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Biomedical subjects

G Morgan

Publications and source records attributed to G Morgan.

At least 199 records · Page 11Linked to original sources
PubMed1994

Early deaths in children undergoing marrow ablative therapy and bone marrow transplantation.

We have reviewed the causes and risk factors for early death in a group of 295 children who underwent any form of first bone marrow transplantation (BMT) between 1978 and 1992. The commonest indications for transplantation were acute lymphoblastic leukaemia 80 (27.1%), neuroblastoma 69 (23.3%), immune deficiency 57 (19.3%) and myeloid leukaemias/myelodysplasia 50 (16.9%). There were 120 (40.6%) allogeneic BMTs, 118 (40%) autologous BMTs, while 51 (17.2%) children usually with severe combine immune deficiency received BMT from a non-HLA-identical parent, sibling or other relative (FBMT). Two were from identical twins and four from matched unrelated donors (MUD). Thirty-three children (11.2%) died in the first 100 days; the main causes of death being infection (n = 5), relapse (n = 7), graft failure (n = 4), GVHD (n = 7) and organ failure with or without infection (n = 6). There was no significant change in the incidence of early deaths in the three successive 5 year periods (1978-82, 1983-87, 1988-92) although there was some shift in the causes. Infections were the commonest cause during the first 5 year period, relapses followed by GVHD in the second period and single organ failure followed by GVHD and infections in the third period. The main causes of early death were relapse after high-dose chemo/radiotherapy and autologous BMT (7 of 9 deaths) and GVHD and infection after allogeneic BMT (9 of 13 deaths). In the group of 51 children undergoing FBMT there were five deaths from infection, three from graft failure, one from organ failure and one from GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗
PubMed1994

Myeloablative therapy and bone marrow transplantation for Langerhans' cell histiocytosis.

Since the Langerhans Cell (LC) is of haemopoietic origin it may be possible to cure Langerhans cell histiocytosis (LCH) by ablating the patient's own haemopoietic system and replacing it with donor bone marrow--a process termed bone marrow transplantation (BMT). This assumes that the LC itself is the fundamentally abnormal cell though BMT is also a logical therapy even if other cells of haemopoietic origin are eventually shown to be the primary cause of LCH. Marrow ablation/BMT has an appreciable morbidity and mortality and has therefore been reserved for the few LCH patients with a very poor prognosis. The results in these patients engenders cautious optimism that myeloablation/BMT in LCH may have a limited role. Myeloablative chemotherapy or radiotherapy followed by autologous bone marrow 'rescue' is also feasible but risks the return of 'untreated' LCH cells, or their precursors, causing exacerbation of disease.

Adolescent↗
PubMed1994

Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model.

The t(14;18) translocation is found in the majority follicular lymphomas and some high grade B-cell lymphomas. This is results in deregulation of the BCL-2 gene and appears to play a role in oncogenesis. Various numbers of cells from a cell line derived spontaneously from a patient with B-cell lymphoma bearing the t(14;18) translocation and negative for the Epstein-Barr virus (EBV) were injected by IP, IV, and SC routes into SCID mice. The mice developed lymphoma bearing the t(14;18) translocation with as few as 5 x 10(6) cells within 28 days. This was determined by histological examination. The higher the cell inoculation the more rapidly the lymphoma developed. Engraftment of the tumour cells was determined by PCR for the t(14;18) breakpoint region on peripheral blood samples and could be detected prior to development of overt lymphoma. Having established a lymphoma model the cells were treated with antisense oligonucleotides to the first open reading frame of the BCL-2 gene prior to inoculation of the SCID mice. Control treatments with sense and nonsense oligonucleotides was also performed. At 28 days the sense, nonsense and untreated cell SCID mice had developed lymphoma, however, the antisense treated group failed to develop lymphoma. The findings demonstrate the modelling of B-cell lymphoma bearing the t(14;18) translocation and the ability to modify the lymphoma process with the use of antisense oligonucleotides to the BCL-2 gene. Reduction of the BCL2 protein suppresses the oncogenic potential of these lymphoma cells confirming that it plays an essential role in the development of malignancy.

Animals↗
PubMed1993

Carrier determination for X-linked agammaglobulinemia using X inactivation analysis of purified B cells.

We report the development of a relatively quick and simple method for the assessment of X inactivation status for carrier determination in families affected by X-linked agammaglobulinemia (XLA). This method utilises an immunomagnetic separation technique for B cell purification and a polymerase chain reaction (PCR) based assay for the determination of methylation status at the androgen receptor (AR) gene locus to assess whether X inactivation is random or non-random at this locus. We report the results we have obtained using this assay to investigate females known to be carriers of various X-linked immunodeficiency disorders. In addition, we investigated four females from different families affected by XLA, two of whom were of unknown carrier status, and we discuss the results obtained with this and other X-inactivation assays. A similar assay has recently been described by Allen et al. (1992) and applied to members of one family affected by XLA.

Agammaglobulinemia↗
PubMed1993

Tyrosine 69 of the first epidermal growth factor-like domain of human factor IX is essential for clotting activity.

Epidermal growth factor (EGF)-like domains are present in many extracellular proteins including clotting factor IX. Those EGF-like domains with the consensus amino acid residues Asp/Asn, Asp/Asn, Asp*/Asn*, Tyr/Phe (where * denotes a beta-hydroxylated residue) bind calcium. Previous NMR studies of the isolated first EGF-like domain of human factor IX suggested that the first 3 consensus residues Asp-47, Asp-49, and Asp-64 were direct ligands for calcium. We now show from mutagenesis studies that Tyr-69 is not a direct ligand for calcium but is essential for the clotting activity of intact factor IX, specifically for the factor VIIIa-dependent activation of factor X. Surprisingly, Tyr-69 is not required for beta-hydroxylation of Asp-64.

Amino Acid Sequence↗
PubMed1993

Tamoxifen reduces bone turnover and prevents lumbar spine and proximal femoral bone loss in early postmenopausal women.

Although widely used for its anti-estrogen properties tamoxifen has estrogen like effects on a number of tissues including bone and liver. Previous studies suggest a preservation of lumbar spine density in postmenopausal women but the effect on the hip had not been addressed. To determine whether tamoxifen prevents bone loss in the early postmenopausal period bone mineral density at the lumbar spine and femoral neck was measured using dual energy X-ray absorptiometry at presentation and 6 monthly thereafter for 1 year in a prospective controlled study. Also indices of bone turnover, serum osteocalcin and urinary hydroxyproline excretion, were assessed. Fifteen early postmenopausal women with Stage I or II breast cancer treated with tamoxifen and 21 normal postmenopausal women were studied. Sex hormone binding globulin and antithrombin III levels in serum were also measured as indices of the hepatic estrogenic activity. Tamoxifen (20 mg daily) prevented bone loss at the femoral neck and lumbar spine. Median rates of change in bone mineral density (%/year) for the tamoxifen group were +0.09%/year in the lumbar spine and 1.4%/year in the femoral neck compared with -2.3%/year and -1.8%/year for the control group (P = 0.04 and 0.03, respectively). Tamoxifen resulted in a significant decrease in both serum osteocalcin and urinary hydroxyproline by 6 months of treatment and this effect persisted for the 12 months of observation. An increase in sex hormone binding globulin and a decline in antithrombin III levels was also observed. These data indicate that, in recently, postmenopausal women tamoxifen prevented bone loss at both the lumbar spine and femur and reduced bone turnover.

Absorptiometry, Photon↗
PubMed1993

Genetic linkage analysis identifies new proximal and distal flanking markers for the X-linked agammaglobulinemia gene locus, refining its localization in Xq22.

Genetic linkage analysis has been instrumental in mapping the gene for X-linked agammaglobulinemia (XLA) to the proximal long arm of the human X chromosome, to Xq22. Due to the relative rarity of this disease the localization of the gene within Xq22 has remained imprecise. We have investigated twenty-nine families affected by XLA and have found no recombinants with the DXS178 locus in over 30 informative meioses. DXS178 is now the most reliable and informative locus for use in pre-natal diagnosis and carrier detection of XLA. In addition, we have identified new closely linked proximal and distal flanking markers for XLA, DXS442 and DXS101, respectively. These loci are separated by 2cM, considerably reducing the extent of DNA within which the XLA locus can be contained. This will open up the way for more directed positional cloning efforts for the isolation of the XLA gene.

Agammaglobulinemia↗
PubMed1993

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes.

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis. Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.

Bone Marrow Transplantation↗
PubMed1993

Immunological responses of Gambians in relation to clinical stage of HIV-2 disease.

This study describes a broad spectrum of cellular and antibody-mediated immune responses found in 28 asymptomatic and 37 symptomatic Gambian patients with HIV-2 infection. It shows that these responses vary according to the stage of infection as described by three clinical staging systems. The first system was a local one based on the signs used for the WHO Bangui clinical definition of AIDS, the second, suggested by WHO, was based on a performance scale, and the third was that used by the Centre for Disease Control. Asymptomatic patients had significantly lower mean CD4 counts, lymphoproliferative and interferon-gamma (IFN-gamma) responses and lower IgG and IgM antibody responses to keyhole limpet haemocyanin (KLH) than controls. These measurements and the size of the skin test reaction to purified protein derivative (PPD) or Candida antigen declined significantly according to the stage of infection. Mean values of the serological markers beta 2-microglobulin and neopterin and antibody titres to Epstein-Barr virus capsid antigen (EBVCA) rose significantly according to severity of disease. The Gambian or WHO clinical staging systems, which are easy and cheap to apply, may serve as an alternative to sophisticated and expensive immunological measurements when trying to stage disease and predict prognosis.

Adult↗
PubMed1993

Dentine hypersensitivity: the measurement in vitro of streaming potentials with fluid flow across dentine and hydroxyapatite.

Stimulus transmission across dentine, in conditions such as dentine hypersensitivity, is considered to occur via a hydrodynamic mechanism. This fluid flow in dentine may then induce a mechanoreceptor response in pulpal nerves. However, when fluid flows through a porous structure electrical potentials are also generated. The aim of this study was to develop a reproducible model system to measure streaming potential across dentine and hydroxyapatite and determine the influence of pressure. Using an acrylic cell, with silver electrodes, streaming potentials were recorded across dimensionally standardized dentine and hydroxyapatite specimens, over a pressure range of 1-6 atmospheres. Streaming potentials were found to be directly proportional to pressure and dependent on the electrical conductivity of the saline used in the cell. The results confirm the limited existing data on streaming potentials across dentine and indicate that at these low pressures excitation of pulpal nerves would not occur. However, if, as may be the case, stimuli applied to dentine create very high pressures, the resultant potentials generated could indeed evoke a neural response. The model system is worthy of further use to study this phenomenon and the factors which may influence it.

Dentin↗
PubMed1993

A new restriction fragment length polymorphism at the DXS101 locus allows carrier detection in a family with X linked agammaglobulinaemia.

The gene responsible for X linked agammaglobulinaemia (XLA) lies in Xq22 and has recently been identified as atk. DXS101 is a polymorphic locus which is closely linked to the disease locus. In this report we describe the identification, by pulsed field gel electrophoresis, of a new polymorphism at the DXS101 locus with a predicted heterozygosity of 4.9%. Despite this low value, we show how this polymorphism has been important in carrier status determination in a family with XLA where assessment was not possible by other means.

Agammaglobulinemia↗
PubMed1993

Pathology of renal dysplasia and bladder aplasia-hypoplasia in a flock of sheep.

Congenital renal disease was detected in a flock of sheep in the English Midlands over 2 successive years (1982 and 1983). A Suffolk ram was removed from the flock and test mated to unrelated Suffolk ewes in another flock; 14 of the resulting 43 lambs born in 1984 had an identical congenital renal disease. Kidneys were examined microscopically from 60 clinically affected neonatal lambs. Kidneys from 7 of the 60 clinically affected neonatal lambs (1, 1983; 6, 1984) were examined ultrastructurally and compared with kidneys from 3 healthy unrelated neonatal lambs. Most affected lambs examined (52/60) had bilaterally small kidneys (< or = 2 g) with fine intracortical cysts and distinct cortical and medullary zones. Kidneys were either grossly normal (3/60 lambs) or multicystic and of normal size to markedly enlarged (5/60 lambs). The bladder was absent or vestigial in most lambs. Microscopically, poorly differentiated ("primitive") tubules were present in renal cortex and medulla. Proximal convoluted tubules, where present, were formed by epithelial cells with distinctive round weakly autofluorescent intracytoplasmic inclusions with the ultrastructural appearance of atypical lysosomes. Loops of Henle, distal convoluted tubules, and juxtaglomerular-peripolar cell complexes were largely absent. Glomerular changes were minimal. Cystic dilatation of nephrons was restricted to proximal convoluted tubules lined by vacuolated epithelium. This distinctive congenital renal dysplasia of sheep was most likely inherited as a dominant trait with complete penetrance.

Animals↗
PubMed1993

Cellular dynamics of growth in sheep and goat synepitheliochorial placentomes: an autoradiographic study.

This paper demonstrates that in sheep and goats the two definitive fetomaternal interface layers are developmentally related. The fetal trophectoderm consists of binucleate and uninucleate cells. The apical microvilli of the trophectoderm interdigitate with a layer consisting of syncytial plaques of limited area bounding the maternal connective tissue. Our previous histological ultrastructural and immunocytochemical work has indicated that throughout pregnancy the fetal binucleate cells migrate to and fuse with the uterine epithelium or its derivatives to form these syncytial plaques which constitute a persistent fetomaternal tissue unique to ruminants. This quantitative autoradiographic study of thymidine incorporation into sheep and goat placentas confirms the central role of the binucleate cell in placental growth, demonstrates that throughout pregnancy all binucleate cells migrate and indicates that most of the nuclei of the syncytial plaques, which appear to have a limited lifespan, derive from binucleate cell fusion.

Animals↗