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Biomedical subjects

E Simpson

Publications and source records attributed to E Simpson.

At least 19 recordsLinked to original sources
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

Rejection of H-Y disparate skin grafts by monospecific CD4+ Th1 and Th2 cells: no requirement for CD8+ T cells or B cells.

We wished to determine whether CD4+ T cells could reject a skin graft that was discordant for a single minor transplantation Ag in the absence of CD8+ T cells or Ab. Transgenic A1(M) mice were constructed that express the rearranged V beta 8.2 and V alpha 10 TCR genes from a T cell clone that is specific for the male Ag (H-Y) in the context of H2-Ek. In addition, the RAG-1(-/-) background was bred onto these mice to eliminate any endogenous TCR rearrangements. As expected, clonal deletion was found to be complete in the thymus of male A1(M) x RAG-1(-/-) mice, while only CD4+ T cells were positively selected and found in the periphery of females. Female A1(M) x RAG-1(-/-) mice were able to rapidly reject (in <14 days) male (but not female) skin grafts in a CD4-dependent fashion. After multiple grafts, it was confirmed that no CD8+ T cells or surface Ig+ B cells were present. An immunofluorescent analysis of spleen cells after grafting showed that the majority of T cells expressed activation markers (CD44, CD25, and intracytoplasmic IL-2) and a significant proportion were making IFN-gamma and IL-4. Surprisingly, the transfer of either Th1 or Th2 CD4+ T cell lines from these mice into T cell-depleted recipients was sufficient to cause a specific rejection of male skin.

Animals↗
PubMed1998

Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution.

The Delta Sxrb interval of the mouse Y chromosome is critical for spermatogenesis and expression of the male-specific minor transplantation antigen H-Y. Several genes have been mapped to this interval and each has a homologue on the X chromosome. Four, Zfy1 , Zfy2 , Ube1y and Dffry , are expressed specifically in the testis and their X homologues are not transcribed from the inactive X chromosome. A further two, Smcy and Uty , are ubiquitously expressed and their X homologues escape X-inactivation. Here we report the identification of another gene from this region of the mouse Y chromosome. It encodes the highly conserved eukaryotic translation initiation factor eIF-2gamma. In the mouse this gene is ubiquitously expressed, has an X chromosome homologue which maps close to Dmd and escapes X-inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode putative products with 98% amino acid identity. In humans, the eIF-2gamma structural gene is located on the X chromosome at Xp21 and this also escapes X-inactivation. However, there is no evidence of a Y copy of this gene in humans. We have identified autosomal retroposons of eIF-2gamma in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicates that X-Y homologues are present in all species tested except simian primates and kangaroo and that retroposons are common to a wide range of mammals. These results shed light on the evolution of X-Y homologous genes.

Amino Acid Sequence↗
PubMed1998

Congenital central hypoventilation syndrome and Hirschsprung's disease.

Five cases of the Hirschsprung's disease-congenital central hypoventilation syndrome (CCHS) association are presented and 41 other published cases reviewed. These children have a distinct pattern of associated features, an equal sex incidence, and a characteristic spectrum of disease severity which suggests that the condition is genetically distinct from other cases of Hirschsprung's disease. While approximately 1.5% of Hirschsprung's disease patients, and 10% of those with total colonic aganglionosis, will have CCHS, up to 50% of CCHS patients will have Hirschsprung's disease. Approximately 20% of CCHS/Hirschsprung patients will also have neuroblastoma or ganglioneuroma, usually multiple. Abnormalities of the eye and autonomic nervous system are also common. The ventilatory abnormality is usually evident on the first day of life. The aganglionosis is also severe, with more than half (59%) of the patients having aganglionosis extending into the small bowel.

Deglutition Disorders↗
PubMed1998

Minor transplantation antigens: mouse models for human host-versus-graft, graft-versus-host and graft-versus-leukemia reactions.

Minor transplantation or histocompatibility (H) antigens are barriers to the transplantation of organs and tissues between genetically non-identical individuals who are matched for transplantation antigens encoded by the major histocompatibility complex (MHC), H2 in mice and HLA in humans. Recognition of minor H antigens by T cells can lead to host-versus-graft (HvG) rejection of organs and, in bone marrow transplantation, to life threatening graft-versus-host (GvH) reactions, although if these can be controlled, clinically useful graft-versus-leukemia (GvL) reactions can be obtained. This review describes the early in vivo studies that laid the foundations of our understanding that minor H antigens are the product of genetic polymorphisms, the subsequent in vitro work which has identified these at the molecular level as peptides presented to T cells by self MHC molecules, and the most recent developments, which have seen the use of minor H specific T cells clones and sophisticated biochemical and molecular biological approaches to identify genes encoding them.

Animals↗
PubMed1997

Qa-1 interaction and T cell recognition of the Qa-1 determinant modifier peptide.

The peptide-binding properties of the nonclassical major histocompatibility complex (MHC) class 1b molecule Qa-1 were investigated using a transfected hybrid molecule composed of the alpha 1 and alpha 2 domains of Qa-1b and the alpha 3 domain of H-2Db. This allowed the use of a monoclonal antibody directed against H-2Db whilst retaining the peptide-binding groove of Qa-1b. By comparison with classical MHC class I molecules, intracellular maturation of the chimeric molecule was inefficient with weak intracellular association with beta 2-microglobulin. However, at the cell surface the hybrid molecules were stably associated with beta 2-microglobulin and were recognized by cytotoxic T lymphocyte (CTL) clones specific for the Qa-1b-presented peptide Qdm (AMAPRTLLL). A whole-cell binding assay was used to determine which residues of Qdm were important for binding to Qa-1b and CTL clones served to identify residues important for T cell recognition. Substitutions at position 1 and 5 did not reduce the efficiency of binding and had little effect on CTL recognition. In contrast, substitutions at position 9 resulted in loss of MHC class I binding. Mass spectrometric analysis of peptides eluted from immunopurified Qa-1b/Db molecules indicated that Qdm was the dominant peptide. The closely related peptide, AMVPRTLLL, which is derived from the signal sequence of H-2Dk, was also present, although it was considerably less abundant. The mass profile suggested the presence of additional peptides the majority of which consisted of eight to ten amino acid residues. Finally, the finding that a peptide derived from Klebsiella pneumoniae can bind raises the possibility that this non-classical MHC class I molecule may play a role in the presentation of peptides of microorganisms.

Amino Acid Sequence↗
PubMed1997

Why do some females reject males? The molecular basis for male-specific graft rejection.

The male-specific minor histocompatibility antigen H-Y plays an important role in both graft rejection and graft-versus-host disease following transplantation of male tissue into females that are completely matched at the major histocompatibility loci. The recent identification of two peptides that, in association with the mouse H-2Kk or human HLA B7 major histocompatibility class I molecules, are recognised by H-Y-specific T cells, has provided evidence for the molecular basis for such anti-H-Y responses. These peptides are encoded by the mouse and human homologues of a ubiquitously expressed Y chromosome gene, Smcy, whilst the equivalent peptides encoded by the X chromosome homologues of this gene fail to be recognised. Genetic studies have demonstrated that, as is the case for other minor histocompatibility antigens, peptide epitopes from several closely linked genes may be required to interact in order to elicit a response against H-Y. Definition of the peptides and the genes that encode these epitopes will allow the development of tolerogenic protocols that could specifically down-modulate the response to H-Y and perhaps even other minor histocompatibility antigens.

Amino Acid Sequence↗
PubMed1997

Ectomesenchymoma: one or two tumors? Case report and review of the literature.

Ectomesenchymoma has not previously been reported in a patient with the cutaneous nevus syndrome. A case of perineal ectomesenchymoma is presented with unusual cytogenetic findings. The significance of these is discussed and the world literature reviewed. This is the first such case reported.

Combined Modality Therapy↗
PubMed1997

Minor histocompatibility antigens.

The existence of transplantation antigens, in addition to those encoded by genes in the MHC, has been known for over half a century. The molecular identification of these additional minor histocompatibility (H) antigens lagged behind that of their MHC counterparts, largely because minor H antigens are recognised by T cells and not by antibodies. In the past year, however, new minor H antigens have been identified at both the genetic and protein level and include Uty, a second novel gene encoding a male-specific epitope in mice, a novel autosomal gene encoding each of the H-13 alleles of mice, and a second male-specific epitope encoded by the SMCY gene.

Animals↗
PubMed1997

An affect-management group for women with posttraumatic stress disorder and histories of childhood sexual abuse.

Systematic research on effective treatment for survivors of childhood sexual abuse with posttraumatic stress disorder (PTSD) is virtually non-existent. The aim of the present study was to compare the effectiveness of an affect-management treatment (AM) group to a wait list control condition for female survivors of childhood sexual abuse with PTSD. Forty-eight female survivors of childhood sexual abuse with PTSD were randomly assigned to either a 15-week affect-management treatment group or to a wait list control condition. All subjects received individual psychotherapy and pharmacotherapy for the duration of the study, and for at least 1-month prior to the study. Controlling for pretreatment scores, subjects who completed the affect-management treatment group (n = 17) reported significantly fewer posttreatment symptoms of PTSD and dissociation than subjects in the wait list control condition (n = 16). Our findings suggest that an affect-management group treatment is beneficial as an adjunct to individual psychotherapy and pharmacotherapy for survivors of childhood sexual abuse with PTSD.

Affect↗
PubMed1997

Analysis of stress levels among medical students, residents, and graduate students at four Canadian schools of medicine.

PURPOSE: To assess stress in medical students, residents, and graduate science students at four Canadian schools of medicine. METHOD: Four schools with different curricula in three different parts of Canada participated in the study: the University of Calgary Faculty of Medicine, the University of Alberta Faculty of Medicine, the Dalhousie University Faculty of Medicine, and the McMaster University Faculty of Health Sciences. All the medical students, residents, and graduate science students at each school were surveyed in 1994-95. The three instruments used were the University of Calgary Stress Questionnaire, the Social Readjustment Rating Scale (SRRS), and the Symptom Checklist-90. Demographic data were compared across all four schools. Analysis of variance was calculated for all test-item scores, utilizing a four (school) by three (program) by two (gender) design, which were all between subject factors. Significant main effects were followed up by using planned comparisons (Newman-Keuls, with a probability level of p < .05). Significant interaction effects were followed up by using an analysis of simple effects. RESULTS: A total of 1,681 questionnaires were returned as follows: 621 of 1,304 (48%) from the medical students, 645 of 1,495 (43%) from the residents, and 415 of 829 (50%) from the graduate science students. There were significant differences between the three groups in the natures and degrees of stress, with the graduate students reporting higher levels of stress. There were significant gender differences as well, with the women reporting higher levels of stress. Overall, stress levels were found to be mild, based on the University of Calgary Stress Questionnaire and the SRRS. CONCLUSION: This study suggests that medical students and residents experience stress at levels that appear acceptable, but ongoing monitoring and the provision of appropriate support systems will continue to be important.

Adaptation, Psychological↗
PubMed1997

Lead foreign body ingestion in children.

Foreign body ingestion is seen commonly in paediatric surgical practice and the vast majority of ingested foreign bodies will pass spontaneously once they have made their way into the stomach. Lead foreign body ingestion in children represents a special case in view of the potential for acute lead intoxication secondary to dissolution and absorption of the ingested lead. Lead dissolves poorly in physiological solutions with the exception of the acid environment of the stomach. We report a case of a 4-year-old child who ingested a lead sinker which was removed from the stomach by emergency endoscopy. This case stimulated a review of the relevant literature and the formulation of a management plan for lead foreign body ingestion in children. The principles of this management plan are observation of the child in hospital and use of a protein pump inhibitor until the foreign body has passed out of the stomach.

Child, Preschool↗
PubMed1997

The male-specific histocompatibility antigen, H-Y: a history of transplantation, immune response genes, sex determination and expression cloning.

H-Y was originally discovered as a transplantation antigen. In vivo primary skin graft responses to H-Y are controlled by immune response (Ir) genes mapping to the MHC. In vitro T cell responses to H-Y are controlled by MHC class I and II Ir genes, which-respectively, restrict CD8 and CD4 T cells: These can be isolated as T cell clones in vitro. T cell receptor (TCR) transgenic mice have been made from the rearranged TCR genes of several of these, of which that specific for H-Y/Db is the best studied. Non-MHC Ir genes also contribute to the control of in vitro CTL responses to H-Y. The Hya/HYA gene(s) encoding H-Y antigen have been mapped using translocations, mutations, and deletions to Yq in humans and to the short arm of the Y chromosome in mice, where they lie in the deletion defined by the Sxrb mutation between Zfy-1 and Zfy-2. Hya/HYA has been separated from the testis-determining gene, Sry/SRY, in both humans and mice and in humans the azoospermia factor AZF has been separated from HYA. In mice transfection of cosmids and cDNAs mapping to the Sxrb deletion has identified two genes encoding H-Y peptide epitopes. Two such epitopes, H-Y/K(k) and H-Y/D(k), are encoded within different exons of Smcy and a third, H-Y/D(b), by a novel gene, Uty. Peptide elution approaches have isolated a human H-Y epitope, H-Y/HLA-B7, and identified it as a product of SMCY. Each of the Hya genes in mice is ubiquitously expressed but of unknown function. Their X chromosome homologues do not undergo X inactivation.

Animals↗
PubMed1997

HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII.

Molecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterized mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

Alleles↗