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Biomedical subjects

L Bell

Publications and source records attributed to L Bell.

At least 37 records · Page 2Linked to original sources
PubMed1998

Bcl-3 expression and nuclear translocation are induced by granulocyte-macrophage colony-stimulating factor and erythropoietin in proliferating human erythroid precursors.

Bcl-3 is a proto-oncogene involved in the chromosomal translocation t(14;19) found in some patients with chronic lymphocytic leukemia. It shares structural similarities with and is a member of the IkappaB family of proteins. In this report, involvement of Bcl-3 in hematopoietic growth factor-stimulated erythroid proliferation and differentiation was examined. In TF-1 cells, an erythroleukemia cell line, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo) greatly enhanced Bcl-3 expression at both the protein and mRNA levels in association with stimulation of proliferation. Bcl-3 protein was also highly expressed in early burst-forming unit-erythroid (BFU-E)-derived erythroid precursors (day 7) and decreased during maturation (days 10 and 14), suggesting that Bcl-3 is involved in normal erythroid proliferation. In these hematopoietic cells, Bcl-3 was hyperphosphorylated. GM-CSF and Epo modulated the subcellular localization of Bcl-3. Upon stimulation of TF-1 cells with GM-CSF or Epo, the nuclear translocation of Bcl-3 was dramatically enhanced. Overexpression of Bcl-3 in TF-1 cells by transient transfection along with the NF-kappaB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus-type 1 (HIV-1) kappaB-TATA-luceriferase reporter plasmid, demonstrating that Bcl-3 has a positive role in transactivation of kappaB-containing genes in erythroid cells. Stimulation with GM-CSF enhanced c-myb mRNA expression in these cells. Bcl-3 in nuclear extracts of TF-1 cells bound to a kappaB enhancer in the c-myb promoter together with NF-kappaB2/p52 and this binding activity was enhanced by GM-CSF stimulation. Furthermore, cotransfection of Bcl-3 with p52 or p50 in TF-1 cells resulted in significant activation of a c-myb kappaB-TATA-luceriferase reporter plasmid. These findings suggest that Bcl-3 may participate in the transcriptional regulation of certain kappaB-containing genes involved in hematopoiesis, including c-myb.

B-Cell Lymphoma 3 Protein↗
PubMed1998

NF-kappaB transcription factors are involved in normal erythropoiesis.

NF-kappaB/Rel designates a widely distributed family of transcription factors involved in immune and acute phase responses. Here, the expression and function of NF-kappaB factors in erythroid proliferation and differentiation were explored. In an erythroleukemia cell line, TF-1, high levels of p105/p50, p100/p52, p65, and IkappaBalpha were detected 24 hours after growth factor deprivation. In response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, significant induction of p52 expression was observed. GM-CSF also induced nuclear translocation of both p52 and p65. No induction of NF-kappaB factors was observed with erythropoietin stimulation of TF-1 cells. Overexpression of p52 and p65 in TF-1 cells by transient transfection resulted in significant induction of a kappaB-TATA-luciferase reporter plasmid, showing that these factors are functional in vivo in erythroid cells. To determine whether NF-kappaB factors may play a role in normal erythropoiesis, levels of these factors were determined in burst-forming unit-erythroid (BFU-E)-derived cells at different stages of differentiation. The NF-kappaB factors p105/p50, p100/p52, and p65 were highly expressed in early BFU-E-derived precursors, which are rapidly proliferating, and declined during maturation. Furthermore, nuclear levels of NF-kappaB factors p50, p52, and p65 were higher in less mature precursors (day 10 BFU-E-derived cells) compared with more differentiated (day 14) erythroblasts. In nuclear extracts from day 10 BFU-E-derived cells, p50, p52, and p65 were able to form complexes, which bound to kappaB sites in the promoters of both the c-myb and c-myc genes, suggesting that c-myb and c-myc may be among the kappaB-containing genes regulated by NF-kappaB factors in normal erythroid cells. Taken together, these data show that NF-kappaB factors are modulated by GM-CSF and suggest they function to regulate specific kappaB containing genes involved in erythropoiesis.

Cell Division↗
PubMed1998

A concept analysis of parent-infant attachment.

A concept analysis, the clarification of a concept, is the first step towards building the foundations of nursing theory, research and practice. As a relevant concept for nurses working with childbearing families, parent-infant attachment is an important part of the body of nursing knowledge. Wilson's method of concept analysis was used to generate antecedents, critical attributes and consequences of parent-infant attachment, highlighting the need to refine measurements of this concept.

Canada↗
PubMed1998

Communicate: organisational issues and their relevance for clinical evaluation.

This paper reports the first findings of a two year project funded by the NHS Executive North Thames to provide an independent evaluation of Communicate, Action for Dysphasic Adults' training programme for carers of older people with communication impairments. The project comprises an organisational evaluation (January-July 1998) to review the use of Communicate by purchasers nationally and in the North Thames health region, and (from September 1998) a clinical evaluation in North Thames region, to investigate outcomes for communicatively impaired people themselves and for training participants. The paper outlines the research design and progress so far before presenting initial findings. It concludes by discussing the relevance of organisational issues and social science research insights to the forthcoming clinical evaluation.

Aphasia↗
PubMed1997

Sex lethal controls dosage compensation in Drosophila by a non-splicing mechanism.

Dosage compensation in Drosophila requires the male-specific lethal (msl) proteins (MSL) to make gene expression from the single male X chromosome equivalent to that from both female X chromosomes. Expression of ms12 is repressed post-transcriptionally by Sex lethal (SXL), a female-specific RNA-binding protein that regulates alternative splicing in the sex-determination hierarchy. Although msl2 RNA is alternatively spliced in males and females, this does not alter its coding potential and splicing is not required for male-specific expression of MSL2 protein. Instead, our results suggest that the association of SXL protein with multiple sites in the 5' and 3' untranslated regions of the mx12 transcript represses its translation in females. Thus, this well characterized alternative splicing factor regulates at least one target transcript by a distinct mechanism.

Alternative Splicing↗
PubMed1997

The development and benefits of nursing protocols for fractured neck of femur patients.

In this article the authors discuss the development, use and auditing of nursing care protocols, which have been implemented and form a guide for nurses caring for patients with fractured neck of femur in Southend Health Care NHS Trust. The development of these protocols occurred after an initial medical audit, which was followed by a far larger multidisciplinary audit, and both of these revealed there was need for changes in the clinical management of such patients; subsequently a large multidisciplinary working group worked together to develop care protocols/pathways to enable closure of the audit loop. The reasons for focusing on fractured neck of femur as a high priority condition are also discussed. All professional groups caring for these patients were involved in the multidisciplinary working group, which was formed to close the audit loop and to improve clinical practices by increasing the systemization and coordination of care. The development of the nursing protocols represented an extremely important part of this process, and the care of about 700 patients was examined during this work. The audit and associated subsequent work have resulted in direct improvements to both patient care and health outcomes, and the authors conclude that there is great value in developing multidisciplinary protocols, particularly those involving nurses, because they spend more time with patients whilst they are in hospital than any other professional group. The benefits of these nursing protocols have been multifold, in particular they have facilitated a clearer flow of patients through the hospital, increased awareness of responsibilities and reduced duplication of effort, and ensured patients receive the best possible care over the 24-hour period.

Emergency Nursing↗
PubMed1996

G-protein alpha subunit Gi(alpha)2 mediates erythropoietin signal transduction in human erythroid precursors.

Erythropoietin induces a dose-dependent increase in cytosolic calcium in human erythroblasts that is mediated by a voltage-independent Ca2+ channel. Inhibition of this response to erythropoietin by pertussis toxin suggests involvement of guanine nucleotide-binding regulatory proteins (G-proteins). The role of G-proteins in regulation of the erythropoietin-modulated Ca2+ channel was delineated here by microinjection of G-protein modulators or subunits into human erythroid precursors. This is the first report on the use of microinjection to study erythropoietin signal transduction in normal precursor cells. Fura-2 loaded day-10 burst-forming units-erythroid-derived erythroblasts were used for microinjection and free intracellular calcium concentration ([Ca(i)]) was measured with digital video imaging. BCECF (1,2',7'-bis(2-carboxyethyl)-5-(and -6-)-carboxyfluorescein) was included in microinjectate, and an increase in BCECF fluorescence was evidence of successful microinjection. Cells were microinjected with nonhydrolyzable analogues of GTP, GTPgammaS or GDPbetaS, which maintain the alpha subunit in an activated or inactivated state, respectively. [Ca(i)] increased significantly in a dose-dependent manner after microinjection of GTPgammaS. However, injection of GDPbetaS blocked the erythropoietin-induced calcium increase, providing direct evidence that activation of a G-protein is required. To delineate which G-protein subunits are involved, alpha or betagamma transducin subunits were purified and microinjected as a sink for betagamma or alpha subunits in the erythroblast, respectively. Transducin betagamma, but not alpha, subunits eliminated the calcium response to erythropoietin, demonstrating the primary role of the alpha subunit. Microinjected antibodies to Gi(alpha)2, but not Gi(alpha)1 or Gi(alpha)3, blocked the erythropoietin-stimulated [Ca(i)] rise, identifying Gi(alpha)2 as the subunit involved. This was confirmed by the ability of microinjected recombinant myristoylated Gi(alpha)2, but not Gi(alpha)1 or Gi(alpha)3 subunits, to reconstitute the response of pertussis toxin-treated erythroblasts to erythropoietin. These data directly demonstrate a physiologic function of G-proteins in hematopoietic cells and show that Gi(alpha)2 is required in erythropoietin modulation of [Ca(i)] via influx through calcium channels.

Calcium↗
PubMed1996

The economic evaluation of the FIRST study: design of a prospective analysis alongside a multinational phase III clinical trial. Flolan International Randomized Survival Trial.

Prospective economic assessments of new pharmaceutical therapies are increasingly being incorporated into phase III clinical trials. We report on the design of an economic evaluation integrated into the Flolan International Randomized Survival Trial (FIRST). Economic evaluation was considered a critical component of the assessment of this therapy given the resources required to administer epoprostenol (Flolan), a therapy that would require lifelong continuous intravenous infusion. Economic secondary endpoints were incorporated in the clinical trial. The economic evaluation of the treatment was integrated into all aspects of study development, including study design, implementation, and monitoring. Since this was a multinational trial, special care was required to ensure that the protocol design was appropriate for all study countries. The economic assessment required the development of several methodologic components: a set of background economic concepts to guide protocol development, a set of resource items to be recorded when required for study participants; a set of data collection instruments for assessment of health-related quality of life for study patients; and a protocol for a resource costing exercise for the study. We report the data elements included in the study design, as well as a discussion of some of the issues faced in developing the economic evaluation for this trial.

Antihypertensive Agents↗
PubMed1996

Glutathione deficiency as a complication of methylmalonic acidemia: response to high doses of ascorbate.

A 7-year-old boy with deficient activity of methylmalonyl coenzyme A mutase (mut-methylmalonic acidemia) was seen in severe metabolic crisis. After hemodialysis and clearance of toxic metabolites, severe lactic acidosis persisted with multiorgan failure. Glutathione deficiency was noted and high-dose ascorbate therapy (120 mg/kg) commenced. Glutathione deficiency may contribute to the lactic acidosis observed during decompensation in patients with methylmalonic acidemia.

Acidosis, Lactic↗
PubMed1996

Results of the economic evaluation of the first study. A multinational prospective economic evaluation. FIRST Investigators. Flolan International Randomized Survival Trial.

We present the prospective economic evaluation that served as a secondary endpoint for the FIRST study, a randomized international multicenter trial of patients with severe congestive heart failure. Although the clinical results of this study were disappointing, we demonstrated the feasibility of incorporating prospective economic evaluation in phase III clinical trials.

Aged↗
PubMed1996

A strategy for collecting pharmacoeconomic data during phase II/III clinical trials.

This article presents an overview of the process and organisational aspects required to support the collection of pharmacoeconomic (PE) data during phase II and phase III clinical trials of pharmaceutical products. The process described requires early involvement of the PE study team in clinical trials design and planning, as well as continuing close collaboration between the PE study team and the clinical study team as the data collection plans are implemented. Adequate resources must be made available for staffing and funding the PE component of data collection and analysis. If the suggested procedures are adequately resourced and implemented, the result should be a comprehensive, complete and accurate database that will allow the PE study team to characterise the economic value of the new drug at the same time as the clinical study team characterise its safety and efficacy. Integrated clinical and economic evaluations are essential for the appropriate use of pharmaceutical products in rapidly changing markets.

Clinical Trials, Phase II as Topic↗
PubMed1995

Why the NHS should abandon the search for the universal outcome measure.

This paper considers the use of outcome measures in the British National Health Service (NHS). Measuring outcomes is a major conceptual and practical problem. Many different measures are currently available yet no consensus has been reached on which should be preferred over others, or about which should take priority when they conflict. Some currently used measures are described, the relationship between these measures and the measured activities are discussed, and fundamental problems with both the measures and their use are revealed. It is shown that however assiduous the search, the 'perfect' outcome measure will always remain elusive.

Commerce↗
PubMed1995

Progress in a Moscow children's burn unit: a joint Russian-American collaboration.

A joint Russian-American paediatric burn programme involving Childrens Hospital No. 9 in Moscow and Project HOPE in Millwood, Virginia emerged from the efforts of burn professionals from both countries in caring for a group of children seriously burned as a result of the train-pipeline catastrophe that occurred in June 1989 in the Ural Mountains. This paper describes the burn unit and its activities during the years 1985-93 and includes: (1) a general description of the physical and administrative structure of the unit; (2) the demography of burn admissions; (3) clinical activities; (4) a comparison of the clinical results of the years before the institution of the combined programme (1985-89) with those achieved during the first 4 years of the combined collaboration (1990-93). Among the important changes that have occurred since the onset of the combined programme are: (1) overall reduction in the crude burn mortality rate; (2) decrease in burn deaths in all burn size groups; (3) dramatic reduction in the length of stay of children with the deepest burns; (4) marked improvement in the take of skin grafts applied to burn wounds and an almost total elimination of complete skin graft failures.

Adolescent↗
PubMed1995

Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia.

This study examined relations of mesiotemporal lobe tissue volumes with neuropsychological (NP) functions in a sample of patients with first episode schizophrenia. Three contiguous compartments of the mesiotemporal lobe were measured on magnetic resonance images, comprising primarily amygdaloid, anterior hippocampal, and posterior hippocampal tissue volumes. NP measures were derived from a comprehensive battery. Decreased volume selectively in the anterior hippocampal formation was associated with lower scores on measures of executive and motor functions usually considered sensitive to the integrity of frontal lobe systems. Measures of other NP functions, and global intellectual ability, were not related to mesiotemporal volumes. The findings that morphologic abnormalities in the mesiotemporal lobe are associated with impairment of frontal lobe functions point to a defect in an integrated functional system that includes both frontal and mesiotemporal components. The findings are consistent with the hypothesis that neurodevelopmental defects affecting the morphology of the anterior hippocampal formation may be manifest later in life as impairments in fronto-limbic control. .

Acute Disease↗
PubMed1995

A randomized, controlled trial of the efficacy of a heparin and vancomycin solution in preventing central venous catheter infections in children.

OBJECTIVE: To determine whether adding vancomycin to central venous catheter (CVC) flush solution would significantly reduce the incidence of bacteremia attributable to luminal colonization with vancomycin-susceptible organisms. STUDY DESIGN: Fifty-five children with cancer and eight children given total parenteral nutrition by the surgery or nutrition support services were randomly assigned to receive a heparin CVC flush solution (n = 31) or a heparin-vancomycin CVC flush solution (n = 32). RESULTS: During 9158 catheter days, 6.5% of the patients in the heparin group and 15.6% of the patients in the heparin-vancomycin group had bacteremia attributable to luminal colonization with vancomycin-susceptible organisms (p = 0.43). The mean rates of bacteremia attributable to luminal colonization with vancomycin-susceptible organisms were 0.6/1000 catheter days in the heparin group and 1.4/1000 catheter days in the heparin-vancomycin group (p = 0.25). There was no significant difference between the groups when the time to the first episode of bacteremia attributable to luminal colonization with a vancomycin-susceptible organism was compared by means of Kaplan-Meier survival estimates. Streptococcus viridans infection was not attributable to luminal colonization. CONCLUSION: The addition of vancomycin to heparin CVC flush solution did not reduce bacteremia with vancomycin-susceptible organisms. Bacteremia with Streptococcus viridans was not related to the use of a CVC.

Adolescent↗