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Biomedical subjects

A Muir

Publications and source records attributed to A Muir.

At least 37 records · Page 2Linked to original sources
PubMed1998

The antiphospholipid syndrome.

The antiphospholipid syndrome is now well established as an important, acquired prothrombotic disorder. Advances are being made in the understanding of the condition and the paradox of the in vitro anticoagulation, and the in vivo prothrombotic tendency. Newer and better assays for the diagnosis of antiphospholipid syndrome can be expected in the near future. Large, multi-centre, controlled trials to determine the optimum treatment of patients who test positive for the antiphospholipid syndrome, but have not suffered a thrombotic event, are required.

Antibodies, Antiphospholipid↗
PubMed1997

Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate beta-cell antigens.

A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt female mice strongly retards diabetogenesis. The present study used the intrathymic route of antigen administration to compare the relative efficacy of peptides/proteins derived from two major candidate pancreatic beta-cell autoantigens, insulin and GAD65, to modulate diabetogenesis. Intrathymic administration of insulin B chain or recombinant human GAD65 significantly suppressed diabetogenesis during a 20-week follow-up period, whereas no protection was mediated by either insulin A chain or a synthetic peptide (A2) derived from it. Quite unexpectedly, two GAD65-derived peptides near the COOH-terminus (p34 and p35) accelerated diabetes onset. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed on cDNAs from isolated islets or whole pancreases of NOD/Lt females 4 weeks after intrathymic injections. Protection mediated by intrathymic administration with either intact islet cells or GAD65 were correlated with an upregulation of mRNA for T-helper 2 (Th2)-associated cytokines (interleukin [IL]-4, IL-10), concomitant with downregulation of Th1-associated interferon (IFN) transcripts (all normalized to T-cell receptor Cbeta transcripts) in islet-infiltrating lymphocytes. Protection mediated by the intrathymic administration of insulin B chain, however, correlated only with a modest upregulation of IL-4 and IL-10 transcript levels, and no diminution in IFN-gamma transcripts. In contrast, the diabetes-accelerating GAD65 p34 and p35 peptides were not associated with an immune deviation, expressing levels of IFN-gamma characteristic of islet-infiltrating lymphocytes in vehicle-injected NOD controls. Hence, Th1-to-Th2 immune deviation provides only a partial explanation for peptide immunotherapy of diabetes in NOD mice. The finding that certain peptides can accelerate rather than retard diabetogenesis as a function of route and age of administration adds a cautionary note to this type of therapy.

Adoptive Transfer↗
PubMed1996

Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.

Acquired hypoparathyroidism (AH) has been considered to result from an autoimmune process but the self-antigens have not been identified. We studied 25 patients with AH, of which 17 had type I autoimmune polyglandular syndrome and 8 had AH associated with autoimmune hypothyroidism. Five of 25 (20%) AH sera reacted to a membrane-associated antigen of 120-140 kD in human parathyroid gland extracts using immunoblot analysis. This is the exact size of the calcium sensing receptor (Ca-SR). The AH sera were then tested by immunoblot using a membrane fraction of HEK-293 cells transfected with Ca-SR cDNA. Eight of 25 (32%) AH sera reacted to a 120-140-kD protein, which closely matched that recognized by the anti-Ca-SR IgG raised in rabbits. The Ca-SR cDNA was translated in vitro into two parts in order to identify the antigenic epitopes. By using this technique, 14 of 25 (56%) AH sera were positive to the extracellular domain of the Ca-SR, whereas none of the AH patients sera reacted to the intracellular domain. The reactivity of the positive sera was completely removed after pre-absorption with the Ca-SR containing membranes. Sera from 50 patients with various other autoimmune diseases as well as 22 normal controls were also tested, and none of them was positive. In conclusion, the Ca-SR has been identified as an autoantigen in AH.

Autoantibodies↗
PubMed1996

Paternally transmitted IDDM2 influences diabetes susceptibility despite biallelic expression of the insulin gene in human pancreas.

Whereas it is well known that the insulin gene (INS) region at 11p15.5 (IDDM2) confers susceptibility to insulin-dependent diabetes mellitus (IDDM), it is still controversial whether the parental origin of IDDM2 influences IDDM susceptibility. We have analysed the Pst I + 1127 polymorphism in 123 USA multiplex families and detected linkage only in male meioses using the affected sibpair analysis (P = 0.009). Application of the transmission/disequilibrium test (TDT) found significantly increased transmission of the IDDM-associated INS allele from fathers heterozygous for INS to their diabetic offspring (P = 0.00002), but the transmission from heterozygous mothers was not significantly different from random expectation. In non-diabetic families, the transmission from parents heterozygous for INS was not significantly different from random expectation in either paternal or maternal meioses. Maternal imprinting of the INS gene in pancreatic islets was originally considered the most favorable explanation for the observed gender-related difference. However, our study has demonstrated biallelic expression of INS in pancreatic tissues from the human fetuses and thus suggests that INS is probably not imprinted in the pancreatic islets.

Alleles↗
PubMed1996

Circadian body temperature rhythms of the solitary cape mole rat Georychus capensis (Bathyergidae).

Simultaneous measurements of activity and telemeterized body temperature were measured under 12:12 LD and constant light conditions in the solitary, subterranean rodent Georychus capensis for 137 consecutive days. The objectives of the study were twofold: a) to determine whether G. capensis display circadian body temperature rhythms similar to those of nonsubterranean mammals, and b) to determine whether body temperature rhythms provide a more reliable measure than those of activity of endogenous circadian rhythms under laboratory conditions. Significant circadian Tb and activity rhythms were recorded under entrained and free-running conditions (i.e., under a light-dark cycle and under constant illumination), confirming the ability of this species to perceive light. Although the maximum daily amplitude of Tb (Rt) between the mean photophase minimum and the mean scotophase maximum was 99% of that predicted by body mass for mammals, G. capensis did not display sustained differences of either the minimum, mean, or maximum Tb between the photo- and scotophases. Nevertheless, most individuals indicated nocturnal activity patterns. Evidence suggests a lack of an obvious endogenous body temperature rhythm. Body temperature may thus not be a reliable measure of endogenous circadian rhythms in this rodent.

Animals↗
PubMed1996

Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity.

Human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed using a PCR-based sequence-specific priming technique in 16 patients with autoimmune polyglandular syndrome type I (APS-I), 31 patients with APS-II, and 110 patients with component diseases of APS-II, including 9 patients with isolated Addison's disease, 43 patients with Hashimoto's thyroiditis, 22 patients with Graves' disease, and 36 patients with vitiligo. No significant associations was observed between HLA and APS-I patients in our data set, nor was sharing of HLA haplotypes by sibling pairs affected by APS I significantly different from the random expectation. Thus, HLA-DRB1 and -DQB1 genes are probably not involved in APS-I. To delineate the associations between HLA-DRB1, DQB1, and APS-II, we analyzed APS-II patients with or without beta-cell autoimmunity [i.e. insulin-dependent diabetes (IDD) and/or islet cell or glutamic acid decarboxylase autoantibodies]. Our results suggest that the association between DR4-DQB1*0302 and APS-II was entirely due to the presence of pancreatic beta-cell autoimmunity, since this haplotype was otherwise not significantly associated with APS-II or with any other of its component diseases. In contrast, the DR3-DQB1*0201 haplotype was associated not only with IDD, but also with APS-II in the absence of pancreatic beta-cell autoimmunity, as were several its component diseases, including isolated Addison's disease, Graves' disease, and Hashimoto's thyroiditis. Interestingly, the frequency of DQB1*0602, a dominantly protective allele against IDD, was not significantly decreased in the APS-II patients with IDD or beta-cell autoimmunity, albeit the patient numbers were small. This phenomenon may suggest that the development of autoimmunity to nonpancreatic endocrine glands may predispose autoimmunity to the pancreatic beta-cells and involve genes other than those of the MHC.

Adolescent↗
PubMed1995

The legal responsibilities of the health-care librarian.

This article discusses the legal responsibilities that information intermediaries have towards the users of their services. The areas of law that affect legal liability are contract law, tort and strict liability. The likelihood of health-care librarians being held liable for the service they provide is assessed, and methods of reducing this risk are discussed. The key issues are: whether the recipient is relying on the information you provide and whether this reliance is reasonable; whether money changed hands; and whether the institution is under a statutory obligation to provide the information. All-embracing exclusion clauses are often used as an attempt to exclude liability, but their validity in law is doubtful, and they should be replaced by more reasonable ones. Adhering to good professional practice, and avoiding interpreting information for laymen are ways of minimizing liability. If court proceedings do take place, professional indemnity insurance can reduce financial loss.

Insurance, Liability↗
PubMed1995

Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.

We reported previously that daily injections of isophane insulin prevented both hyperglycemia and insulitis in nonobese diabetic (NOD) mice (Atkinson, M., N. Maclaren; and R. Luchetta. 1990. Diabetes. 39:933-937). The possible mechanisms responsible include reduced immunogenicity of pancreatic beta-cells from "beta-cell rest" and induced active immunoregulation to insulin (Aaen, IK., J. Rygaard, K. Josefsen, H. Petersen, C. H. Brogren, T. Horn, and K. Buschard. 1990. Diabetes. 39:697-701). We report here that intermittent immunizations with insulin or its metabolically inactive B-chain in incomplete Freund's adjuvant also prevent diabetes in NOD mice, whereas immunizations with A-chain insulin or with BSA do not. Adoptive transfer of splenocytes from B-chain insulin-immunized mice prevented diabetes in recipients co-infused with diabetogenic spleen cells, an effect that was abolished by prior in vivo elimination of either CD4+ or CD8+ cells. Insulin immunization did not reduce the extent of intraislet inflammation (insulitis); however, it did abolish expression of IFN-gamma mRNA within the insulitis lesions. Immunizations with insulin thus induce an active suppressive response to determinants on the B-chain that converts the insulitis lesion from one that is destructive to one that is protective.

Animals↗
PubMed1995

Intrafamilial and case-control association analysis of D2S152 in insulin-dependent diabetes.

We have performed intrafamilial and case-control association studies to examine the previously reported linkage disequilibrium between D2S152 and a type 1 diabetes susceptibility gene on chromosome 2q31-q33 (IDDM7). Significant linkage disequilibrium was observed in our subset of 47 Florida affected sibpair families (p < 0.02) but not in the other 57 USA families. We were not able to detect any significant associations between IDDM and D2S152 using case-control studies in a Caucasian data set of 270 unrelated diabetic patients and 370 normal controls ascertained from Florida, or in a Chinese data set of 90 patients and 169 normal controls. Our results suggest that linkage disequilibrium between IDDM7 and D2S152 must be very loose.

Alleles↗
PubMed1995

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27.

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.

Chromosome Mapping↗
PubMed1995

Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies.

LMP2 and LMP7, two subunits of the proteasomes encoded in the major histocompatibility complex, are speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Their possible role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) has not been documented. In this study of Caucasian subjects, we have analyzed the polymorphisms of four genes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1) in 198 unrelated IDDM patients and 192 normal controls ascertained from the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4-DQB1*0302 haplotype. To determine whether the apparent associations between LMP genes and IDDM resulted from the strong linkage disequilibria observed between LMP and HLA-DR/DQ genes, we compared LMP gene frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independent effects on IDDM susceptibility.

Autoimmune Diseases↗
PubMed1994

High risk HLA-DR/DQ genotypes for IDD confer susceptibility to autoantibodies but DQB1*0602 does not prevent them.

Although HLA class II genes are important in insulin-dependent diabetes (IDD), their influence on the expression of IDD-associated autoantibodies (aAb) is unclear. We compared HLA-DRB1 and DQB1 gene frequencies in several Caucasian groups: 191 normal controls, 378 IDD patients, and 357 non-diabetic relatives of which 250 had no aAb, 107 had at least one aAb (79 ICA+, 31 GAD65+ and 49 IAA+), and 23 had both ICA+ and IAA+. We found that the frequencies of DR3/4 or DQB1*0201/0302 heterozygotes were significantly higher in aAb+ relatives compared to aAb- relatives. The frequencies of DR4/4 or DR4/X (X = non 3 or 4) and DQB1*0302/X (X = 0201 or 0302) in aAb+ relatives were not different from the aAb- relatives (which were enriched for these haplotypes), but were significantly higher than normal controls. The frequencies of DR3/X or DQB1*0201/X were decreased in both aAb+ relatives and IDD patients. Interestingly, the dominant IDD-protective DQB1*0602 allele allowed the development of individual aAbs (10% of ICA+ and 8% IAA+ relatives had the allele), but was not observed in any high risk double aAb+, or GAD65Ab+ relatives. The latter finding was similar to that in our patients with IDD, in that only two of them (0.5%) had a DQB1*0602 allele. In conclusion, HLA-encoded susceptibilities to disease-relevant autoantibody production and IDD are concordant with the susceptibility alleles, but discordant for the protective DQB1*0602. Thus HLA genotyping for DQB1*0602 would impact on the selection of aAb+ relatives for disease prevention trials.

Adolescent↗