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Biomedical subjects

A Fletcher

Publications and source records attributed to A Fletcher.

At least 109 records · Page 6Linked to original sources
PubMed1996

Characterization and distribution of SNARE proteins at neuroendocrine nerve endings.

Substantial evidence now exists to support a defined complex of interacting proteins, comprised of soluble, vesicle and plasma membrane components, as the core of a general membrane fusion mechanism. Specializations to the general secretory model occur based on cell-specific differences in Ca2+ regulation, secretory organelle types and secretory dynamics. The variation in secretory properties may also result, in part, from isoform diversity and selective-pairing of the molecular components of the core complex. The present report attempts to identify the SNARE proteins found in isolated peptidergic nerve endings of the rat neurohypophysis. The results demonstrate the presence of synaptosomal-associated protein of 25 kD, syntaxin and synaptobrevin as membrane-associated proteins in these nerve endings. Furthermore, we have utilized sucrose density gradient subcellular fractionation and immunoprecipitation protocols to investigate the synaptobrevin isotypes present on secretory granules and to probe using electrophysiological methods their functional relationship to secretion. Secretory granules were found to contain only the synaptobrevin 2 isoform, although the nerve endings themselves were found to possess in addition, synaptobrevin 1 and the closely related protein cellubrevin. Analysis of the secretory characteristics of single nerve endings using membrane capacitance measurements together with Botulinum B toxin dialysis demonstrated the critical importance of synaptobrevin 2 to both the rapid exocytotic release and a slower secretory process, that perhaps includes secretory granule recruitment and priming, in these peptidergic nerve endings.

Animals↗
PubMed1996

Amelanotic superficial spreading malignant melanoma mimicking Bowen's disease.

A 67-year-old woman presented with a scaly, erythematous plaque, for which a clinical diagnosis of Bowen's disease was made. However, incisional biopsy established the diagnosis of amelanotic superficial spreading malignant melanoma. Biopsy thus avoided the use of inappropriate destructive therapy, such as cryotherapy or cautery. This case illustrates the importance of obtaining a histological diagnosis, prior to treatment, in suspected cases of Bowen's disease.

Aged↗
PubMed1996

An immunohistochemical study of the dermal infiltrate and epidermal staining for interleukin 1 in 12 cases of Sweet's syndrome.

Interleukin 1 (IL-1) has been proposed as a possible mediator in Sweet's syndrome. We examined all cases of Sweet's syndrome (n = 12) presenting to the department over a 10-year period, from 1982 to 1992, for the presence of IL-1 and also assessed the nature of the dermal inflammatory infiltrate in those cases. Staining for IL-1 alpha and IL-1 beta was stronger in control tissues than in Sweet's syndrome. This may possibly be explained by the release of IL-1 alpha and IL-1 beta into the dermis in Sweet's syndrome. Contrary to recent reports, we found that neutrophils predominated in all cases examined, although histiocytes were present in increased numbers indicating their possible role in the pathophysiology of Sweet's syndrome.

Epidermis↗
PubMed1995

First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635.

The selective 5-HT1A receptor radioligand, [11C]WAY-100635 ([11C]N-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2- pyridyl)cyclohexanecarboxamide), has been injected intravenously into healthy male volunteers and studied by PET (positron emission tomography). The results provide the first delineation of 5-HT1A receptors in living human brain and demonstrate the potential to use [11C]WAY-100635 for the study of central 5-HT1A receptors in patients with psychiatric and neurological disorders and for the investigation of the pharmacology of drugs acting on the central nervous system.

Adult↗
PubMed1995

A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635.

WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride) is an achiral phenylpiperazine derivative that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a standard antagonist in further studies of 5-HT1A receptor function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

The selective 5-HT3 receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system.

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT3 receptor antagonist, WAY 100289, on spatial learning and memory in the water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source of cholinergic projections to cortex and hippocampus. The representative cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline (1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before lesioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards improvement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY100289 improved performance at all three doses, though ameliorative effects of nicotine and arecoline were more marked also in lesioned rats. These results show that WAY100289 improved spatial learning in animals impaired after lesions to cholinergic projection nuclei, which may reflect an interaction with cholinergic transmission to enhance cognitive function. However, in the present study, WAY100289 appeared to be less effective than direct cholinergic agonists.

Animals↗
PubMed1995

Attenuation of CCK-induced aversion in rats on the elevated x-maze by the selective 5-HT1A receptor antagonists (+) WAY100135 and WAY100635.

The present study determined the effect of pretreatment with "silent" selective 5-HT1A receptor antagonists on cholecystokinin (CCK)-mediated effects on rat behaviour in the elevated x-maze model of anxiety. In the absence of 5-HT1A receptor antagonists, non-sulphated cholecystokinin-octapeptide (CCK-8ns; 10 and 50 micrograms/kg, i.p.; 30 min prior to testing) produced an anxiogenic profile of behaviour on the x-maze, reducing the number of open arm entries and the number of exploratory head dips, while increasing the level of risk-assessment as measured by the number of stretched-attend postures. CCK-8ns did not, however, alter ambulatory activity. Two 5-HT1A receptor antagonists were employed in these experiments: (+)WAY100135 (the active enantiomer of N-tert-butyl-3-(4-(2-methoxyphenyl)piperzin-1-yl)- 2-phenylpropronamine) [sequence: see text] and WAY100635 (N-[2-[4(2-methoxyphenyl)-1-piperazinyl-1-piperazinyl]-N-2- pyridinyl)cyclohexanecarbonate [sequence: see text] trihydrochloride). When administered 10 min prior to CCK-8ns, (+) WAY100135 and 0.3 mg/kg s.c.) significantly attenuated profile of CCK-8ns. (+)WAY100135 was also demonstrated to significantly inhibit postsynaptic 5-HT1A receptor-mediated 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin)-induced 5-HT syndrome at the same dose used in the x-maze experiment. Neither (+)WAY100135 nor WAY100635 had any affects on ambulatory activity. These results support a CCK/5-HT1A receptor interaction in the modulation of aversion in rats exposed to the elevated x-maze.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Protease-modified erythrocytes: CD55 and CD59 deficient PNH-like cells.

The increased susceptibility to homologous complement in paroxysmal nocturnal haemoglobinuria (PNH) is known to be associated with the deficiency of the membrane complement inhibitors CD59 and CD55. Proteases have been used in this study to modify normal human RBC to complement sensitive PNH-like cells. To investigate the protective role of CD59 and CD55, the relationship between the content of CD59 and CD55 and the complement susceptibility of the PNH-like cells has been determined. The differential resistance of the enzyme-treated RBC to complement-mediated injury was measured by acidified serum lysis. Pronase-treated erythrocytes lacked both CD59 and CD55 and were very susceptible to complement-mediated lysis. Papain treatment of RBC reduced the CD55 content but did not affect CD59 and induced slight susceptibility to complement-mediated lysis. Trypsin treatment of RBC destroyed 80% of CD59, had little effect on CD55 (unless incubation was extended) and slightly increased susceptibility to lysis. Thus, partial CD55 and CD59 activity was sufficient to protect cells from complement-mediated lysis. In the reactive lysis assay, anti-CD55 and anti-CD59 induced haemolysis, anti-CD59 having the more pronounced effect. Lysis was enhanced when RBC were treated by both antibodies simultaneously.

Antibodies, Monoclonal↗
PubMed1995

The NHS research and development programme and its impact on health care library and information resource centres.

This paper looks at the likely impact of the NHS research and development (R & D) programme on health care library and information centres. A brief description of the NHS R&D programme stresses the importance of the management of research and development findings to its success. This paper identifies a number of obstacles to the successful dissemination of R&D findings and discusses the role of health care libraries and information centres in overcoming some of these. It focuses on the essential contribution they can make in supporting the use of systematic reviews as the main source of quality evidence on the effectiveness of health care interventions.

Evidence-Based Medicine↗
PubMed1995

Evaluation of short-course therapy with cefixime or rifampin for eradication of pharyngeally carried group A streptococci. The Ontario GAS Study Group.

Therapy to eradicate pharyngeally carried group A streptococci (GAS) has increasingly been used in the management of institutional outbreaks and is now recommended for household contacts of patients with streptococcal toxic shock syndrome. In this randomized, controlled trial, contacts of patients with GAS infections were screened for pharyngeal GAS colonization. Those whose cultures were positive were randomized to receive either cefixime (8 mg/[kg.d]; maximum 400 mg) or rifampin (20 mg/kg; maximum, 600 mg) once a day for 4 days. Two to five days following completion of therapy, repeated cultures were negative for 13 (38%) of 34 rifampin recipients and 71 (77%; 95% CI, 69%-85%) of 97 cefixime recipients. At 10-14 days after treatment, only 53% of cefixime recipients remained culture-negative. Rates of successful clearance improved with increasing age (P < .01); among 17 adults who received cefixime, the success rate was 94%. Four days of therapy with rifampin is not effective for eradication of pharyngeally carried GAS. Four days of therapy with cefixime may be effective for adults, but further studies are needed.

Adolescent↗
PubMed1995

Measuring the effects of antihypertensive therapy upon the quality of life.

After an explosion of interest at the beginning of the 1990s in measuring quality of life in hypertensive patients, the past few years have seen relatively few studies in this area. This is partly because when new drugs were compared, in general, no clear advantage was observed for any particular drug or class of antihypertensive. More recently the emphasis on choosing antihypertensive treatments that have been shown to be effective in reducing cardiovascular morbidity and mortality, as well as constraints on resources, have focused attention on older drugs such as diuretics. Only a few trials have measured quality of life on a diuretic, but the largest and most powerful of these found no evidence that diuretics impair quality of life.

Antihypertensive Agents↗
PubMed1995

Regressing cutaneous lymphomas of T-cell and B-cell lineage.

We report two cases of regressing cutaneous lymphoma. The first case is a CD30-positive T-cell lymphoma with immunogenetic evidence of clonality. The second case is a diffuse large-cell non-Hodgkin's lymphoma of B-cell lineage in which clonality was established by immunogenetic analysis and in situ hybridization for light-chain mRNA.

Aged↗
PubMed1995

The enantiomers of zacopride: an intra-species comparison of their potencies in functional and anxiolytic models.

1. The 5-HT3 receptor antagonist, zacopride, and its enantiomers, R(+)-zacopride and S(-)-zacopride, were examined in three pharmacological models: (i) 5-HT-induced depolarization of the mouse isolated vagus nerve preparation, (ii) the 5-HT-evoked von Bezold-Jarisch reflex in the mouse, and (iii) the mouse light:dark box model of anxiety. Other standard 5-HT3 receptor antagonists were also included for comparison in these studies. 2. Racemic zacopride, and both of the enantiomers, displayed potent 5-HT3 receptor antagonist activity in the isolated vagus nerve and in the von Bezold-Jarisch model. No 5-HT3 receptor agonist or partial agonist effects of these compounds were detected. 3. In the isolated vagus nerve, R(+)-zacopride and ondansetron were surmountable 5-HT3 receptor antagonists (pA2 values of 9.3 and 8.3, respectively), whereas racemic zacopride, S(-)-zacopride and tropisetron were insurmountable antagonists, markedly suppressing the maximum response to 5-HT. 4. In vivo, racemic zacopride, R(+)-zacopride, S(-)-zacopride and WAY100289 were potent antagonists of the 5-HT-evoked von Bezold-Jarisch reflex, with minimum effective doses (lowest dose required to reduce the reflex by > or = 85%; MED85) of 1.0, 3.0, 0.3 and 3.0 micrograms kg-1, s.c., respectively. 5. Racemic zacopride, R(+)-zacopride and S(-)-zacopride were active in the mouse light:dark box model of anxiety, with similar potencies (minimum effective dose 1 microgram kg-1, s.c.) and similar active dose-ranges (1-1000 micrograms kg-1, s.c.). 6. The doses of racemic zacopride, R( + )-zacopride and S(-)-zacopride required to block 5-HT3receptors in vivo correlated reasonably well with their potencies in an anxiety model within the same species. In these studies, there was no evidence of a marked difference between the anxiolytic potencies ofR( + )-zacopride and S(-)-zacopride.

Animals↗
PubMed1995

Relative positions of two clusters of human alpha-L-fucosyltransferases in 19q (FUT1-FUT2) and 19p (FUT6-FUT3-FUT5) within the microsatellite genetic map of chromosome 19.

Five on the seven cloned human fucosyltransferase genes have been mapped to two clusters, one on 19q and the other on 19p. Comparative DNA sequence analysis showed the Généthon microsatellite D19S596 lies 2.2 kb downstream of the coding region of FUT1, indicating that the cluster comprising the closely linked FUT1 and FUT2 genes is located 4 cM distal to D19S412 (lod score 13.7) and 9 cM proximal to D19S571 (lod score 11.7). Polymorphic markers of FUT3, FUT5, and FUT6 were used for linkage analysis with 14 Généthon microsatellites in Indonesian families. These three loci constitute a cluster on 19p, located between the Généthon microsatellites D19S216 and D19S567, which are known to be only 1 cM distant from each other. Two cross-overs, one between FUT6 and FUT3 and the other between FUT3 and FUT5, suggest the gene order 19pter-D19S216-FUT6-FUT3-FUT5-D19S567++ +-cen. Comparison of genetic and physical maps suggests that the FUT6-FUT3-FUT5 cluster is located on 19p13.3 and the FUT1-FUT2 cluster on 19q13.3. FUT6, FUT3 and FUT5 genes share more than 85% homology and encode three similar, but distinct alpha(1,3) fucosyltransferases. FUT1 and FUT2 share about 70% homology and encode two distinct alpha(1,2)fucosyltransferases. No sequence homology was found between the genes of the two clusters. The members of each of these two clusters have probably emerged by duplication and divergent evolution of two unrelated ancestor genes.

Base Sequence↗