Biomedical subjects

J Gasson

Publications and source records attributed to J Gasson.

12 recordsLinked to original sources

PubMed2003

The effects of a one unit blood donation on auto-haemodilution and coagulation.

The effect of haemodilution on coagulation has been extensively investigated. We investigated auto-haemodilution following a 10% blood loss (480 ml) and its effect on coagulation. Ten healthy, unstarved volunteers were enrolled. One unit of blood was taken from each volunteer. Concurrently blood was taken from the opposite arm prior to and immediately after the blood donation, and at 1, 2, 4 and 6 hours. It was tested for thrombelastography, haematocrit and endorphins. There was a significant decrease in r-time from the control sample to the sample taken immediately post blood donation. This value returned to baseline at 1 hour post donation and did not change again. There were no other significant changes in thromboelastographic parameters. Fractional plasma noradrenaline changes were significantly raised at 1 hour post donation (P = 0.048), returning to baseline by 2 hours post donation. The haematocrit showed a rapid (approximately 4%) fall during donation followed by a slow, but progressive decrease over six hours, falling by a mean of 8.3% from pre-donation values. A state of relative hypercoagulability is found immediately after a rapid 10% loss in circulating blood volume. This may be related to the rapid immediate haemodilution. It is unlikely that the sympathetic response to blood loss plays a role. However, after the initial drop, slow restoration of circulating blood volume by autodilution takes six to eight hours, and is not associated with enhanced coagulation. Of interest is that a 10% blood loss in a healthy person does not require volume replacement.

Antithrombin III↗

PubMed2001

Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels.

Mice with targeted mutations in genes required for Notch signal transduction die during embryogenesis, displaying overt signs of hemorrhage due to defects in their vascular development. Surprisingly, directed expression of a constitutively active form of Notch4 within mouse endothelial cells produces a similar vascular embryonic lethality. Moreover, patients with mutations in Notch3 exhibit the cerebral vascular disorder, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These findings underscore the importance of Notch signaling in vascular development; however, they do not identify the specific functional defect. Here, we report that Notch1, Notch3, Notch4, Delta4, Jagged1 and Jagged2 are all expressed in arteries, but are not expressed by veins. These findings identify an aspect of Notch signaling that could contribute to the mechanism by which this pathway modulates vascular morphogenesis.

Animals↗

PubMed2001

The notch receptor and its ligands are selectively expressed during hematopoietic development in the mouse.

Members of the Notch family of transmembrane receptors are found on primitive hematopoietic precursors, and Notch ligand expression has been demonstrated on the surface of stromal cells, suggesting a role for Notch signaling in mammalian blood cell development. The current report examines the expression of Notch receptors and their ligands in murine hematopoietic tissues to determine: A) which blood cell lineages in the adult are influenced by Notch activity, and B) whether fetal hematopoiesis in the embryo involves the Notch pathway. In the adult mouse, a combination of flow cytometry, immunohistochemistry and Northern analysis was used to examine Notch receptor or ligand expression in bone marrow and spleen. In the embryo, Northern analysis and in situ hybridization were used to characterize Notch receptor and ligand expression in fetal liver on embryonic day 12 (E12) through E17, an active period encompassing both erythropoiesis and granulopoeisis. Flow cytometry demonstrated the presence of Notch1 and Notch2 receptors on bone marrow-derived myeloid cells but not on erythroid cells positive for the marker, Ter-119. In situ hybridization of E12 through E17 fetal liver demonstrated widespread expression of Jagged1 and Delta1 in a pattern similar to but less abundant than that of the erythropoietin receptor. Taken together with earlier functional results, the current expression data suggest a role for Notch activity in establishing definitive hematopoiesis in fetal liver, as well as a selective use of Notch signaling in adult erythropoiesis and granulopoiesis. Notch receptors in the adult are most likely utilized by early erythroid precursors and intermediate-stage granulocytes, but not by terminally differentiating cells of either subset.

Animals↗

PubMed2000

Magnetic resonance imaging of rheumatoid arthritis in metacarpophalangeal joints.

OBJECTIVE: To report the development of high-resolution targeted magnetic-resonance imaging (MRI) techniques (not using injections of contrast media) to investigate and monitor rheumatoid arthritis (RA) in the metacarpophalangeal (MCP) joints. DESIGN AND PATIENTS: A total of 25 RA patients (age range 30-68 years) with varying degrees of disease severity ranging from early onset through active disease to the burnt-out stage, were imaged. (One patient subsequently underwent surgery and histological data was obtained.) A series of 10 control subjects were also studied--two for each 10-year age range. All the RA subjects were assessed for disease activity using standard clinical criteria and radiography as part of normal procedures. MRI was carried out using a targeted system and novel radiofrequency coil. Images of the MCP were performed at very high resolution with 1.5 mm slice thickness and in-plane resolution 130 microns. Standard gradient-echo (GE) sequences were used for anatomical imaging, multiple-echo GE sequences used to produce effective spin-spin relaxation time (T2*) maps and optimised binomialpulse presaturation used in conjunction with a GE sequence to generate magnetization-transfer (MT) ratio maps. RESULTS: High-quality high-resolution images of the MCP joints were obtained which highlighted normal anatomy and key features characterising the disease state (e.g. pannus, bone erosions, vascularity). Accurate measurements of T2* and MT with variations of +/- 4% and +/- 2% respectively were achieved. In active disease, variations in T2* and MT could be determined throughout areas of pannus, clearly demonstrating the heterogeneity of this erosive tissue. Pannus in MCP joints with active destruction was found to have high values of T2* varying from 25 ms to 40 ms with pockets up to 100 ms, whereas pannus present in chronic destruction, or burnt-out disease, had T2* values ranging from 21 to 29 ms. MT-active tissue was uniformly distributed in burnt-out disease, which was confirmed histologically in one case, compared with a more heterogeneous distribution in active disease. CONCLUSION: The MRI sequences and targeted system developed allow high-resolution studies of RA disease progression and activity. The data confirm the variable pattern of the disease and, in particular, heterogeneity of pannus.

Adult↗

PubMed1995

Modified birdcage coils for targeted imaging.

The design of a radiofrequency coil of U-shaped geometry, specifically intended to image individual knuckle joints of the hand, has been investigated. The coil geometry is that of a "split and opened" birdcage coil. The optimum leg positions for such a U-shaped coil have been theoretically predicted using a novel technique that considers both the signal-to-noise ratio and the homogeneity of the field-of-view. Two particular coils of this type have been constructed, each optimum for a different size of image space and assuming a different source of image noise (sample-dominated or coil-dominated). The experimentally determined radiofrequency fields produced by the coils correspond well to theory. Either coil can be used to obtain good-quality, high-resolution (130 microns x 130 microns in-plane) images in vivo of the first, second, or fifth metacarpophalangeal joints of the hand, sites of particular interest in the study of arthritis.

Arthritis↗

PubMed1990

The repeated sequence CATT(A/T) is required for granulocyte-macrophage colony-stimulating factor promoter activity.

The hematopoietic growth factor GM-CSF (granulocyte-macrophage colony-stimulating factor) is expressed by activated but not resting T lymphocytes. Previously, we localized GM-CSF-inducible promoter activity to a 90-bp region of GM-CSF 5'-flanking sequences extending from bp -53 to +37. To more precisely identify the GM-CSF DNA sequences required for inducible promoter activity in T lymphocytes, we have performed mutagenesis within a region of GM-CSF 5'-flanking sequences (bp -57 to -24) that contains the repeated sequence CATT(A/T). Mutations that do not alter the repeated CATT(A/T) sequence do not eliminate inducible promoter activity, whereas mutation or deletion of either of the CATT(A/T) repeats eliminates all inducible promoter activity in T-cell lines and in primary human T lymphocytes. Thus, both copies of the direct repeat CATT(A/T) are required for mitogen-inducible expression of GM-CSF in T cells.

Animals↗

PubMed1988

Transcriptional and posttranscriptional modulation of myeloid colony-stimulating factor expression by tumor necrosis factor and other agents.

Granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF) are necessary for proliferation and differentiation of myeloid hematopoietic cells. Fibroblasts stimulated by tumor necrosis factor alpha (TNF alpha) and several other agents are a rich source of these CSF. The GM-CSF synthesized by these cells had the same molecular weight and glycosylation pattern as that produced by activated T lymphocytes, as shown by [35S]methionine labeling studies. Northern (RNA) blot analysis showed that the fibroblasts had trace levels of G- and GM-CSF mRNA. Both G- and GM-CSF mRNA concentrations coordinately increased after exposure of the cells to TNF alpha (greater than or equal to 5 ng/ml), 12-O-tetradecanoylphorbol 13-acetate (TPA) (greater than or equal to 5 x 10(-10) M), or cycloheximide (20 micrograms/ml). Both TNF alpha and TPA increased levels of G- and GM-CSF mRNA in the absence of new protein synthesis. Transcriptional run-on studies demonstrated that fibroblasts constitutively transcribed GM-CSF, and transcription was enhanced 3.0-fold by TNF alpha and 2.5-fold by TPA and was unchanged by cycloheximide. The stability of G- and GM-CSF transcripts was determined after exposure of the cells to actinomycin D; the half-lives of G- and GM-CSF mRNA in unstimulated cells were less than 0.25 h and were increased 2- to 16-fold in cells cultured with TNF, TPA, or cycloheximide. In summary, both transcriptional and posttranscriptional signals acted coordinately to modulate the levels of G- and GM-CSF mRNAs in fibroblasts.

Bone Marrow↗

PubMed1987

Granulocyte-macrophage colony-stimulating factor. Sensitive and receptor-mediated regulation by 1,25-dihydroxyvitamin D3 in normal human peripheral blood lymphocytes.

We show that 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), the most hormonally active metabolite of vitamin D3, modulates sensitively and specifically both the protein and messenger RNA accumulation of the multilineage growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). The regulation of GM-CSF expression is seen in both normal human mitogen-activated T lymphocytes and T lymphocytes from a line (S-LB1) transformed with human T cell lymphotropic virus 1 (HTLV-1). In contrast, cells from a HTLV-1 transformed T lymphocyte line (Ab-VDR) established from a patient with vitamin D-resistant rickets type II with undetectable 1,25(OH)2D3 cellular receptors are resistant to the action of 1,25(OH)2D3. Inhibition of GM-CSF expression by 1,25(OH)2D3 can occur independently of interleukin 2 regulation and is probably mediated through cellular 1,25(OH)2D3 receptors. We conclude that 1,25(OH)2D3 may be important in the physiology of hematopoiesis.

Calcitriol↗

PubMed1987

Recombinant human TNF alpha stimulates production of granulocyte colony-stimulating factor.

Tumor necrosis factor alpha (TNF alpha) stimulates production of granulocyte colony-stimulating factor (G-CSF) protein and mRNA in fibroblast cells. In contrast, TNF beta is at least 1,000-fold less potent than TNF alpha in increasing levels of G-CSF and GM-CSF activity and mRNA. The fibroblasts produce G-CSF and GM-CSF mRNA in a coordinate fashion after exposure to TNF. The ability of TNF alpha to stimulate production of CSF in fibroblasts may be pivotal to regulation of hematopoiesis.

Adult↗

PubMed1987

Effects of granulocyte-macrophage colony-stimulating factor and erythropoietin on leukemic erythroid colony formation in human early erythroblastic leukemias.

Erythroid colonies from five patients with an early erythroblastic leukemia were obtained in "serum-free" cultures in the presence or absence of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and homogeneous native erythropoietin (Epo). Erythroid colonies with abnormal morphology and karyotype could be grown in different culture conditions. Their erythroid nature was ascertained by the presence of carbonic anhydrase I and glycophorin A. Leukemic erythroid progenitors strongly differed from normal progenitors in that spontaneous colonies were always obtained, sometimes with an extremely high plating efficiency (up to 5.7%). Colonies were found to be autonomous from exogenous hematopoietic growth factors because they were still obtained with a high plating efficiency at an average of one cell per culture in the absence of any added growth factor. No evidence for an autocrine secretion of Epo or GM-CSF emerged because Epo or GM-CSF could not be detected by biologic or radioimmunologic assays from the culture supernatant or cellular extracts of the leukemic cells and that Epo or GM-CSF antibodies did not block autonomous growth. In all cases, however, hematopoietic growth factors increased the plating efficiency of the abnormal erythroid progenitors. In the two "de novo" leukemias, leukemic erythroid progenitors responded primarily to Epo, whereas in the three other patients' (chronic myeloid leukemia) blast crisis they responded maximally to GM-CSF plus Epo. Recombinant erythroid-potentiating activity had no effect in any of these cases. These results suggest that the leukemic erythroid clonogenic cells arise from expansion of erythroid progenitors at different levels of differentiation (ie, CFU-E or BFU-E, depending upon the disease) and that autonomous growth is not related to a secretion of Epo or GM-CSF.

Cell Cycle↗

PubMed1977

Erythrocytes cultured from bone marrow.

The long-range objective of this study is in vitro tissue culture of bone marrow stem cells to produce erythroid cells of sufficient volume for clinical transfusion. Bone marrow from dogs and patients was cultured in 29 experiments lasting up to 15 weeks. Peripheral erythroid cells from dogs were cultured in three control experiments. Optimal tissue culture media was NCTC 109 augmented with vitamin B12, erythropoietin (EP), folic acid, and 9% fetal protein in 60 mm glass Petri dishes. Additional media and Step III EP was added at 2 to 4 day intervals. Peripheral erythroid cells in culture all were dead within 4 weeks. Marrow erythroic cells in culture proliferated as demonstrated by (1) Fe59 incorporation into cells during culture, (2) H3 thymidine uptake into cultured cells, (3) microscopic evidence of mitoses, and (4) total erythrocyte concentration in cultures far exceeding that of peripheral culture controls. For as yet unexplained reasons the total mature red blood cell concentration in the culture media remained essentially constant throughout the studies. This is a first step in achieving the ultimate goal of bulk erythrocyte production from tissue culture.

Animals↗

PubMedDate not supplied

Recombinant human TNF induces production of granulocyte-monocyte colony-stimulating factor.

Tumor necrosis factor (TNF) is synthesized by macrophages exposed to endotoxin. It produces haemorrhagic necrosis of a variety of tumours in mice and is cytostatic or cytocidal against various transformed cell lines in vitro, but viability of normal human or rodent cells is unaffected. The role of TNF is unlikely to be restricted to the rejection of tumours. Colony-stimulating factors (CSFs) are required for survival, proliferation and differentiation of haematopoietic progenitor cells. The haematopoietic growth factor known as granulocyte-monocyte colony-stimulating factor (GM-CSF) has the ability to stimulate proliferation and differentiation of normal granulocyte-monocyte and eosinophil stem cells and enhance the proliferation of pluripotent, megakaryocyte and erythroid stem cells. In addition, GM-CSF stimulates a variety of functional activities in mature granulocytes and macrophages, for example inhibition of migration, phagocytosis of microbes, oxidative metabolism, and antibody-dependent cytotoxic killing of tumour cells. We show here that TNF markedly stimulates production of GM-CSF messenger RNA and protein in normal human lung fibroblasts and vascular endothelial cells, and in cells of several malignant tissues.

Bone Marrow↗