Biomedical subjects
Publications and source records attributed to S Bailey.
Using a variety of alpha-hydroxy hydroxamic acid derivatives, the size and shape of the S1' pocket for the CD23 processing metalloprotease has been explored. It has been demonstrated that a P1' 2-naphthylmethyl group occupies most of the available space and gives excellent selectivity against fibroblast collagenase (matrix metalloproteinase-1, MMP-1) and other MMPs.
Improved assays for the molybdenum enzyme dimethylsulfoxide reductase (DMSOR) with dimethyl sulfoxide (DMSO) and with dimethyl sulfide (DMS) as substrates are described. Maximum activity was observed at pH 6.5 and below and at 8.3, respectively. Rapid-scan stopped-flow spectrophotometry has been used to investigate the reduction of the enzyme by DMS to a species previously characterized by its UV-visible spectrum [McAlpine, A. S., McEwan, A. G., and Bailey, S. (1998) J. Mol. Biol. 275, 613-623], and its subsequent reoxidation by DMSO. Both these two-electron reactions were faster than enzyme turnover under steady-state conditions, indicating that one-electron reactions with artificial dyes were rate-limiting. Second-order rate constants for the two-electron reduction and reoxidation reactions at pH 5.5 were (1.9 +/- 0.1) x 10(5) and (4.3 +/- 0.3) x 10(2) M-1 s-1, respectively, while at pH 8.0, the catalytic step was rate-limiting (62 s-1). Kinetically, for the two-electron reactions, the enzyme is more effective in DMS oxidation than in DMSO reduction. Reduction of DMSOR by DMS was incomplete below approximately 1 mM DMS but complete at higher concentrations, implying that the enzyme's redox potential is slightly higher than that of the DMS-DMSO couple. In contrast, reoxidation of the DMS-reduced state by DMSO was always incomplete, regardless of the DMSO concentration. Evidence for the existence of a spectroscopically indistinguishable reduced state, which could not be reoxidized by DMSO, was obtained. Brief reaction (less than approximately 15 min) of DMS with DMSOR was fully reversible on removal of the DMS. However, in the presence of excess DMS, a further slow reaction occurred aerobically, but not anaerobically, to yield a stable enzyme form having a lambdamax at 660 mn. This state (DMSORmod) retained full activity in steady-state assays with DMSO, but was inactive toward DMS. It could however be reconverted to the original resting state by reduction with methyl viologen radical and reoxidation with DMSO. We suggest that in this enzyme form two of the dithiolene ligands of the molybdenum have dissociated and formed a disulfide. The implications of this new species are discussed in relation both to conflicting published information for DMSOR from X-ray crystallography and to previous spectroscopic data for its reduced forms.
This paper reports on the health needs of a sample of juvenile offenders appearing before a Manchester Court during the month of August 1992. Of the 192 subjects interviewed (74% of those listed), 19% had significant medical problems, 42% a history of substance abuse and 7% psychiatric problems requiring further treatment. Substantial numbers (26%) engaged in a variety of dangerous behaviours. Custodial remands were common (21%), particularly in those with multiple psychosocial difficulties.
Glucocorticoids have been used in the treatment of acute lymphoblastic leukaemia (ALL) for many years, initially as the only agent and then as part of multiagent chemotherapy. In ALL 20% of patients are resistant to glucocorticoids at presentation but this rises to greater than 70% on relapse. It has recently been reported that the glucocorticoid receptor inhibits activity of the AP-1 transcription factor by the ligand-dependant binding of glucocorticoid receptor (GR) to the fos and jun components of AP-1. Since AP-1 is necessary for cell proliferation, the upregulation or over-expression of AP-1 may be a mechanism of resistance to glucocorticoids. The aim of the study was to investigate whether AP-1 levels correlate with in vitro glucocorticoid resistance. In vitro sensitivity to glucocorticoids was measured using the MTT assay. AP-1 levels were quantified using gel shift analysis: a consensus sequence for the AP-1 binding site was synthesised, labelled with 32P and incubated with nuclear extracts of leukaemic blasts from 14 ALL and 26 CLL patients. Leukaemic blasts were treated with prednisolone or with vehicle alone before preparation of nuclear extracts. The gels were dried and bands quantified using a phosphorimager, using an appropriate internal standard and correcting for protein loading and cytoplasmic contamination of nuclear extracts. The patient samples fell into two distinct groups with respect to their sensitivity to glucocorticoids: AP-1 levels were significantly higher (p < 0.02) in sensitive blasts than resistant ones. There was no significant change in AP-1 levels after treating blasts for 4 hours with 0.2 mM prednisolone. No change was seen in CLL samples. These data show that glucocorticoid resistance is not associated with increased AP-1. Conversely, glucocorticoid resistance in these samples was apparently associated with decreased AP-1 levels in ALL samples. Whether this has any causal relationship to glucocorticoid resistance is unknown. Clearly, further studies on the role of AP-1 and related transcription factors is essential for understanding the control of proliferation and apoptosis in ALL.
BACKGROUND: Practicum training for preventive medicine residents often occurs in agencies whose community is geographically defined and whose governance is closely linked to public election. We were unsure about the financial ability of such departments to support training and are concerned that over-reliance on traditional health departments might not be best for either medically indigent populations or preventive medicine. We, therefore, sought to apply a public health model--based on a strategic partnership between nursing and preventive medicine--to a large health care organization. The result was formation of a mini-health department, suitable for fully accredited preventive medicine practicum training, within the Alvin C. York Veterans Affairs Medical Center, Murfreesboro, TN. This Center serves a defined population of 21,594 patients and about 1600 employees. The theoretical framework for the new department was based on demonstration of a close fit between the competencies expected of preventive medicine physicians by the American College of Preventive Medicine (ACPM) and activities required by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Because of JCAHO requirements, many healthcare organizations already pay for preventive medicine services. CONCLUSIONS: By placing preventive medicine training faculty into existing budget slots at our institution, systemwide personnel costs for prevention decreased by about $36,000 per year, even as personnel funding for preventive medicine physicians increased from about $24,000 to $376,000 per year. Moreover, there was dramatic, sustained improvement in 17 indicators of preventive care quality as determined by an external peer review organization. In addition to providing a new venue for training, this model may also improve the quality and reach of preventive services, decreased fixed costs for service delivery, and yield new employment opportunities for preventive medicine physicians.
BACKGROUND: For adolescents, there is no specific needs assessment instrument that assesses significant problems that can benefit from specified interventions. A new instrument (S.NASA) was developed by incorporating and adapting three well established adult needs assessment instruments. The S.NASA covers 21 areas of functioning including social, psychiatric, educational and life skills. METHOD: Client and carer interviews were conducted by different researchers. A week later the interviews were repeated using a crossover design. Significant (cardinal) problems were generated from the clinical interviews using a pre-defined algorithm. Final need status (three categories) was made by clinicians assessing the cardinal problems against defined interventions. The interventions were generated from discussions with clinicians and a survey of appropriate professionals working with adolescents. RESULTS. Pre-piloting led to the final version being administered to 40 adolescents from secure units, forensic psychiatric and adolescent psychiatric services. There were 25 males and 15 females, mean age 15.5 years. Overall there were moderate to good inter-rater and test-retest reliability coefficients, the test-retest reliability coefficients for the total scores on the needs assessment interviews ranged from 0.73 to 0.85. Consensual and face validity was good, the adolescents and staff finding the instrument useful and helpful. CONCLUSIONS: This new needs assessment instrument shows acceptable psychometric properties. It should be of use in research projects assessing the needs and the provision of services for adolescents with complex and chronic problems.
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With more and more people choosing to die at home, palliative care is an increasingly important field. The challenge for those of us working in the field is to develop a comprehensive system of care that will provide high quality, in-home support. Such support involves a large network of formal and informal caregivers--family members, caregiving friends, homemakers and a variety of health care providers--who collaborate together and with the individual to provide holistic care. Thus, co-ordination, collaboration and communication are essential if this network is to meet the physical, psychological, social and spiritual needs of the dying and their families.
This article describes the first results from the recent revision to The ONS classification of local and health authorities of Great Britain to allow for boundary changes. For each local and health authority of Great Britain as at April 1999 it presents 'most similar' authorities as measured by a selection of 37 socioeconomic and demographic variables from the 1991 Census. These results will assist local and health authorities in identifying other appropriate authorities for comparative studies. A second article, to be published in Population Trends 99, will present the results of the analysis to identify groups of authorities in a hierarchy of new Clusters, Groups and Families for the revised classification.
Since the transfer of nursing education from hospitals to tertiary institutions, debate regarding the competence of new graduates has continued. To date this issue has not been thoroughly researched. The lack of research related to the competence of degree graduates in New Zealand provided the impetus for this study, which was aimed toward identifying how graduates perceived their clinical performance during their first year of practice. A convenience sample of 30 graduates was surveyed after 3 months and 7 months in practice, using an adapted form of a questionnaire devised by Ryan and Hodson (1992). The results showed that over time, graduates generally required less direction in all areas of clinical competence. After 7 months in practice, the majority of the graduates rated their performance in nursing skills, communication skills, and professionalism at the expected level or above. However, some still required direction with using theory and research in practice, with meeting client's psychosocial needs and with teaching clients. In the leadership competency, after 7 months, most graduates saw themselves functioning at the expected level related to client care and needed less direction in unit management skills. However, many of the unit management skills were rated as 'not applicable' indicating that new graduates are not initially placed in a management role. Implications for nursing education and limitations of the research are discussed.
"Debates about United States border control policies have generally ignored the human costs of undocumented migration. We focus attention on these costs by estimating the number, causes and location of migrant deaths at the southwest border of the United States between 1993 and 1997.... Deaths from hyperthermia, hypothermia and dehydration increased sharply from 1993 to 1997 as intensified border enforcement redirected undocumented migration flows from urban crossing points to more remote crossing areas where the migrants are exposed to a greater risk of death."
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The crystal structure of the molybdenum enzyme dimethylsulphoxide reductase (DMSOR) has been determined at 1.9 A resolution with substrate bound at the active site. DMSOR is an oxotransferase which catalyses the reduction of dimethylsulphoxide (DMSO) to dimethylsulphide (DMS) in a two stage reaction which is linked to oxygen atom transfer and electron transfer. In the first step, DMSO binds to reduced (Mo(IV)) enzyme, the enzyme is oxidised to Mo(VI) with an extra oxygen ligand and DMS is released. Regeneration of reduced enzyme is achieved by transfer of two electrons, successively from a specific cytochrome, and release of the oxygen as water. The enzyme, purified under aerobic conditions, is in the oxidised (Mo(VI)) state. Addition of a large excess of DMS to the oxidised enzyme in solution causes a change in the absorption spectrum of the enzyme. The same reaction occurs within crystals of the enzyme and the crystal structure reveals a complex with DMSO bound to the molybdenum via its oxygen atom. X-ray edge data indicate that the metal is in the Mo(IV) state. The DMSO ligand replaces one of the two oxo groups which ligate the oxidised form of the enzyme, suggesting very strongly that this is the oxygen which is transferred during catalysis. Residues 384 to 390, disordered in the oxidised enzyme, are now clearly seen in the cleft leading to the active site. The side-chain of Trp388 forms a lid trapping the substrate/product.
A series of hydroxamic acids related to the non-selective matrix metalloprotease inhibitor Batimastat is described, which inhibits the proteolytic cleavage of the low affinity IgE receptor from cell membrane preparations. Limited SAR studies suggest that the structural requirements for effective inhibition are distinct from those required for the inhibition of collagenase.
A series of hydroxamic acids related to the non-selective matrix metalloproteinase inhibitor Batimastat has been prepared, some members of which are potent inhibitors of the processing of the low affinity IgE receptor (CD 23). Increased activity is obtained by appropriate substitution at the alpha-position, whilst selectivity is gained by use of a P1' benzyl group in conjunction with a C-terminal primary amide.
A study was made of the perceptions among relevant service providers of the mental health needs of young people considered for secure placement. Information was obtained in 1996 from 75% of departments of child and adolescent psychiatry, forensic psychiatry, social services children's services, youth justice, probation, secure units and young offender institutions in England and Wales. The findings confirm that highly disturbed young people, who may be a danger to themselves and others, may present to a wide range of services, and that their mental health needs are neither well recognized, widely understood, nor adequately met. Availability of appropriate levels and types of expertise and resource is patchy and strictly limited, within secure settings and in local community services across all agencies.
There is a paucity of literature relating to adolescent females who offend. This retrospective case note study of 100 consecutive referrals of girls aged 11-17 in care to an Adolescent Forensic Mental Health Service describes a group of disturbed girls at the extreme of the continuum. Sixty-eight girls had assaulted at least one person; a further 10 had caused damage to objects; 76 had deliberately harmed themselves; 90 had behaved in a way which was against the law in the 6 months prior to assessment, although only 42 had been charged with an offence. The referrers only correctly documented violent and aggressive behaviours in 54% of cases. Eleven girls had ever been statemented as having special educational needs. Seventy-one had been abused in some way, the majority having been multiply abused. Of the violent girls, 50% had misused substances. More abused girls had been violent to objects (49.3%) or set fires (21.1%). A high number of deliberately self-harming girls had a mental illness (13.6%), and a significantly high number of deliberately self-harming girls misused substances (50%) and had been sexually abused (53.9%). Areas for future research are discussed.