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Biomedical subjects

I R Mackay

Publications and source records attributed to I R Mackay.

At least 145 records · Page 8Linked to original sources
PubMed1990

Pharmacokinetics, tissue distribution, and cell localization of [35S]methionine-labeled recombinant human and murine alpha interferons in mice.

The pharmacokinetics, tissue distribution, cell localization, and penetration into tumor xenografts of recombinant [35S]methionine-labeled human alpha interferon (HuIFN-alpha) and murine alpha interferon (MuIFN-alpha) were examined in mice. Both interferons (IFNs) were removed from the blood in a rapid biphasic manner; HuIFN-alpha was cleared faster than MuIFN-alpha. Tissues were analyzed for radioactivity and over 90% of the IFNs was accounted for. The IFNs were detected predominantly in liver, kidney, gastrointestinal tract, pancreas, spleen, and lung. The levels of MuIFN-alpha compared with HuIFN-alpha were greater in the liver, spleen, and lung and less in the kidney, pancreas, and gastrointestinal tract. Heart, brain, testes, thymus, lymph nodes, fat, skin, and skeletal muscle contained much lower but measurable levels of both IFNs. There was penetration of HuIFN-alpha into tumor xenografts. The pharmacokinetics of IFN-alpha were independent of the strain of mouse, BALB/c or CBA, immune deprivation, or the presence of a tumor xenograft. Autoradiography of tissue sections from mice given injections of HuIFN-alpha or MuIFN-alpha indicated focal radioactivity in proximal convoluted tubules in the kidney and diffuse radioactivity in the liver, gastrointestinal tract, and pancrease. MuIFN-alpha, but not HuIFN-alpha, showed intense localization in cells in hepatic sinusoids, marginal zones in the spleen, and pulmonary alveolar walls, suggesting uptake by cells of the monocyte/macrophage lineage in these sites. The study shows the utility of biosynthetic labeling for pharmacokinetic studies of cytokines, clear differences in tissue distribution of IFN-alpha according to its species of origin, and targeting of homologous IFN-alpha to cells of the monocytic lineage.

Animals↗
PubMed1990

A neonatally tolerant mouse model to assess pathogenicity of human autoantibodies.

Since certain autoimmune diseases, including myasthenia gravis and pemphigus vulgaris can be reproduced in mice by passive transfer of immunoglobulins from affected patients, we assessed whether this procedure could be optimised. Repeated injections of human IgG into mice during pregnancy induced tolerance to human IgG in the litter, and this persisted for at least 9 months. We show that three different human autoantibodies, to mitochondria, centromere and collagen, were retained in the serum of neonatally tolerized mice, but pathogenic effects of these particular autoantibodies were not demonstrable over the four week time scale of our experiments. However, our model should be applicable to studies on human autoantibodies which might damage the appropriate tissue in a heterologous species.

Animals↗
PubMed1990

New murine model for hepatocellular carcinoma: transgenic mice expressing metallothionein-ovine growth hormone fusion gene.

Hepatocellular carcinomas developed at a high frequency in the livers of transgenic (C57BL/6 X SJL/J)F1 mice under the influence of growth hormone. Three lines of giant transgenic mice expressing a mouse metallothionein-ovine growth hormone fusion gene were generated. The giant mice weighed twice as much as control littermates. The three lines of giant mice expressing very high levels of growth hormone were bred over several generations. Mice from all three lines developed hepatocellular tumors, including adenoma and carcinoma. The occurrence of tumors was age-dependent, and their incidence increased to 70% of the mice studied after 43 weeks of age. Pathologic changes in the livers resembled those observed in rats in which hepatocellular carcinomas are induced chemically. Transgenic mice carrying the metallothionein-ovine growth hormone fusion gene represent a new model for hepatocellular carcinogenesis. This model exemplifies the oncogenic potential for a sustained proliferative growth stimulus within an organ.

Adenoma↗
PubMed1990

Imaging the plantaris tendon with ultrasound.

A quick, non-invasive method of imaging plantaris using real-time ultrasound is described. Preoperative scanning of patients who may require the use of plantaris as a tendon graft will identify those with congenital absence of plantaris and so avoid an unnecessary surgical exploration.

Foot↗
PubMed1990

Inhibition of enzyme function by human autoantibodies to an autoantigen pyruvate dehydrogenase E2: different epitope for spontaneous human and induced rabbit autoantibodies.

Antibodies to the mitochondrial autoantigen M2, characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC), react with the E2 subunit of the pyruvate dehydrogenase enzyme (PDH-E2). We examined the effect of disease sera on the enzyme activation catalysed by the PDH complex. Inhibition of enzyme activity was observed in 19 of 24 sera of patients with PBC with a level of greater than 90% inhibition in 14 at a serum dilution of 1/50. The onset of inhibition by serum was rapid, within the time of mixing, and the inhibitory activity was shown to reside in the immunoglobulin fraction of the serum. The immunoglobulin fraction of control sera from patients with other liver diseases (n = 26) and healthy persons (n = 8) failed to produce inhibitory activity. In addition sera from four rabbits, intensively immunized with a recombinant human M2 autoantigen, gave anti-M2 reactions by fluorescence, ELISA and immunoblotting, but did not inhibit the activity of PDH. The failure of experimentally induced M2 antibodies in rabbits to inhibit is interesting in view of the reactivity of the natural M2 autoantibodies of PBC with the highly conserved site on the enzyme which carries the essential lipoic acid cofactor.

Animals↗
PubMed1990

Mouse strain differences in susceptibility to sporidesmin-induced biliary tract injury.

Biliary tract injury was examined in four inbred strains of mice orally dosed with 500 micrograms of the fungal toxin sporidesmin. Semiquantitative histological analysis was used to assess the grade of necroinflammatory changes in the gall bladder, intra- and extrahepatic biliary tree and lobular parenchyma. Injury was greatest in the C57BL/6 and C3H strain mice and was least in SJL/J mice. In these strains injury was greatest at 4 days and had regressed by 10 days. In BALB/c mice the damage, although similar to that in SJL/J mice at 4 days, persisted at the same severity at day 10 and was accompanied by periductal fibrosis and occasionally by obliteration of ducts typical of sclerosing cholangitis. Analysis of the time-course of development of the lesions in C57BL/6 mice showed that the primary target for the toxin is the biliary epithelium. The severity of the lesions within the liver increased centripetally and the worst affected ducts were found at the confluence of the lobar ducts with the common bile duct. The variation in the degree of damage and rate of healing between strains may be due to differences in sporidesmin excretion in bile or interactions with biliary epithelial cells and/or efficacy of protective cellular repair mechanisms.

Animals↗
PubMed1990

Associations between HLA and antibodies to collagen in rheumatoid arthritis.

Associations between HLA types and serum antibodies to native and denatured type II collagen were sought in 105 patients with rheumatoid arthritis (RA). Antibodies were measured using a solid phase radioimmunoassay. There were no significant associations between any HLA antigen (A, B, or DR) and a high antibody titre to native collagen. There were significant associations, however, between HLA antigens and high antibody titres to denatured collagen. Although DR4 did not show an association, the phenotype A2+DR4+ did; this was not related to A2 as A2+DR- was not associated with a high antibody titre. No single B locus antigen showed an association, but several B locus antigens, B12, B15, and B40, were included in phenotypes with A2 and DR4 which were associated with a high antibody titre to denatured collagen. These HLA associations with anticollagen type II are best explained by a gene other than DR4 (but in linkage with it) which may regulate the antibody response to denatured collagen. If so, this would represent an HLA gene in addition to DR4 that is active in RA.

Antibodies↗
PubMed1990

Comparison of augmentation of human natural killer cell cytotoxicity by interferon-alpha subtypes.

The capacity of 3 interferon-alpha (IFN-alpha) subtypes, alpha 1, alpha 2 and alpha 4, to augment human natural killer cytotoxicity after exposure in vitro was shown to be dose-dependent and to differ according to subtype. With 10(2) IU/ml, the lowest IFN concentration used, stimulation of NK activity by IFN-alpha 2 was consistently and significantly greater than by IFN-alpha 4 or IFN-alpha 1. An IFN-alpha analogue in which arginine and lysine residues 121 and 122 were replaced by 2 leucines was generated by site-directed in vitro mutagenesis of the IFN-alpha 4 gene; at equivalent concentrations of antiviral activity, this analogue was 10-fold less effective in NK stimulation. There was a lack of correlation between NK-stimulatory and other activities of the IFN-alpha subtypes and the mutant, suggesting that different biological activities may be mediated by different regions of the IFN-alpha molecule.

Cytotoxicity, Immunologic↗
PubMed1990

An immunologic and genetic study of asthma in workers in an aluminum smelter.

The cause or causes of asthma among employees in aluminum smelters is unknown. We attempted to ascertain whether such workers who developed asthma differed in respect to indices of immunological function and certain genetic markers. Data were collected from 33 asthmatic and 127 nonasthmatic potroom workers. Asthmatic workers had significantly lower mean serum levels of immunoglobulin (Ig)M; however, mean levels of IgG and IgA, median levels of IgE, the capacity for recall of delayed type hypersensitivity, levels of immune complexes, and frequency of antinuclear or other autoantibodies did not differ from values for nonasthmatic workers. Asthma was found to develop on a background of atopy in 21 workers (64%), whereas there were no features of atopy in 12 workers (36%). Cigarette smoking had independent effects on immunological function. In respect to genetic markers, there was a higher frequency among asthmatic workers of the alpha-1-anti-trypsin deficiency phenotype MS, but the frequency of blood groups, Gm allotypes, or human leucocyte antigen types was similar. The study established that the profile of immune function, or genetic markers tested, did not differ essentially for workers in an aluminum smelter who did or did not develop asthma; however, there was an indication of heterogeneity in causation, as judged by "atopy-related" and "non-atopy-related" groups in the asthma population.

Adult↗
PubMed1990

Nucleotide sequence of a cDNA encoding the lipoate acetyl transferase (E2) of human heart pyruvate dehydrogenase complex differs from that of human placenta.

Tissue specific isoforms of an enzyme autoantigen were sought in an attempt to explain a possible disease-associated translocation of the enzyme. A human heart cDNA clone (0.66 kb) coding for part of the lipoate acetyl transferase component of pyruvate dehydrogenase complex, recently identified as one of the major autoantigens of primary biliary cirrhosis was isolated. The cloned cDNA corresponded to nucleotides 1545-2201 of a previously published placental sequence, but showed some differences which give rise to differences in the inferred amino acid sequences of proteins. This may indicate the existence of tissue-specific isoforms of the lipoate acetyl transferase component of pyruvate dehydrogenase complex coded for by a multi-gene family.

Acetyltransferases↗
PubMed1989

Participation of healthy volunteers in research projects.

Research that involves healthy normal volunteers frequently is performed. This article examines ethical guide-lines for the recruitment of healthy volunteers in research projects. Ethical decisions on projects that are based on patient-volunteers or healthy normal volunteers should balance the risk to the volunteer and the collective benefit to the community. For healthy normal volunteers that risk should be minimal or trivial. Investigators should follow recruitment practices that avoid approaches to persons who are dependent upon them in some way, and should carry the day-to-day ethical responsibility even after institutional ethical approval has been granted. Pilot studies and self-experimentation readily can transgress ethical guide-lines. Compensation for mishaps or injuries that occur during research in which there is no question of negligence (for example, an unforeseeable reaction in a phase-1 drug trial) is an unresolved issue which should be addressed by the research community. It is recommended that action be taken to ensure that healthy volunteers who participate in approved research have redress in the rare event of an accident, whether this is a result of negligence, chance or misadventure. Hospitals/institutions or other bodies that sponsor research should extend their insurance to cover specifically such unforeseeable events in which there may be liability, and to have the facility for a payment of beneficence in the case of accidents in which liability cannot be established.

Australia↗
PubMed1989

Reactivity of primary biliary cirrhosis sera with a human fetal liver cDNA clone of branched-chain alpha-keto acid dehydrogenase dihydrolipoamide acyltransferase, the 52 kD mitochondrial autoantigen.

Antimitochondrial autoantibodies recognizing 68 to 74 and 50 to 52 kD inner membrane mitochondrial antigens are characteristically present in sera of patients with primary biliary cirrhosis. The biochemical identification of the antigens, however, has remained elusive. We report herein that the 52 kD antigen is the dihydrolipoamide acyltransferase of the branched-chain alpha-keto acid dehydrogenase complex. This was demonstrated by three experiments through the use of recombinant fusion protein expressed in Escherichia coli from a cDNA insert encoding the human autoantigen. First, 33 of 37 primary biliary cirrhosis patients exhibiting reactivity toward the 50 to 52 kD mitochondrial antigen by immunoblotting also showed reactivity toward the recombinant fusion protein. Second, absorption of primary biliary cirrhosis sera with recombinant fusion protein, but not with an irrelevant recombinant clone, the F-specific rat liver antigen, was effective in absorbing out reactivity against the 50 to 52 kD mitochondrial antigen but not the 68 to 74 kD antigen. Third, complete removal of reactivity toward all four different isoelectric point polypeptides at 50 to 52 kD was observed in two-dimensional gel analysis. Furthermore, primary biliary cirrhosis sera were analyzed with mitochondria from three sources, rat liver, human placenta and bovine heart, in order to compare reactivity patterns and to determine precisely the comparative molecular weights of the autoantigens in the three species. The availability of recombinant autoantigens will provide improved diagnostic tests and, more importantly, will allow definite issues in primary biliary cirrhosis to be studied, including identification of immunodominant epitopes, the significance of autoantigen recognition and the establishment of autoreactive T cell clones.

Acyltransferases↗