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Biomedical subjects

M Dexter

Publications and source records attributed to M Dexter.

18 recordsLinked to original sources
PubMed2001

Continuous intrathecal baclofen infusion for children with cerebral palsy: a pilot study.

OBJECTIVES: To determine whether continuous intrathecal baclofen infusion (CIBI) would decrease spasticity and improve function in children with spastic cerebral palsy. DESIGN: Prospective study with measurement of changes from baseline assessed at regular intervals for 6 months following the intervention. PATIENTS: Two subjects aged 8 and 9 years with cerebral palsy. Inclusion criteria included severe spasticity and age greater than 4 years. STUDY CENTRE: Department of Rehabilitation, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. RESULTS: Both subjects had clinically significant reductions in lower limb spasticity from a single intrathecal dose of baclofen (screening procedure), and had intrathecal pumps implanted. An intensive physical therapy programme was provided for both subjects in the 1-3-month period after commencing CIBI, in order to maximize functional gains. Modified Ashworth Scale scores remained reduced during the 6-month study period. There was a clinically significant increase in upper limb function for Subject 1. Gross Motor Function Measure scores decreased from 22% to 19% for Subject 1, and increased from 6% to 10% for Subject 2 over the study period. Paediatric Evaluation of Disability Inventory scores for Subject 1 showed a reduction in the level of caregiver assistance required, while Subject 2 showed significant improvement in the functional mobility domain. The major changes noted in the parent questionnaires were reduction in tone, increased range of motion and reduced time taken helping with activities of daily living such as toilet and dressing. No significant side-effect was seen after the screening procedure or after continuous intrathecal infusion. Both subjects' parents felt their child was improved following the intervention. CONCLUSIONS: Children with spastic cerebral palsy can have their spasticity effectively reduced with CIBI. In this study of two children, the clinical improvements were encouraging, and it is proposed that CIBI may be of benefit to those patients whose level of spasticity severely interferes with function. Further studies using multidimensional assessment approaches, with larger numbers of children, are warranted.

Baclofen↗
PubMed1999

A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal.

The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is functionally implicated in their survival and proliferation. We have used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in cells cultured in IL-3 blocked factor-dependent self-renewal but not factor-dependent survival: Cells undergo cell cycle arrest and cease proliferating but do not apoptose. This was accompanied by differentiation down the monocytic and granulocytic pathways. Differentiation occurred in the presence of IL-3 and did not require addition of exogenous differentiation growth factors such as G-CSF or GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA-2 activation. These biological effects were obtained with levels of exogenous GATA-2 representing less than twofold increases over endogenous GATA-2 levels and were not observed in cells overexpressing GATA-1/ER. Similar effects on proliferation and differentiation were also observed in primary progenitor cells, freshly isolated from murine bone marrow and transduced with a GATA-2/ER-containing retrovirus. Taken together, these data suggest that threshold activities of GATA-2 in hematopoietic progenitor cells are a critical determinant in influencing self-renewal versus differentiation outcomes.

Animals↗
PubMed1997

Multilineage gene expression precedes commitment in the hemopoietic system.

We have tested the hypothesis that multipotential hemopoietic stem and progenitor cells prime several different lineage-affiliated programs of gene activity prior to unilineage commitment and differentiation. Using single cell RT-PCR we show that erythroid (beta-globin) and myeloid (myeloperoxidase) gene expression programs can be initiated by the same cell prior to exclusive commitment to the erythroid or granulocytic lineages. Furthermore, the multipotential state is characterized by the coexpression of several lineage-affiliated cytokine receptors. These data support a model of hemopoietic lineage specification in which unilineage commitment is prefaced by a "promiscuous" phase of multilineage locus activation.

Animals↗
PubMed1995

Cloning of the murine homolog of the leukemia-associated PML gene.

PML, a Ring-finger protein, participates in the disruption of normal myeloid differentiation when fused to the retinoic acid receptor alpha (RAR alpha) by the translocation between chromosomes (Chrs) 15 and 17 in acute promyelocytic leukemia (APL). As an initial step in the characterization of PML in species other than human, a murine cDNA clone of the PML gene was isolated and sequenced, and the intron/exon organization of the murine locus determined. The predicted amino acid sequence of the mouse PML protein shows 80% similarity to that of its human homolog. However, the mouse and human proteins show greater than 90% similarity in the proposed functional domains of the proteins. Despite its role in the etiology of APL, PML expression is not detectably altered during granulocytic differentiation in a murine in vitro system. Chromosomal localization of the Pml locus by somatic cell hybrids and by linkage analysis indicates that the gene maps to a region of mouse Chr 9 with known linkage homology to the region on human Chr 15q to which PML has been localized.

3T3 Cells↗
PubMed1993

Targeted in vivo infection with a retroviral vector carrying the interleukin-3 (multi-CSF) gene leads to immortalization and leukemic transformation of primitive hematopoietic progenitor cells.

To measure the effect of endogenous IL-3 (Multi-CSF) expression on hematopoietic cells in vivo, we have infected several kinds of hematopoietic cell populations with retroviral vectors carrying the IL-3 gene (M3MuV) in vitro and injected the virus-producing cells into mice to "target" the virus to sites of hematopoiesis. Mast cell lines (Elut cells) or multipotent cell lines (FDC-Pmix) were infected with MPSV-based replication defective retroviral vectors carrying either the neomycin resistance gene alone (M3neoV) or the neomycin gene plus the IL-3 gene (M3MuV). These cell lines produced infective retroviral particles consisting of the replication defective vectors and helper virus constitutively produced by the target cell populations. Irradiated and non-irradiated virus-producing Elut cells and the virus-producing FDC-Pmix cells were transplanted into syngeneic mice to "target" virus infection to the sites of hemopoiesis. Control mice injected with M3neoV-producing cells did not develop a disease up to 6 months following transplantation, whereas mice injected with M3MuV-producing cells developed a myeloproliferative disease within 3 months. Hematopoietic cell lines were rescued from diseased and control mice. In all cases these cell lines were of host origin. Cell lines derived from control mice were of basophil/mast cell morphology only, and required IL-3 for their continued proliferation (similar to cell lines derived from uninfected animals), whereas the cell lines generated from spleen and bone marrow cells of host mice with myeloproliferative disease carried the M3MuV vector, were G418 resistant and IL-3 independent. The biologic properties of M3MuV infected host derived cell lines varied considerably. Some were multipotential and could be induced to differentiate in response to stromal cells and serum factors, others were more restricted to the granulocyte/macrophage lineage but were also differentiation inducible, and some were blocked in differentiation at the myeloblast/promyelocyte stage. We conclude that the injected donor cells acted as "infectious centers" to facilitate the infection of host hematopoietic cells with the M3MuV vector. Our results indicate that the "targeted" in vivo infection of primitive hematopoietic cells with M3MuV can initiate the immortalization and leukaemogenesis of multipotential and lineage restricted progenitor cells.

Animals↗
PubMed1991

Effects of the steel gene product on mouse primordial germ cells in culture.

Mutations at the steel (sl) and dominant white spotting (W) loci in the mouse affect primordial germ cells (PGC), melanoblasts and haemopoietic stem cells. The W gene encodes a cell-surface receptor of the tyrosine kinase family, the proto-oncogene c-kit. In situ analysis has shown c-kit messenger RNA expression in PGC in the early genital ridges. The Sl gene encodes the ligand for this receptor, a peptide growth factor, called here stem cell factor (SCF). SCF mRNA is expressed in many regions of the early mouse embryo, including the areas of migration of these cell types. It is important now to identify the role of the Sl-W interaction in the development of these migratory embryonic stem cell populations. Using an in vitro assay system, we show that SCF increases both the overall numbers and colony sizes of migratory PGC isolated from wild-type mouse embryos, and cultured on irradiated feeder layers of STO cells (a mouse embryonic fibroblast line). In the absence of feeder cells, SCF causes a large increase in the initial survival and apparent motility of PGC in culture. But labelling with bromodeoxyuridine shows that SCF is not, by itself, a mitogen for PGC. SCF does not exert a chemotropic effect on PGC in in vitro assays. These results suggest that SCF in vivo is an essential requirement for PGC survival. This demonstrates the control of the early germ-line population by a specific trophic factor.

Animals↗
PubMed1991

Retroviral vectors related to the myeloproliferative sarcoma virus allow efficient expression in hematopoietic stem and precursor cell lines, but retroviral infection is reduced in more primitive cells.

Retroviral vectors are considered to be the most suited vehicles for somatic gene therapy with hematopoietic stem cells as targets. Retrovirus-mediated gene transfer into differentiation-restricted hematopoietic precursor (FDC-P1, FDC-P2) and multipotent progenitor (stem) cell lines (FDC-Pmix) is inefficient. Two cellular restrictions are involved. One is specific for stem but not precursor cells and is at the level of transcription. Due to a unique property of the transcriptional control region of the myeloproliferative sarcoma virus (MPSV), vectors derived from MPSV are not affected by this block. The second restriction occurs before proviral DNA synthesis and integration. This inhibition of effective viral infection depends on the state of differentiation, being more pronounced in multipotent clonogenic blast cells. This block to retroviral infection affects all retroviral vectors tested.

Animals↗
PubMed1990

Growth factor-assisted chemotherapy--the Manchester experience.

Stimulation of red cell production by erythropoietin and of granulocyte production by granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) has been demonstrated in several clinical studies. The first study to show that a human CSF could be used to shorten the period of neutropenia and reduce the risk of serious infection following intensive combination chemotherapy was carried out in Manchester using G-CSF. The period of neutropenia was significantly shortenened (by a median of 80%) and the neutrophil count levels were restored and above normal by 14 days after chemotherapy. In view of these results a further study was undertaken to examine the possibility of using intensive two weekly chemotherapy under cover of G-CSF. Treatment with Doxorubicin at doses of 75, 100, 125 and 150 mg/m2 was followed by infusion of G-CSF for 11 days. The neutrophil counts returned to normal within 12-14 days, allowing the delivery of up to three cycles of high dose chemotherapy at 14 day intervals. These studies demonstrated that intensive chemotherapy with dose-limiting myelodepression can be given with increased frequency under cover of G-CSF. Our studies using GM-CSF have also shown that administration by continuous i.v. infusion can reduce the period of life-threatening neutropenia following high dose Melphalan (120 mg/m2) without resort to autologous bone marrow transplantation (ABMT). In this study the period of granulocytopenia following Melphalan (less than 500 g x 10(9)/m2) was less than 15 days. This compares favourably with other series using high dose Melphalan followed by ABMT without CSF, where the duration of severe neutropenia was prolonged beyond three weeks. Although it appears that G-CSF and GM-CSF should be given either by continuous i.v. infusion or s.c. injection at doses between 3-10 micrograms/kg/day to obtain maximum biological effect, a great deal more work is required to determine optimum schedules and investigate the possibility of using more than one bioregulator.

Agranulocytosis↗
PubMed1990

Lack of response of bone marrow, in vitro, to growth factors in congenital neutropenia.

Severe congenital neutropenia has a poor outlook. In vitro clonogenic assays using recombinant growth factors may improve understanding of the underlying pathogenetic mechanisms and identify those in whom growth factors might be clinically useful. Marrow from a boy with congenital neutropenia was cultured with a variety of recombinant growth factors. The results show that the neutropenia did not result from a lack of myeloid progenitors but that these progenitors could not produce mature neutrophils. Bone marrow transplantation is being considered as the most likely approach to correct neutropenia.

Agranulocytosis↗
PubMed1989

Aberrant expression of the multi-CSF gene in hematopoietic precursor and stem cell lines initiates leukemogenic progression.

Tumorigenesis of hemopoietic cells and acquisition of factor independence as a consequence of aberrant growth factor release are closely correlated. In previous work we were able to dissect two stages leading to growth factor autonomy of cells: the first step requires the secretion of the constitutively expressed CSF gene product and extracellular interaction with its cognate receptor. This requirement for external stimulation is abrogated by a second step. We were interested in characterizing the parameters that influence the conversion from nonautonomous to autonomous growth properties of hematopoietic precursor cells. The frequency with which this alteration occurs varies and correlates with the level of growth factor production. However, a significant increase of CSF production accompanying the progression to autonomy could not be detected. We thus conclude that there is no direct link between level of CSF production and acquisition of true autonomy but an indirect influence enhancing the frequency of genetic alteration(s) that lead to growth autonomy. Lang et al. have suggested that the acquisition of autonomous growth occurs due to internal receptor-ligand interaction. Indeed, Keating and Williams have claimed that PDGF may react with an intracellular PDGF receptor resulting in autocrine stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Rates of mutation to growth factor autonomy and tumorigenicity differ in hematopoietic stem and precursor cells expressing the multilineage colony-stimulating factor gene.

At least two separate but interdependent events are required to attain autonomous growth as a consequence of ectopic expression of the multilineage colony-stimulating factor gene in hematopoietic progenitor cells. The rate at which the second event occurs is more than 3 orders of magnitude higher in precursor cell lines (FDC-P1 or FDC-P2) than in stem cell lines (FDC-Pmix). Autonomous, but not density-dependent, growth is tightly coupled to tumorigenicity in precursor cells; however, neither growth-factor-independent nor autonomously growing stem cell lines are tumorigenic.

Animals↗
PubMed1987

Changes in minor transcripts from the alpha 1 and beta maj globin and glutathione peroxidase genes during erythropoiesis.

We have analysed the transcriptional regulation of the murine alpha 1 and beta maj globin genes and the glutathione peroxidase (GSHPx) gene, which are all highly expressed during erythropoiesis. The levels of minor RNAs compared to the major message were monitored throughout differentiation within the erythroid lineage. For each gene, upstream transcripts arise from distinct clusters of sites which are regulated differently during differentiation: some occur only during early erythropoiesis, some occur early and persist to the terminal stages, while others accumulate later and roughly in parallel with the main RNA transcript. In addition, opposite strand transcripts from the GSHPx gene were found in increasing amounts during later stages of erythropoiesis. The initiation sites for specific subsets of these minor transcripts lie close to sequences known to be involved in globin gene regulation (i.e. the TATA, CAAT and the CACCCT boxes) or other conserved sequences; others lie close to developmentally regulated DNase I hypersensitive sites around the globin and GSHPx genes.

Animals↗
PubMed1987

Progress in T cell biology.

We outline recent work in our laboratories on thymus progenitors, lineages within the thymus, interactions between regulatory and effector lymphocytes, splitting the CD4 (T4) T cell subset, and Ir and Is genes. We highlight the possibilities for future research opened up by the demonstration that certain marrow-derived cell lines can repopulate thymic lobes in culture, and also the deep insight into the logical structure of the lymph node provided by our ability to make an exact comparison between two-cell-type and three-cell-type immunoregulatory clusters.

Animals↗