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Biomedical subjects

R Haynes

Publications and source records attributed to R Haynes.

At least 19 recordsLinked to original sources
PubMed2006

What are children's trusts? Early findings from a national survey.

BACKGROUND: The Children Act 2004 and National Service Framework for Children, Young People and Maternity Services require fuller integration of health, education and social services for children and young people in England and Wales. The UK government supported the establishment of 35 experimental children's trust pathfinders (henceforth called children's trusts) in England. METHODS: A questionnaire was completed by managers in all 35 children's trusts a year after their start. Children's trust documents were examined. Census and performance indicators were compared between children's trust areas and the rest of England. RESULTS: Children's trust areas had demographic and social characteristics typical of England. All children's trusts aimed to improve health, education and social services by greater managerial and service integration. All had boards representing the three sectors; other agencies' representation varied. Two-thirds of children's trusts had moved towards pooling budgets in at least some service areas. At this stage in their development, some had prioritized joint procurement or provision of services, with formal managerial structures, while others favoured an informal strategic planning, co-ordination and information sharing approach. The commonest priorities for services development were for disabled children (16 children's trusts), followed by early intervention (11) and mental health services (8). CONCLUSIONS: The diverse strategies adopted by these 35 children's trusts during their first year is due to their own characteristics and to the way government strategy developed during this period. Whilst some prioritized organizational development, joint financing and commissioning, and information sharing, others laid more emphasis on mechanisms for bringing front-line professionals closer together. Their experiences are of value to others deciding how best to integrate children's services.

Adolescent↗
PubMed2005

High-dose chemotherapy and peripheral blood stem cell support in refractory gestational trophoblastic neoplasia.

We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) in the largest series so far reported. In all, 11 patients have been treated at three Trophoblast Centres between 1993 and 2004. The conditioning regimens comprised either Carbop-EC-T (carboplatin, etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin, etoposide and melphalan) or ICE (ifosfamide, carboplatin, etoposide). Two patients had complete human chorionic gonadotrophin responses, one for 4 and the other for 12 months. Three patients had partial tumour marker responses for 1-2 months. High-dose chemotherapy and HSCS for GTN is still unproven. Further studies are needed, perhaps in high-risk patients who fail their first salvage treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours.

High-dose regimes containing etoposide, carboplatin and an oxazaphospharine can salvage 30-40% of patients with relapsed or refractory male germ cell tumours (GCTs). The additional benefit of paclitaxel in such high-dose therapy has not been tested. Between March 1995 and November 2002, 36 male GCT patients were treated with Carbop-EC-T (paclitaxel 75 mg x m(-2), etoposide 450 mg x m(-2), carboplatin AUC 10 on days -7, -5 and -3 and cyclophosphamide 60 mg x kg(-1) on days -5 and -3) followed by peripheral blood stem cell infusion (day 0). The 1-year overall survival rate for all patients is 67% (median follow-up 29 months). For the 24 patients with cisplatin-sensitive disease, the 1-year overall and event-free survivals are 88 and 64%, respectively. For those with cisplatin refractory or absolutely refractory disease, the 1-year overall survival is 25%. In all, 12 patients relapsed at a median duration of 5 months, 11 of whom have died. There were also six treatment-related deaths, five associated with pneumonitis. Pulmonary toxicity has been reported with paclitaxel in other high-dose regimes. Since altering our protocol so that paclitaxel is infused over 24 h with steroid prophylaxis, only one of 18 patients (13 testicular GCTs and five other tumour types) has had a treatment-related death. Our results suggest that Carbop-EC-T may enable a greater proportion of patients with relapsed and refractory GCTs to enter long-term remission.

Adult↗
PubMed2002

Heparan sulfate abnormalities in exostosis growth plates.

Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the exostosis growth plates. This functional knockout of the exostosis chondrocytes' ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.

Child↗
PubMed2001

Cataract surgery in a community hospital outreach clinic: patients' costs and satisfaction.

A cataract day surgery service for the population of central Norfolk, UK, was provided by the main ophthalmic department in a district general hospital and in an outreach clinic in a community hospital 40 km distant. The outreach clinic aimed to extend the accessibility of this particular service in a rural area where many patients faced long journeys to the main hospital. Samples of 201 patients attending the main hospital for day cataract surgery and 198 patients attending the outreach clinic for the same procedure were identified. Patients were interviewed and given questionnaire forms to establish their general health before the operation, their arrangements to get to hospital and their satisfaction with the clinic and the care they had received. The sample of patients attending the outreach clinic was slightly older, less affluent and in slightly poorer general health than the patients attending the main hospital. The two samples were similar in terms of visual acuity after the operation, complication rates, satisfaction with the outcome of the operation and subsequent use of health services. The journey to hospital was quicker, more convenient and less costly for the outreach clinic patients than the main hospital patients. The net benefit to patients of the outreach clinic was estimated as pounds sterling 39,000 per annum. Satisfaction with administrative matters, facilities at the two clinics and the care received was high in both samples, but patients were significantly more satisfied with arrangements at the smaller outreach clinic. This evidence suggests that an outreach clinic in a small community hospital can provide cataract day surgery under local anaesthesia as effectively as a district centre, at a reduced social cost and with positive social benefits. Further study of heath service costs is vital, but political pressure to acknowledge patient preferences for more local services is growing.

Aged↗
PubMed2001

p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator.

Iron is involved in essential biochemical reactions ranging from respiration to DNA synthesis. Consequently, iron deprivation has been proposed as a strategy for inhibition of tumor cell growth. We recently described a novel iron chelator, tachypyridine [N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane], and demonstrated that it not only inhibited growth of cultured tumor cells, but was actively cytotoxic. Here we explore the mechanisms underlying tachpyridine cytotoxicity. Using several criteria, including time-lapse video microscopy, DNA staining and TUNEL assays, tachpyridine was shown to specifically induce apoptotic cell death. Further, unlike numerous cytotoxic chemotherapeutic drugs which induce apoptosis by activating p53-dependent pathways, tachpyridine-mediated cell death did not require p53 activation. Although immunoblotting revealed rapid accumulation of p53 following treatment with tachpyridine, p21(WAF1) was not induced. Further, neither cytotoxicity nor apoptosis required p53. p53 null human lung cancer H1299 cells transfected with an ecdysone-inducible p53 exhibited equivalent sensitivity to tachpyridine in the presence and absence of p53, demonstrating the lack of requirement for p53 in an isogenic cell system. Further, time-lapse video microscopy and TUNEL assays demonstrated that both p53 null and p53 wild-type cells underwent apoptotic cell death in response to tachpyridine. In addition, in 55 human cancer cell lines the mean GI(50) of tachpyridine in cells with mutant p53 was virtually identical to the GI(50) in cells with wild-type p53. These results demonstrate that tachpyridine initiates an apoptotic mode of cell death that does not require functional p53. Since over 50% of human tumors contain a functionally defective p53 that reduces sensitivity to commonly used chemotherapeutic agents, such as etoposide and cisplatin, the ability of tachpyridine to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy.

Anticarcinogenic Agents↗
PubMed2001

A comparison of cardiovascular risk factors among Indo-Asian and caucasian patients admitted with acute myocardial infarction in Kuala Lumpur, Malaysia and Birmingham, England.

Indo-Asians in the UK are at an increased risk of coronary artery disease (CAD); this may be a reflection of their cardiovascular risk factor profile as well as of a more sedentary lifestyle. We hypothesised that Indo-Asians in Malaysia and the UK may exhibit a similar cardiovascular risk factor and physical activity profile, which would be more adverse compared with caucasians. We studied 70 consecutive Indo-Asian patients admitted to hospitals in Kuala Lumpur, Malaysia (n=42; 35 males; mean age 60.6 years, SD 11.8); and Birmingham, England (n=28; 20 males; mean age 60.8 years, SD 12.9). Both groups of Indo-Asian patients were compared with 20 caucasian patients (13 males; mean age 62.7 years, SD 9.4) admitted with myocardial infarction from Birmingham. There was a higher prevalence of diabetes among Indo-Asians in both countries than among caucasians (p=0.0225). By contrast, caucasians had a higher prevalence of hypercholesterolaemia (p=0.0113), peripheral vascular disease (p=0.0008), regular alcohol consumption (p<0.0001) and family history of CAD (p=0.0041). There were no significant differences in mean age, body mass index or blood pressures. There was a significantly lower leisure activity score (p=0.001) and total physical activity score (p=0.003) among Indo-Asians in both countries than among caucasians. This survey has demonstrated differences in cardiovascular risk factors among Indo-Asian and caucasian patients. The high prevalence of diabetes, as well as the lower physical activity and sedentary lifestyles among Indo-Asians, in both Malaysia and the UK, may in part contribute to the high incidence of CAD in this ethnic group.

Aged↗
PubMed2000

Deprivation and poor health in rural areas: inequalities hidden by averages.

Poor health and social deprivation scores in 570 wards in East Anglia, UK, were much less associated in rural than in urban areas. The deprivation measure most closely related to poor health in the least accessible rural wards was male unemployment, but use of this measure did not remove the urban-rural gradient of association strength. Neither did replacing wards by smaller enumeration districts as the units of analysis. The differences between urban and rural correlations were removed by restricting the comparison to wards with the same unemployment range and combining pairs of rural wards with similar deprivation values. Apparent differences between rural and urban associations are therefore not due to the choice of deprivation indices or census areas but are artifacts of the greater internal variability, smaller average deprivation range and smaller population size of rural small areas. Deprived people with poor health in rural areas are hidden by favourable averages of health and deprivation measures and do not benefit from resource allocations based on area values.

Cultural Deprivation↗
PubMed1999

Accidents to preschool children: comparing family and neighbourhood risk factors.

Accidental injury in young children is more common among poorer families and in deprived areas but little is known about how these factors interact. This paper describes a study to measure the contribution of individual family factors and area characteristics in determining risk of accidental injury among preschool children. We conducted a population based study of preschool accident and emergency attendances over two years in and around the city of Norwich, UK. Information on individual families was extracted from the district child health information system while "social areas" were constructed from adjacent census enumeration districts with homogeneous social and demographic characteristics. Statistical analysis was by multilevel modelling. Accidental injury rates were much higher in deprived urban neighbourhoods than in affluent areas but the multilevel analysis showed that, for all accidents, much of the variation in rates was accounted for by factors at the individual level i.e. male sex, young maternal age, number of elder siblings and distance from hospital, with a smaller, but independent, influence of living in a deprived neighbourhood. The model for more severe injuries was similar except single parenthood was now significant at the level of individuals and the effect of area deprivation was stronger. We conclude that preschool accidental injuries are influenced by factors operating at both the level of individual families and between areas. This evidence suggests that both social policy changes to improve child care among unsupported young families and targeting accident prevention measures at a local level towards deprived neighbourhoods would reduce accidents.

Accidents↗
PubMed1999

Effects of distances to hospital and GP surgery on hospital inpatient episodes, controlling for needs and provision.

Age and sex adjusted inpatient episode ratios were calculated from hospital records over a two year period for 555 census wards in Cambridgeshire, Norfolk and Suffolk, UK. Hospital episodes were divided into acute, psychiatric and geriatric specialties, and elective and emergency acute admissions were distinguished. Variations in inpatient episode ratios between wards were compared with census indicators of the 'needs' of local populations for inpatient services, measures of the local provision of hospital and other related services, and measures of the distance to the nearest general practitioner surgery and the distance to the nearest hospital. Hospital episodes were found to be strongly related to both distance measures, but the associations were partially explained by a tendency for the health status of local populations (measured by the needs indicators) to be worst in urban areas close to health services. Including needs and provision variables together with the distance variables explained most of the variations in age and sex adjusted inpatient ratios for small areas. Needs were the most important determinants of emergency acute and psychiatric inpatient rates, but service provision was more important for elective acute and geriatric inpatients. Controlling for needs and provision, distance to hospital produced 17% reduction in acute episodes, 37% reduction in psychiatric episodes and 23% reduction in geriatric episodes over the range of distances observed. Distance to nearest GP surgery reduced elective acute episodes by up to 15% after controlling for confounders. These results demonstrate that the NHS is falling short of its aim to provide fair access to services irrespective of geography, and new policies will be required if geographical inequities are to be reduced.

England↗
PubMed1999

Mortality, long-term illness and deprivation in rural and metropolitan wards of England and Wales.

The relationships between mortality, limiting long-term illness and indicators of social deprivation were investigated using regression analysis on data for rural wards, metropolitan wards and the remaining wards in England and Wales. Regional differences were controlled. In rural wards, people had better health than average and slightly better health than would be expected from their deprivation scores. Average levels of health in rural areas were only weakly related to deprivation, which was partly but not fully due to the restricted range of average deprivation values in rural wards. In metropolitan areas, relatively poor levels of health were largely explained by social deprivation, but people in Inner London were healthier than might be expected from measures of deprivation. The relationship between health and social deprivation is therefore not uniform over England and Wales, but varies between geographical types of area. One consequence is that resource allocation on the basis of social deprivation would put the populations of rural areas and Inner London at an advantage.

Adolescent↗
PubMed1998

Urban-rural variations in suicides and undetermined deaths in England and Wales.

BACKGROUND: Given that a high proportion of undetermined deaths are thought to be suicides, the objective of the study was to compare the geography of the two verdicts, with emphasis on urban-rural differences, to determine whether the likelihood of a death being classified as suicide varies according to location. METHODS: Standardized mortality ratios (SMRs) were mapped for the local authority districts of England and Wales, using data aggregated over the period 1989-1992. Districts were classified according to population density, and SMRs calculated for each quartile. Finally, regression equations were obtained to model the relationship of suicide and undetermined death with a series of risk factors. RESULTS: Both male and female undetermined deaths showed a significant deficit in the most sparsely populated districts and a significant excess in the most densely populated districts. Female suicides were also significantly high in densely populated districts, but male suicides were highest in the most rural areas (SMR 110, 95 per cent confidence intervals 105-115). District variations in both verdicts were associated with the proportion of single-person households for both sexes, but male suicides and male undetermined deaths were associated with additional predictors, consistent with their distinct geographical distributions. CONCLUSIONS: Differences in suicide methods, the likelihood of communicating suicidal intent and, perhaps, variations in access to psychiatric services might be contributory factors to the observed differences between the verdicts. The results suggest that recorded suicides are a biased subset of actual suicides, particularly for males, and that the study of suicide verdicts alone is potentially misleading.

England↗
PubMed1997

Effect of labour market conditions on reporting of limiting long-term illness and permanent sickness in England and Wales.

STUDY OBJECTIVE: To identify any bias in the reporting of limiting long term illness and permanent sickness due to labour market conditions, and show the absence of the effect in mortality rates. DESIGN: A geographically based study using data from the 1991 census. Standardised ratios for mortality and long term illness in people aged 0-64 years and permanent sickness in people of working age were compared with Carstairs deprivation scores in multilevel models which separated the effects operating at three geographical scales: census wards, travel to work areas, and standard regions. Holding ward and regional effects constant, variations between travel to work areas were compared with long term unemployment rates. SETTING: Altogether 8690 wards and 262 travel to work areas in England and Wales. MAIN RESULTS: Variations in mortality, limiting long term illness, and permanent sickness were related to Carstairs deprivation scores and standard region. With these relationships controlled, limiting long term illness and permanent sickness were significantly related to long term unemployment levels in travel to work areas, but mortality was not affected. Self reported morbidity was more sensitive to variations in long term unemployment rates in conditions of high social deprivation than in affluent populations. CONCLUSIONS: Limiting long term illness and permanent sickness measures may reflect a tendency for higher positive response in difficult labour market conditions. For average social deprivation conditions, standardised limiting long term illness for people aged 0-64 years was 20% higher in travel to work areas where employment prospects were relatively poor compared with areas with relatively good employment prospects. This casts doubt on the use of limiting long term illness as an indicator of objective health care needs for resource allocation purposes at national level.

Adolescent↗
PubMed1997

Activation of MAP kinases in airway smooth muscle.

To test the hypothesis that mitogen-activated protein (MAP) kinases are activated by contractile agonists in intact nonproliferating airway smooth muscle, kinase activities were compared in resting and stimulated canine tracheal smooth muscle. Kinase activities in sodium dodecyl sulfate extracts were assayed by a gel renaturation method. Myelin basic protein kinase activities corresponding to ERK1 and ERK2 immunoreactive proteins were activated twofold above the basal level within 5 min by 1 microM carbachol. MAP kinase activity assayed in crude homogenates using a synthetic peptide substrate (APRTPGGRR) also increased twofold above basal in muscles stimulated with 1 microM carbachol. Two protein kinases separated by Mono-Q chromatography were identified on Western blots as ERK1 and ERK2 MAP kinases. Carbachol stimulation increased caldesmon phosphorylation in intact muscle, and purified caldesmon was a substrate for activated murine ERK2 MAP kinase. Activated ERK2 MAP kinase added to Triton X-100-permeabilized fibers potentiated Ca2+-induced contraction. The results show that ERK MAP kinases are activated after stimulation of muscarinic receptors in airway smooth muscle, which is consistent with coupling of MAP kinases to phosphorylation of caldesmon in vivo.

Animals↗
PubMed1996

Activation of MAP kinases and phosphorylation of caldesmon in canine colonic smooth muscle.

1. Phosphorylation of caldesmon was assayed in canine colonic circular smooth muscle strips labelled with 32P and stimulated with 10 microM acetylcholine. Caldesmon was isolated by two-dimensional non-equilibrium pH gel electrophoresis. Stimulation with acetylcholine increased caldesmon phosphorylation significantly from a basal level of 0.6 +/- 0.07 to 1.1 +/- 0.15 mol P1 (mol caldesmon)-1 after 2 min. 2. MAP kinase activities were measured in SDS extracts of muscle by a gel reconstitution method using myelin basic protein. Myelin basic protein kinase activities were observed at 38, 44, 50 and 57 kDa by the gel reconstitution method. Endogenous caldesmon kinase activities were also identified by the gel reconstitution method at 38, 44 and 50 kDa. The 38 and 44 kDa kinases comigrated with proteins labelled by anti-ERK1 MAP kinase antibodies on Western blots. Both 38 and 44 kDa MBP kinase activities increased significantly during contractions induced by 10 microM acetylcholine, 0.1 microM neurokinin A and 70 mM potassium. 3. Phorbol dibutyrate (0.1 microM) potentiated activation of MAP kinases and contraction of depolarized muscles while producing a decrease in fura-2 fluorescence ratio. This suggests that protein kinase C activation is coupled to MAP kinase activity in colonic smooth muscle. 4. MAP kinases isolated form muscle homogenates by Mono Q chromatography were assayed using the specific MAP kinase substrate peptide APRTPGGRR. Stimulation of muscles for 2 min with 10 microM acetylcholine activated both ERK1 and ERK2 MAP kinase activities 2-fold. 5. To determine the effects of caldesmon phosphorylation by MAP kinase on the cross-bridge cycle, actin sliding velocity was measured with an in vitro motility assay. Unphosphorylated turkey gizzard caldesmon (3 microM) significantly reduced mean sliding velocity. Phosphorylation of caldesmon with sea star ERK1 MAP kinase reversed the inhibitory effect of caldesmon on sliding velocity. The results are consistent with a protein kinase cascade being activated by contractile agonists in gastrointestinal smooth muscle which activates ERK MAP kinases leading to phosphorylation of caldesmon. Phosphorylation of caldesmon in vivo may reverse inhibitory influences of caldesmon on cross-bridge cycling.

Acetylcholine↗
PubMed1996

Acrylic bone-cement. Influence of mixer design and unmixed powder.

The effects of hand mixing with two different mechanical mixing systems (fixed versus rotating central axis) on unmixed powder content, macroporosity, density, and bending strength of acrylic bone-cement are compared. The effects of voids and unmixed powder on cement bending strength are also evaluated. In acrylic cement, both unmixed powder monomer and voids 1 mm and larger can be easily visualized and analyzed on radiographs of 3-mm-thick samples. Image analysis allowed demonstration of a significant increase in unmixed powder content (P < .0001), in cement prepared using a vacuum mixing system with a fixed central axis compared with both the rotating axis system and hand mixing. The rotating-axis system produced cement of higher density compared with hand mixing only (P = .004). There was a significant correlation between the number of voids measured per square centimeter and cement bending strength (P < .0001), as well as an independent and significant correlation between unmixed powder content and cement bending strength (P < .0001). Mechanical mixing using a fixed central axis produced significantly weaker cement compared with both hand mixing (P < .015) and the rotating-central-axis system (P < .0001). A 15% drop in strength between the two mechanical mixing systems was observed. It is therefore concluded that the use of different rotating systems in mechanical mixers can influence void and unmixed powder content and, consequently, the mechanical properties of acrylic cement, and that unmixed powder is an independent factor affecting the bending strength of the cement.

Acrylates↗