Biomedical subjects
Publications and source records attributed to P Laing.
This paper reports a retrospective analysis of blood use in 27 children undergoing major spinal surgery in Liverpool in 1990. Overall 133 units of blood were cross-matched, but only 60 units (45%) were used. The results of the analysis show a significant difference between the operative techniques used in elective spinal surgery. This hospital has now introduced new guidelines for the cross-matching of blood.
A case report of an unreduced dislocation of the elbow requiring late open reduction is presented, and the literature is reviewed. Early reduction of elbow dislocation, by closed or open means, is of paramount importance if good functional results are to be obtained. Closed reduction of an elbow dislocation is unlikely to be successful if attempted later than 21 days after the injury. The results are acceptable if open reduction is undertaken within 3 months of the injury, but after 6 months the results are disappointing and arthroplasty is an alternative.
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The development of a shear transducer, small enough to be worn comfortably under a normal foot, is described, along with a microcomputer controlled data logger. Walks up to 8 s can be recorded and the information downloaded to any IBM compatible computer. Software then allows easy analysis of the peak shear stresses. Calibration curves show the transducers to have a linear response up to 35N and preliminary data from the measurement of shear stresses under the normal foot, and their relationship to vertical pressures, is presented. A patent application (number 9109463.1) has been filed for the device in the United Kingdom.
A high affinity tritiated azido-diphenylpiperazine derivative, 3-azido[3H]GBR-12935, was synthesized as a potential photoaffinity probe of the dopamine transporter. Initially, the reversible binding of 3-azido[3H]GBR-12935 to crude synaptosomal membranes from the rat striatum was characterized. Specific binding was sodium dependent and inhibited by a variety of drugs that are known to potently inhibit dopamine uptake. Other neurotransmitter uptake inhibitors, as well as cis-flupenthixol, a potent inhibitor of [3H]GBR-12935 binding to piperazine binding sites, failed to inhibit specific binding at concentrations of less than or equal to 10 microM. A good correlation was observed between the relative potencies of these drugs in inhibiting dopamine uptake into synaptosomes and in inhibiting specific 3-azido[3H]GBR-12935 binding to rat striatal membranes (r = 0.95, p less than 0.01). These data suggest that 3-azido[3H]GBR-12935, like other diphenylpiperazines such as [3H]GBR-12935 and [3H]GBR-12909, binds primarily to the dopamine transporter under defined assay conditions. After UV photolysis of crude synaptosomal membranes preincubated with 3-azido[3H]GBR-12935 (1-2 nM), a single radiolabeled polypeptide with an apparent molecular mass of 80 kDa was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Photoincorporation of 3-azido[3H]GBR-12935 into this polypeptide was inhibited selectively by compounds that inhibit the uptake of dopamine (but not other biogenic amines) and was completely dependent on the presence of Na+. No photolabeled proteins were observed when cerebellar membranes were substituted for striatal membranes. Essentially complete adsorption of the radiolabeled 80-kDa polypeptide to wheat germ agglutinin and elution with N-acetyl-D-glucosamine strongly suggest that the dopamine transporter polypeptide photolabeled by 3-azido[3H]GBR-12935 is glycosylated.
Immunization of rabbits with certain H1N1 influenza viruses, including the neurotropic strains NWS/33 and WSN/33 and the New Jersey/76 strain, resulted in the production of autoantibodies to a brain-specific protein of 37 kDa that is present in various species, including humans. Autoantibodies were produced to brain only; various other tissues tested were negative. These antibodies were not elicited by other influenza A or B viruses, including closely related recombinant strains, but were elicited by the isolated hemagglutinin of A/Bellamy/42 strain and by formaldehyde-fixed WSN virus--demonstrating that infection was not essential for the induction of autoantibodies. In histological studies, reaction with anti-viral antisera was specific to gray matter and was confined to sera that recognized the 37-kDa protein. Antibody binding was prominent in regions comprised of neuronal cell bodies in cellular layers of the dentate gyrus, hippocampus, cerebral cortex, and cerebellum and was undetectable in myelin-rich regions, such as the corpus callosum. The 37-kDa protein, therefore, appears to be a neuronal antigen. Antibodies directed against this protein may be involved in the pathogenesis of one or more of the neuropsychiatric disorders that occur after infection with influenza.
The relationship between rat red blood cell (RBC) glycophorins and the antigens recognised by anti-rat RBC antibodies was examined. Initially, murine monoclonal antibodies specific for surface epitopes on whole rat RBCs were tested for their reactivity with RBC membranes on Western blots and two were found which reacted with blotted antigens. These antibodies recognised two bands corresponding to the major PAS-stainable bands of rat RBC membranes (i.e., the glycophorins) and a number of minor bands, thus demonstrating that the bands are antigenically related. This band-pattern was remarkably similar to that obtained with mouse anti-rat RBC serum. Digestion with neuraminidase altered the electrophoretic mobility of most of the bands, providing additional evidence that they are sialoglycoproteins, although sialic acid was shown not to contribute to their antigenicity. The glycophorin nature of the major antigens was verified by reelectrophoresis and blotting of bands excised from SDS gels, which showed that they were interconvertible monomeric and dimeric forms of the same polypeptide chain. It is suggested that rat RBC glycophorins are a related family of sialoglycoproteins with the high molecular weight members being formed by dimerization of five lower molecular weight polypeptide chains in various combinations.
Recent discoveries in the field of virus receptors have revolutionized our concepts of viral pathogenesis. The lysis of cells resulting from virus infection or immune recognition of infected cells is seen as merely one facet of a spectrum of pathogenic mechanisms which may be subtle and complex. This is particularly relevant to the central nervous and immune systems which share cell-surface receptors for various neuropeptides and neurotransmitters. A number of viruses are now known to share receptors for such endogenous ligands; indeed, some viruses (e.g., human immunodeficiency virus and vaccinia) may themselves be structural analogs of these ligands. There is, therefore, considerable scope for interference by viruses in the normal functioning of the brain and neuroendocrine systems. Brief reactive psychoses are occasionally reported as acute sequels to viral infections, but generally these are regarded as unrelated to schizophrenia. An opposite viewpoint is presented in the article: i.e., that the only reason these reactive psychoses do not progress to schizophrenia is that the majority of individuals affected are not predisposed genetically to schizophrenia. Conceivably, therefore, the genetic predisposition to schizophrenia may be attributable to genes which determine idiosyncratic differences in immune responsiveness to common viral pathogens.
An erythrocyte autoantigen has been identified by means of monoclonal autoantibodies raised by immunizing mice with rat red blood cells (RBC). The autoantibodies reacted with intact rat and mouse RBC as judged by a cellular radioimmunoassay, and with a 52K band on western blots of rat and mouse RBC. They did not react with intact sheep RBC or blotted sheep erythrocyte membranes. Although anti-rat erythrocyte antibodies did react with bands in the molecular weight region of 50-55 K (on blots of rat erythrocyte membranes), these bands were susceptible to neuraminidase digestion, thus distinguishing them from the 52 K band recognized by monoclonal autoantibodies. The implications of the above results for the known autoantibody specificity of suppression is discussed, and it is suggested that they favour the existence of autoantigen-specific suppressor cells.
In order to examine how rat erythrocytes stimulate erythrocyte autoantibody production at the molecular level, we have identified rat erythrocyte antigens by immunoprecipitation and western blotting using monoclonal antibodies and antisera. A novel non-radioactive immunoprecipitation technique was used, which employed biotin as a label and a luminescent detection system. The new method was validated by comparison with conventional immunoprecipitation using 125I. Glycophorins of relative molecular mass (Mr) 81,000 and 38,000 were found to be the major antigenic components of rat erythrocytes, while band 3 (the most abundant erythrocyte membrane protein) was not recognized by rat-specific antibodies. The same surface antigens were recognized by sera from mice producing erythrocyte autoantibodies and by sera from mice in which autoantibody production was suppressed. Nine other minor rat-specific antigens were identified by blotting, ranging in Mr from 23,000 to 147,000. Analysis of the integral membrane proteins of rat and mouse erythrocytes by sodium dodecyl sulphate (SDS) electrophoresis followed by silver or periodic acid-Schiff (PAS) stains revealed differences between the glycophorins, but not between rat and mouse band 3. Thus, the major antigenic differences correspond to discernible biochemical differences between rat and mouse erythrocyte sialoglycoproteins.
Proteins separated by SDS gel electrophoresis and transferred to a nitrocellulose sheet can be visualised by 'probing' with peroxidase-linked reagents which are detected by luminescence. A modified luminescent substrate is described containing 4-methylumbelliferone which enhances light emission four-fold. Using the modified substrate, luminescent detection was found to be more sensitive than chromogenic detection of peroxidase using 4-chloro-1-napthol. The new technique was used in conjunction with the immunoblot method to demonstrate antigenic differences between rat and mouse erythrocytes.
Burnet's "forbidden clone" theory would predict that in patients with Graves' disease the pathogenic thyroid-stimulating autoantibody (TSab)-secreting clones arise by somatic mutation. Because each lymphocyte and its progeny are permanently committed to producing antibodies of a single light chain type, a clone arising by somatic mutation occurring in a single cell would be expected to produce autoantibodies of exclusively kappa or exclusively lambda type in an individual patient. Using affinity chromatographic techniques and monoclonal antibodies, we investigated the light chain type of TSab in 11 patients with Graves' disease. In all patients tested, TSab activity was confined to a single light chain type, confirming the recent work of Zakarija who used affinity chromatography with polyclonal antisera, but contrasting with earlier studies which used immuno-precipitation methods. Furthermore, the light chain type was lambda in 10 of the 11 patients. These observations provide support for the forbidden clone theory. In addition, the marked preponderance of patients producing TSab of the lambda-light chain type indicates that TSab are more likely to arise from the lambda repertoire of clones than from the kappa repertoire and suggests that immunoglobulin light chain V genes may be genetic determinants for susceptibility to Graves' disease.
We studied the light chain type of autoantibodies to acetylcholine receptor (AChR) by affinity chromatography with monoclonal anti-kappa and anti-lambda antibodies. The autoantibodies in four of eight myasthenic patients were of a single light chain type; the others comprised both types. In Graves' disease and cold-reactive hemolytic anemia, the pathogenic autoantibodies are confined to a single light chain type in individual patients, and in other diseases, doubtfully pathogenic autoantibodies are invariably mixtures of both light chain types. AChR antibodies may comprise both pathogenic and nonpathogenic types of autoantibody.
A competitive fluorometric ELISA was developed which enabled pair-wise comparisons of the antigen-binding characteristics of thyroid microsomal autoantibodies (TMaab) and their antigen-binding fragments from different individuals. Antibodies rendered undetectable to the protein-A-enzyme conjugate by removal of their Fc-regions (F(ab')2's) were tested for their ability to inhibit the antigen-binding of intact thyroid microsomal autoantibodies (TMaab). Only F(ab')2's derived from TMaab-containing sera were capable of displacing TMaab, some being capable of complete displacement of allogeneic TMaab. The antigen-binding of Tgaab was unaffected, except by F(ab')2's derived from Tgaab-containing sera. The high degree of overlap observed in the specificity of TMaab suggests that different sera recognize the same epitopes. In this respect the autoimmune response to the microsomal antigen was shown to resemble that to thyroglobulin, which involves few epitopes. Cross-tolerance is postulated to be the mechanism underlying the tissue-specificity and epitope-restriction of thyroid autoantibodies.
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Some autoimmune diseases tend to cluster within families, patients with one such disease showing an increased tendency to develop certain other autoimmune diseases within the same group. We have investigated the possibility that this clustering arises because some patients produce autoantibodies which cross-react with antigenic determinants which are shared by diverse tissues. Our data indicate that this is not the case, at least so far as thyroid and gastric autoimmune diseases are concerned. This observation increases the likelihood that the real explanation for such clustering concerns sharing of idiotypic determinants by the different pathogenic clones involved or by their precursors.
Maori participation in the 1991 health care reforms is considered against the background of their involvement in health reforms since the turn of the century. Throughout this period Maori have consistently sought autonomous health care. Traditional indigenous healers have provided healing for Maori as they have for other indigenous people, such as Aborigines, Pacific Islands people and Canadian Indians. Maori, including western health care professionals, submitted that healers should be included among the health care services personnel providing core health services. They argued this on the basis of their health status and of their rights with respect to the Treaty of Waitangi. The influence of the 1977 WHO resolution, concerning the role of traditional healers in attaining 'Health for All by the Year 2000', is considered in relationship to Maori health initiatives and how the 1991 health care reforms may impact upon them, and the bicultural policy that has guided Maori health developments over the last decade. Evaluating Maori health and the health care reforms in terms of Maori participation, the status of traditional indigenous healers and the future of Maori health initiatives leaves Maori in no doubt that they have some hard work ahead to maintain the position they held prior to the reforms.