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Biomedical subjects

M J Burton

Publications and source records attributed to M J Burton.

At least 37 records · Page 2Linked to original sources
PubMed1997

SB-216641 and BRL-15572--compounds to pharmacologically discriminate h5-HT1B and h5-HT1D receptors.

Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl-2-propanol), which display high affinity and selectivity for h5-HT1B and h5-HT1D receptors, respectively. In receptor binding studies on human receptors expressed in CHO cells, SB-216641 has high affinity (pKi = 9.0) for h5-HT1B receptors and has 25-fold lower affinity at h5-HT1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h5-HT1D (pKi = 7.9) than 5-HT1B receptors. Similar affinities for these compounds were determined on native tissue 5-HT1B receptors in guinea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [35S]GTPgammaS binding assay and in a cAMP accumulation assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor binding affinities. In the cAMP accumulation assay, results from pK(B) measurements on the compounds again correlated with receptor binding affinities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D receptor mediated responses.

Animals↗
PubMed1996

GR127935 acts as a partial agonist at recombinant human 5-HT1D alpha and 5-HT1D beta receptors.

In this study we have investigated the functional activity of GR127935 (2-methyl-1,2,4 oxadiazol-3-yl)-biphenyl-[4-carboxylic acid 4-methoxy-3-(4-methyl-piperazine-1-yl]-amide) at human 5-HT1D alpha and 5-HT1D beta receptors which have been expressed in a Chinese Hamster Ovary (CHO) cell line. Using [35S] GTP gamma S binding to cell membranes as a measure of receptor-G protein coupling. GR127935 showed partial agonist activity in both 5-HT1D alpha and 5-HT1D beta receptor expressing cells (Emax: 29 and 31% above basal control; pEC50: 8.6 and 9.7, respectively). GR127935 also acted as a potent antagonist at the 5-HT1D alpha (app. pA2 8.5) and 5-HT1D beta (app. pA2 9.1) receptors. From studies measuring cAMP accumulation in cultured CHO cells GR127935 also displayed partial agonism, as well as acting as a potent antagonist at the 5-HT1D alpha receptors which stimulate cAMP levels and 5-HT1D beta receptors which inhibit cAMP levels (app. pA2 8.6 and 9.7, respectively). The 5\-HT1-like receptor antagonist methiothepin showed negative intrinsic activity at both receptors in the [35S]GTP gamma S binding assay only. From studies using the receptor alkylating agent EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) the 5-HT1D alpha cell line displayed a lack of receptor reserve but it was evident in the 5-HT1D beta cell line. In previous studies we have also shown that agonist stimulation of 5-HT1D alpha receptors increases cAMP levels which may be due to high receptor expression. Further investigation using up to 1 microM EEDQ to reduce 5-HT1D alpha receptor number did not reveal an underlying inhibitory adenylyl cyclase response. In conclusion, GR127935 acts as a partial agonist, as well as a potent antagonist, at the human 5-HT1D alpha and 5-HT1D beta receptors when expressed in CHO cells.

Adenylyl Cyclases↗
PubMed1996

Characterization of a descending system that enables crossed group II inhibitory reflex pathways in the cat spinal cord.

In the cat, stimulation of group II afferents from hindlimb muscles evokes different crossed reflex actions depending on the integrity of the spinal cord: with the cord intact, extensor motoneurons are inhibited by activation of contralateral group II afferents; after spinal transection, the same stimuli excite these neurons (crossed extension reflex). We have investigated the mechanisms underlying this descending control. To delimit the descending pathway, the effects of funicular lesions of the thoracic cord on the crossed actions on motoneurons were examined. Bilateral lesions of the dorsolateral funiculi abolished the crossed IPSPs as effectively as complete spinal section. If either dorsolateral funiculus was spared, the IPSPs remained. To examine whether serotonergic fibers were involved, the effects of agents selective for 5-hydroxytryptamine (5-HT)1A receptors were examined. After abolishing the crossed IPSPs by spinal transection, systemic administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.1-1.3 mg/kg, i.v.) restored the crossed inhibition. This effect was antagonized by the selective 5-HT1A receptor antagonist WAY-100135 (0.7-3.7 mg/kg, i.v.). The simplest explanation of these findings is that a serotonergic pathway, descending via the dorsolateral funiculi and acting via 5-HT1A receptors, is involved: with the spinal cord intact, the pathway would be tonically active and thus enable the crossed inhibition. This raises the possibility that a serotonergic pathway is involved in the selection of specific spinal reflex patterns via 5-HT1A receptors.

Afferent Pathways↗
PubMed1996

Cochlear histopathologic characteristics following long-term implantation. Safety studies in the young monkey.

OBJECTIVE: To evaluate the safety of cochlear implantation in children 2 years of age or younger using a non-human primate model. DESIGN: Histopathologic study. SUBJECTS: Five macaque monkeys. INTERVENTION: A commercially produced electrode array was implanted for 3 years. RESULTS: Histologic examination demonstrated the biocompatibility of the scala tympani electrode array. Limited soft-tissue growth and new bone growth were observed in the lower basal turn. There was no evidence of intracochlear infection. Evidence of minimal insertion trauma was seen. Hair cell loss was, in general, confined to the region of the electrode array, with normal hair cell populations toward the apex, although there was evidence of hair cell preservation adjacent to the array. At least 20% of spiral ganglion cells were preserved even in regions with a smaller proportion of hair cells. CONCLUSIONS: Even after extended periods of implantation, the electrode array is well tolerated, and there is substantial preservation of neural elements.

Animals↗
PubMed1996

Titanium-anchored prostheses in otology.

In the late 1970s, Per-Ingvar Branemark and coworkers in Goteberg, Sweden, successfully introduced osseointegrated titanium implants into clinical practice. They had achieved the previously elusive goal of producing stable, secure percutaneous implants anchored in underlying cortical bone. Two applications of these implants to otology were obvious: (1) to provide a coupling for bone-conduction hearing aids and (2) to provide fixation points for anchoring of auricular prostheses. Before describing the current state of these clinical applications and considering future potential uses, the authors review the basis for titanium osseointegration.

Bone Conduction↗
PubMed1994

Cochlear implantation in young children: histological studies on head growth, leadwire design, and electrode fixation in the monkey model.

For safe cochlear implantation in children under 2 years of age, the implant assembly must not adversely affect adjacent tissues or compromise head growth. Furthermore, growth changes and tissue responses should not impair the function of the device. Dummy receiver-stimulators, interconnect plugs, and leadwire-lengthening systems were implanted for periods of 36 months in the young monkey to effectively model the implantation of the young child. The results show that implanting a receiver-stimulator package has no adverse effects on skull growth or the underlying central nervous system. The system for fixing the electrode at the fossa incudis proved effective. There was marked osteoneogenesis in the mastoid cavity, resulting in the fixation of the leadwire outside the cochlea. This study provides evidence for the safety of cochlear implantation in young subjects.

Animals↗
PubMed1994

Cochlear implantation in children: labyrinthitis following pneumococcal otitis media in unimplanted and implanted cat cochleas.

Pneumococcal otitis media is frequent in young children and could lead to labyrinthitis post-implantation. To assess the risk, and methods of minimizing it by a graft to the round window around the electrode entry point, we have used a cat animal model of pneumococcal otitis media. Twenty-one kittens were used in the study. Thirty-two cochleas were implanted when the kittens were 2 months of age. Fourteen cochleas were implanted without using a graft (12 were available for study); 9 had a fascial graft, and 9 a Gelfoam graft (7 were available for study). The implanted kittens had their bullae inoculated with Streptococcus pneumoniae 2 months after implantation and were sacrificed 1 week later. There were also 9 unimplanted control ears which were inoculated when the animals were 4 months of age. Labyrinthitis occurred in 44% of unimplanted control, 50% of implanted ungrafted, and 6% of implanted grafted (fascia and Gelfoam) cochleas. There was no statistically significant difference between the unimplanted control and the implanted cochleas (p < 0.05). There was, however, a difference between the implanted-ungrafted and implanted grafted cochleas, but not between the use of fascia and Gelfoam to graft the round window entry point. As a result, the data indicates that cochlear implantation does not increase the risk of labyrinthitis following pneumococcal otitis media, but it is desirable to use fascia as a graft to the round window around the electrode entry point.

Animals↗
PubMed1994

Swallowing in motor neurone disease.

Ninety-two patients with motor neurone disease have been assessed clinically and radiologically for evidence of swallowing problems. At the time of examination, moderate or severe swallowing difficulty was present in 89% of those whose disease had presented as bulbar palsy, in 45% of those in whom the disease began many months before as progressive muscular atrophy and in 29% of those with amyotrophic lateral sclerosis. Patients with more severe swallowing symptoms appeared more likely to have abnormal findings on videofluoroscopy overall. However, not all patients with an abnormal radiological picture had swallowing difficulties. It is suggested that radiological signs should only be used within the context of clinical symptoms and signs in the selection of patients for palliative surgery. Thirteen patients with pseudobulbar symptoms and signs had a cricopharyngeal myotomy performed: two suffered major post-operative complications. However, the satisfaction rate was 89% and we recommend cricopharyngeal myotomy for such patients. Pharyngostomy was performed for seven patients unable to initiate swallowing, six had post-operative complications.

Age of Onset↗
PubMed1994

Nonorganic hearing loss in cochlear implant candidates.

Five patients undergoing assessment for cochlear implantation have been found to have a nonorganic hearing loss (pseudohypacusis). This phenomenon has not been reported previously in this patient population. The cases are presented and the causes, detection, and management of this condition are discussed.

Adolescent↗
PubMed1992

Thrombospondin receptor expression in human neutrophils coincides with the release of a subpopulation of specific granules.

The extracellular matrix (ECM) protein thrombospondin (TSP) binds specifically to polymorphonuclear leucocyte (PMN) surface receptors and promotes cell adhesion and motility. TSP receptor expression increases 30-fold after activation with the synthetic chemotactic peptide, N-formylmethionyl-leucylphenylalanine (FMLP) or the Ca2+ ionophore A23187, in combination with cytochalasin B. The expression of TSP receptors was correlated with the exocytosis of both specific and azurophil granules. Newly expressed TSP receptors are not derived from easily mobilized specific granules since agents that trigger some specific granule release [phorbol myristate acetate (PMA), FMLP or ionophore A23187 alone] do not increase TSP receptor expression. In this study we used the anion-channel blocker, 4,4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS) to investigate the source of these newly expressed receptors. When PMNs were exposed to cytochalasin B and FMLP or to cytochalasin B and ionophore A23187 in the presence of 30-100 microM-DIDS, TSP receptor expression increased coincidently with vitamin B12-binding protein release from specific granules. Under these same conditions, the release of the azurophil granule component, myeloperoxidase, was significantly inhibited. Using agonists that cause release of specific granules, or both specific granules and azurophil granules, we determined that DIDS blocked the release of PMA-mobilized specific granules and cytochalasin B plus FMLP- or cytochalasin B plus ionophore A23187-mobilized myeloperoxidase-containing azurophil granules but not specific granules mobilized by cytochalasin B plus FMLP or cytochalasin B plus ionophore A23187. These results suggested that PMNs contain at least two subpopulations of specific granules: one that is easily mobilized, lacks TSP receptors and is inhibitable by DIDS, and one that is difficult to mobilize, contains a large pool of TSP receptors and the release of which is enhanced in the presence of DIDS.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Steady-state evoked potentials to amplitude modulated tones in the monkey.

A frequency-specific, objective assessment of hearing thresholds is required for use in subjects unable to perform behavioural audiometry. One such method using steady-state evoked potentials (SSEPs) in response to amplitude-modulated tones was evaluated in an experimental animal, the macaque monkey. An amplitude-modulation frequency of 165 Hz was found to produce optimum response detection in the anaesthetised animal. Auditory thresholds determined by a computerised automatic response detection system accurately reflected behavioural thresholds previously described in this species.

Animals↗
PubMed1991

Human neutrophil adherence to thrombospondin occurs through a CD11/CD18-independent mechanism.

Thrombospondin (TSP), a 450-kDa trimeric glycoprotein secreted by platelets and endothelial cells at sites of tissue injury or inflammation, may play an important role in polymorphonuclear leukocyte (PMN) adherence to blood vessel walls before diapedesis. We have examined the adherence of PMN to TSP and compared it to adherence to other extracellular matrix proteins. PMN adherence to TSP-coated plastic was complete by 60 min with spreading completed by 2 h. The kinetics of adhesion and spreading on TSP were similar to that of vitronectin (VN), laminin (LN), and fibronectin (FN). Activation of PMN with the calcium ionophore A23187 or the chemotactic peptide FMLP increased PMN adherence to LN and FN, but not to TSP or VN, suggesting that PMN activation may differentially regulate expression of TSP and VN receptors as compared to LN and FN receptors. The specificity of PMN adherence to TSP was confirmed by competition with saturating amounts of TSP and inhibition with anti-TSP antibodies. mAb A6.1, which binds to the protease-resistant core of TSP, was the most effective in blocking PMN adherence to TSP. Using TSP proteolytic fragments, we demonstrated that the primary interaction of PMN with TSP was mediated through the 140-kDa COOH-terminal domain. Inasmuch as the 140-kDa fragment of TSP contains an Arg-Gly-Asp sequence similar to the cell recognition site of FN and VN, we determined whether RGDS peptides would inhibit PMN adhesion. RGDS did not significantly inhibit PMN adhesion to TSP, VN, or LN, but reduced PMN adhesion to FN by 50%. To determine if PMN adhesion to TSP was mediated by a beta 2 integrin receptor such as LFA-1, MO-1, or p150,95, we performed adhesion assays using PMN isolated from patients with leukocyte adhesion deficiency that lack beta 2 receptors. Leukocyte adhesion deficiency PMN exhibited normal adherence to TSP. In contrast, adherence to VN, LN, and FN was reduced by 95%. Therefore, adherence to TSP is probably not mediated by a beta 2 integrin receptor. These data contribute to the accumulating evidence that PMN can interact with extracellular matrix proteins through a CD11/CD18-independent process.

Antigens, CD↗
PubMed1991

Long-term results of submandibular duct transposition for drooling.

This study examines the long-term results and morbidity of submandibular duct transposition in drooling children. Twenty-two patients, aged 3 to 18 years, with neurological dysfunction and excessive drooling underwent submandibular duct transposition between 1984 and 1987. In January 1990, 20 patients were reviewed. Their degree of drooling pre-operatively, immediately post-operatively and currently was assessed. The rate of improvement and the occurrence of complications were noted. Drooling was 'much better' in the early post-operative period in 17 of the 20 patients, and this improvement was invariably noted within three weeks. In the three other patients drooling was 'better'. Deterioration occurred in only three patients over the entire follow-up period. Complications all occurred in the first 18 months following surgery; they consisted of salivary retention cysts in four and transient submandibular gland swelling in a fifth patient.

Adolescent↗
PubMed1991

The surgical management of drooling.

As with all branches of surgery, selection of the appropriate operative procedure for a particular patient involves careful weighing of all the alternatives and full discussion with the patient and carers. Each of the procedures described has its devotees and detractors. For an individual patient, however, the risks of each, the likely postoperative course and the results of the surgery--both in terms of the expected chance of improvement in drooling and the presence or otherwise of residual scarring or taste--must be balanced to determine the optimum plan for treatment. The long-term results of submandibular duct transposition for drooling in the author's own institution have recently been reported. An initial improvement in the drooling of all patients was maintained for at least two years in 17 of 20 patients. Only two patients experienced complications requiring further surgery (ranulas in each case). It is suggested that these very satisfactory results, achieved without external scarring and without compromising the sense of taste, support the contention that submandibular duct transposition is the surgical treatment of choice for children and young people with cerebral palsy who drool excessively.

Child↗