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Biomedical subjects

E M Thompson

Publications and source records attributed to E M Thompson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Expression of the multifunctional extracellular matrix protein thrombospondin in crescentic glomerulonephritis.

Thrombospondin is a multifunctional 450 kD glycoprotein which may be secreted into the extracellular matrix by a wide variety of cells. Occasional foci of immunoreactive thrombospondin have previously been demonstrated within normal human glomeruli. A specific polyclonal antibody directed against thrombospondin 1 was used to examine the distribution of this regulatory glycoprotein in renal biopsies from patients with a variety of renal diseases, including rapidly progressive glomerulonephritis associated with circulating antibodies to neutrophils, active or quiescent systemic lupus erythematosus, and membranous nephropathy, together with normal renal tissue. The results demonstrated the marked up-regulation of thrombospondin expression in acutely inflamed renal tissue with strongly positive, predominantly extracellular staining of glomerular crescents, although cytoplasmic staining of epithelial cells was also seen, indicating that these cells may contribute to thrombospondin accumulation at these sites. Occasional segmental mesangial staining was seen in cases of active lupus and rapidly progressive glomerulonephritis, while some focal interstitial staining around peritubular capillaries was seen in all renal tissue examined. These results suggest that thrombospondin may play an important role in the regulation of cellular recruitment, proliferation, and function in crescentic glomerulonephritis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Mutation in the carboxy-terminal propeptide of the Pro alpha 1(I) chain of type I collagen in a child with severe osteogenesis imperfecta (OI type III): possible implications for protein folding.

A young girl presented with severe type III osteogenesis imperfecta; her otherwise healthy mother also had a mild connective tissue disorder with blue sclerae and recurrent joint dislocations. Skin fibroblast cultures from the child produced both normal and post-translationally over-modified type I collagen. The mutant collagen was poorly secreted but had normal thermal stability. Cyanogen bromide peptide maps of the abnormal protein indicated a C-terminal mutation. The mother's cells produced only normal-appearing collagens. Mismatch analysis and extensive sequencing of cDNAs covering the suspect region did not reveal any potentially causal changes in the triple helical domains of either the alpha 1(I) or alpha 2(I) chains. However, examination of the C-propeptide sequences revealed two heterozygous single base changes in the child. One, an A->C changing threonine to proline at residue 29 of the alpha 2(I) C-propeptide was also present in the mother and maternal grandfather but not in 50 unrelated control individuals. The second, a T->C altered the last amino acid residue of the alpha 1(I) C-propeptide from leucine to proline and had occurred de novo in the affected child. This mutation highlights the importance of the C-propeptides in molecular assembly but it is not clear how such an extreme mutation causes the delay in triple helix formation indicated by the extensive over-modification and reduced secretion of the mutant type I collagen. It may inhibit intrachain disulfide bonding or possibly affect the association of the procollagen chain with an intracellular "chaperone" protein that normally assists the assembly of trimeric procollagen molecules.

Amino Acid Sequence↗
PubMed1996

Selective renal transplantation in primary hyperoxaluria type 1.

Primary hyperoxaluria type I (PHI) is a cause of end-stage renal disease in young people. It is caused by deficient activity of hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT), which results in hyperoxalemia and hyperoxaluria. The consequent urolithiasis and nephrocalcinosis result in renal impairment, with further reduction in oxalate excretion and eventual systemic oxalosis. Historically, renal transplantation has yielded very poor results in these patients because of recurrent oxalosis of the graft. Within the last 10 years, combined hepatorenal transplantation has been successfully applied, simultaneously correcting the metabolic lesion in the liver and replacing the damaged kidneys. It has, however, become apparent that medical therapy with vigorous hydration, inhibitors of stone formation and pyridoxine (AGT co-factor), may be successful at delaying, and occasionally in preventing, urolithiasis in some hyperoxaluric patients, particularly those whose hyperoxaluria is reduced by pyridoxine. This, together with intensive perioperative management and modern surgical methods of stone management such as lithotripsy, laser or ultrasound stone fragmentation, and percutaneous nephrolithotomy, means that renal transplantation alone may be feasible in selected patients. We describe a patient with PHI with clinical and biochemical evidence of significant residual AGT activity who underwent a successful live-related renal transplantation with excellent renal function and no stone recurrence 1 year posttransplantation. The appropriate transplantation strategies for these complex patients are discussed and include isolated renal transplantation for those patients who are without significant systemic oxalosis and have evidence of residual AGT activity.

Adult↗
PubMed1996

Fc gamma RIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease.

An allotypic variant of Fc gamma RIIa, Fc gamma RIIa-HR (Fc gamma RIIa-R131), has been shown in vitro to reduce the capacity of phagocytic cells to bind and internalize IgG-containing immune complexes. Our aim was to determine whether this allotypic variant was associated with susceptibility to SLE and the development of lupus nephritis, as previous studies have suggested. Fc gamma RIIA genotype analysis was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 215 Caucasoid, 70 Afro-Caribbean, and 46 Chinese patients with SLE, and in 259,77 and 49 ethnically matched controls, respectively. Distribution of Fc gamma RIIa genotypes between the patients and ethnically matched controls was not significantly different in the three populations studied. No association between the Fc gamma RIIa-HR allotype and nephritis was found. Our results suggest that the Fc gamma RIIa-HR allotype is not a major factor predisposing to the development of SLE, or to lupus nephritis.

Base Sequence↗
PubMed1996

Chromatin structure and gene expression in the preimplantation mammalian embryo.

The preimplantation period of mammalian development encompasses the formation of the zygote, the activation of the embryonic genome, the first cellular polarizations and the beginning of cellular differentiation. It is a period of transitions; protamines are replaced by histones, maternal control of development is succeeded by zygotic control, the highly methylated haploid parental genomes form a diploid genome which undergoes a wave of demethylation. It is also a period of manipulation of embryos for improvements in animal production; embryos are transferred, cryopreserved, cloned, microinjected with transgene constructs. This paper reviews the role that dynamic changes in chromatin structure and nuclear architecture play in the biological transitions of the preimplantation embryo. Data on the nature of these changes is presented, avenues of research that are opening up are discussed and potential applications in animal production are proposed.

Animals↗
PubMed1995

Real time imaging of transcriptional activity in live mouse preimplantation embryos using a secreted luciferase.

Study of gene expression kinetics during preimplantation mammalian development is difficult because of the limited amount of material and the usually destructive, static nature of molecular analyses. We describe continuous, noninvasive monitoring of gene expression in preimplantation embryos by using a secreted luminescent reporter, Vargula luciferase. Transgene expression profiles were followed by assaying aliquots of culture medium or by direct visualization of Vargula luciferase secretion from living embryos in real time through photon imaging. With this approach, it is possible to observe epigenetic modulations of gene expression and to link this over time to the developmental capacity of individual embryos. In addition, by developing a strategy where expression from integrated transgenes is enhanced relative to that from nonintegrated DNA, we provide evidence that rapid detection of transgene integration prior to the blastocyst stage should be possible. Thus, imaging of Vargula luciferase secretion may also be useful in the early screening of embryos, for example, in the production of transgenic livestock.

Animals↗
PubMed1995

Plasminogen activator inhibitor-2 expression in inflamed appendix.

Plasminogen activator inhibitors are thought to be responsible for the abolition of fibrinolytic activity in inflamed peritoneum. This reduction in the fibrin clearing capacity of the peritoneum promotes the formation of intra-abdominal adhesions. High concentrations of plasminogen activator inhibitor-2 (PAI-2) have been previously found in inflamed peritoneal tissue using immunoassays, but it is undetectable in normal peritoneum. The aim of this study was to localize plasminogen activator inhibitor-2 production in tissue by in situ mRNA hybridisation. Sections of normal and inflamed human appendix were hybridised with a digoxigenin labelled cDNA probe. In normal appendix staining was confined to macrophages in the mucosa. Macrophage staining was also seen in inflamed tissue but with a wider distribution throughout the appendix wall. PAI-2 was also localized to mesothelial cells of inflamed but not normal appendix. Cell identities were confirmed using immunohistochemistry directed against cell specific markers. Staining was absent from control slides incubated with plasmid DNA or PAI-2 probe following ribonuclease digestion. The identification of the cells expressing the PAI-2 gene in peritoneum increases our understanding of the pathophysiological process leading to fibrin deposition within the abdomen during peritonitis.

Appendicitis↗
PubMed1995

Expression of the HSP 70.1 gene, a landmark of early zygotic activity in the mouse embryo, is restricted to the first burst of transcription.

Activation of the mouse embryonic genome at the 2-cell stage is characterized by the synthesis of several alpha-amanitin-sensitive polypeptides, some of which belong to the multigenic hsp 70 family. In the present work we show that a member of this family, the HSP 70.1 gene, is highly transcribed at the onset of zygotic genome activation. Transcription of this gene began as early as the 1-cell stage. Expression of the gene continued through the early 2-cell stage but was repressed before the completion of the second round of DNA replication. During this period we observed that the level of transcription was modulated by in vitro culture conditions. The coincidence of repression of HSP70.1 transcription with the second round of DNA replication was not found for other transcription-dependent polypeptides synthesized at the 2-cell stage.

Animals↗
PubMed1995

Progressive maturation of chromatin structure regulates HSP70.1 gene expression in the preimplantation mouse embryo.

In the widely studied model organisms, Drosophila and Xenopus, early embryogenesis involves an extended series of nuclear divisions prior to activation of the zygotic genome. The mammalian embryo differs in that the early cleavage phase is already characterized by regulated cell cycles with specific zygotic gene expression. In the mouse, where major activation of the zygotic genome occurs at the 2-cell stage, the HSP70.1 gene is among the earliest genes to be expressed. We investigated the developmentally regulated expression of this gene during the preimplantation period, using a luciferase transgene, with or without flanking scaffold attachment regions (SARs). Cleavage stage-specific modifications in expression profiles were examined in terms of histone H4 acetylation status, topoisomerase II activity, and the localisation of HMG-I/Y, a nuclear protein with known affinity for the AT-tracts of SARs. We demonstrate that HSP70.1-associated transcription factors are not limiting, and that instead, there is a progressive maturation of chromatin structure that is directly involved in HSP70.1 regulation during early mouse development.

Animals↗
PubMed1995

A gene for cleidocranial dysplasia maps to the short arm of chromosome 6.

Cleidocranial dysplasia (CCD) is an autosomal dominant generalized bone dysplasia characterized by mild-to-moderate short stature, clavicular aplasia or hypoplasia, supernumerary and ectopic teeth, delayed eruption of secondary teeth, a characteristic craniofacial appearance, and a variety of other skeletal anomalies. We have performed linkage studies in five families with CCD, with 24 affected and 20 unaffected individuals, using microsatellite markers spanning two candidate regions on chromosomes 8q and 6. The strongest support for linkage was with chromosome 6p microsatellite marker D6S282 with a two-point lod score of 4.84 (theta = .03). Furthermore, the multipoint lod score was 5.70 in the interval between D6S282 and D6S291. These data show that the gene for autosomal dominant CCD is located within a 19-cM interval on the short arm of chromosome 6, between D6S282 and D6S291.

Chromosome Mapping↗
PubMed1995

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Education, Medical↗
PubMed1994

Scaffold attachment regions stimulate HSP70.1 expression in mouse preimplantation embryos but not in differentiated tissues.

Eukaryotic interphase chromatin is thought to be organized into topologically discrete, independent domains acting as units upon which differential patterns of gene expression are established. Sequences which attach chromatin to in vitro preparations of a nucleoprotein matrix (scaffold attachment regions [SARs]) may act as domain boundaries, but their role remains poorly defined compared with those of other elements such as locus control regions. We have produced mice homozygous for a transgene which is transcribed as early as the activation of the embryonic genome at the two-cell stage and which is expressed ubiquitously in a number of differentiated tissues. Transgenic lines were generated in the presence or absence of flanking SAR sequences, creating an original model which enabled us to examine the effects of these elements at different developmental stages. In the preimplantation mouse embryo, flanking SARs stimulated transgene expression in a copy-dependent manner. In contrast, in the differentiated tissues of newborn and adult mice, no significant SAR-dependent increase in transgene expression was found, correlation with copy number was lost, and position effects were observed. These results suggest a limited capacity of SARs to act as insulating elements but are consistent with a proposed model of SAR-mediated chromatin opening and closing.

Aging↗
PubMed1994

A systematic search for uniparental disomy in carriers of chromosome translocations.

A systematic search was made for uniparental disomy in carriers of apparently balanced chromosome translocations who also had unexplained abnormalities of mental or physical development. Of 65 families studied, biparental origin of both translocated chromosomes was demonstrated in 64, and only 1 case of maternal uniparental disomy of chromosome 14 was detected in the carrier of a Robertsonian t(13q14q). We conclude that uniparental disomy is a rare occurrence in this population.

Chromosome Aberrations↗
PubMed1994

Glomerular expression of interleukin-1 receptor antagonist and interleukin-1 beta genes in antibody-mediated glomerulonephritis.

Interleukin-1 (IL-1) is a powerful proinflammatory cytokine whose function is modulated by a natural IL-1 receptor antagonist (IL-1ra). There are few data about kinetics of in vivo synthesis of IL-1ra at tissue level, except in response to bacterial endotoxin. The purpose of this study was to examine the kinetics of local expression of IL-1ra gene in relation to IL-1 beta gene in a model of anti-glomerular basement membrane antibody-mediated glomerulonephritis. Rats were killed in groups of 5 or 6 at 0, 4, 6, 24, 48, and 96 hours after induction of glomerulonephritis. Messenger RNA for IL-1ra and IL-1 beta was undetectable by Northern blot in normal glomeruli but increased markedly 4 to 6 hours after induction of nephritis. The increase in IL-1ra mRNA was more sustained than that of IL-1 beta mRNA. In situ hybridization showed that IL-1 beta mRNA increased diffusely within glomeruli, while IL-1ra mRNA was expressed more discretely. Expression of these mRNA in noninflamed tissues, spleens and lungs, was different, particularly increase in IL-1ra mRNA was more substantial than that of IL-1 beta. These observations suggest that differential expression of IL-1ra and IL-1 beta might focus inflammation in glomeruli while protecting more distant sites. They also raise the possibility of reducing glomerular injury by therapeutic measures that upregulate glomerular synthesis of IL-1ra while reducing that of IL-1 beta.

Animals↗
PubMed1994

Oral cephalosporins: newer agents and their place in therapy.

Cefprozil, cefpodoxime and loracarbef are three new oral cephalosporins available for the treatment of common community-acquired infections. They share with other cephalosporins a low incidence of side effects and offer the convenience of twice-daily dosing. These agents can be considered effective, although expensive, alternatives to traditional antibiotics in the treatment of skin, respiratory tract and urinary tract infections. Oral cefpodoxime offers an alternative to intramuscular antibiotics in the treatment of uncomplicated gonorrhea.

Administration, Oral↗