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Biomedical subjects

D Clark

Publications and source records attributed to D Clark.

At least 73 records · Page 4Linked to original sources
PubMed2001

Rural palliative care needs: a survey of primary care professionals in Powys, Wales.

The county of Powys in rural Wales has a population of about 125,000 people and no district general hospitals. In 1999, 12 Macmillan general practitioner clinical facilitators were appointed as part of a pilot project aiming to provide a coordinated framework for the commissioning of specialist cancer and palliative care services, extended clinical care to cancer and non-cancer patients, and an educational intervention to raise the standards of generalist palliative care. A survey of facilitators, general practitioners, district nurses and community hospital nurses was undertaken early in the project. Palliative care formed a small but significant part of respondents' workload. Specialist palliative care services were seen as helpful but distant from the patients. Pain and symptom control were seen to be problematic in patients with diagnoses other than cancer. Services that provided 24-hour nursing care at home were thought to be in need of development by most respondents.

Attitude of Health Personnel↗
PubMed2001

Risk based urban watershed management under conflicting objectives.

Ecological impairment and flooding caused by urbanization can be expressed numerically by calculating the risks throughout the watershed (floodplain) and along the main stems of the streams. The risks can be evaluated in terms of the present and/or future. This article describes the methodologies for ascertaining the risks in the Geographical Information Systems (GIS) environment. The objectives of urban flood controls and ecological preservation/restoration of urban waters are often conflicting and, in the past, the sole emphasis on flood control led to destruction of habitat and deterioration of water quality. An optimal solution to these two problems may be achieved by linking the risks to the concepts of risk communication, risk perception, and public willingness to pay for projects leading to ecological restoration and ecologically sustainable flood control. This method is appropriate because, in each case, public funds are used and the projects require approval and backing of policy makers and stakeholders. This article briefly describes a research project that attempts to resolve the conflict between the flood protection and stream ecological preservation and restoration and suggests alternative ways of expressing benefits of urban stream flood control and restoration projects.

Cities↗
PubMed2000

Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo.

Increased survival of C57BL/6 renal allografts following portal vein donor-specific pretransplant immunization of C3H mice is associated with increased expression of the molecule OX2 seen on host dendritic cells, along with a marked polarization in cytokine production from lymphocytes harvested from the transplanted animals, with preferential production of IL-4, IL-10, and TGF-beta on donor-specific restimulation in vitro, and decreased production of IL-2, IFN-gamma, and TNF-alpha compared with non-portal vein-immunized control transplanted mice. The increased renal allograft survival and the altered cytokine production are abolished by infusion of anti-mouse OX2 mAb (3B6). Infusion of a soluble OX2:Fc immunoadhesin can itself produce significant prolongation of xeno- and allografts in mice. We have used FITC-conjugated OX2:Fc to characterize cells expressing a ligand (OX2L) for OX2, and provide evidence that subpopulations of LPS-stimulated splenic macrophages, Con A-activated splenic T cells, and the majority (>80%) of gammadeltaTCR(+) T cells express this ligand. We show below that F4/80(+), OX2L(+) splenic macrophages, admixed with OX2:Fc, represent a potent immunosuppressive population capable of causing more profound inhibition of alloreactivity in vitro or in vivo than that seen using either OX2:Fc or OX2(+) (or OX2L(+)) cells alone. Immunoregulation by this OX2L(+) population occurs in an MHC-restricted fashion.

Animals↗
PubMed2000

Transcription through nucleosomes.

Transcriptionally active genes in eukaryotes still retain most of the Chromatin packaging that is characteristic of eukaryotic DNA. Nucleosomes and even some higher order structure are present, although the histones may be chemically modified, for example by acetylation or phosphorylation, as part of the activation process. The presence of nucleosomes on the coding region of active genes raises the question: How does an RNA polymerase transcribe such a template? We have attempted to answer this question with relatively simple model systems involving a template carrying a single positioned nucleosome. We have shown that when a phage polymerase, SP6, transcribes such a template, the histone octamer of the nucleosome is not released into solution. Instead it is retained on the same DNA molecule, but displaced from its original binding site. Further studies have allowed us to propose a detailed model, which appears to hold not only for SP6 but also for transcription by the much larger RNA polymerase III from yeast. Our most recent results, obtained by electron cryomicroscopy, confirm and refine this model.

DNA↗
PubMed2000

Psychopathy and the predictive validity of the PCL-R: an international perspective.

Its controversial past notwithstanding, psychopathy has emerged as one of the most important clinical constructs in the criminal justice and mental health systems. One reason for the surge in theoretical and applied interest in the disorder is the development and widespread adoption of reliable and valid methods for its measurement. The Hare PCL-R provides researchers and clinicians with a common metric for the assessment of psychopathy, and has led to a surge in replicable and meaningful findings relevant to the issue of risk for recidivism and violence, among other things. Most of the research thus far has been based on North American samples of offenders and forensic psychiatric patients. We summarize this research and compare it with findings from several other countries, including England and Sweden. We conclude that the ability of the PCL-R to predict recidivism, violence, and treatment outcome has considerable cross-cultural generalizability, and that the PCL-R and its derivatives play a major role in the understanding and prediction of crime and violence.

Antisocial Personality Disorder↗
PubMed2000

D-Amphetamine potentiates muscimol-induced disinhibition of A10 dopaminergic neurons in the rat.

UNLABELLED: Evidence suggests that sensitisation to the behavioural effects of d-amphetamine involves a late-onset (>3 hrs), long-term potentiation (LTP)-like change at medial prefrontal cortex (mPFC)-regulated synapses on A10 dopaminergic (DA) neurons. Since muscimol-induced excitation of A10 DA neurons is dependent on mPFC-regulated afferents, this assay was used to assess whether d-amphetamine enhances the driving of A10 DA neurons by the mPFC, as would be predicted if it resulted in the conditions necessary for LTP. Animals were administered d-amphetamine or saline, 3-4.5 hrs prior to recording. In the acute condition, animals were drug-naïve prior to d-amphetamine, whilst in the challenge condition, animals had previously received d-amphetamine (or saline) each day for 6 days. Recording took place on withdrawal day 2. Muscimol produced significantly less inhibition of A10 DA neurons from animals administered d-amphetamine (rather than saline), but only when d-amphetamine had been chronically administered beforehand (i.e. in the challenge condition). Hence, although the studies fail to provide evidence that acute d-amphetamine administration produces the conditions necessary for LTP, chronic d-amphetamine administration appears to potentiate the impact on A10 DA neurons of mPFC-regulated excitatory activity, thus strengthening the link between this potentiation and the sensitisation process. KEYWORDS: Ventral tegmental area, excitatory amino acids, medial prefrontal cortex, non-DA neurons, synaptic plasticity, behavioural sensitisation.

Analysis of Variance↗
PubMed2000

The medial prefrontal cortex plays an important role in the excitation of A10 dopaminergic neurons following intravenous muscimol administration.

Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evidence suggests that this increase in activity is produced by disinhibition following the inhibition of GABAergic ("non-dopaminergic") cells in the ventral tegmental area. We hypothesized that the activation of A10 cells by muscimol is likely to be at least partly caused by the action of excitatory afferents. To verify this, A10 cells were isolated from ipsilateral afferent sources which utilise excitatory amino acids (which play an important role in the activity of these neurons), using hemisections at the level of the subthalamic nucleus (or just anterior to the subthalamic nucleus), electrolytic lesions of the pedunculopontine tegmental nucleus, or a combination of both. Following hemisections, and hemisections combined with lesions of the pedunculopontine tegmental nucleus, muscimol inhibited rather than excited A10 dopaminergic neurons. The pedunculopontine tegmental nucleus itself appeared to make little intrinsic contribution to muscimol-induced excitation, although the results suggested that part of the excitation which originates in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was investigated using electrolytic lesions of documented sources of excitatory amino acidergic afferents to the ventral tegmental area: the medial prefrontal cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again produced inhibition, an effect qualitatively and quantitatively similar to that in the hemisected groups. Habenular lesions blocked muscimol-induced excitation without producing inhibition, whilst amygdalar lesions produced no significant change in the effects of muscimol. The results suggest that under normal circumstances, an active excitation counteracts and exceeds the direct inhibitory effects of muscimol on the activity of A10 dopaminergic neurons. Furthermore, this activation appears to be produced by the action of excitatory (probably excitatory amino acidergic) afferents arising from the medial prefrontal cortex, and possibly the lateral habenular nucleus. Insofar as the excitation of A10 dopaminergic neurons, which is produced by certain drugs of abuse, and which may play a crucial role in their sustained use, has its basis in excitation following disinhibition, this excitation may provide a novel target for therapeutic intervention in addiction.

Amygdala↗
PubMed2000

The effect of food on the bioavailability of oral gemifloxacin in healthy volunteers.

The effect of food on the bioavailability of gemifloxacin was investigated at two doses (320 and 640 mg) in healthy male and female volunteers. A total of 21 subjects entered the open label, four-period crossover study. Each subject received single oral doses of 320 and 640 mg in the fasted state and after a high fat meal, on separate dosing occasions in a randomised fashion. There was on average, a 3% (95% CI (0.88, 1.07)) and 12% (95% CI (0.79, 0.97)) reduction in AUC and a 12% (95% CI (0.76, 1.02) and 14% (0.75, 1.00) reduction in Cmax after the 320- and 640-mg doses, respectively. The results indicate a minor effect of food on bioavailability of gemifloxacin (320 and 640 mg). Such a reduction in systemic exposure would be considered to be not clinically relevant. Tmax data were inconclusive but indicated a possible slight delay in Tmax of, on average, 0.75 and 0.21 h after the 320- and 640-mg doses, respectively. Delays of this magnitude in reaching maximum concentrations are unlikely to be of clinical importance for an antibiotic drug. Both 320 and 640 mg gemifloxacin were well tolerated in fed and fasted states by healthy volunteers. It can be concluded therefore, that gemifloxacin can be taken with and without food.

Adult↗
PubMed2000

Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex.

Proliferating cell nuclear antigen (PCNA) is required for mismatch repair (MMR) and has been shown to interact with complexes containing Msh2p or MLH1 (refs 1-4). PCNA has been implicated to act in MMR before and during the DNA synthesis step, although the biochemical basis for the role of PCNA early in MMR is unclear. Here we observe an interaction between PCNA and Msh2p-Msh6p mediated by a specific PCNA-binding site present in Msh6p. An msh6 mutation that eliminated the PCNA-binding site caused a mutator phenotype and a defect in the interaction with PCNA. The association of PCNA with Msh2p-Msh6p stimulated the preferential binding of Msh2p-Msh6p to DNA containing mispaired bases. Mutant PCNA proteins encoded by MMR-defective pol30 alleles were defective for interaction with Msh2p-Msh6p and for stimulation of mispair binding by Msh2p-Msh6p. Our results suggest that PCNA functions directly in mispair recognition and that mispair recognition requires a higher-order complex containing proteins in addition to Msh2p-Msh6p.

Amino Acid Sequence↗
PubMed2000

The influence of retinopathy of prematurity on ocular growth.

PURPOSE: Retinopathy of prematurity (ROP) stage 3 eyes that require treatment have a greater tendency to myopia compared with eyes with mild ROP. As the mechanisms controlling this myopia are as yet ill understood, we undertook this study to investigate what effect the initial stage of ROP and modality of treatment had on ocular growth. METHODS: Eighty-five children were assessed. All children were refracted and underwent 'through-the-lid' biometry using the Zeiss Humphrey biometer 820. The printout obtained was then recorded on video so that the scan could be captured on computer for formal calibration and measurement by a masked observer. Differences in the distribution of variables between the stages of ROP were analysed by one-way analysis of variance, non-parametric Kruskal-Wallis one-way analysis of variance or Mann-Whitney U-test as appropriate. RESULTS: A difference between the stages of ROP was apparent only for posterior segment length (PSL) (R: p = 0.03; L: p = 0.05) and a borderline difference for anterior chamber depth (ACD) (R: p = 0.06; L: p = 0.06). However, if stage 3 was divided into categories of treated and untreated, axial length (AL) achieved borderline significance (R: p = 0.07; L: p = 0.05) but with no difference between laser-treated and the other stages for AL. Lens thickness (LT) also appears to be influenced by type of treatment (R: p = 0.06; L: p = 0.13). Myopia was associated with stage 3 (R + L: p = 0.0001) and if stage 3 was subdivided the significance was maintained only for the laser- and cryotherapy-treated eyes. CONCLUSIONS: Laser-treated eyes were less myopic than those treated with cryotherapy. AL does not explain all the myopia found in stage 3 treated eyes. The study confirms the tendency towards anterior segment arrest in stage 3 ROP.

Biometry↗
PubMed2000

Long-term follow-up of ischaemic retinopathy in the antiphospholipid syndrome with lupus-like disease.

PURPOSE: Antiphospholipid syndrome (APS), as an acquired prothrombotic disorder, is increasingly being recognised as an important cause of systemic venous and arterial thrombosis. The defining feature of the condition is the presence of raised levels of antibodies to negatively charged phospholipids in the serum. METHODS: We describe 2 cases of APS with ocular involvement and review the recent literature. Both patients experienced acute visual loss. It was the presenting symptom in one case--a finding that led to the diagnosis of the syndrome. RESULTS: Management with anticoagulation therapy, in which the International Normalised Ratio (INR) has been maintained at or above 3, resulted in reperfusion of the ischaemic retina and stabilisation of the retinopathy in one patient, whilst in the other case, where the INR was less than 3, irreversible visual loss occurred. CONCLUSION: Anticoagulation with warfarin appears to result in reperfusion of ischaemic retina with stabilisation of the neovascular process when the INR is greater than 3.

Adult↗
PubMed2000

Induction of remission after donor leucocyte infusion for the treatment of relapsed chronic idiopathic myelofibrosis following allogeneic transplantation: evidence for a 'graft vs. myelofibrosis' effect.

A 54-year-old man showed evidence of disease progression and a reduction in donor chimaerism by molecular microsatellite analysis 6 months after an allogeneic peripheral blood stem cell transplant for chronic idiopathic myelofibrosis. He was treated with a single infusion of donor leucocyte infusions (DLI), which led to the development of mild acute graft versus host disease (GVHD) and the rapid restoration of full donor haemopoiesis. This subsequently led to a progressive reduction in marrow fibrosis from grade IV to grade I over the following 6 months. We believe that this is the first report to provide clear evidence for the efficacy of DLI in this setting, which also provides evidence for the existence of a T-cell-mediated 'graft vs. myelofibrosis' effect similar to that seen against other haematological malignancies.

Chronic Disease↗
PubMed2000

Nitric oxide inhibition of tobacco catalase and ascorbate peroxidase.

We used a variety of nitric oxide (NO) donors to demonstrate that NO inhibits the activities of tobacco catalase and ascorbate peroxidase (APX). This inhibition appears to be reversible because removal of the NO donor led to a significant recovery of enzymatic activity. In contrast, APX and catalase were irreversibly inhibited by peroxynitrite. The ability of NO and peroxynitrite to inhibit the two major H2O2-scavenging enzymes in plant cells suggests that NO may participate in redox signaling during the activation of defense responses following pathogen attack.

Ascorbate Peroxidases↗
PubMed2000

Non-Hodgkin's lymphoma of the sinonasal tract.

OBJECTIVES: A review of the presenting features, management, and outcome of extranodal non-Hodgkin's lymphoma (NHL) of the sinonasal tract during a 10-year period in Nottingham, UK. STUDY DESIGN: Twenty-four patients received a diagnosis of extranodal NHL of the nasal cavity, paranasal sinuses, or both, from 1987 to 1996. The patients' data were collected prospectively in the Nottinghamshire Lymphoma Registry. METHODS: All patients' records and their histology were reviewed along with data entered into the Nottinghamshire Lymphoma Registry, noting the patient's age, sex, presenting symptoms and signs, staging, computed tomography findings, histology, treatment, complications, and outcome. RESULTS: The 24 patients with extranodal NHL of the sinonasal tract represent 1.63% of the 1,457 patients with NHL seen in the 10-year period of this study in Nottinghamshire. The median age was 72 years (range, 42-96 y), with a male dominance (male-to-female ratio: 15:9). Most patients presented with nonspecific nasal symptoms such as nasal obstruction and epistaxis. Only one patient had a relapse involving the central nervous system after treatment. All the histology was reviewed and showed a predominance of large B-cell subtype (21 patients). The overall 5-year survival was 40% (95% CI, 19%-61%) and 33% for 10-year (95% CI, 12%-54%). The cause-specific survival at 5 years and 10 years was 62% (95% CI, 39%-86%). CONCLUSIONS: A high degree of suspicion and appropriate use of computed tomography scans and surgical biopsy are the keys to the management of NHL.

Adult↗
PubMed2000

Severe retinopathy of prematurity and its association with different rates of survival in infants of less than 1251 g birth weight.

BACKGROUND: There is controversy over whether improved survival of preterm infants has resulted in a higher incidence of severe (grade 3 or greater) retinopathy of prematurity (ROP). AIM: To compare survival rates and rates of > or = stage 3 ROP-that is, with a high risk of sequelae-in preterm infants in five English cities where, anecdotally, the incidence of ROP is reported to show considerable variation. METHODS: All infants of birth weight < 1500 g and or gestational age < 32 weeks, born in 1994 in one of the cities or transferred in within 48 hours, were studied. The populations were adjusted for case mix variation using CRIB (clinical risk index for babies, a disease severity scoring system). The incidence of severe ROP, the actual death rate, and that adjusted for disease severity were determined. RESULTS: The rate of severe ROP per 1000 births was higher in city 1 than in all the other cities. This increase in comparison with city 2 and city 4 was significant (city 1, 167 (95% confidence interval (CI) 96 to 260); city 2, 24 (6 to 59); city 4, 16 (1 to 84)). A significant difference was not seen between city 1 and cities 3 (23 (1 to 120)) and 5 (74 (21 to 79)). The relative risk of developing severe ROP in city 1 compared with all the other cities was 5.5 (2.5 to 11.9). The actual death rate per 1000 births in city 1 was significantly lower than that predicted by modelling death against CRIB score (city 1: actual 270; predicted 385 (95% CI 339 to 431)). In contrast, the other cities had actual death rates as predicted, or worse than predicted, by CRIB. INTERPRETATION: A significantly higher incidence of severe ROP was identified in one of the five cities studied. Variation in survival rates among high risk infants may explain this observation.

England↗
PubMed2000

Macmillan Carers Schemes in England: results of a multicentre evaluation.

Maintaining sick and elderly people at home, particularly as they approach the end of life, is a long-established challenge for health and social care services. Over the past 30 years palliative care providers have attempted a variety of innovations in this area. We report on a descriptive study of seven pilot Macmillan Carers Schemes in England. The schemes sought to provide practical and emotional help to cancer patients and families living in their own homes. Data are available on 624 referrals to the schemes over a 1-year period. Emphasizing comparisons between schemes, we report on reasons for and sources of referral, services offered, number and duration of visits and tasks undertaken. We consider the views of informal carers who made use of the service, the perceptions of Macmillan carers themselves, and we compare financial costs of schemes. It is concluded that the schemes have the potential for further development but face problems, which reflect on their borderline position between 'health' and 'social care'. Current policy changes may be beneficial to the schemes in this respect.

Aged↗
PubMed2000

Common threads? Palliative care service developments in seven European countries.

Since the late 1960s hospice and palliative care services have been developing in many European countries. Although attention has been given to patterns of development in specific national contexts, so far we lack a comparative understanding of how these services are organized and delivered. Such a comparison poses certain practical and methodological difficulties. It does, however, allow a wider view of the current provision of palliative care in Europe, together with a consideration of implications for the future. We report on an analysis of palliative care developments in seven European countries which gave attention to early origins, patterns of provision, and structural and policy integration. We conclude that, despite different processes of development, the emergent discipline of palliative care now finds its most congenial home within the structures of the formal health care system. Accordingly, inequities between the seven countries can be more clearly identified, posing continuing challenges to policy makers and planners who operate with a European perspective.

Europe↗