Biomedical subjects
Publications and source records attributed to E Simpson.
The reason the maternal immune system does not reject a foetus may involve the downregulation of T-cell receptors specific for paternal antigens. A similar mechanism may help explain the remission seen in autoimmune patients during pregnancy.
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This study examined the relationship between childhood sexual abuse and symptoms of a newly proposed complex posttraumatic stress disorder or disorder of extreme stress not otherwise specified (DESNOS). Compared to 34 women without histories of sexual abuse, 74 survivors of sexual abuse showed increased severity on DESNOS symptoms of somatization, dissociation, hostility, anxiety, alexithymia, social dysfunction, maladaptive schemas, self-destruction and adult victimization. In addition, a logistic regression found that a complex of symptoms representing DESNOS was significantly related to a history of sexual abuse. Consistent with other studies, the results of this study provide support for the idea that symptoms of DESNOS characterize survivors of sexual abuse.
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This study examined the construct validity of the Trauma Symptom Checklist-40 (TSC-40; Elliot & Briere, 1992) in a sample of 130 female psychiatric inpatients. Consistent with other findings, the TSC-40 displayed criterion-related validity in relation to childhood sexual abuse. Survivors of sexual abuse obtained significantly higher scores than those without such a history on the overall TSC-40 and on each of the six subscales, except the Depression subscale. Convergent validity of three subscales was demonstrated, and divergent validity on the total TSC-40 and each of its subscales was established. Further, among a range of abuse-effects measures, the Sexual Abuse Trauma Index (SATI) subscale was the most powerful predictor of sexual abuse. The SATI and Dissociation subscales were the subscales most sensitive to the specific features of the sexual abuse.
Rejection of male tissue grafts by genotypically identical female mice has been explained by the existence of a male-specific transplantation antigen, H-Y (ref. 1), but the molecular nature of H-Y antigen has remained obscure. Hya, the murine locus controlling H-Y expression, has been localized to delta Sxrb, a deletion interval of the short arm of the Y chromosome. In mice, H-Y antigen comprises at least four distinct epitopes, each recognized by a specific T lymphocyte clone. It has recently been shown that one of these epitopes, H-YKk, is a peptide encoded by the Y-linked Smcy gene, presented at the cell surface with the H-2Kk major histocompatibility complex (MHC) molecule. However, deletion mapping and the analysis of variable inactivation of H-Y epitopes has suggested that the Hya locus may be genetically complex. Here we describe a novel mouse Y chromosome gene which we call Uty (ubiquitously transcribed tetratricopeptide repeat gene on the Y chromosome). We identify the peptide WMHHNMDLI derived from the UTY protein as an H-Y epitope, H-YDb. Our data formally demonstrate that H-Y antigen is the product of more than one gene on the Y chromosome.
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Seven cases of urachal anomalies are presented. The spectrum of the disorder and the criteria for ultrasound diagnosis are described. Six of seven cases were correctly diagnosed pre-operatively with diagnostic ultrasound, but one case with no cystic component was missed. The appearance of a fixed, midline, cystic, extraperitoneal swelling between the umbilicus and the bladder should suggest the diagnosis.
Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed with transgenic mice expressing the cognate antigenic protein under the control of the H-2Kb promoter. Double-transgenic mice show negative selection of thymocytes at the CD4+8+TCRlo to CD4+8+TCRhi transition stage. A few CD8+ T cells, however, escape clonal deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can develop low but detectable levels of antigen-specific cytotoxic function after stimulation in vitro in the presence of IL-2.
OBJECTIVE: To assess family physician learning needs related to the care of patients with schizophrenia. METHODS: Questionnaires were mailed to all family physicians and general practitioners practising in southern Alberta. Physicians were asked to indicate the number of patients with schizophrenia cared for, their interest in improving the care the provided, their preferred learning methods, and the content they wished to learn. RESULTS: A total of 539 surveys were returned for a return rate of 43.8%. Over half of the physicians (53.5%) indicated that they saw 1 to 2 patients with schizophrenia each month. Almost half (48.5%) indicated they were somewhat or very interested in increasing the care provided. Primary learning needs included increasing their knowledge of psychopharmacologic agents and monitoring and adjusting medications. Lectures and half-day workshops were the preferred learning methods. CONCLUSION: Our study was helpful in identifying the types of education that physicians wanted as well as the duration of the programming prior to the development of teaching interventions.
The male-specific transplantation antigen, H-Y, causes rejection of male tissue grafts by genotypically identical female mice and contributes to the rejection of human leukocyte antigen-matched male organ grafts by human females. Although first recognized 40 years ago, the identity of H-Y has remained elusive. T cells detect several distinct H-Y epitopes, and these are probably peptides, derived from intracellular proteins, that are presented at the cell surface with major histocompatibility complex (MHC) molecules. In the mouse, the gene(s) controlling H-Y expression (Hya) are located on the short arm of the Y chromosome between the zinc-finger genes Zfy-1 and Zfy-2. We have recently identified Smcy, a ubiquitously expressed gene, in this region and its X-chromosome homologue, Smcx. Here we report that Smcy encodes an H-YKk epitope that is defined by the octamer peptide TENSGKDI: no similar peptide is found in Smcx. These findings provide a genetic basis for the antigenic difference between males and females that contributes towards a tissue transplant rejection response.
Although the microvascular endothelium has been identified as the primary target site for the initiation of pancreatic islet graft rejection, little is known of the microvascular and cellular mechanisms involved, partly due to the lack of adequate models. Herein, we present a model for the in vivo assessment of the microcirculation of pancreatic islet grafts in mice. Isolated islets of Langerhans from immunocompetent hairless mice and immunoincompetent athymic nude mice were transplanted syngeneically into a specially designed dorsal skinfold chamber mounted on nondiabetic recipients. The islets' microcirculation was visualized by means of intravital fluorescence microscopy, and microcirculatory parameters were quantitatively analysed over a period of 14 days in the awake animal. Between day 2 and 4 after transplantation 84% (31/37; hairless mice) and 69% (36/52; nude mice) of the islet grafts revealed capillary sprouts and formation of new microvessels. On day 6, these sprouts were found interconnected, and red blood cell movement within the newly formed microvascular network was observed. The process of angiogenesis and revascularization was completed within 10 days after transplantation yielding a glomerulus-like network of capillaries as known for pancreatic islets in situ. Functional capillary density of the islet grafts ranged between 650 and 700 cm-1 in both hairless and nude mice. Within the islets' microvessels neither accumulation of leukocytes nor leukocyte-endothelial cell interaction was observed, indicating the lack of rejection and inflammation in these syngeneic islet grafts. We propose that this model provides a wide spectrum of promising experimental approaches for the study of microcirculatory and cellular mechanisms in free pancreatic islet transplantation.
MHC class II genes have been shown to influence the development of the autoimmune disease insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic (NOD) mouse. In human IDDM it has been suggested that the presence of an aspartate at position 57 of the DQ beta-chain might be important in determining resistance to development of IDDM. The involvement of MHC class II genes in IDDM was investigated through the introduction of MHC encoding transgenes. We show that introduction of a mutated I-Ag7 Ab gene which encodes an aspartate at position 57 reduces the incidence of IDDM but does not prevent insulitis, sialadenitis, or the development of insulin and nuclear autoantibodies.
Allelic exclusion of T cell receptor (TCR) genes is incomplete: a significant percentage (10-30%) of normal human and mouse peripheral T cells express two surface TCR alpha chains, and a small percentage of peripheral human T cells have been reported to express two surface TCR beta chains. A proportion of thymocytes in TCR transgenic mice rearrange endogenous T cell receptor genes, and peripheral T cells with two TCR alpha chains, transgenic and endogenous, have been reported. T cell clones with more than a single TCR heterodimer on their surface might be expected to show specificity for more than one cognate antigen: we report here a T cell clone with dual antigen specificity, isolated from an F5 TCR influenza nucleoprotein (NP 366-374/Db)-specific transgenic female mouse which had rejected an H-2-matched male skin graft. It was selected in vitro by stimulation with male H-2b spleen cells in the absence of the NP366-374 peptide but has specificity for both H-Y/Db and NP366-374. This contrasted with the single NP366-374/Db specificity shown by a control clone isolated from a Rag1-/- F5 mouse. The dual antigen specificity was associated with the rearrangement of endogenous TCR genes and cell surface expression of these as well as the TCR transgene.
New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.
Immune responses of mice with T-cell receptor (TCR)gamma delta+ T cells but lacking TCR alpha beta+ cells because of a disruption in the TCR alpha gene, were analysed against alloantigens, soluble protein antigen, killed Mycobacterium tuberculosis and exogenous superantigen. Rejection of skin allografts mismatched for classical major histocompatibility complex (MHC) plus multiple minor H antigens was virtually abrogated but the presence of mismatched Qa-1 non-classical MHC antigens on donor tissue resulted in a significant proportion of TCR alpha-/- mice rejecting such grafts. In view of the proposed role for gamma delta T cells in mycobacterial responses, and particularly against self- or mycobacterial heat-shock protein HSP 65, we examined these responses in TCR alpha-/- mice. Local responses after immunization were low in lymph nodes and no component of these was directed against mycobacterial HSP 65. However, splenic T cells from mutant mice responded strongly to either purified protein derivative (PPD) or M. tuberculosis. Our findings indicate that TCR alpha-/- mice are selectively compromised: while responses to (undefined) mycobacterial antigens were substantial, responses to some other target antigens such as MHC alloantigens and HSP 65, believed to be preferentially recognized by gamma delta receptors, were poor or absent. However, the fact that the mutant mice more readily rejected allografts that are mismatched for the non-classical MHC antigen Qa-1 in addition to classical MHC and minor-H incompatibility, indicates that in some mice the residual immune response, presumed to be by gamma delta cells, is sufficient to cause skin graft rejection and that recognition of non-classical MHC antigens may play an important part in the response.
A genetic map of the mammalian Y chromosome cannot be produced by standard Mendelian methods because the Y does not participate in meiotic exchange over the majority of its length. However, deletion mapping of the mouse Y chromosome is facilitated by the fact that its short arm carries the histocompatibility-Y (Hya) locus. This locus encodes male-specific (H-Y) antigens that can be selected against in tissue culture by the technique of immunoselection. To produce cells carrying deletions, cytotoxic T lymphocytes (CTLs) specific for H-Y antigens were cocultured with a lymphoblastoid cell line derived from a mouse carrying the portion of the short arm defined by the Sxra translocation on the distal end of its X chromosome. H-Y antigen-loss variant cells that contained Y-specific deletions were identified. Molecular, karyotypic, and immunological analysis of the deletion variants allowed us to define up to 16 ordered intervals and suggested an overall organization of Sxra. The analysis also suggests that at least two and up to five distinct loci encode H-Y antigens.