Search PubMed⌕ Search

Biomedical subjects

E M Thompson

Publications and source records attributed to E M Thompson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cerebral cortical dysplasia and digital constriction rings in Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is characterised by aplasia cutis congenita of the scalp and variable degrees of terminal transverse limb defects. Short fingers and hypoplastic nails also occur in this predominantly autosomal dominant syndrome which displays marked variability of expression and lack of penetrance in some cases. We describe a boy with AOS whose sister is also mildly affected. Their mother has hypoplastic fifth toenails which may represent very mild expression of the syndrome. Brain (computed tomography) imaging to investigate mild left hemiparesis in the boy demonstrated severe cortical dysplasia of central, occipital and anterior regions of the right cerebral hemisphere. A variety of brain and cranial malformations has been reported in AOS but dysplasia of the cerebral cortex has not been noted previously. In addition, the boy and his sister have apparent constriction rings present on the toes which are uncommon in AOS.

Cerebral Cortex↗
PubMed1999

Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people. This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications. Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia. The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty. Obligate female carriers are generally clinically and radiographically indistinguishable from the general population, although some cases have phenotypic changes consistent with expression of the gene defect. The SEDL gene has been localized to Xp22 (refs 8,9) in the approximately 2-Mb interval between DXS16 and DXS987 (ref. 10). Here we confirm and refine this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in two families. In one candidate gene we detected three dinucleotide deletions in three Australian families which effect frameshifts causing premature stop codons. The gene designated SEDL is transcribed as a 2.8-kb transcript in many tissues including fetal cartilage. SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport.

Adolescent↗
PubMed1999

Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF.

Autologous peripheral blood stem cell (PBSC) transplantation results in rapid hematologic recovery when sufficient numbers of CD34+ cells/kg are infused. Recent studies suggest that filgrastim (G-CSF) administration following transplantation leads to more rapid neutrophil recovery and lower total transplant costs. This study compares the use of G-CSF (5 microg/kg/day) with sargramostim (GM-CSF) 500 microg/day from day 0 until neutrophil recovery (ANC >1500/mm3) in patients with breast cancer or myeloma who had PBSC mobilized with the combination of cyclophosphamide, etoposide, and G-CSF. Twenty patients (13 breast cancer and seven myeloma) received GM-CSF and 26 patients (14 breast cancer and 12 myeloma) received G-CSF. The patients were comparable for age and stage of disease, and received stem cell grafts that were not significantly different (CD34+ x 10(6)/kg was 12.5 +/- 11.1 (mean +/- s.d.) for GM-CSF and 19.8 +/- 18.5 for G-CSF; P = 0.10). The use of red cells (2.8 vs 2.3 units), and platelet transfusions (2.5 vs 3.1) was similar for the two groups, as was the use of intravenous antibiotics (4.3 vs 4.6 days) and the number of days with temperature >38.3 degrees C (2.3 vs 1.8). Platelet recovery was also similar in both groups (platelets >50,000/mm3 reached after 11.8 vs 14.9 days). The recovery of neutrophils, however, was faster using G-CSF. ANC >500/mm3 and >1000/mm3 were reached in the GM-CSF group at 10.5 +/- 1.5 and 11.0 +/- 1.7 days, respectively, whereas with G-CSF only 8.8 +/- 1.2 and 8.9 +/- 2.2 days were required (P < 0.001). As a result, patients given G-CSF received fewer injections than the GM-CSF patients (10.9 vs 12.3). Resource utilization immediately attributable to the use of growth factors and the duration of pancytopenia, excluding hospitalization, were similar for the two groups. This study suggests that neutrophil recovery occurs more quickly following autologous PBSC transplant using G-CSF in comparison to GM-CSF, but the difference is not extensive enough to result in lower total cost.

Breast Neoplasms↗
PubMed1999

Development of scarring and renal failure in a rat model of crescentic glomerulonephritis.

BACKGROUND: The aim of this study was to develop and characterize a rat model of crescentic glomerulonephritis which progresses to glomerulosclerosis and renal failure. METHODS: Glomerulonephritis was induced in Wistar Kyoto rats by a single injection of rabbit anti-glomerular basement membrane antiserum. Albuminuria and serum creatinine were monitored. Kidneys were examined, from 2.5 h to 44 days, using light-microscopy and immunohistochemistry. To characterize the glomerular inflammatory infiltrate, glomeruli were digested to single cells and analysed by fluorescence-activated cell sorter (FACS) and by immunohistochemistry on cytospins. RESULTS: Rats developed albuminuria by 4 days and increased serum creatinine by day 18. Histology showed glomerular fibrinoid necrosis by day 4 and cellular crescents in a mean of 63% of glomeruli by day 11. By 6 weeks, rats had developed renal failure (mean creatinine >300 micromol/l) with 94% of the glomeruli showing glomerulosclerosis. The kidneys were also affected by severe interstitial nephritis and tubular loss. The glomeruli were infiltrated by monocytes/ macrophages (ED1+) and CD8+ (OX8+) cells. FACS analysis showed that CD8+ cells did not express T-cell markers (CD3, TCRalphabeta or TCRgammadelta) or the NK-cell marker (NKR-P1). FACS analysis of peripheral blood mononuclear cells demonstrated a population of monocytes reactive with OX8, and double-labelling of cytospin preparations of glomerular digests showed that a proportion of the CD8+ cells were a subset of ED1+ monocyte/macrophages. CONCLUSIONS: We have characterized a reproducible model of crescentic glomerulonephritis which rapidly progresses to chronic renal failure with glomerulosclerosis and tubulo-interstitial scarring. This model will be useful for testing new therapeutic approaches in crescentic glomerulonephritis.

Animals↗
PubMed1998

Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice.

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 x BXSB)F1 and (BXSB x (B10 x BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (chi(2) = 15.68, p = 7.5 x 10(-5)), as was D1Mit12 at 63.1 cM (chi(2) = 20.17, p = 7.1 x 10(-6)). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (chi(2) = 17.28, p = 3.2 x 10(-5)). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.

Animals↗
PubMed1998

Differential preimplantation regulation of two mouse homologues of the yeast SWI2 protein.

Epigenetic regulation of gene expression through modification of chromatin organization is an important mechanism in the development of eucaryotic organisms. We investigated the developmentally regulated expression of the mouse mBRG1 and mbrm genes, which are homologous to the yeast SWI2 gene. Both proteins are involved in chromatin remodeling as components of the mammalian SWI/SNF complex. The analysis was performed at a time in mouse development when the formation of a functional zygotic nucleus is closely linked to extensive chromatin modifications. Reverse transcription-polymerase chain reaction (RT-PCR) analysis in mature oocytes and through the first cleavage stages showed that both genes were highly expressed as maternal products but that they subsequently exhibited considerable differences in their level of expression when the transition to zygotic transcription occurred. Immunodetection of the two proteins with specific antibodies paralleled the RT-PCR analysis. The mBRG1 protein was present throughout preimplantation development, whereas zygotic mbrm was clearly detectable only when differentiation first occurs at the blastocyst stage. At this stage, mbrm was restricted to the inner cell mass. Cell type-specific expression of mbrm was also observed after in vitro differentiation of embryonic stem cells. These results indicate that the two murine homologues of SWI2 have substantially different roles in chromatin organization during the onset of embryonic development.

Animals↗
PubMed1998

Mouse embryos do not wait for the MBT: chromatin and RNA polymerase remodeling in genome activation at the onset of development.

In Xenopus and Drosophila embryos, activation of the zygotic genome occurs after a series of rapid nuclear divisions in which DNA replication occupies most of the cell cycle. In these organisms, it has been proposed that zygotic transcription does not begin until a threshold nucleocytoplasmic ratio has been obtained in which repressive factors are titrated out and interphase becomes long enough to allow synthesis of transcripts. In mammalian embryos, however, a model of threshold nucleocytoplasmic ratios does not seem to apply, as beginning with the 1-cell stage, there are regulated cell cycles with the expression of zygotic transcripts during the cleavage period. By taking advantage of the slower kinetics at the onset of mouse development, we have characterized changes in chromatin structure and the basal transcription machinery throughout the transition from transcriptional incompetence, to minor activation of the zygotic genome during the 1-cell stage, and through major genome activation at the 2-cell stage. Further maturation of chromatin structure continues through subsequent cleavage cycles as a foundation for the first cellular differentiations in the blastocyst. The epigenetic chromatin modifications that occur during the cleavage period may have long range and inheritable effects and are undoubtedly important in the ability of the mammalian oocyte to remodel previously defined nuclear structures and cell fates.

Animals↗
PubMed1998

Preferential nuclear location of a transgene does not depend on its transcriptional activity during early mouse development.

Changes in chromatin structure play an important role in regulation of the HSP70.1 gene during mouse preimplantation development. Using in situ PCR we have now examined whether the spatial organization of an HSP70.1 luciferase transgene within the nucleus is also a factor in regulating its expression. The transgene showed a preferential localization towards the nuclear periphery throughout preimplantation development. This preferential location was independent of the level of constitutive activity of the transgene and did not change when transgene expression was induced through core histone hyperacetylation at the eight-cell stage or by heat shock in blastocysts. In contrast, at the two-cell stage, when embryos are unable to continue development after heat shock, thermal stress provoked a significant disruption of the nuclear location of the transgene. These results do not agree with a recent model of embryonic genome activation in mice which hypothesizes that directed, active movement of DNA within the nucleus is a determinant factor in establishing early patterns of gene expression. Instead, they are consistent with models proposing that chromatin segments are restricted to nuclear subregions, but that they remain free to undergo substantial Brownian motion.

Acetylation↗
PubMed1998

High mobility group 1 (HMG1) protein in mouse preimplantation embryos.

High mobility group 1 protein (HMG1) has traditionally been considered a structural component of chromatin, possibly similar in function to histone H1. In fact, at the onset of Xenopus and Drosophila development, HMG1 appears to substitute for histone H1: HMG1 is abundant when histone H1 is absent after the midblastula transition histone H1 largely replaces HMG1. We show that in early mouse embryos the expression patterns of HMG1 and histone H1 are not complementary. Instead, HMG1 content increases after zygotic genome activation at the same time as histone H1. HMG1 does not remain associated to mitotic chromosomes either in embryos or somatic cells. These results argue against a shared structural role for HMG1 and histone H1 in mammalian chromatin.

Amino Acid Sequence↗
PubMed1998

Prediction of transgene integration by noninvasive bioluminescent screening of microinjected bovine embryos.

Transgenesis in domestic species, as a research tool and in biotechnological applications, has been limited by the expense of producing transgenic offspring by standard microinjection techniques. A major factor is the inefficiency of maintaining large numbers of recipient females, when a high percentage of these carry nontransgenic fetuses. There are two approaches to reduce this cost, the fusion of transfected fetal fibroblasts with enucleated oocytes, and the screening of microinjected embryos for transgene integration in blastocysts, prior to transfer. Here, we develop a luminescent screening system to select transgenic bovine embryos. A transgene with scaffold attachment regions flanking the murine HSP70.1 promoter linked to firefly luciferase cDNA, was microinjected into pronuclei of in vitro produced zygotes. At the blastocyst stage, the transgene was induced by heat shock (45 degrees C, 15 min) and 4-6 h later, luciferase expression was analyzed by photon counting imaging. Screened blastocysts were transferred to recipients and day 50 fetuses or calves were analyzed by PCR and Southern blot for transgene integration. When nonluminescent blastocysts were transferred, transgene integration was never observed. Of 13 fetuses derived from luminescent blastocysts, 3 contained integrated transgenes that were functional in all tissues examined. Image analysis of the signal emitted by positive blastocysts revealed that 9 nontransgenic fetuses were obtained from blastocysts that exhibited a localized luminescent signal. On the other hand, 3 of 4 fetuses derived from blastocysts that emitted light over more than 70% of their surface were transgenic. Thus, by selecting luminescent blastocysts on the basis of both signal intensity and distribution, the number of recipient females required to produce transgenic offspring can be greatly reduced. Using this technique it should also be possible to improve the efficiency of transgenesis by microinjection through studies in which vector design and integration conditions are examined at the blastocyst stage.

Animals↗
PubMed1998

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.

The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.

Animals↗
PubMed1998

The causes of sporadic and 'senile' chorea.

BACKGROUND: Although 'senile' chorea is commonly listed in the differential diagnosis of chorea, the condition is poorly defined. Indeed, the existence of such an entity is debated. There are few contemporary prospective studies of sporadic chorea in the elderly. METHODS: Detailed prospective study of patients presenting with undiagnosed chorea over a three year period to a Movement Disorder Clinic. RESULTS: Twelve patients, aged 50 to 89 years, were identified. The final diagnoses were Huntington's disease, confirmed on genetic testing in six, antiphospholipid antibody syndrome in two, and hypocalcaemia, tardive dyskinaesia and basal ganglia calcification in each of the three remaining cases. Only one patient remained undiagnosed despite extensive investigation. CONCLUSIONS: The majority of patients with 'senile' chorea actually have Huntington's disease even in the absence of a family history. Rarer causes of chorea still need to be considered in the elderly when Huntington's disease has been excluded by DNA analysis.

Aged↗
PubMed1998

The origins of marine bioluminescence: turning oxygen defence mechanisms into deep-sea communication tools.

Bioluminescence, the emission of ecologically functional light by living organisms, emerged independently on several occasions, yet the evolutionary origins of most bioluminescent systems remain obscure. We propose that the luminescent substrates of the luminous reactions (luciferins) are the evolutionary core of most systems, while luciferases, the enzymes catalysing the photogenic oxidation of the luciferin, serve to optimise the expression of the endogenous chemiluminescent properties of the luciferin. Coelenterazine, a luciferin occurring in many marine bioluminescent groups, has strong antioxidative properties as it is highly reactive with reactive oxygen species such as the superoxide anion or peroxides. We suggest that the primary function of coelenterazine was originally the detoxification of the deleterious oxygen derivatives. The functional shift from its antioxidative to its light-emitting function might have occurred when the strength of selection for antioxidative defence mechanisms decreased. This might have been made possible when marine organisms began colonising deeper layers of the oceans, where exposure to oxidative stress is considerably reduced because of reduced light irradiance and lower oxygen levels. A reduction in metabolic activity with increasing depth would also have decreased the endogenous production of reactive oxygen species. Therefore, in these organisms, mechanisms for harnessing the chemiluminescence of coelenterazine in specialised organs could have developed, while the beneficial antioxidative properties were maintained in other tissues. The full range of graded irradiance in the mesopelagic zone, where the majority of organisms are bioluminescent, would have provided a continuum for the selection and improvement of proto-bioluminescence. Although the requirement for oxygen or reactive oxygen species observed in bioluminescent systems reflects the high energy required to produce visible light, it may suggest that oxygen-detoxifying mechanisms provided excellent foundations for the emergence of many bioluminescent systems.

Adaptation, Physiological↗
PubMed1997

Systemic lupus erythematosus, thrombocytopenia, microangiopathic haemolytic anaemia and anti-CD36 antibodies.

Thrombocytopenia in patients with acute systemic lupus erythematosus (SLE) frequently presents the clinician with considerable diagnostic and therapeutic difficulties. In this Grand Round, we present a 48-yr-old woman with a 7 yr history of lupus, who presented with acute proliferative glomerulonephritis and nephrotic syndrome, pneumonia, profound hypocomplementaemia and a severe microangiopathic haemolytic anaemia with associated thrombocytopenia. Her thrombocytopenia proved initially refractory to conventional immunosuppressive therapy, and corticosteroids, and resolved only with plasma exchange and repeated fresh frozen plasma infusions. Serological testing revealed high-titre antinuclear antibodies (ANA) and markedly raised antibodies to double-stranded (ds) DNA, but no significant elevation in anticardiolipin antibodies. Platelet-associated IgG and IgM and antibodies to the CD36 glycoprotein antigen, expressed on platelets and endothelium, were detected in the serum. We address some of the difficult diagnostic and management issues raised by this complex patient and the possible immunopathological links between antibodies to CD36, immune-mediated red cell destruction, thrombocytopenia and thrombotic microangiopathic haemolytic anaemia.

Anemia, Hemolytic, Autoimmune↗
PubMed1997

Does medical audit lead to explicit standards? Experience with thrombolysis in four UK hospitals.

The setting of explicit standards against specific criteria is a recognized part of the medical audit cycle, but often in practice it has been neglected, implicit judgements being used instead. The conduct of a study to evaluate audit among physicians in four UK district general hospitals provided an opportunity to encourage the setting of explicit standards and observe the results. The subject chosen for audit by the participating physicians was the extent of use of intravenous thrombolysis in patients with suspected acute myocardial infarction (AMI). Standard setting was requested at initial peer review meetings held to review baseline results. This was followed up by a written request to lead consultants and subsequent telephone calls. Two out of the four participating hospitals set technical standards, which excluded patients with contra-indications from the denominator. The other two hospitals set population standards as requested, one with considerable reluctance and scepticism. Each hospital set separate standards for definite AMIs and for probable AMIs. Six out of the eight standards set were achieved in at least one of four audits conducted in each hospital. Time trends were difficult to interpret because of small numbers. The amount of discussion between the lead consultant and colleagues about standards was highly variable, but there was no clear relationship between the process for agreeing standards in a particular hospital and subsequent attainment.

Chest Pain↗
PubMed1997

Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos.

In the mouse embryo, transcriptional activation begins during S/G2 phase of the first cell cycle when paternal and maternal chromatin are still in separate nuclear entities within the same cytoplasm. At this time, the male pronucleus exhibits greater transcriptional activity than the female pronucleus. Since acetylation of histones in the nucleosome octamer exerts a regulatory influence on gene expression, we investigated changes in histone acetylation during the remodeling of paternal and maternal chromatin from sperm entry through to minor genome activation and mitosis. We found (1) neither mature sperm nor metaphase II maternal chromatin stained for hyperacetylated histone H4; (2) immediately following fertilization, hyperacetylated H4 was associated with paternal but not maternal chromatin while, in parthenogenetically activated oocytes, maternal chromatin became hyperacetylated; (3) in zygotes, differential levels and patterns of hyperacetylated H4 between male and female pronuclei persisted throughout most of G1 with histone deacetylases and acetyltransferases already active at this time; (4) when transcriptional differences are observed in S/G2, male and female pronuclei have equivalent levels of H4 hyperacetylation and DNA replication was not required to attain this equivalence and (5) in contrast to the lack of H4 hyperacetylation on gametic chromatin, chromosomes at the first mitosis showed distinct banding patterns of H4 hyperacetylation. These results suggest that sperm chromatin initially out-competes maternal chromatin for the pool of hyperacetylated H4 in the oocyte, that hyperacetylated H4 participates in the process of histone-protamine exchange in the zygote, and that differences in H4 acetylation in male and female pronuclei during G1 are translated across DNA replication to transcriptional differences in S/G2. Prior to fertilization, neither paternal nor maternal chromatin show memory of H4 hyperacetylation patterns but, by the end of the first cell cycle, before major zygotic genome activation at the 2-cell stage, chromosomes already show hyperacetylated H4 banding patterns.

Acetylation↗
PubMed1997

Embryoglycans regulate FGF-2-mediated mesoderm induction in the rabbit embryo.

Several peptide growth factors, including members of the fibroblast growth factor (FGF) superfamily, are potential inducers of mesoderm in vertebrates. Receptor binding of basic FGF (FGF-2) is promoted by cell surface or extracellular matrix proteoglycans. The substantial biosynthesis of proteoglycans by embryonic cells (called embryoglycans) and their potential role as ligands for growth factor receptors led us to examine the role of embryoglycans that carry the developmentally regulated oligosaccharide epitope TEC 1, in the binding of FGF-2 to cultured rabbit inner cell masses (ICMs). Culture of isolated ICMs in the presence of FGF-2 gave rise to well delimited colonies with migrating cells at the periphery. In these cells, TEC 1 staining shifts from a punctate pattern over the entire membrane, to an apical, finely granular distribution with some internalization. This shift occurs after 96 hours in culture. Here we show that: (1) migrating cells are mesoderm-like in phenotype; (2) antibodies against TEC 1 blocked FGF-2 mediated differentiation in vitro; (3) antibodies against TEC 1 selectively blocked binding of FGF-2 to ectodermal receptors and, vice versa, the binding of TEC 1-specific antibodies to ectodermal cells can be competed by excess FGF-2; (4) the same switch in TEC 1 staining patterns was observed in vivo, between the day 7 and the day 9 rabbit embryo. These data suggest the involvement of defined species of embryonic cell surface epitopes in the regulation of FGF-2 receptor binding. Moreover, this proposed binding activity is temporally restricted to ectodermal cells and disappears early during differentiation. Thus, the apical TEC 1 redistribution can be considered as the earliest indicator of mesoderm formation.

Animals↗