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Biomedical subjects

A Stevens

Publications and source records attributed to A Stevens.

At least 37 records · Page 2Linked to original sources
PubMed2003

Toxicity, recurrence and survival after adjuvant radiotherapy treatment for FIGO stage I cancer of the endometrium.

We conducted a retrospective observational study to determine the rate of toxicity, pattern of tumour recurrence and survival associated with radiotherapy treatment for FIGO stage I cancer of the endometrium. All patients had undergone definitive surgery and had been referred to the oncology department of the University Hospital Birmingham, U.K. Two hundred and forty-five women were included in the study; 228 patients were treated with radiotherapy; 160 had external beam radiation alone; 32 had vaginal vault brachytherapy alone; 36 patients had both modalities; and 17 patients were not given radiotherapy. There were nine cases of Grade 3 and 4 radiation reactions, of which four were acute, four were late and one was acute and late toxicity. The severity of both acute and late radiation effects was significantly associated with the delivery of vault brachytherapy (external beam radiotherapy alone compared with brachytherapy alone (1/158 vs 3/32; P = 0.02). Thirty-four patients were diagnosed with tumour recurrence (11 distant, 14 local, 4 patients had both distant and local disease and 5 patients had recurrence diagnosed at the time of death). Patients who received no radiotherapy were at greater risk of local pelvic tumour recurrence (P < 0.0001; hazard ratio [HR] 9.6, 95% confidence interval (CI) 3.5-26.3). Vaginal vault brachytherapy had no discernible effect on the pattern of tumour recurrence. Forty-six patients died during the follow-up period, 28 of these were attributable to carcinoma of the endometrium. There was no difference in survival between the four treatment groups (P = 0.68). The overall 5-year survival rate in our study group was 89.6% (85.4-93.8%). In a proportional hazards model, tumour grade (HR 2.0 per level [1.25, 3.17]; P = 0.004]) and age (HR 1.74 per 10 years [1.12, 2.69]; P = 0.01) were the only factors found to have an independent influence on survival. This study suggests that, although pelvic radiation may not alter overall survival, it does reduce the risk of local disease recurrence. In this study population, vaginal vault brachytherapy using a vaginal stock/dobbie showed no additional benefits compared with external beam radiotherapy; it was, however, associated with a higher rate of both acute and late radiation effects.

Adult↗
PubMed2002

Failure of steroid regulation of the MMTV promoter in a small cell lung cancer cell line is caused by a DNA sequence flanking the glucocorticoid response element.

We have previously described a panel of human small cell lung carcinoma (SCLC) cell lines that have profound glucocorticoid resistance, resulting from various molecular defects in glucocorticoid signalling. However, in one SCLC cell line, CORL103, the cause of the resistance is unknown. These cells are refractory to dexamethasone stimulation of MMTV even when exogenous wild-type glucocorticoid receptor (GR) is co-transfected. This is in contrast to cell lines DMS79 and CORL24 where resistance is overcome by transfection of the wild-type receptor. Sequencing of the GR from CORL103 cells revealed two point mutations, but neither of these induced dominant negative activity. Steroid hormone resistance extended to mineralocorticoid and progesterone receptor (MR, PR) activation of MMTV-luc, whereas oestrogen and thyroid hormone receptor transactivation were normal. A simpler reporter, TAT3-luc, containing three copies of the tyrosine aminotransferase glucocorticoid response element (GRE), was responsive when transfected into CORL103 cells with GR, MR and PR expression vectors and activated with their respective ligands. Similarly, pHH-luc and pAH-luc (truncated MMTV variants containing the GRE region, both derived from a different strain of MMTV), were effectively transactivated with dexamethasone. This suggests that the minor changes in the flanking sequence of the MMTV promoter are critically important in determining steroid responsiveness in CORL103 cells. We propose that minor differences in MMTV may determine recruitment of co-factors, which destabilise GR binding to the MMTV GREs. These findings represent a new, selective, model of glucocorticoid resistance that may explain specific cell and target gene differences in glucocorticoid sensitivity.

3' Flanking Region↗
PubMed2002

Genetic engineering of the glucocorticoid receptor by fusion with the herpes viral protein VP22 causes selective loss of transactivation.

The development of methods for engineering proteins with novel properties opens the way to manipulating intracellular processes in a therapeutically useful way. Glucocorticoids, acting via glucocorticoid receptors (GR), are potent anti-inflammatory agents, acting to oppose nuclear factor kappa B (NF kappa B) function. The herpes viral protein, VP22, has been reported to confer intercellular trafficking activity on 'cargo' proteins, potentially facilitating gene therapy with intracellular proteins. VP22GR, resulting from the addition of VP22 to the N terminal of GR, was equipotent with the wild-type GR in opposing NF kappa B p65-driven expression of an NF kappa B reporter gene. Surprisingly, VP22GR was incapable of inducing transactivation of positive glucocorticoid reporter genes (MMTV-luc and TAT3-luc). Furthermore, the VP22GR had powerful dominant negative activity on both endogenous and exogenous GR transactivation. VP22GR was cytoplasmic in quiescent cells, and after hormone addition underwent nuclear translocation to share the same distribution as the GR. The ability of the VP22GR to selectively confer and enhance glucocorticoid-dependent transrepression of NF kappa B may be of use therapeutically in e.g. transplant rejection, inflammatory arthritis or asthma.

Animals↗
PubMed2001

Lattice Boltzmann equation hydrodynamics.

By inserting position and time dependent "source" or "forcing" terms into the microscopic evolution equation of a lattice Boltzmann fluid and treating the generalized scheme within the usual Chapman-Enskog methodology, we show that the emergent dynamics of the lattice fluid may be usefully transformed. Our method of adjustment is demonstrated by implementing the cylindrical polar coordinate form of the continuity and momentum equations on a rectangular lattice and generating results for pipe flow. With straightforward systematic adjustment of the simulation, our approach produces results in excellent agreement with theory.

Journal Article↗
PubMed2001

Master-slave synchronization in chaotic discrete-time oscillators.

In this paper, we study a simple discrete-time neural oscillator model that, in certain parameter regimes, exhibits periodic or chaotic dynamics. The present model with intrinsically chaotic dynamics is capable of spatiotemporal information processing: in response to constant external stimulation, the oscillator can switch into different chaotic states restricted to distinct parts of the phase space. Of particular interest is the processing of time-dependent input in a master-slave configuration of two coupled oscillators. Here, the response of an oscillator is studied by driving it with the signal of the other. Following the input, the response system adapts to the state of the drive. For a chaotic drive, we can observe generalized synchronization. The onset of adaptation to the drive state by the response is accompanied by on-off intermittency resulting in irregular bursting behavior.

Journal Article↗
PubMed2001

Repellent signaling by Slit requires the leucine-rich repeats.

Slit is a repellent axon guidance cue produced by the midline glia in Drosophila that is required to regulate the formation of contralateral projections and the lateral position of longitudinal tracts. Four sequence motifs comprise the structure of Slit: a leucine-rich repeat (LRR), epidermal growth factor-like (EGF) repeats, a laminin-like globular (G)-domain, and a cysteine domain. Here we demonstrate that the LRR is required for repellent signaling and in vitro binding to Robo. Repellent signaling by slit is reduced by point mutations that encode single amino acid changes in the LRR domain. By contrast to the EGF or G-domains, the LRR domain is required in transgenes to affect axon guidance. Finally, we show that the midline repellent receptor, Robo, binds Slit proteins with internal deletions that also retain repellent activity. However, Robo does not bind Slit protein missing the LRR. Taken together, our data demonstrate that Robo binding and repellent signaling by Slit require the LRR region.

Alleles↗
PubMed2001

Volumes of cancer surgery for breast, colorectal and ovarian cancer 1992-97: Is there evidence of increasing sub-specialization by surgeons?

The 'Calman-Hine Report' (1995) recommended that cancer surgery should be limited to 'high-volume' consultants. Through an analysis of 5 years of Hospital Episode Statistics for the West Midlands region (1992-1997), we have investigated whether there is evidence of increasing numbers of patients with breast, colorectal or ovarian cancer being treated by high throughput, i.e. sub-specialist surgeons, who carry out more than a threshold level of primary cancer resections annually. The proportion of cases treated by the high-volume breast, colorectal and ovarian cancer surgeons increased annually during the 5 years. The absolute number of consultant firms who undertook breast cancer resections reduced during the 5 years; but the number doing colorectal and ovarian surgery increased. Throughout the 5 years, half of the ovarian cancer resections were carried out by consultant firms who did very few procedures - less than 5 of these procedures annually. The relatively high case-load, the elective nature of breast cancer surgery and an early policy change have undoubtedly facilitated the move towards sub-specialization. The weaker trends for colorectal and ovarian cancer surgery suggest continued monitoring is required to ensure that there is a reduction in the proportion of people treated by surgeons who undertake few cancer resections annually.

Breast Neoplasms↗
PubMed2001

Characterization of a prolactin gene polymorphism and its associations with systemic lupus erythematosus.

OBJECTIVE: Hyperprolactinemia is associated with systemic lupus erythematosus (SLE), but the mechanism is unknown. Prolactin is expressed in T lymphocytes and is under the control of an alternative promoter region. We characterized a G/T single-nucleotide polymorphism (SNP) at position -1149 of this promoter and assessed its prevalence in patients with SLE. METHODS: Electrophoretic mobility shift assays (EMSAs) were performed to determine DNA protein complex formation in the prolactin promoter. Transient transfection of reporter gene constructs containing the G/T promoter alleles into the Jurkat T cell line were used to determine transcription activity. Peripheral blood lymphocytes (PBLs) were treated in vitro with phytohemagglutinin (PHA) to determine levels of prolactin messenger RNA (mRNA). RESULTS: EMSAs indicated that binding of a GATA-related transcription factor was altered by the G/T SNP at position -1149. Transient transfection studies in Jurkat cells showed that the G allele consistently produced higher promoter activity. PHA treatment of PBLs in vitro induced a greater increment of prolactin mRNA from patients with the GG(-1149) genotype than from those with the TT(-1149) genotype. Disease association studies in a cohort of SLE patients demonstrated an increased frequency of the prolactin -1149 G allele compared with control subjects. CONCLUSION: We found a functionally significant polymorphism that alters prolactin promoter activity and mRNA levels in the lymphocytes. Altered local prolactin production by immune cells may contribute to disease progression by affecting T cell function.

Alleles↗
PubMed2001

Dynamic regulation of EEG power and coherence is lost early and globally in probable DAT.

Electroencephalographic (EEG) findings in dementia of Alzheimer type (DAT) include slowing of alpha frequency, loss of alpha band power, increased theta and delta power and reduced coherence. Here it is evaluated whether a) EEG acquisition during different functional states facilitates the detection of DAT-associated EEG changes, and b) EEG changes in mild DAT are topographically confined or global. Power spectra and coherence of EEGs from 29 patients with mild probable DAT and 28 age- and sex-matched controls were compared during three cognitive states. Group differences in power spectra and coherence were largest during resting with eyes open, yielding a 77% correct classification result. Already in early stages of probable DAT, EEG changes were topographically wide-spread. The task-related up- and down-regulation of power and coherence was impaired already in mild probable DAT. We propose to augment clinical EEG assessment by including a quantitative analysis of the dynamic power and coherence changes from rest, eyes closed to eyes open in suspected DAT.

Aged↗
PubMed2001

In-vehicle distraction and fatal accidents in England and Wales.

The paper describes the coding and analysis of a database of police fatal accident reports to investigate the extent to which in-vehicle distraction is a contributory factor in vehicle crashes. A particular focus has been the involvement of mobile telephones and entertainment systems. Analysis of accidents occurring over the period 1985-1995 shows that in-vehicle distraction is reported as a contributory factor in about 2% of fatal accidents (although this figure may be a conservative estimate). Specific examples of distraction attributed to entertainment systems and telephones have been identified. Electronic driver information systems are also of particular interest, but have not featured in the available data. Work is progressing, on an annual cycle, to obtain, code and analyse further data and this is expected to provide an invaluable source of information for accident researchers.

Accidents, Traffic↗
PubMed2001

A statistical model for length of psychiatric in-patient treatment and an analysis of contributing factors.

OBJECTIVE: Direct illness costs in psychiatry are strongly related to the length of in-patient stay (LOS). Prior studies have shown that LOS depends upon many factors; however, there is no systematic work on their interrelation and relative contribution. METHOD: A detailed statistical analysis of the factors explaining LOS for n = 4,706 consecutive admissions (1994-97) to the psychiatric hospital of the University of Tübingen is presented. RESULTS: The distribution of LOS follows an exponential decay function, suggesting a hazard-based process. Cox regression indicates that the incidence of discharge and hence LOS is modulated by a number of illness-related and other factors, and their relationship is explored. CONCLUSION: While a linear model is commonly assumed, LOS in psychiatry is governed by a hazard-based process. As a tool in quality management, LOS data for psychiatric hospitals might be routinely analyzed and the effects of non-illness-related factors minimized.

Adolescent↗
PubMed2001

Lacrimal duct stenosis and other ocular toxicity associated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer.

Certain side-effects of chemotherapy are well recognized but ocular toxicity is often underestimated. This retrospective study was undertaken after we became aware of a case of irreversible lacrimal duct stenosis in a woman receiving adjuvant chemotherapy for early stage breast cancer. Using the chemotherapy records, 128 patients who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer over a 2 1/2-year period were identified. The case notes of these patients were reviewed and an 18% incidence of ocular side-effects, including four other cases of epiphora, was identified. The epiphora resolved fully on completion of chemotherapy in these four patients but not in the index patient. The optimal management of these side-effects is unclear but it needs to be tailored to the particular toxicity experienced by the patient.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Judging outcomes in psychosocial interventions for dementia caregivers: the problem of treatment implementation.

PURPOSE: In published dementia caregiver intervention research, there is widespread failure to measure the level at which treatment was implemented as intended, thereby introducing threats to internal and external validity. The purpose of this article is to discuss the importance of inducing and assessing treatment implementation (TI) strategies in caregiving trials and to propose Lichstein's TI model as a potential guide. DESIGN AND METHODS: The efforts of a large cooperative research study of caregiving interventions, Resources for Enhancing Alzheimer's Caregiver Health (REACH), illustrates induction and assessment of the three components of TI: delivery, receipt, and enactment. RESULTS: The approaches taken in REACH vary with the intervention protocols and include using treatment manuals, training and certification of interventionists, and continuous monitoring of actual implementation. IMPLICATIONS: Investigation and description of treatment process variables allows researchers to understand which aspects of the intervention are responsible for therapeutic change, potentially resulting in development of more efficacious and efficient interventions.

Adaptation, Psychological↗
PubMed2001

If the NHS introduced a '50 procedures a year' policy, what proportion of consultant firms would be affected?

BACKGROUND: Governments, insurers, quality assurance agencies and others have used the higher volume = better quality relationship as a basis for health policy. This relationship is probably real enough to justify these policies. However, even if it were not real, there are other reasons why these and other organizations such as the National Health Service (NHS) may favour high-volume providers. This paper attempts to answer the question: 'If, for common elective procedures, the NHS instituted a high-volume purchasing policy that requires consultant firms to perform a minimum of "50 procedures a year", what proportion of consultant firms would be affected?' The aims of this study were to estimate the proportion of NHS consultant firms that perform common elective procedures less than 50 times a year and to estimate the proportion of firms that would have to stop providing these procedures if a '50 procedures a year' purchasing policy were introduced. METHOD: A descriptive analysis was carried out and modelling was performed on data stored in an NHS health episode statistics database of patients treated in West Midlands NHS facilities. For each of 12 common elective procedures we assumed that a volume threshold of at least 50 a year were set, and calculated the proportion of NHS consultant firms undertaking each procedure who performed less than 50 of those procedures each year and the proportion of firms who would have had to stop providing each procedure. RESULTS: All firms performing some procedures, e.g. cataract extraction, did so at least 50 times a year. By contrast, no firm repaired more than 50 recurrent inguinal hernias a year. If a volume threshold of at least 50 procedures a year were set for a basket of 12 common elective procedures, then about 40 per cent of firms would no longer be eligible to provide a procedure. Even if a lower 'one a month' threshold were set, about 20 per cent of firms would still not be eligible to provide that procedure. CONCLUSION: Introduction of a high-volume policy would affect a considerable number of firms, as many NHS consultant firms perform some common elective procedures infrequently. Some consultants would see the introduction of a high-volume policy as an opportunity to further specialize and super-specialize. Others would see it as a policy that restricts them to providing a narrower range of procedures, makes their professional practice less interesting, and reduces their professional autonomy. Postgraduate training institutions need to consider the possibility and implications of high-volume policies, as many junior doctors would probably need to learn to provide a narrower range of skills than at present.

Elective Surgical Procedures↗