Immunologic aspects of endocrine diseases.
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Addison Disease↗
Biomedical subjects
J R Baker
Publications and source records attributed to J R Baker.
Megabacteriosis in exhibition budgerigars.
Megabacteriosis is a common cause of illness and death in exhibition budgerigars. The clinical signs are variable but include weight loss, difficulty in swallowing, vomiting, diarrhoea and sudden death due to haemorrhage. Significant lesions are confined to the proventriculus which becomes inflamed, dilated and ulcerated, and loses its normal architecture, and to the gizzard in which there are degenerative changes in the koilin layer.
Animals↗
Causes of mortality and parasites and incidental lesions in dolphins and whales from British waters.
Detailed post mortem examinations were carried out on 18 dolphins and whales found dead on the coast of the United Kingdom. The commonest causes of death were pneumonia and entanglement in fishing gear. Of the non-fatal conditions, parasitoses of various organs were common and there was a wide variety of other conditions. In total 124 diseases and other lesions were found, giving an average of 6.9 conditions per animal.
Animals↗
Causes of mortality and parasites and incidental lesions in harbour porpoises (Phocoena phocoena) from British waters.
Detailed post mortem examinations were carried out on 41 harbour porpoises (Phocoena phocoena) found dead on the coast of the United Kingdom. The commonest causes of death were entanglement in fishing gear, and parasitic and bacterial pneumonia. Among the non-fatal conditions parasitoses of various organs were common and there was a very wide variety of other conditions. In total 295 diseases and other lesions were found, an average of 7.2 per animal.
Animals↗
The pathology of phocine distemper.
The gross and microscopic pathology of phocine distemper is described. The most striking features were pulmonary congestion and emphysema associated with proliferation of type II pneumocytes, often forming syncytia. Secondary bacterial infection was common and associated with marked atrophy of lymphoid tissues and degenerative changes in the mucosa of the airways.
Animals↗
The role of bacteria in phocine distemper.
The death of many seals believed to be infected with phocine distemper virus was found to be associated with a variety of mainly opportunistic bacterial pathogens. The bacteria most frequently involved were Bordetella bronchiseptica, Corynebacterium species and a variety of Streptococci. Seals dying on different parts of the coast of Britain were infected with these organisms in differing proportions.
Animals↗
The immune response in chronic hepatitis B virus infection: the "core" of the problem?
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Chronic Disease↗
T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism.
PURPOSE: Patients with adult-onset idiopathic hypoparathyroidism (AOIH) often have antibodies against the parathyroid glands and other tissues, suggestive of immune activation. The purpose of this study was to determine whether T-cell activation is also a component of the endocrine disease. PATIENTS AND METHODS: We identified eight patients with idiopathic hypoparathyroidism diagnosed after the age of 30 years at two tertiary care centers and evaluated peripheral blood lymphocyte subset phenotype frequencies using monoclonal antibodies and flow cytometry. Control subjects were 13 patients with Graves' disease (five thyrotoxic and eight euthyroid) and 110 healthy volunteers. In two of the patients with AOIH, we also determined the mitogenic response to parathyroid cell membranes in peripheral lymphocytes. RESULTS: Patients with AOIH had higher than normal frequencies of the following phenotypes (p less than 0.05 versus controls, one-way analysis of variance): CD4, helper T cells; CD29/CD4, inducer of helper T cells; CD16 and CD56, natural killer cells; and CD3/DR, activated T cells coexpressing DR. Patients with Graves' disease had significantly higher than control frequencies of CD25 (T cells bearing the interleukin-2 receptor), CD3/DR, and CD26 (also a marker of T-cell activation); whereas the frequency of CD29/CD4 was significantly less than the control frequency. Neither of the two AOIH patients tested showed lymphocyte proliferation in response to parathyroid or thyroid cell membrane fractions. CONCLUSIONS: Generalized T-cell activation represents a novel feature associated with AOIH. Although we could not demonstrate parathyroid-specific lymphocyte clonal expansion, these data are suggestive of a generalized immune disturbance possibly related to autoimmunity, in which one of the manifestations is hypoparathyroidism.
Adult↗
Natural killer cell activity from pregnant subjects is modulated by RU 486.
Natural killer cells form an integral component of the body's innate immune system. Natural killer cell activity is reduced during pregnancy, especially in the latter half. To investigate the role progesterone may play in immunomodulating natural killer cell activity during pregnancy, we evaluated the effect of RU 486 on natural killer cells isolated from pregnant subjects. Natural killer cell activity was measured with an 18-hour, Chromium 51 release, microcytotoxicity assay with K-562 cells as target cells. We demonstrated that RU 486, in a concentration range from 5 to 40 mumol/L, augmented natural killer activity threefold to fivefold over baseline. This augmentation of activity was suppressed to baseline by the addition of excess progesterone. The addition of hydrocortisone resulted in an insignificant reduction in this augmented activity. This study suggests that progesterone may play a role as an immunomodulating factor in maternal acceptance of the fetal allograft.
Adolescent↗
Subcellular distribution of hydralazine in rat single vascular muscle cells.
High specific activity (20 Ci/mmol) tritiated hydralazine (3Hyd) distribution in isolated, cultured vascular muscle cells was determined to identify the sites of Hyd binding. 3Hyd dose-dependently bound to extracellular protein and to the area of organelles which secrete these proteins. Increased extracellular binding after Hyd pre-exposure suggests new binding sites may be exacerbated as a result of Hyd interactions. These experiments suggest a potentially important feature of the mechanism of action of this directly acting vasodilator.
Animals↗
Ex vivo gene therapy of familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by a deficiency in the receptor that clears low density lipoprotein (LDL) from the serum (reviewed in Ref. 1 and 2). Patients with one abnormal LDL receptor allele have moderate elevations in plasma LDL and suffer premature coronary artery disease (CAD). Approximately 5% of all patients under 45 who have had a myocardial infarction carry this trait. Patients with two abnormal LDL receptor genes (homozygous deficient patients) have severe hypercholesterolemia and life-threatening coronary artery disease in childhood. Strategies for treating patients with FH are directed at lowering the plasma level of LDL. In heterozygotes, this is accomplished through the administration of drugs that stimulate the expression of LDL receptor from the normal allele (2). This therapeutic approach is not effective in the treatment of homozygous deficient patients, especially those that retain less than 2% of residual LDL receptor activity. Partial amelioration of hyperlipidemia has been achieved in some homozygous deficient patients by diverting the portal circulation through a portacaval anastomosis (3) and by chronic plasmapheresis therapy (4). A more direct approach has been to correct the deficiency of hepatic LDL receptor by transplanting a liver that expresses normal levels of LDL receptor. Three patients that survived this procedure normalized their serum LDL-cholesterol (5-9). We have used an authentic animal model for FH, the Watanabe Heritable Hyperlipidemic rabbit (WHHL), to develop gene therapies for the homozygous form of FH (10-13). The WHHL rabbit has a mutation in its LDL receptor gene which renders the receptor completely dysfunctional (12) leading to severe hypercholesterolemia, diffuse atherosclerosis, and premature death. The potential efficacy of gene therapy for FH is supported by a series of studies we have performed in the WHHL rabbit in which we have achieved metabolic improvement (14-18). Liver tissue was removed from WHHL rabbits and used to isolate hepatocytes and establish primary cultures. A functional rabbit LDL receptor gene was transduced into a high proportion of hepatocytes using recombinant retroviruses, and the genetically corrected cells were transplanted into the animal from which they were derived. Transplantation of the genetically corrected, autologous hepatocytes was associated with a 30-40% decrease in serum cholesterol that persisted for the duration of the experiment (4 months, Ref. 18). Recombinant derived LDL receptor RNA was detected in liver for at least 6 months. There was no apparent immunological response to the recombinant derived LDL receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Short-term synchrony of motor unit discharge during weak isometric contraction in Parkinson's disease.
Short-term synchrony between the discharges of motor units has been assessed in Parkinson's disease (PD) and normal man. The discharges of single motor units were recorded in the extensor digitorum communis (EDC) muscle of the forearm or the tibialis anterior (TA) muscle of the leg during weak, voluntary isometric contraction. Short-term synchrony was defined as a narrow peak (total width less than 25 ms) in cross-correlograms constructed from the discharges of pairs of motor units. There was no difference in the incidence of short-term synchrony between PD and normal age-matched subjects for either the EDC or TA muscle. On average, 60% of pairs of motor units exhibited synchrony, but this varied between 0% and 100% for both groups. The amount of short-term synchrony was assessed as the probability (above chance) of discharge of one motor unit with respect to the other. In TA, but not EDC, this index was greater for PD than for normal subjects. The high indices of synchrony in TA in PD were not related to lower discharge rates of motor units. Parkinson's disease subjects, but not normal subjects, also showed broad correlations that were invariably associated with periodic discharges in the range 4-6 Hz. In some instances, a peak of short-term synchrony was observed superimposed on the broad correlation. The periodic correlograms were often associated with overt tremor which accompanied the contraction. Motor units occasionally discharged paired impulses (doublet discharges) with short interspike intervals of 5-15 ms (normal and PD) or, as a more persistent feature in PD, longer interspike doublets (20-60 ms) associated with periodic synchrony (4-6 Hz). The abnormal discharge characteristics of motor units are discussed in relation to the bulbospinal control of presynaptic drive to motor neurons in PD.
Adult↗
Magnetic resonance imaging mapping of brain function. Human visual cortex.
Magnetic resonance imaging (MRI) studies of human brain activity are described. Task-induced changes in brain cognitive state were measured using high-speed MRI techniques sensitive to changes in cerebral blood volume (CBV), blood flow (CBF), and blood oxygenation. These techniques were used to generate the first functional MRI maps of human task activation, by using a visual stimulus paradigm. The methodology of MRI brain mapping and results from the investigation of the functional organization and frequency response of human primary visual cortex (V1) are presented.
Brain Mapping↗
Identification of localized autoantibody epitopes in thyroid peroxidase.
Recent reports have disagreed on the nature of the autoantibody epitopes in thyroid peroxidase (TPO). We used immunoprecipitation of recombinant human TPO constructs to determine if localized autoantibody binding sites exist in this autoantigen. In vitro transcription and translation of TPO cDNA fragments yielded 35S-labeled products consisting of either full-length protein (933 amino acids) or N-terminal peptides of 631, 455, and 120 amino acids. Immunoprecipitates analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed that the Hashimoto's sera consistently precipitated the full-length and the 631 amino acid products, but not the shorter N-terminal peptides. An additional construct resulting in a full-length TPO peptide with an internal deletion of amino acids 4-455 was also made, and this product was also precipitated by the Hashimoto's sera. A fusion protein consisting of maltose binding protein followed by amino acids 456-933 of human TPO was produced in Escherichia coli and subjected to Western blot analysis using the Hashimoto's sera. The Hashimoto's sera reacted with the MalTose binding protein TPO (MBP/TPO) fusion protein, but not a control fusion protein (MBP/LacZ alpha). Together, these results indicate the presence of localized autoantibody epitopes in the portion of the human TPO molecule from amino acids 456 to 933, with at least one binding site located between amino acids 456 and 631.
Autoantibodies↗
Immunoreactivity to Yersinia enterocolitica antigens in patients with autoimmune thyroid disease.
Recent reports have suggested that Yersinia enterocolitica proteins encoded by a 72-kilobase virulence plasmid (known as release proteins and now identified as YOP2-5) are antigens recognized specifically by patients with Graves' disease and of potential etiological importance in this disorder. To examine this hypothesis, we evaluated immune responses to YOP in patients with autoimmune thyroid disease and in normal controls. Humoral responses to Yersinia were assessed using Western blots of crude Y. enterocolitica membrane proteins, Yersinia release proteins (YOP2-5), and human thyrocyte membranes. Twenty-four of 25 Graves' and 10 of 18 Hashimoto's patients showed reactivity with the release proteins, primarily the 67-, 46-, 36-, and 25-kilodalton bands. However, 17 of 24 normal subjects also demonstrated serological reactivity to the release proteins, and the pattern of reactivity of these sera was similar to that in the thyroid patients. No correlation was noted between serological reactivity to the release proteins and thyroid hormone levels. Patients and controls with serological reactivity to YOP also showed reactivity with Yersinia membranes. In addition to the serological studies, cellular immune responses were determined by peripheral blood mononuclear cell proliferation assays. Cellular reactivity to the release proteins was present in four of five Graves' and both Hashimoto's patients tested, but also in two of six nonthyroid illness patients with serological immunity to the release proteins. Intrathyroidal lymphocytes obtained from two Graves' patients demonstrated marked proliferation in response to the release proteins. These results indicate that there is no unique pattern of serological reactivity against Yersinia membranes or the release proteins in patients with autoimmune thyroid diseases and suggest that any causal relationship between Yersinia infection and Graves' disease may be related to T-cell immunity.
Antibodies, Bacterial↗
Analysis of human TSH receptor gene and RNA transcripts in patients with thyroid disorders.
Human TSH receptor (hTSH-R) gene and RNA transcripts were analyzed by Southern and Northern blots in patients with various thyroid disorders, and in tissue cell lines. A 1.4 Kb cDNA encoding the extracellular human TSH-R domain was used as a probe. Southern analysis revealed two constant bands of 11.0 and 5.0 Kb (hTSH-R) in the thyroid and human white cell samples studied, regardless of the disease process. Northern analysis showed a predominant band at about 4.4 Kb in the thyroid tissues but not in non-thyroid tissue or cell lines tested. There were no gene rearrangements or abnormal transcripts in Graves' disease or multinodular goiter samples. In contrast, the labelled cDNA TSH-R probe did not bind to RNA isolated from 1 of 2 papillary cancer samples. A portion of the unique area of the h-TSH receptor (approximately nucleotides 1100-1230) was directly sequenced in thyroid glands from patients with Graves' disease, multinodular goiter, and differentiated thyroid cancer. No mutations or polymorphisms were identified in these samples, as compared to normal thyroid or control placenta, although further definition of sequence variation in other areas of the TSH receptor, as well as in more samples, needs to be performed. The present study indicates the normal patterns of DNA and RNA hybridization in a variety of thyroid tissues and disease states, and demonstrates that pathologic thyroid samples, with the possible exception of thyroid cancer, were not associated with specific nucleotide abnormalities in the unique area of the TSH receptor that was studied.
Adult↗
Generalized approach to inverse problems in tomography: image reconstruction for spatially variant systems using natural pixels.
A major limitation in tomographic inverse problems is inadequate computation speed, which frequently impedes the application of engineering ideas and principles in medical science more than in the physical and engineering sciences. Medical problems are computationally taxing because a minimum description of the system often involves 5 dimensions (3 space, 1 energy, 1 time), with the range of each space coordinate requiring up to 512 samples. The computational tasks for this problem can be simply expressed by posing the problem as one in which the tomograph system response function is spatially invariant, and the noise is additive and Gaussian. Under these assumptions, a number of reconstruction methods have been implemented with generally satisfactory results for general medical imaging purposes. However, if the system response function of the tomograph is assumed more realistically to be spatially variant and the noise to be Poisson, the computational problem becomes much more difficult. Some of the algorithms being studied to compensate for position-dependent resolution and statistical fluctuations in the data acquisition process, when expressed in canonical form, are not practical for clinical applications because the number of computations necessary exceeds the capabilities of high-performance computer systems currently available. Reconstruction methods based on natural pixels, specifically orthonormal natural pixels, preserve symmetries in the data acquisition process. Fast implementations of orthonormal natural pixel algorithms can achieve orders of magnitude speedup relative to general implementations. Thus, specialized thought in algorithm development can lead to more significant increases in performance than can be achieved through hardware improvements alone.
Algorithms↗
Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits.
Familial hypercholesterolemia (FH) is an inherited disorder in humans that is caused by a deficiency of low density lipoprotein receptors (LDLRs). An animal model for FH, the Watanabe Heritable Hyperlipidemic rabbit, was used to develop an approach for liver-directed gene therapy based on transplantation of autologous hepatocytes that were genetically corrected ex vivo with recombinant retroviruses. Animals transplanted with LDLR-transduced autologous hepatocytes demonstrated a 30 to 50 percent decrease in total serum cholesterol that persisted for the duration of the experiment (122 days). Recombinant-derived LDLR RNA was harvested from tissues with no diminution for up to 6.5 months after transplantation.
Animals↗