Search PubMed⌕ Search

Biomedical subjects

S Harrison

Publications and source records attributed to S Harrison.

At least 73 records · Page 4Linked to original sources
PubMed1996

End of the line? Tramtrack and cell fate determination in Drosophila.

Cell differentiation reflects the balance of two opposing influences, pathways which confer specialized properties on specific cells or groups of cells, and antagonising mechanisms which modulate responsiveness to such differentiative cues. It appears that the zinc finger protein Tramtrack (Ttk) fulfils the latter function in the CNS and PNS of Drosophila. Ttk seems to be able to inhibit neural development by down-regulating competence to respond to neuralising signals. We speculate, however, that restriction of neural competence is merely one example of a more general ability of Ttk to influence differentiation and that, given its widespread expression profile, Ttk might be implicated in a number of differentiative events.

Animals↗
PubMed1996

Health Management Guide. Disease management.

Disease management has been described as a comprehensive, integrated approach to care and reimbursement based on the natural course of a disease. It requires a management approach which brings together research evidence, best practice and inter-professional and inter-agency working. Starting with the ideal of continuity of care for individual patients, it implies structured co-ordination of care over time and across primary, secondary and tertiary settings. The appeal of disease management is that it promises reduced costs, combined with increased quality of care and patient satisfaction. But the concept is open to different definitions and interpretations and its effectiveness in improving UK healthcare is still largely untested. This Health Management Guide removes the mystique behind disease management and puts it in the context of existing knowledge and practice. Treating it as a concept, rather than a specific technique, it distinguishes between its different potential applications, offers practical guidance on implementation, and reports on how NHS organisations are taking it forward.

Asthma↗
PubMed1996

General practice fundholding in the UK National Health Service: evidence to date.

The published evidence on the effects of General Practitioner Fundholding, a major feature of the 1991 reorganization of the UK National Health Service, is reviewed with regard to the source and character of the evidence, as well as the findings on the outputs (including referrals, prescribing, service shifts, and the attitudes of various actors); the processes (inter- and intra-organizational); and the inputs (costs). An overall assessment based on this evidence is presented; the latest political and organisational developments in NHS primary care are outlined; and the future of GP fundholding is discussed.

Cost-Benefit Analysis↗
PubMed1995

The eastern Australian childhood nevus study: prevalence of atypical nevi, congenital nevus-like nevi, and other pigmented lesions.

BACKGROUND: Various melanocytic lesions are frequently observed. An understanding of phenotypic factors and environmental stimuli that are associated with these lesions may help explain their pathogenesis. OBJECTIVE: This study was undertaken to determine the prevalence of atypical nevi, blue nevi, cafe-au-lait macules, congenital nevus-like nevi, halo nevi, nevi spili, nevi 5 mm or more in diameter, and skin-colored melanocytic nevi in a population of schoolchildren and to explore risk factors including solar radiation in the development of these melanocytic lesions. METHODS: A cross-sectional study was performed by the same medical investigators to examine schoolchildren in three Australian cities that span a wide range of latitudes. RESULTS: Data from 1123 white Australian schoolchildren, 6 to 15 years of age, were analyzed. Acquired melanocytic nevi (atypical nevi, nevi > or = 5 mm in diameter, and skin-colored nevi) were more likely to develop in older fair-skinned subjects who had freckles and lived closest to the equator. Café-au-lait macules and congenital nevus-like nevi were observed in 36.3% and 4.4% of the total population, respectively. Prevalence for both these types of melanocytic lesions increased significantly with decreasing latitude. Halo nevi were present in 5.3% of the subjects and were usually solitary. These lesions were related to the presence of atypical nevi primarily by virtue of their size rather than of other features of clinical atypia. CONCLUSION: Like melanocytic nevi in general, large and atypical nevi are strongly influenced by geographic location and, by implication, degree of solar radiation. The same can be said for congenital nevus-like nevi, which suggests that many so-called congenital nevi are in fact acquired early in life.

Adolescent↗
PubMed1995

A cluster of cases of streptococcal necrotizing fasciitis in Gloucestershire.

We describe the first cluster of cases of necrotizing fasciitis (NF) in this century in the United Kingdom (UK). Between 1 January and 30 June 1994 there were six cases (five confirmed, one probable) of Streptococcus pyogenes NF in west Gloucestershire, population 320,000. Two cases died. The first two patients probably acquired their infections during the course of elective surgery performed in the same operating theatre, possibly from a nasopharyngeal carrier amongst the theatre staff. The remaining infections were community-acquired. Of 5 S. pyogenes isolates there were 2 M1 strains, 1 M3, 1 M5 and 1 M non-typeable strain. S. pyogenes NF had not been recorded in west Gloucestershire in the preceding 10 years and the incidence of S. pyogenes bacteraemia in England and Wales had not risen in the past 5 years. The two presumably theatre-acquired infections raised several issues. The need for detailed bacteriological investigation of all cases of post-surgical NF was confirmed. Clusters of S. pyogenes infection following surgery should be managed by closure of the operating theatre until all staff have been screened for carriage. Closure of an operating theatre and screening of staff following a sporadic case is probably not justified because of the infrequency of surgical cross-infection with S. pyogenes. Regular, routine screening of theatre staff is neither practical nor necessary.

Aged↗
PubMed1995

A policy agenda for health care rationing.

In any system of third party payment for health care, such care will be rationed. A clear policy agenda will be focused upon three questions: Who should ration? What mechanisms should exist for making and implementing rationing decisions? What are the criteria by which rationing should occur?

Decision Making↗
PubMed1995

Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus.

1. We have investigated the role of phosphodiesterase isoenzymes in modulating electric field stimulation (EFS), substance P and capsaicin-induced contraction of the guinea-pig isolated main bronchus. 2. Non-adrenergic non-cholinergic contractile responses were elicited by EFS (3 Hz, 20 s) in the guinea-pig isolated main bronchus in the presence of the non-selective muscarinic antagonist, atropine (0.1 microM), the non-selective beta-adrenoceptor antagonist, propranolol (1 microM), the neutral endopeptidase inhibitor, thiorphan (10 microM) and the cyclo-oxygenase inhibitor, indomethacin (5 microM). The type III, type III/IV, type IV and type V phosphodiesterase isoenzyme inhibitor, SKF 94836, benzafentrine, Ro-20-1724 and zaprinast respectively, significantly attenuated the contractile response to EFS. The IC50 (95% confidence limits) value for SKF 94836, benzafentrine, Ro-20-1724 and zaprinast was 8.3 microM (0.89-78); 0.7 microM (0.1-4.5); 0.5 microM (0.2-1.2) and 13 microM (2-87) respectively. 3. The phosphodiesterase isoenzyme inhibitors, SKF 94836, Ro-20-1724 and zaprinast, partially attenuated the contractile response to substance P (10 nM). Benzafentrine significantly inhibited the contractile response to substance P, yielding an IC50 value of 1.9 microM (0.9-3.8). 4. The phosphodiesterase isoenzyme inhibitor, Ro-20-1724 (0.1-100 microM) failed to reduce significantly the contractile potency of capsaicin (P > 0.05). In contrast, SKF 94836 (1 microM), benzafentrine (10 microM) and zaprinast (100 microM) significantly reduced the contractile potency of capsaicin (P < 0.05). 5 The selective phosphodiesterase isoenzyme inhibitors, SKF 94836, benzafentrine, Ro-20-1724 andzaprinast (0.01-100 microM) reversed in a concentration-dependent manner the contractile response toexogenously administered capsaicin (EC50) yielding ICm values of 3.91 microM (0.68-22); 3.37 microM (1.86-6.11); 0.366 microM (0.201-0.564) and 50.1 microM (18.6- 135) respectively.6 In conclusion, phosphodiesterase isoenzymes appear to regulate the contractile response to electricalfield stimulation and our results provide circumstantial evidence for a regulatory role ofphosphodiesterase type IV isoenzyme on sensory nerve function in vitro.

Animals↗
PubMed1995

Early responses of trans-activating factors to growth hormone in preadipocytes: differential regulation of CCAAT enhancer-binding protein-beta (C/EBP beta) and C/EBP delta.

Using the 3T3-F442A preadipocyte line as a model of GH-dependent differentiation, early changes in the DNA-binding affinity of transcription factors in response to GH addition were investigated. Addition of 50 ng/ml human GH to cells in chemically defined medium led to a rapid increase in binding activity of activator protein 1 (AP-1) and CCAAT enhancer-binding protein (C/EBP), which was significant at 30 min and reached maximal induction by 2 h (3-fold for AP-1, 2.5-fold for C/EBP). Induction in AP-1 DNA binding correlates with a concomitant GH trans-activation of c-jun and c-fos genes described previously. Using specific antibodies in electrophoretic mobility shift assays and Western blots, it was shown that the increase in activity of C/EBP is the result of an increase in synthesis of two alternatively translated forms of C/EBP beta: 40-C/EBP beta and 23-C/EBP beta. This increase in protein was not accompanied by alteration in mRNA level and could be blocked by a Janus kinase 2 tyrosine kinase inhibitor and a C kinase inhibitor at concentrations shown to inhibit GH-dependent activation of microtubule-associated protein (MAP) kinases. Concomitant with the translationally activated increase in C/EBP beta, a GH-dependent increase was observed in C/EBP delta transcription. This was accompanied by an increase in mRNA for C/EBP delta, which was superinduced by cycloheximide and, unlike the increase in C/EBP beta protein, was not observed with insulin. Thus GH exerts its effects on C/EBP isoforms at two levels: transcriptional activation of C/EBP delta and translational activation of C/EBP beta. It is proposed that GH-dependent phosphorylation results in the efficient translation of 40-C/EBP beta and 23-C/EBP beta (the mouse homolog of the inhibitor liver-enriched inhibitory protein), and that together with the induction of C/EBP delta, these may be involved in initiating the adipocyte differentiation program.

3T3 Cells↗
PubMed1995

Localization of the response elements of a gene induced by intermittent growth hormone stimulation.

Three regions required for the expression of a mouse major urinary protein (MUP) transgene were identified by a deletion analysis. One of these was located upstream of the cap site between -2139 and -1800, another was the proximal promoter region downstream of -324 and the third lay within the 338 nucleotide intron 1. Both the proximal promoter and intron 1 are involved in sexually dimorphic expression of the transgene (male/female ratio 20), which is dictated by the different temporal profiles of circulating GH in the two sexes. The data also indicated that the region between exons 3 and 7 may contribute to full expression in males and that a region between -718 and -324 may contribute towards the low expression level that obtains in females, but compared with the three principal regions the effects of these regions are relatively minor. We propose (1) that full expression of the transgene requires the co-operation of transcription factors bindings to the three principal regions and (2) that the difference in expression between the sexes relates to interactions between transcription factors bound to the proximal promoter and to sites in intron 1. Our results complement earlier in vitro footprinting and gel-retardation studies of the homologous rat apha 2u-globulin genes. These identified a number of response elements, including putative C/EBP and AP1 sites in the proximal promoter and intron 1 respectively and three putative psi NF-1 sites, two in the proximal promoter and one in intron 1, but proof of the functionality of these sites in regulating transcription was lacking. The proximal promoter also contained a 34 nucleotide sequence that has 70% identity with the SPI GH response element.

Alpha-Globulins↗
PubMed1994

Non-specific effects of the tachykinin NK1 receptor antagonist, CP-99,994, in antinociceptive tests in rat, mouse and gerbil.

We have examined the antinociceptive activity of the potent and selective tachykinin NK1 receptor antagonist, CP-99,994, and its less active enantiomer, CP-100,263, in a variety of models in rat, mouse and gerbil. Administered systemically to gerbil or mouse CP-99,994 but not CP-100,263 stereo selectively inhibited a caudally directed biting and scratching elicited by intrathecal administration of the tachykinin NK1 receptor agonist, GR73632. In contrast, both CP-99,994 (ED50 = 3 (1-6) mumol.kg-1 s.c.) and CP-100,263 (4 (2-10)), were equipotent at inhibiting acetylcholine-induced abdominal constrictions in mice. Similarly, both enantiomers were also equipotent in reducing formalin-induced licking in gerbil (CP-99,994 (10.1 (5.7-18.6)), CP-100,263 (13.8 (7.8-27.1)) and rat (100 mumol.kg-1 s.c.). Finally, in the spinalised, anaesthetised rat, CP-99,994 dose-dependently and significantly inhibited the flexion reflex evoked by noxious pinch (5.0 (3.3-7.5) mumol.kg-1 i.v.), whereas the less active enantiomer, CP-100,263, was without significant effect when tested up to 30 mumol.kg-1. Our results demonstrate that in the spinal cord, CP-99,994 exhibits a tachykinin NK1 receptor mediated antinociceptive action.

Analgesics↗
PubMed1994

Structural domains of agrin required for clustering of nicotinic acetylcholine receptors.

Agrin is an extracellular matrix component which promotes the clustering of nicotinic acetylcholine receptors (nAChRs) and other proteins at the neuromuscular junction. This aggregation process is one of the earliest steps in synapse formation. Expression of highly active isoforms of agrin, generated by alternative splicing, is restricted to neurons in the central nervous system (CNS) including motoneurons. In the experiments reported here we investigate the regions of agrin necessary for nAChR clustering activity using two different methods. First, we expressed truncated soluble forms of the agrin protein in mammalian cells and assessed their clustering activity. Second, we generated a panel of monoclonal antibodies (mAbs) against agrin and mapped their epitopes. Several mAbs block agrin-induced aggregation of nAChRs. One of the mAbs, Agr86, binds exclusively to the CNS-specific splicing variants and thus identifies an epitope common only to these more active isoforms. Mapping of the Agr86 epitope suggests that alternative splicing results in a distributed conformational change in the agrin protein. Taken together our data suggest that four domains in the C-terminal 55 kDa of agrin contribute to its nAChR clustering activity.

Agrin↗
PubMed1994

Secretion of eukaryotic growth hormones in Escherichia coli is influenced by the sequence of the mature proteins.

We report the construction of secretion plasmids expressing the fusion proteins, OmpA::pGH (pSpGH.01) and OmpA::hGH (phGH.01), and compare the secretion of mature porcine growth hormone (pGH) and human growth hormone (hGH) employing Escherichia coli. E. coli [phGH.01] secreted 10-15 micrograms hGH/ml/A600 cells into the periplasmic space, representing 30% of total periplasmic proteins. E. coli [pSpGH.01], however, secreted 30-fold less mature pGH. On the basis that both pSpGH.01 and phGH.01 are stably maintained in E. coli and in vitro transcription/translation data showed equivalent expression of OmpA::pGH and OmpA::hGH precursors, we attribute the higher secretion of hGH to the translocation-competent OmpA::hGH protein configuration. Two OmpA::GHF (growth hormone fusion) precursors, OmpA::GHF.02 and OmpA::GHF.03, both with hGH helix 3/helix 4 together instead of the pGH equivalent, secreted mature proteins as efficiently as OmpA::hGH. We propose that hGH helices 3 and 4 in these OmpA::GHF precursors play a major role in the folding of the precursor to a translocation-competent state, mimicking the translocation-competent nature of the OmpA::hGH precursor.

Animals↗
PubMed1994

Developing an information booklet to meet the needs of intensive care patients and relatives.

Changes in the economic climate and the delivery of health care require that preoperative information programmes are effective and efficiently implemented. In order to be effective the pre-operative programme must meet the information needs of intensive care unit (ICU) patients and their relatives. Efficiency can be achieved through a structured pre-operative programme which provides a framework for teaching. The need to develop an ICU information booklet in a large teaching hospital in Northern Ireland has become essential to provide relevant information and improve the quality of service for patients and relatives, as set out in the White Paper, 'Working for Patients', (DoH, 1989). The first step in establishing a patient education programme was to ascertain patients' and relatives' informational needs. A 'needs assessment' identified the pre-operative information needs of ICU patients and their relatives (McGaughey, 1994) and the findings were used to plan and publish an information booklet. The ICU booklet provides a structure for preoperative visits to ensure that patients and relatives information needs are met.

Critical Care↗
PubMed1994

Sunlight: a major factor associated with the development of melanocytic nevi in Australian schoolchildren.

BACKGROUND: Case-control studies have identified melanocytic nevi (MN) as the most important phenotypic risk factor for melanoma. A knowledge of any environmental factors that cause MN may facilitate prevention of melanoma. OBJECTIVE: This study was undertaken to explore the possible role of ambient solar irradiation in the development of MN in children. METHODS: With a standard protocol developed after international consultation, the same medical observers examined children in three Australian cities (Melbourne, Sydney, and Townsville) that span a wide range of latitude. RESULTS: A total of 1123 Australian schoolchildren 6, 9, 12, and 15 years of age were surveyed. Larger numbers of MN were found (mean 65.4 MN, standard deviation 52.9) than in previous studies of children. Prevalence increased with diminishing latitude (51.1 in Melbourne, 66.5 in Sydney and 77.2 in Townsville), particularly in children 6 and 9 years of age. Although nevus numbers were higher in children with light skin and hair, blue eyes, and freckling, the latitude gradient remained after adjustment for these and other factors in multivariate analysis. CONCLUSION: Latitude of residence, and by implication ambient UV radiation, is strongly related to nevus prevalence in young Australian children. However, these differences diminish with age and may disappear by 15 years of age.

Adolescent↗
PubMed1994

Site-specific transgene insertion: an approach.

Methods to improve the production of transgenic animals are being developed. Conventional transgenesis, involving microinjection of DNA into fertilized eggs, has a number of limitations. These result from the inability to control both the site of transgene insertion and the number of gene copies inserted. The approach described seeks to overcome these problems and to allow single copy insertion of transgenes into a defined site in animal genomes. The method involves the use of embryonic stem cells, gene targeting and the FLP recombinase system.

Animals↗