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Biomedical subjects

E Fitzsimons

Publications and source records attributed to E Fitzsimons.

At least 19 recordsLinked to original sources
PubMed2005

Person Focused Training: a model for delivering positive behavioural supports to people with challenging behaviours.

BACKGROUND: Person Focused Training is introduced as a model of service delivery for people with severe challenging behaviours. It is defined as training and supporting staff to conduct functional assessments and to design and implement positive behavioural support for specific individuals with challenging behaviours. METHOD: Longitudinal outcome data are presented from 138 behaviour support plans developed by staff over a seven year period were analysed to determine reductions in frequency of challenging behaviours. Degree of behaviour change was determined across topography of behaviour, gender, age, level of disability, location of residence and role of course participant. RESULTS: Results indicate that the implementation by staff of behaviour support plans are associated with significant improvement in 77% of cases at an average follow-up of 22 months after implementation of support plans. Only location of residence was identified as related to reduction in challenging behaviours with large residential centres being associated with lower rates of behavioural improvement. CONCLUSIONS: It is argued that Person Focused training may represent an alternative to existing models of supporting individuals with challenging behaviours. The implications of front-line staff designing and implementing behaviour support plans for the organisation of services and the role of the clinical psychologist are considered.

Adult↗
PubMed2000

Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.

ATP-Binding Cassette Transporters↗
PubMed1998

Severe vincristine toxicity in combination with itraconazole.

We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.

Adult↗
PubMed1997

CD34 positive PBPC expanded ex vivo may not provide durable engraftment following myeloablative chemoradiotherapy regimens.

We have previously demonstrated that CD34+ cells, selected from peripheral blood progenitor cells (PBPC), can be expanded in ex vivo culture and can be infused in tandem with unmanipulated PBPC with little or no toxicity. In this study, four patients (two non-Hodgkin's lymphoma (NHL), two multiple myeloma (MM)) received myeloablative conditioning prior to stem cell rescue using ex vivo expanded cells alone. The two patients with NHL received cyclophosphamide and total body irradiation (CY/TBI) and the two patients with MM, busulphan and melphalan (Bu/M). One case received an inadequate CFU-GM dose, despite expansion, and in one case the expanded cells were contaminated. No definitive conclusions may therefore be drawn concerning engraftment in these two cases. However, the other two cases received high doses of committed progenitors. Following infusion of the expanded material, all four patients failed to show sustained neutrophil engraftment and none showed evidence of platelet engraftment. Back-up, unmanipulated PBPC were therefore infused on days 14, 34, 32 and 28 and subsequently all four cases achieved satisfactory engraftment of both neutrophils and platelets. In conclusion, we feel that, CD34+ cells, expanded ex vivo using the conditions described in this report, may not provide durable engraftment following fully myeloablative conditioning.

Adult↗
PubMed1996

Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow.

The characterization of many cytokines involved in the control of hematopoiesis has led to intense investigation into their potential use in ex vivo culture to expand progenitor numbers. We have established the optimum ex vivo culture conditions that allow substantial amplification of transient engrafting murine stem cells and which, simultaneously, augment the ability to sustain serial bone marrow transplantation (BMT). Short-term incubation of unfractionated BM cells in liquid culture with stem cell factor (SCF) and interleukin-11 (IL-11) produced a 50-fold amplification of clonogenic multipotential progenitors (CFU-A). Following such ex vivo expansion, substantially fewer cells were required to rescue lethally irradiated mice. When transplanted in cell doses above threshold for engraftment, BM cells expanded ex vivo resulted in significantly more rapid hematopoietic recovery. In a serial transplantation model, unmanipulated BM was only able to consistently sustain secondary BMT recipients, but BM expanded ex vivo has sustained quaternary BMT recipients that remain alive and well more than 140 days after 4th degree BMT. These results show augmentation of both short-term recovery posttransplant and the ability to serially transplant marrow by preincubation in culture with SCF and IL-11.

Bone Marrow Transplantation↗
PubMed1996

CD34-positive cells isolated from cryopreserved peripheral-blood progenitor cells can be expanded ex vivo and used for transplantation with little or no toxicity.

PURPOSE: The objectives of this phase I study were to assess the feasibility of using cryopreserved peripheral-blood progenitor cells (PBPC) for large-scale CD34 selection and subsequent expansion, and the safety of their use for reinfusion following chemoradiotherapy. PATIENTS AND METHODS: For 10 patients with nonmyeloid malignancy, an aliquot from a PBPC harvest was recovered from liquid nitrogen, and CD34 selected using the Isolex system (Baxter Healthcare, Newbury, United Kingdom) and expanded for 8 days ex vivo in a medium free of animal proteins but supplemented with autologous serum, stemcell factor (SCF), interleukin-1 beta (IL-1 beta), IL-3, IL-6, and erythropoietin. RESULTS: The mean increase for cell number was 21-fold, for colony-forming units-granulocyte/macrophage (CFU-GM) 139-fold, and for burst-forming units-erythroid (BFU-E) 114-fold. The expanded cells were reinfused in tandem with unmanipulated material (> or = 25 x 10(4) CFU-GM/kg). The patients did not experience any adverse effects immediately on cell infusion or within 48 hours. The 10 index patients were compared with 10 historical controls for parameters of myelosuppressive morbidity. In this small study, there were no differences in either neutrophil or platelet recovery between the patients who received expanded cells and historical controls. CONCLUSION: These data demonstrate that CD34 cells can successfully be selected from cryopreserved material, expanded ex vivo on a large scale, and safely reinfused following myeloablative conditioning regimens.

Adolescent↗
PubMed1994

Efficient isolation of human CD34 positive hemopoietic progenitor cells by immune panninga.

In this study we have assessed the use of soybean agglutinin (SBA) and CD34 microcellector devices for the selection of CD34 positive hemopoietic progenitor cells. Burst forming unit-erythroid (BFU-E), colony forming unit-granulocyte/macrophage (CFU-GM) and the recently developed multipotential human colony forming unit-type A (CFU-A) clonogenic assays were used to measure progenitor numbers in the starting mononuclear cell (MNC), the SBA negative, the nonadherent CD34 negative and the adherent CD34 positive fractions during panning. CFU-A progenitors were present at a relatively high incidence in the MNC fraction (220 per 10(5) MNC) and were enriched 15-fold in the adherent CD34 positive fraction. This progenitor incidence and enrichment were similar to those of CFU-GM and BFU-E. The mean recovery for CD34 positive cells was 2.3 x 10(6) cells per marrow aspirate. Analyses by flow cytometry demonstrated that 1-5% of input MNC were CD34 positive, that the purity of the CD34 fraction was approximately 80% and that the calculated recovery for CD34 positive cells was 61%. Recoveries for CFU-GM, BFU-E and CFU-A were between 18 and 40%. CFU-A progenitors were found exclusively in the adherent CD34 positive fraction, whereas a significant proportion of both CFU-GM and BFU-E were present in the nonadherent CD34 negative fraction. We propose that the Applied Immune Sciences (AIS) flasks preferentially bind the cells which express CD34 most strongly and that this is reflected in the finding of primitive CFU-A only in the CD34 positive fraction, with lineage-restricted progenitors found in both CD34 positive and negative fractions. This hypothesis is strengthened by data on long-term bone marrow cultures in which the CD34 positive fraction is better able to maintain output of CFU-GM compared with the CD34 negative fraction. In conclusion, relatively pure populations of CD34 positive cells may be rapidly and efficiently isolated from bone marrow samples with good recovery. The isolated cells show enhanced colony forming capacity in standard clonogenic assays and in the multipotential CFU-A assay.

Antigens, CD↗
PubMed1994

Sideroblastic anaemia.

The startling morphological abnormalities of sideroblastic anaemia contrasts our uncertainty about its cause. Studies are hampered by the fact that the abnormality resides in the dividing and differentiating erythroblast which is difficult to obtain pure and in large numbers, and in which many levels of metabolic control must coexist. Recent molecular biology approaches have confirmed abnormalities of erythroid delta-aminolaevulinic acid synthase as the cause of X-linked, pyridoxine-responsive sideroblastic anaemia and mitochondrial DNA deletions as the most common cause of congenital macrocytic sideroblastic anaemia. They have also identified a second X-linked sideroblastic anaemia locus linked to phosphoglycerate kinase and associated with ataxia. An association between sideroblastic anaemia and the use of an oral copper chelating agent has highlighted unexplained links between erythroid copper and iron metabolism. Management decisions in relation to pyridoxine treatment, iron reduction, family studies, genetic counselling and antenatal diagnosis have in recent years become of practical relevance to families with known cases of congenital sideroblastic anaemia and careful documentation of the clinical outcome of these cases and of other family members is invaluable. Parallel and integrated studies on the molecular biology of erythroid differentiation are revealing the range of possible controlling influences on erythroblasts and defining the circumstances for each, allowing studies on the cause of the most prevalent form of sideroblastic anaemia (the idiopathic acquired form) and those inherited forms that are not X-linked to be approached with a much clearer perspective.

5-Aminolevulinate Synthetase↗
PubMed1994

Aplastic anaemia associated with fenbufen: a report of two cases.

We report two cases of aplastic anaemia occurring in patients after exposure to the NSAID fenbufen. In each case, the patient had not been exposed to other drugs in this class, and was on no concomitant medication which has previously been associated with this complication. Failure of in vitro growth of haemopoietic progenitor cells in clonogenic assays confirmed the diagnosis of aplasia, and also confirmed that aplasia induced by this agent is not due to the presence of any humoral inhibitory factor, but to an intrinsic abnormality in the pluripotent stem cells. Aplastic anaemia is a recognized, but extremely rare, complication of exposure to NSAIDs of any chemical subtype.

Aged↗
PubMed1994

Abnormal haem biosynthesis in the chronic anaemia of rheumatoid arthritis.

OBJECTIVES: The chronic microcytic anaemia of rheumatoid arthritis (RA) occurs despite the presence of adequate reticulo-endothelial iron stores. The red cell microcytosis is evidence of impaired haemoglobin production. This study has examined possible abnormalities of erythroid haem biosynthesis that may contribute to the anaemia. METHODS: 5-Aminolaevulinate (ALA) synthase and ferrochelatase activities were assayed in whole bone marrow and in purified erythroblasts from patients with RA and in control subjects. All patients were iron replete with demonstrable iron in the bone marrow. RESULTS: ALA synthase activity was significantly reduced in both whole bone marrow and purified erythroblasts from patients with the anaemia of RA. Erythrocyte protoporphyrin levels were raised in nine of 12 patients tested while ferrochelatase activity was normal. CONCLUSION: These abnormalities provide absolute evidence of abnormal erythroblast haem biosynthesis and iron metabolism in the anaemia of RA and most likely reflect decreased ALA synthase mRNA translation and some abnormality of erythroblast iron transport. Further studies using highly purified erythroblast populations will attempt to identify the causal factors leading to this abnormal erythroblast metabolism.

5-Aminolevulinate Synthetase↗
PubMed1993

Contrasting effects of rh-MIP-1 alpha and TGF-beta 1 on chronic myeloid leukemia progenitors in vitro.

In chronic myeloid leukemia (CML) an abnormality at the stem cell level results in unregulated expansion of myeloid progenitors. The mechanism underlying this uncontrolled proliferation remains unclear. An in vitro clonogenic assay which detects the human counterpart of the murine colony forming unit (CFU) CFU-A/CFU-S day 12 was described in a report of our recent findings. CML bone marrow samples were found to proliferate in the CFU-A assay, producing colonies morphologically indistinguishable from normal controls. The bcr/abl transcripts were sought in the RNA from individual colonies using the polymerase chain reaction (PCR). For the five CML samples tested to date, the majority of CFU-A colonies at diagnosis or in early chronic phase were found to be bcr/abl positive. For normal controls both macrophage inflammatory protein-1 alpha (MIP-1 alpha) and transforming growth factor-beta 1 (TGF-beta 1) inhibited the proliferation of CFU-A colonies when directly added to the assay. In contrast, CML progenitors responded normally to TGF-beta 1, but showed no response to MIP-1 alpha. In suicide assays, for five normal bone marrow samples, CFU-A progenitors induced into S-phase returned to a quiescent state after treatment with MIP-1 alpha. CML progenitors demonstrated inherently high cycle status which showed no definite response to MIP-1 alpha. However, TGF-beta 1 resulted in quiescence of CML progenitor cycling. In conclusion, the primitive progenitors from CML samples were inhibited normally by TGF-beta 1 but showed no response to MIP-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1993

Mixed colony formation in vitro by the heterogeneous compartment of multipotential progenitors in human bone marrow.

The physiology of the human haemopoietic primitive progenitor populations can be studied in normal and disease states by clonal in vitro cultures in which the primitive progenitor cells proliferate and differentiate to form mixed colonies. For many applications it is essential that such assays detect a high proportion of primitive progenitor cells. We describe an in vitro assay which detects a high incidence of human CD34+ multipotential progenitor cells. Bone marrow mononuclear cells (MNC) or selected CD34+ cells were plated at low cell concentrations in semisolid agar cultures with synergizing growth factor combinations. The optimum growth factor combination of conditioned medium from Mia PaCa-2 cells (Mia-CM), recombinant granulocyte-macrophage colony-stimulating factor and recombinant stem cell factor (SCF) supported the formation of macroscopic (> or = mm) colonies (97% of which were multilineage), at an average incidence of 250/10(5) MNC. The colony-forming cells (human colony-forming unit, type A) detected, showed a low cycling status (7.3%) and the macroscopic colonies had a high replating efficiency (46%), reflecting their probable primitive nature. This assay should prove invaluable, for studies on the regulation of proliferation of the multipotential compartment and in studies involving the assessment of these cells in transplantation and neoplastic disease.

Antigens, CD↗
PubMed1992

Viral-associated haemophagocytosis with parvovirus-B19-related pancytopenia.

Viral-associated haemophagocyte syndrome in response to infection with human parvovirus B19 was seen in 2 patients with hereditary spherocytosis. Depressed reticulocyte response during acute parvovirus infection is a known cause of hypoproliferative crises in patients with reduced erythrocyte lifespan; the observation of parvovirus-associated haemophagocytosis could account for the pancytopenia that may accompany human parvovirus B19 infection.

Adult↗
PubMed1991

Erythroid 5-aminolaevulinate synthase activity during normal and iron deficient erythropoiesis.

Reduced erythroblast 5-aminolaevulinate (ALA) synthase activity was observed during iron/haem deficient erythropoiesis. Enzyme activity was reduced approximately threefold to levels similar to those previously detected during sideroblastic erythropoiesis. This response would appear to be erythroblast specific as haem deficiency is known to stimulate hepatic ALA synthase activity. It is, however, unclear as to whether this reduced enzyme activity relates to iron deficiency or to the consequent haem deficiency.

5-Aminolevulinate Synthetase↗
PubMed1990

Failure of deferoxamine to improve iron overload in chronic hemodialysis patients.

We prospectively studied the in vivo dialytic clearance of iron after deferoxamine (DFO) administration in four stable iron-overloaded chronic hemodialysis patients by quantifying iron concentration in blood entering and leaving the dialyzer and in dialysate after infusions of DFO. No significant arteriovenous iron differences were demonstrated. The mean ratio of venous to arterial iron approached identity at 1.005. All dialysate concentrates used contained large amounts of iron (300-610 micrograms/dl). No changes in efferent versus afferent dialysate iron concentration could be demonstrated. We conclude (a) iron removal during dialysis with DFO was not demonstrated; (b) the dialysate concentrate tested contained large amounts of iron; (c) in view of potentially significant toxicity, and lack of demonstrable therapeutic benefit, caution in prescribing DFO chelation therapy for iron overload is recommended.

Deferoxamine↗