PubMed Health⌕ Search

Biomedical subjects

A Clements

Publications and source records attributed to A Clements.

At least 19 recordsLinked to original sources
PubMed2000

Involvement of the medial septum in stress-induced relapse to heroin seeking in rats.

Intermittent footshock stress has been shown to reinstate extinguished drug-taking behaviour in rats, but the brain areas involved in this effect are to a large degree unknown. Here we studied the role of the septum in stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin for 9-10 days (three 3-h sessions per day, 0.1 mg/kg per infusion). Following training, extinction sessions were given for 8-13 days by substituting saline for heroin, and then tests for reinstatement of heroin seeking were carried out. Reversible inactivation of the medial septum with tetrodotoxin (TTX; 1-5 ng, infused 25-40 min before the test sessions) reliably reinstated heroin seeking, mimicking the effect of 15 min of intermittent footshock. This effect of TTX was not observed after infusions made 1.5 mm dorsally into the lateral septum. In other experiments, it was found that infusions of a low, subthreshold dose of TTX (0.5 ng) into the medial septum, when combined with 2 min of footshock that in itself was ineffective, reinstated heroin seeking. Furthermore, electrical stimulation (400 microA pulses, 100 micros duration, 100 Hz frequency) of the medial septum during exposure to 10 min of intermittent footshock attenuated footshock-induced reinstatement of heroin seeking. These data suggest a role for the medial septum in stress-induced relapse to drug seeking. The septum is thought to be involved in neuronal processes underlying behavioural inhibition, thus we speculate that stressors provoke relapse by interfering with these processes.

Animals↗
PubMed2000

Doctors who kill themselves: a study of the methods used for suicide.

Medical practitioners have a relatively high rate of suicide. Death entry data for doctors who died by suicide or undetermined cause between 1979 and 1995 in England and Wales were used to compare methods used for suicide by doctors with those used by the general population. Methods used were analysed according to gender, occupational status and speciality, to assess the extent to which access to dangerous means influences the pattern of suicide. Self-poisoning with drugs was more common in the doctors than in general population suicides (57% vs. 26.6%; OR=3.65, 95% CI 2.85-4. 68), including in retired doctors. Barbiturates were the most frequent drugs used. Half of the anaesthetists who died used anaesthetic agents. Self-cutting was also more frequently used as a method of suicide. The finding that the greater proportion of suicide deaths in doctors were by self-poisoning may reflect the fact that doctors have ready access to drugs, and have knowledge of which drugs and doses are likely to cause death. The specific finding that a large proportion of suicides in anaesthetists involved anaesthetic agents supports this explanation. Availability of method may be a factor contributing to the relatively high suicide rate of doctors. This fact might influence clinical management of doctors who are known to be depressed or suicidal.

Adult↗
PubMed1999

Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A.

The human p300/CBP-associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N- and C-terminal protein segments. A correlation of the structure with the extensive mutagenesis data for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N- and C-terminal protein segments as playing an important role in histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme-bound forms of the related N-acetyltransferases, HAT1 (yeast histone acetyltransferase 1) and SmAAT (Serratia marcescens aminoglycoside 3-N-acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure-function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.

Acetylation↗
PubMed1998

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia).

BACKGROUND: Impairments in both basal activity and activation of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in chronic fatigue syndrome (CFS; neurasthenia). We sought to replicate these findings and examined basal activity of the HPA in a carefully selected sample of patients with CFS. METHODS: Basal activity of the HPA was assessed using salivary and urinary cortisol collection over a 24-hour period in 22 (12 male; 10 female) patients meeting criteria for CFS and appropriate controls. RESULTS: Salivary and urinary cortisol measures did not differ between CFS patients and controls. CONCLUSIONS: Basal activity of the HPA was not reduced in CFS patients. Reasons for the failure to replicate previous findings are discussed.

Adult↗
PubMed1998

Clinical supervision: insider reports of a private world.

An exploratory study, funded by the Department of Health, London and the Scottish Home and Health Department, Edinburgh, was conducted over an 18-month period to provide an informed view on possible assessment tools that could be used to assess the impact of clinical supervision (CS) in nursing and to report on the CS activities in 23 selected sites in England and Scotland. The study not only examined the utility of several standardized research instruments, to be reported separately, but also explored the experience of a small sub-sample of nurses (n = 34) engaged in CS, as supervisors and supervisees. Interviews were undertaken to help better understand some of the issues involved around the domains of structure, process and outcome. Respondents reported an enthusiasm for the opportunity to talk meaningfully to a trusted colleague about their personal circumstances at work. Such opportunities were particularly welcomed by nurses who wished to reflect upon their own practice with patients, especially when dealing with their clinical conditions which were upsetting, or otherwise challenging, and sometimes harrowing. Substantive and methodological areas of interest for future research are suggested.

Adult↗
PubMed1997

Chronic fatigue syndrome: a qualitative investigation of patients' beliefs about the illness.

The chronic fatigue syndrome is a disabling chronic condition of uncertain cause. Previous studies have found that patients seen in hospital clinics with the syndrome often strongly believe that their illness is physical in nature and minimize the role of psychological and social factors. There is also evidence that patients cope by avoiding activity. However, almost all of these studies have assessed illness beliefs only by questionnaire. The aim of this study was to explore the nature and origin of illness beliefs in more detail using in-depth interviews and a qualitative analysis of patient responses. Sixty-six consecutive referrals meeting Oxford criteria for chronic fatigue syndrome were recruited. Analysis of responses indicated that, whereas the most commonly described explanation for the illness was a physical one, more than half the patients also believed "stress" had played a role. Patients believed that they could partially control the symptoms by reducing activity but felt helpless to influence the physical disease process and hence the course of the illness. Patients reported that they had arrived at these beliefs about the illness after prolonged reflection on their own experience combined with the reading of media reports, self help books, and patient group literature. The views of health professionals played a relatively small role. There is potentially a considerable opportunity to help patients arrive at a wider and more enabling explanation of their illness when they first present to primary care.

Adaptation, Psychological↗
PubMed1996

Increased prolactin response to buspirone in chronic fatigue syndrome.

We studied the endocrine and subjective responses that followed acute administration of the 5-HT1A receptor agonist buspirone (0.5 mg/kg orally) in 11 male patients with chronic fatigue syndrome (CFS) and a group of matched healthy controls. Patients with CFS had significantly higher plasma prolactin concentrations and experienced more nausea in response to buspirone than did controls. However, the growth hormone response to buspirone did not distinguish CFS patients from controls. Our data question whether the enhancement of buspirone-induced prolactin release in CFS is a consequence of increased sensitivity of post-synaptic 5-HT1A receptors. It is possible that the increased prolactin response to buspirone in CFS could reflect changes in dopamine function.

Adolescent↗
PubMed1996

Aggregation and metal-binding properties of mutant forms of the amyloid A beta peptide of Alzheimer's disease.

The fibrillogenic properties of Alzheimer's A beta peptides corresponding to residues 1-40 of the normal human sequence and to two mutant forms containing the replacement Ala21 to Gly or Glu22 to Gln were compared. At pH 7.4 and 37 degrees C the Gln22 peptide was found to aggregate and precipitate from solution faster than the normal A beta, whereas the Gly21 peptide aggregated much more slowly. Electron microscopy showed that the aggregates all had fibrillar structures. Circular dichroism spectra of these peptides revealed that aggregation of the normal and Gln22 sequences was associated with spectral changes consistent with a transformation from random coil to beta sheet, whereas the spectrum of the Gly21 peptide remained almost unchanged during a period in which little or no aggregation occurred. When immobilised by spotting onto nitrocellulose membranes the peptides bound similar amounts of the radioisotope 65Zn2+. Of several competing metal ions, tested at 20x the concentration of Zn2+, Cu2+ displaced > 95% of the radioactivity from all three peptides and Ni2+ produced >50% displacement in each case. Some other metal ions tested caused lesser displacement, but Fe2+ and Al3+ were without effect. In a saturation binding assay, a value of 3.2 microM was obtained for the binding of Zn2+ to A beta but our data provided no evidence for a reported higher affinity site (107 nM). The results suggest that the neuropathology associated with the Gly21 mutation is not due to enhanced fibrillogenic or different metal-binding properties of the peptide and that the binding of zinc to amyloid peptides is not a specific phenomenon.

Alzheimer Disease↗
PubMed1995

Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12.

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.

Chromosomes, Human, Pair 12↗
PubMed1994

Detection of Mycobacterium bovis infection in skin test-negative cattle with an assay for bovine interferon-gamma.

Mycobacterium bovis was isolated from respiratory secretions and lymph nodes from 15 skin test-negative cattle which exhibited interferon-gamma responses. These field cases, identified by blood testing, constituted a significant proportion of skin test-negative cattle which had been subjected to extensive post mortem examinations. Typical tuberculous lesions were found in seven of them. The consequences of cattle with early tuberculosis infection not being detected by traditional tuberculin testing are considered.

Animals↗
PubMed1993

Failure to find linkage between schizophrenia and genetic markers on chromosome 21.

We sought evidence for the involvement of mutations in the amyloid precursor protein gene (APP) in the pathogenesis of schizophrenia in two ways. First, linkage analysis was performed in a sample of 24 families multiply affected with schizophrenia. The genotypes were studied for GT12 (D21S210), a highly polymorphic microsatellite marker at the APP locus. Second, we used single strand conformation analysis (SSCA) to screen for mutations in exon 17 of APP in one affected member from each family and in a sample of 44 unrelated patients. In addition, we looked for linkage between schizophrenia and a series of highly polymorphic markers situated at approximately 20cM intervals along the long arm of chromosome 21. We were unable to find evidence for linkage to GT12 or the other markers studied. SSCA did not reveal any mutations in exon 17 of AP. We conclude that mutations within APP are an unlikely cause of schizophrenia. Moreover, this study provides no evidence for a major gene for schizophrenia on chromosome 21, and linkage can be excluded from much of this region under some genetic models.

Adult↗
PubMed1993

Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid beta/A4 peptide.

We assessed the fibrillogenic properties of synthetic peptides corresponding to residues 13-26 of beta/A4 amyloid, containing either the normal sequence (beta 13 26) or the mutations Glu22 to Gln (beta 13-26Q22) and Ala21 to Gly (beta 13-26G21). The kinetics of aggregation were monitored at 37 degrees C and pH 7.4 by measuring the amount of peptide remaining in solution, using reverse-phase high performance liquid chromatography. Negative stain electron microscopy revealed that all of the peptides formed fibrils. However, beta 13-26Q22 showed greatly accelerated fibril formation compared to the other two. The results suggest that the Q22 mutation confers increased amyloidogenic properties on the beta/A4 peptide, whereas the G21 mutation acts by a different pathogenic mechanism.

Alanine↗
PubMed1992

No evidence for a pseudoautosomal locus for schizophrenia. Linkage analysis of multiply affected families.

Evidence for a pseudoautosomal locus for a schizophrenia susceptibility gene was sought by two forms of analysis of 25 multiply affected families. Firstly, in the sample as a whole there was an excess of same-sex over mixed-sex siblings compared with that expected. Secondly, linkage analysis was performed in six of the families. The genotypes were studied for DXYS14, a highly polymorphic marker in the telomeric pseudoautosomal region. No evidence for positive linkage was found with two-point analysis under eight different genetic models for the mode of transmission. A non-parametric, sibling-pair analysis also failed to detect linkage. Our findings provide no evidence for linkage within the pseudoautosomal region; same-sex concordance must arise from some other mechanism.

Blotting, Southern↗