immunotherapy.

Amino Acid Sequence↗
PubMed1999

Neuroprotective actions of novel and potent ligands of group I and group II metabotropic glutamate receptors.

The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia. Previous studies have also shown that activation of group II mGlu receptors may contribute to neuroprotective mechanisms in vitro and in vivo. Three potent group II mGlu agonists--LY354740, LY379268 and LY389795--were found to attenuate both NMDA excitotoxicity and staurosporine-induced neuronal cell death. LY354740 and LY379268 were protective against transient global ischemia in gerbils when dosed intraperitoneally. These results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful agents in the therapeutic treatment of neurodegenerative disease.

Animals↗
PubMed1998

Neuroprotective effects of a systemically active group II metabotropic glutamate receptor agonist LY354740 in a gerbil model of global ischaemia.

The neuroprotective effects of a novel Group II metabotropic glutamate receptor (mGluR) agonist, LY354740, have been evaluated in a gerbil model of global ischaemia. When administered at 50 mg/kg, i.p., 30 min and 6 h after a 3 min period of bilateral carotid artery occlusion (BCAO), the compound reduced the damage to CA1 hippocampal neurones to a significant level. However, when the ischaemic insult was made more severe, by increasing the period of occlusion to 4 and 5 min, the neuroprotective effects of LY354740 were reduced. From these findings, it would appear that Group II mGluRs may play a role in ischaemic damage in the gerbil hippocampus and that agonists at these receptors are potential neuroprotective agents.

Animals↗
PubMed1998

Quantitation of the oligosaccharides of human serum IgG from patients with rheumatoid arthritis: a critical evaluation of different methods.

Several different chromatographic methods and a lectin-based assay have been compared for the quantitation of oligosaccharides released from immunoglobulin G (IgG). The analysis of a series of IgG samples purified from the serum of rheumatoid arthritis patients was carried out by these methods to evaluate the percentage of the glycoforms having 0, 1 or 2 galactose residues (G0, G1 and G2) in order to (a) identify the method that can be most widely used for quantitation, (b) accurately define the range of G0 values found in patients with rheumatoid arthritis, and (c) make available a series of characterised standards for distribution to clinical chemistry laboratories. The chromatographic methods involved: release of oligosaccharides by glycoamidase A after protease digestion followed by HPLC analysis of aminopyridine derivatives on reverse phase and normal phase columns; hydrazinolysis treatment with exoglycosidases (G0 mix) and Biogel P4 chromatography of 2-aminobenzamide (2-AB) derivatives; hydrazinolysis and weak anion exchange or normal phase HPLC of 2-AB derivatives; release of oligosaccharides by PNGase F and either Biogel P4 chromatography of 2-AB derivatives or HPAEC-PAD analysis of native oligosaccharides. The G0 values given by these methods compared favourably with each other and a dot blot assay of denatured IgG interaction with Ricinus communis agglutinin and Bandeiraea simplicifolialectin II. The HPLC and HPAEC methods give additional information that may be important in less routine assays.

Arthritis, Rheumatoid↗
PubMed1997

A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740.

Non-specific metabotropic glutamate receptor (mGluR) agonists have previously been shown to potentiate responses of spinal neurones to ionotropic glutamate receptor agonists. In this study we show that LY354740, which is a highly selective Group 2 mGluR agonist with nanomolar potency in vitro, also mimics the above effects following local ejection on spinal neurones in vivo, an action which is blocked by a Group 2 antagonist. Despite its polar nature, LY354740 is also active given either by the i.v. or the oral route (2.5-20 mg/kg) and thus will be a useful agent for investigating the role of Group 2 mGluRs both physiologically and clinically.

Administration, Oral↗
PubMed1997

A detailed lectin analysis of IgG glycosylation, demonstrating disease specific changes in terminal galactose and N-acetylglucosamine.

Serum IgG from rheumatoid arthritis patients contains a decreased number of oligosaccharide structures ending in galactose and thus there is an increase in N-acetylglucosamine as the terminal sugar, compared with healthy individuals. The relationship between these two sugars varies depending on the disease examined: IgG from patients with rheumatoid arthritis, juvenile onset chronic arthritis and Crohn's disease are at one extreme, and exhibit a reciprocal galactose:N-acetylglucosamine relationship, while Sjögren's syndrome and osteoarthritis IgG are at the other extreme, exhibiting a parallel increase in the expression of both galactose and N-acetylglucosamine. These results may occur as a consequence of more than one glycosylation site which is differentially glycosylated, but more likely by changes in the level of bisecting N-acetylglucosamine.

Acetylglucosamine↗
PubMed1997

L-selectin expression on the surface of peripheral blood leucocytes from rheumatoid arthritis patients is linked to disease activity.

Recruitment of mononuclear cells from the circulation to sites of inflammation relies on migration across vessel endothelium. T and B cells, macrophages and neutrophils infiltrate synovial tissue of rheumatoid arthritis (RA) patients. The authors have analysed the numbers of circulating CD3+, CD19+ lymphocytes, monocytes, and granulocytes expressing adhesion molecules (L-selectin, CD44 and CD11a), together with levels of expression in RA patients compared to healthy individuals. Numbers of leucocytes expressing the adhesion molecules detected were similar in RA and control groups. Lower levels of expression of L-selectin on all cells were found in RA patients compared to controls. Expression of L-selectin on T and B cells was found to correlate with disease activity in RA. The authors have observed a characteristic pattern of adhesion molecule expression in RA patients, particularly when analysing the relationships between cells. The close regulation of these molecules between RA patients and healthy individuals is discussed.

Adult↗