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Biomedical subjects

D Wall

Publications and source records attributed to D Wall.

At least 19 recordsLinked to original sources
PubMed2002

Paediatric training for family doctors: principals and practice.

BACKGROUND: There is controversy as to how best to train general practitioners for the paediatric challenges they will meet in practice, in particular what should be included in training, what should be left out and how long should it last? SUBJECTS AND METHODS: All 615 general practice principals referring to 6 hospitals were surveyed (40% response rate). SETTING: West Midlands region of England. STUDY DESIGN: Postal questionnaire. STATISTICS: Quantitative and qualitative assessment of responses. Quantitative responses were analysed by hospital, decade of qualification, and duration of paediatric training. Qualitative responses were analysed using grounded theory. RESULTS: Satisfaction with training was directly related to its duration, with low levels of satisfaction for less than 6 months paediatrics, moderate levels for 6-11 months, and high levels with 12 months or more. The most important item of training was recognition of the sick child. Acute and chronic paediatrics was generally well covered. Psychosocial aspects, public health and immunisation were poorly addressed. Neonatal resuscitation and first day checks were seen as relevant, but neonatal intensive care was not. CONCLUSIONS: At least 6 months of paediatrics is necessary for GPs in training, but longer paediatric exposure further increases their satisfaction with training. GPs have a biopsychosocial rather than biomedical approach to their child patients, suggesting potential benefits from a greater emphasis on psychosocial and public health aspects at the expense of neonatal intensive care. Recognition of the sick child is essential, and acute and chronic organic illness should be covered in breadth. Possible future models for GP training in paediatrics are discussed.

Education, Medical↗
PubMed2002

Isolex 300i CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: We have previously reported that repeated cycles of high-dose therapy (HDT), can be supported by unmanipulated autologous PBPC. Here we investigate whether purified CD34+ cells, obtained by immunomagnetic separation using the Isolex 300i device, can support such therapy. METHODS: Twenty-nine consecutive patients with metastatic breast cancer had PBPC mobilized and harvested following chemotherapy and G-CSF (10 microg/kg per day). Patients with > 4.0 x 10(6)/kg CD34+ cells in the apheresis product underwent CD34-selection using the Isolex 300i (v2.0) device. All cells collected were equally divided into three aliquots and cryopreserved. Patients who did not achieve this threshold had unmanipulated cells collected and stored. Patients subsequently received three cycles of HDT with paclitaxel (175 mg/m2), thiotepa (300 mg/m2) and either ifosfamide (10 g/m2) or cyclophosphamide (4 g/m2). It was intended for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e 1/3 for each cycle) and to compare hemopoietic recovery between patients receiving CD34-selected cells or unmanipulated cells. RESULTS: Thirteen of the 29 patients (45%) did not mobilize sufficient CD34+ cells to undergo CD34-selection. The remaining 16 patients underwent CD34-selection with a median purity of 84.3% (range: 16.3-96.1%) and yield of 34% (range: 1-60%). Fifteen of these patients proceeded to HDT and 42 of the planned 45 cycles were administered. Nine patients had all three HDT cycles supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (range: 0.04-3.01). Three of the 15 patients required infusion of 'back-up' unmanipulated cells because of delayed neutrophil recovery. Of the 13 patients whose PBPCs did not undergo CD34+ cell selection, 11 proceeded to HDT with a median of 3.2 x 10(6)/kg (range: 2.0-4.4) unselected cells infused per cycle and 31 of 33 planned cycles were delivered. When hemopoietic recovery was compared between cycles of HDT supported by CD34-selected (n = 34) and unmanipulated cells (n = 31), there was a modest slowing in the patients receiving CD34-selected cells; time to ANC > 1.0 x 10(9)/L = 11 days versus 10 days (P = 0.0122) and platelets > 20 x 10(9)/L = 14 days versus 13 days (P = 0.0009). No difference in recovery to 50 x 10(9)/L was observed (P = 0.54). CONCLUSION: We have demonstrated that Isolex 300i CD34-selected cells are capable of supporting multiple cycles of HDT. However, we were unable to acquire sufficient CD34+ cells to perform this processing in 45% (13/29) of patients and further improvements in yield are required to overcome the modest delay in neutrophil and platelet recovery.

Adult↗
PubMed2002

CliniMACS CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: Traditionally, following high-dose therapy (HDT), unmanipulated autologous PBPC are infused. Alternatively, purified CD34+ cells can now be obtained by immunomagnetic separation using the CliniMACS device. Limited data currently exist examining hemopoietic recovery with such cells. METHODS: Ten patients with advanced breast cancer had PBPC mobilized with docetaxel (100 mg/m2) and G-CSF (10 microg/kg per day), harvested and processed using the CliniMACS CD34-selection device and equally divided into three aliquots for cryopreservation. Unmanipulated 'back-up' cells were also collected on a separate day of the same mobilization, divided into three and cryopreserved. Patients subsequently received three cycles of HDT with cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2). The intent was for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e., 1/3 for each cycle). If, however, hemopoietic recovery was delayed after Cycle 1, 1/3 of the unmanipulated cells were infused following Cycle 2 and the remaining CD34-selected cells (2/3) were used to support Cycle 3. RESULTS: PBPC from 10 patients underwent CD34-selection with a resulting median purity of 93% (range: 76-98%) and yield of 62% (range: 16-93%). Of the 10 patients, only two were able to be supported with CD34-selected cells for all three cycles of HDT. The remaining eight patients required unmanipulated 'back-up' cells to support Cycle 2. Three patients also required infusion of 'back-up' unmanipulated cells because of persistent neutropenia (n = 1) or thrombocytopenia (n = 2) following cycles initially supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (0.7-2.6) (n = 20) and unselected cells was 1.7 (1.4-2.8) (n = 10). Comparing hemopoietic recovery between cycles of HDT supported by CD34-selected (n = 20) and unmanipulated cells (n = 10) there was a significant slowing with the CD34-selected cells; time to ANC > 1.0 = 13 days versus 10 days, platelets > 20 = 17 days versus 13 days, > 50 = 25 versus 17 days (all P values < 0.001). There was no correlation between the dose of CD34-selected cells infused and neutrophil/platelet recovery. DISCUSSION: We have demonstrated that, although unmanipulated PBPC achieve rapid hemopoietic recovery (at modest CD34 doses of < or = 2.8 x 10(6)/kg), CliniMACS-selected CD34+ cells (in the doses utilized in this study of < or = 2.6 x 10(6)/kg) result in significantly prolonged recovery.

Adult↗
PubMed2002

Comprehensive essential gene identification as a platform for novel anti-infective drug discovery.

In large part, antimicrobial drug discovery is driven by the breadth and quality of both potential drug targets and available chemical libraries to screen. Traditionally, targets have been few in number and have been limited to those with known function, from which biochemical assays could be implemented into drug screens. Iterations of this same basic approach, applied to a few biochemically-defined targets have identified a limited set of novel antibiotics and even fewer antifungal agents. Indeed, in the last 50 years less than 30 antimicrobial targets have been exploited commercially. Within infectious disease, the industry was driven largely by chemistry-based approaches, simply making new analogs to existing drugs to overcome the growing problem of drug resistance. Elitra Pharmaceutical s approach has been to enable true functional genomics on a genome-wide scale. Elitra s vision has been to identify all of the essential genes directly in the key pathogenic organisms. Having moved rapidly towards the completion of this goal, we are now faced with the enviable challenge of prioritizing enormous target sets and developing novel sensitive screens for those best suited as definitive drug targets. These highly sensitive, cell-based screening paradigms enable re-screening of even well screened chemical libraries to reveal new chemical entities displaying novel modes of action against new targets. In parallel, we have also begun to shift the paradigm from screening targets singly, towards genome-wide approaches to drug screening.

Anti-Infective Agents↗
PubMed2001

Characterisation of the anticoagulant properties of a range of structurally diverse sulfated oligosaccharides.

In this study, 17 sulfated oligosaccharides were assessed by the activated partial thromboplastin time (APTT) test for their anticoagulant activity and nine were found to exhibit significant activity. Chain length, monosaccharide makeup, and linkage all appear to be critical factors in determining anticoagulant activity, with the most active compounds being five- to sixfold less potent than unfractionated heparin (UFH). Phosphomannopentaose sulfate (PI-88), one of the most active sulfated oligosaccharides and a promising anticancer drug, was selected for further study. PI-88 gave a more linear APTT dose-response curve and displayed less patient-to-patient variation than UFH, with its activity being neutralised by protamine sulfate. However, PI-88 showed considerable species-to-species variation in its anticoagulant effect. It was found that PI-88 acted as an anticoagulant by enhancing the ability of heparin cofactor II (HCII) to inhibit thrombin, and did not act via antithrombin III (AT-III) in either inhibiting Factor Xa or thrombin. PI-88 also mildly prolonged the prothrombin time (PT), whilst it had no platelet pro-aggregatory activity, nor did it demonstrate direct fibrinolytic activity. Thus, PI-88 represents a potential antithrombotic agent deserving further study.

Animals↗
PubMed2001

Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.

BACKGROUND: It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease. METHODS: We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study. RESULTS: After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients. CONCLUSIONS: There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

Administration, Oral↗
PubMed2001

An international biodiversity observation year.

The International Geophysical Year (IGY), which took place between July 1957 and December 1958, helped us to rethink the world. At a time when there was a major paradigm shift in our understanding of the physical world, the international collaboration of the IGY helped to reset the discipline. The International Biodiversity Observation Year (IBOY) is now occurring at a time when our dependence on, and understanding of, biodiversity is being acknowledged as a paradigm shift in our present view of the world. Although the benefits of IGY were initially intellectual with practical effects remaining unknown until many years later, the benefits of greater knowledge of biodiversity will support efforts towards sustainability and affect the quality of life, both now and in the future. By providing the framework for international collaborations between scientists involved in every aspect of life on Earth, IBOY has the potential to redefine our current understanding of biodiversity in a manner similar to how IGY helped redefine the geophysical world.

Journal Article↗
PubMed2001

Resuscitating paediatric induction: an action research approach.

OBJECTIVES: To establish teaching objectives, methods and assessment for a paediatric induction programme. DESIGN: Action research over a 2-year period. PARTICIPANTS: 88 doctors from three hospitals. MAIN OUTCOME MEASURES: These were end-of-course evaluations, using Likert scales, and free comments; independent evaluation by the West Midlands Deanery 4 months after courses, in which participating and non-participating units were compared, and summative assessment of trainees involving multiple-choice questions, a basic life-support scenario and an illness scenario. RESULTS: 88 participants attended four 3-day courses over 2 years. Mean satisfaction ratings were very high for content, personal value, and presentation. There was a significant rise in Deanery evaluation scores, compared with non-significant change in other hospitals, and there were excellent pass rates for trainees. CONCLUSIONS: Trainees strongly approve of induction with clear objectives, active teaching, and validated assessment.

Curriculum↗
PubMed2001

A new approach to improving facilities for resident hospital doctors.

The British Medical Association and the Department of Health recently agreed tougher systems to force NHS trusts to improve living conditions for resident doctors. Central to the proposals is the system of monitoring pioneered in the West Midlands, described below, which has resulted in significant improvements in the facilities provided by the region's trusts in the last 3 years.

Accreditation↗
PubMed2001

Sharing learning through narrative communication.

This paper examines key aspects of the learning experiences of ten speech and language therapy (SLT) students on clinical placements, as revealed by an analysis of 102 narrative accounts. We argue that when students on placements tell stories of their learning experiences the process of recounting them can help them to reflect on and consolidate what they have learned and to have this learning validated by peer, clinician or tutor audiences. Thus, sharing learning through narrative communication is itself further learning from the original experience. We show how students evaluate their learning experiences, how their growing confidence is mediated by clinicians and how such narratives are shared in normal student interaction. Tutors might use the insights from narrative learning to raise students' awareness of their own learning, and thus to improve it.

Education↗
PubMed2000

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

Adolescent↗
PubMed2000

Docetaxel effectively mobilizes peripheral blood CD34+ cells.

We prospectively evaluated docetaxel (100 mg/m2) with G-CSF (10 microg/kg S.C., daily) for mobilization efficiency in 26 patients with breast cancer. The minimum target yield was >4.5 x 10(6) CD34+ cells/kg (optimum = 9 x 10(6)/kg), sufficient to support the subsequent three cycles of high-dose therapy (HDT). The peak days for peripheral blood (PB) CD34+ cells were day 8 and day 9. Seven collections began on day 7, 16 on day 8 and three on day 9. The median peripheral blood progenitor cell (PBPC) CD34+ cell content ranged from 1.2 to 5.9 x 10(6)/kg per day during days 7 to 11 with a median CD34+ content of the total 72 PBPC collections of 3.4 x 10(6)/kg (0.07-15.6). Fifteen patients obtained a PBPC collection exceeding 5 x 10(6)/kg on a single day of collection. Following a median 3 days collection for each patient (range 2-4), the median total CD34+ for all individual sets of collections was 9.7 x 10(6)/kg (range 1.0-28.4). We were able to achieve the minimum CD34+ cell target yield in 22 of 26 patients with one cycle of mobilisation chemotherapy and in two of these patients a second collection yielded sufficient cells. Twenty-two patients have subsequently received repetitive HDT and PBPC transplantation with 57 cycles of HDT having been delivered. For all 57 cycles, the median time to absolute neutrophil count (ANC) >0.5 x 10(9)/l and 1.0 x 10(9)/l was 10 days (range 8-22) and 11 days (range 8-23), respectively. The median time to platelets greater than 20 x 10(9)/l, 50 x 10(9)/l and 100 x 10(9)/l was 13 days (range 11-23), 17 days (range 12-53) and 23 days (range 18-70), respectively. We conclude that docetaxel with G-CSF effectively mobilises PBPCs with apheresis needing to be commenced approximately 8 days after docetaxel administration.

Adult↗
PubMed2000

Teaching the consultant teachers: identifying the core content.

OBJECTIVES: To determine the key themes for teaching hospital consultants how to teach. DESIGN: 1. In-depth interviews with a total of 19 experts, consultants and junior doctors to identify key topics. 2. Literature review from 1969 to obtain the main themes from the medical educational literature. 3. Analysis of the main themes in 11 'Teaching the teachers' courses. 4. Triangulation of interview data, literature themes and teaching courses content to generate 15 criteria for a questionnaire. 5. Questionnaire study to 593 senior and junior hospital doctors. SETTING: Hospitals in the West Midlands Region in England. SUBJECTS: Consultants and junior hospital doctors. RESULTS: Overall, 441 doctors replied (74% response rate). The top five themes were giving feedback constructively, keeping up to date as a teacher, building a good educational climate, assessing the trainee and assessing the trainee's learning needs. Results showed no statistically significant differences in the order of themes for all groups analysed, including seniority, gender, specialty, origin by medical school and consultants of different ages. CONCLUSIONS: Consultants need teaching in these topics. There are implications for funding and providing these courses for postgraduate deans, Royal Colleges and universities. Further research is needed to evaluate whether such an initiative does produce better teaching and learning, and a better educational climate in hospitals.

Consultants↗
PubMed2000

Corpus cavernosum as an alternative means of intravenous access in the emergency setting.

BACKGROUND: The present study was designed to investigate the feasibility of using the corpus cavernosum as an alternative means of intravenous access in the emergency setting. METHODS: The feasibility of achieving the infusion flow rates was first ascertained using direct intracavernous infusion of normal saline. The effect of atropine and adrenaline when given via this route was then studied. Hypovolaemic shock was then induced in dogs who were then actively resuscitated via this route using normal saline, Haemaccel and whole blood. RESULTS: Infusion flow rates were achieved for normal saline of 32.3, 50.3 and 67.3 mL per min at 100, 200 and 300 mmHg pressure, respectively. The peak effects of atropine and adrenaline via this route were seen at approximately 1 min after injection. Resuscitation using this method was uniformly successful in all dogs via the corpus cavernosum, with all reaching or exceeding their premorbid central venous pressure (CVP), and approaching or reaching their premorbid mean arterial pressure (MAP). In comparison the control dog's CVP and MAP did not rise during the period of observation after it was bled. CONCLUSIONS: The corpus cavernosum is a practical alternative means of intravenous access in the emergency setting in the dog model.

Adrenergic Agonists↗
PubMed2000

Comparison of three methods of CD34+ cell enumeration in peripheral blood: dual-platform ISHAGE protocol versus single-platform, versus microvolume fluorimetry.

BACKGROUND: Quantitation of peripheral blood (PB) CD34(+) cells is now an established method for timing PBPC harvesting. Recent refinements to the dual-platform ISHAGE gating strategy for CD34(+) cells has seen the introduction of microbeads to enable absolute counting of cells on a single instrument platform. This eliminates the need for total WBCC performed on an automated hematology analyzer and potentially increases the analytical precision of the methodology. At the same time, alternative methods for CD34(+) cell enumeration have started to emerge, notably microvolume fluorimetry, which forms the basis of the fully-automated STELLer CD34 method using the Imagn 2000. METHODS: We performed a three-way evaluation of these methods. Sixty-eight samples of PB from 42 patients undergoing PBPC mobilization were analyzed by all three methods and correlations between all three calculated. The two-platform ISHAGE method was used as the reference method. RESULTS: Precision and linearity of the single-platform and STELLer CD34 assays were excellent. Correlation with the dual-platform reference method was also excellent (single-platform method slope = 1.03, intercept = -0.03 and R(2) = 0.9325, STELLer CD34 assay slope = 0.827, intercept = 4.27, R(2) =0.8215). Bias, determined by Bland-Altman analysis, was 1.16 and -1.62 for single platform and STELLer CD34 assay respectively. CONCLUSION: The three methods of CD34(+) cell enumeration gave equivalent results. The single-platform methodology negated the need for a separate white cell analyzer, while the STELLer CD34 methodology was technically the simplest.

Antigens, CD34↗