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Biomedical subjects

A Clements

Publications and source records attributed to A Clements.

At least 19 recordsLinked to original sources
PubMed2002

Suicide in female nurses in England and Wales.

BACKGROUND: Female nurses appear to have an increased risk of suicide but the reasons are unknown. METHOD: We have concluded a study of nurse suicides (N = 106) in England and Wales, including a psychological autopsy study (N = 42) and case-control comparison with living nurses (N = 84). RESULTS: Nearly three-quarters of the nurse suicides had previous contact with psychiatric services and almost half had been psychiatric in-patients in the past. There were particularly marked differences between the cases and controls for current psychiatric disorder (90.5% v. 7.1%, OR = 68.5), personality disorder (38.1% v. 12%, OR = 32), and history of deliberate self-harm (71.4% v. 2.4%, OR = 58.5). Family background and social factors (especially concerning interpersonal relationships) also distinguished the two groups. Smoking and serious alcohol abuse were much more frequent in the suicides. There was some indication that while many of the suicides were in contact with psychiatric services, care may not have been optimal in some cases. CONCLUSIONS: The most important strategies for suicide prevention in nurses are in prevention, detection and management of psychiatric disorders. In assessing suicide risk a history of DSH and the presence of comorbid psychiatric and personality disorders are particularly important.

Adult↗
PubMed2001

Crystal structure of the mouse p53 core DNA-binding domain at 2.7 A resolution.

The p53 tumor suppressor is a sequence-specific DNA-binding protein that activates transcription in response to DNA damage to promote cell cycle arrest or apoptosis. The p53 protein functions in a tetrameric form in vivo and contains four domains including an N-terminal transcriptional activation domain, a C-terminal regulatory domain, a tetramerization domain, and a central core DNA-binding domain that is the site of the majority of tumor-derived mutations. Here we report the 2.7-A crystal structure of the mouse p53 core domain. Like the human p53 core domain in complex with DNA, the mouse p53 core domain adopts an immunoglobulin-like beta sandwich architecture with a series of loops and short helices at opposite ends of the beta sandwich. Comparison of the DNA-bound and DNA-free p53 core domains reveals that while the central beta sandwich architecture remains largely unchanged, a loop region important for DNA binding undergoes significant rearrangement. Although this loop region mediates major groove DNA contacts in the DNA-bound structure, it adopts a conformation that is incompatible with DNA binding in the DNA-free structure. Interestingly, crystals of the DNA-free core domain contain a noncrystallographic trimer with three nearly identical subunit-subunit (dimer) contacts. These dimer contacts align the p53 core domains in a way that is incompatible with simultaneous DNA binding by both protomers of the dimer. Surprisingly, similar dimer contacts are observed in crystals of the human p53 core domain with DNA in which only one of the three p53 protomers in the asymmetric unit cell is specifically bound to DNA. We propose that the p53 core domain dimer that is seen in the crystals described here represents a physiologically relevant inactive form of p53 that must undergo structural rearrangement for sequence-specific DNA binding.

Animals↗
PubMed2001

Generation and characterization of monoclonal antibodies against the E6 and E7 oncoproteins of HPV.

Generation of three monoclonal antibodies (MAbs) to the major oncoproteins of human papillomavirus (HPV) was accomplished by an intense prime/boost regimen. Mice were primed with expression vectors expressing either the E6 or E7 oncoproteins of HPV-16 followed by boosting with a vaccinia virus construct and a replication-defective E1-deleted adenoviral recombinant of the human strain 5, and last, with baculovirus-derived HPV-16 E6 and E7 proteins in incomplete Freunds' adjuvant. Splenocytes were then fused with a myeloma cell line. The vaccination protocol generated one anti-E7 MAb of the IgM isotype and two anti-E6 MAbs of the IgG1 subisotype. The MAbs were tested for functionality in standard laboratory assays and found to detect the E6 and E7 proteins, respectively. The E7 MAb cross-reacted with the HPV-1a E7 oncoprotein. The binding sites of the MAbs were mapped to defined regions of each viral protein.

Amino Acid Sequence↗
PubMed2001

Suicide in doctors: a study of risk according to gender, seniority and specialty in medical practitioners in England and Wales, 1979-1995.

STUDY OBJECTIVE: To investigate the suicide risk of doctors in England and Wales, according to gender, seniority and specialty. DESIGN: Retrospective cohort study. Suicide rates calculated by gender, age, specialty, seniority and time period. Standardised mortality ratios calculated for suicide (1991-1995), adjusted for age and sex. SETTING: England and Wales. SUBJECTS: Doctors in the National Health Service who died by suicide between 1979 and 1995, identified by death certificates. Population at risk based on Department of Health manpower data. MAIN RESULTS: Two hundred and twenty three medical practitioners in the National Health Service who died by suicide or undetermined cause were identified. The annual suicide rates in male and female doctors were 19.2 and 18.8 per 100 000 respectively. The suicide rate in female doctors was higher than in the general population (SMR 201.8; 95% CI 99.7, 303.9), whereas the rate in male doctors was less than that of the general population (SMR 66.8; 95% CI 46.6, 87.0). The difference between the mortality ratios of the female and male doctors was statistically significant (p=0.01), although the absolute suicide risk was similar in the two genders. There were significant differences between specialties (p=0.0001), with anaesthetists, community health doctors, general practitioners and psychiatrists having significantly increased rates compared with doctors in general hospital medicine. There were no differences with regard to seniority and time period. CONCLUSIONS: There is an increased risk of suicide in female doctors, but male doctors seem to be at less risk than men in the general population. The excess risk of suicide in female doctors highlights the need to tackle stress and mental health problems in doctors more effectively. The risk requires particular monitoring in the light of the very large increase in the numbers of women entering medicine.

Adult↗
PubMed2001

How some HIV clinics handle substance abuse.

HIV providers routinely deal with substance use issues that sometimes affect patients' ability to adhere to antiretroviral therapy. For this reason, some HIV clinics and AIDS service organizations in major cities have started their own substance use programs, ranging from inpatient care to day treatment and counseling. Here's a quick look at what is bring offered.

Ambulatory Care Facilities↗
PubMed2001

Evaluation of the impact of two educational interventions on GP management of familial breast/ovarian cancer cases: a cluster randomised controlled trial.

BACKGROUND: It has been suggested that primary care should become more involved in providing genetic services, such as basic risk assessment, to enable patients with a moderate/high risk to be referred and those with a low risk to receive reassurance and advice from their general practitioner (GP). However, GPs currently lack knowledge and confidence in this area. AIM: To investigate the effect of an in-practice educational session and information pack on GP management of familial breast/ovarian cancer cases. DESIGN OF STUDY: Cluster randomised controlled trial. SETTING: GP principals in 170 practices in Oxfordshire and Northamptonshire. Of the 688 GPs, 426 (62%) participated. METHOD: Practices were randomised either to Group A (receiving an inpractice educational session plus information pack), Group B (receiving an information pack alone), or Group C (receiving neither an educational session nor a pack). The main study outcome was the proportion of GPs making the correct referral decision on at least five out of six family history vignettes. A secondary outcome was GPs' reported confidence in managing patients with a family history of breast/ovarian cancer, measured by a score that was generated by combining responses to four questions. RESULTS: There was a 40% (95% CI = 30-50%, P < 0.001) improvement in the proportion of GPs who made the correct referral decision on at least five out of the six vignettes in Group A (111/140 [79%]) compared with Group C (controls) (63/162 [39%]), and a 42% (95% CI = 31-52%, P < 0.001) improvement in Group B (100/124 [81%]) compared with the control group. There was a trend in reported confidence in the management of individuals with a family history of breast/ovarian cancer from a mean confidence score of 2.3 in Group A to 2.0 in Group B and 1.5 in Group C (P < 0.001). CONCLUSION: Providing GPs with an information pack significantly improved referral decisions regarding patients with a family history of breast/ovarian cancer. Although extremely well received, an in-house educational session produced no additional improvements. There were, however, greater levels of reported confidence in the group who received the educational session in addition to the information pack.

Breast Neoplasms↗
PubMed2000

Oligomerization properties of the viral oncoproteins adenovirus E1A and human papillomavirus E7 and their complexes with the retinoblastoma protein.

Human papillomavirus 16 E7 (HPV16 E7) and adenovirus 5 E1A (Ad5 E1A) are encoded by highly divergent viruses yet are functionally similar in their ability to bind the retinoblastoma (pRB) tumor suppressor protein, causing the aberrant displacement of E2F trancription factors. The amino acid residues of HPV16 E7 that are necessary for stability, for inhibition of pRB function, and for cell transformation are also necessary for E7 oligomerization. However, neither the specific oligomerization state of HPV16 E7 nor of Ad5 E1A as a function of pRB-binding has been characterized. To gain insight into HPV16 E7 and Ad5 E1A oligomerization properties, sedimentation equilibrium experiments were performed with recombinant HPV16 E7 and Ad5 E1A proteins. These studies reveal that, despite the overall functional similarities between these proteins, monomers, dimers, and tetramers of HPV16 E7 were detected while only reversible monomer-dimer association was identified for Ad5 E1A. The apparent K(d(monomer)-(dimer)) of HPV16 E7 is approximately 100-fold lower than that of a comparable region of Ad5 E1A, and it is concluded that under physiological protein concentrations HPV16 E7 exists primarily as a dimer. Sedimentation equilibrium experiments of pRB/Ad5 E1A and of pRB/HPV16 E7 complexes demonstrate that the tight association of pRB with the viral oncoproteins does not disturb their inherent oligomerization properties. Taken together, this study demonstrates significant differences between the Ad5 E1A and HPV16 E7 oligomerization states that are potentially related to their distinct structures and specific mechanisms of pRB-inactivation.

Adenovirus E1A Proteins↗
PubMed2000

Coexpression of proteins in bacteria using T7-based expression plasmids: expression of heteromeric cell-cycle and transcriptional regulatory complexes.

This report describes the development and application of a dual vector coexpression system for the overproduction of heteromeric cell cycle and transcriptional regulatory protein complexes in bacteria. To facilitate these studies we constructed a T7-based expression plasmid, pRM1 that contains an origin of replication derived from p15A, and a gene encoding kanamycin resistance. This expression vector is compatible with ColE1-derived plasmids found in the pET family of T7 expression vectors, which encode ampicillin resistance. It also has the same multiple cloning sites as the pET- derived pRSET vector, allowing easy shuttling between the two expression vectors. Cotransformation of the pRM1 and pET-derived expression vectors into an Escherichia coli strain such as BL21(DE3) results in a significant level of coexpression of heteromeric protein complexes. We demonstrate the applicability of combining the pRM1 and pET-derived vectors for the coexpression of cell cycle regulatory components, pRB/E7 and pRB/E1a, and the transcriptional regulatory complexes, SRF/SAP-1 and SRF/Elk-1. We further use the pRB/E1a complex to demonstrate that these coexpressed complexes can be purified to homogeneity for further studies. Use of the pRM1 vector in combination with the pET-derived vectors should be generally applicable for the large-scale coexpression and purification of a wide variety of heteromeric protein complexes for biochemical, biophysical, and structural studies.

Bacteriophage T7↗
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↗