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Purification and characterization of a calf thymus protein active on lipid metabolism.

1. This work concerns the purification of a calf thymus protein that increases the binding of human 125I-labeled low density lipoprotein (LDL) on both human skin fibroblasts and a special line of rat liver cells, BRL 3A. 2. It was found that the thymus gland affects cholesterol metabolism via an activation of the LDL receptor pathway. 3. Moreover, the thymus protein active on the LDL receptor pathway has a different amino acid composition and molecular weight from other well-characterized thymic peptides.

Amino Acids↗

Thymic involution in the suspended rat model for weightlessness: decreased glucocorticoid receptor concentration.

Hindlimb muscle atrophy, thymic involution and adrenal hypertrophy in rats during spaceflight can be simulated using suspension models. Skeletal muscle and thymus are sensitive to glucocorticoids (GC) and previous studies have demonstrated that muscle atrophy in suspended rats is associated with increased GC receptor concentration. The objectives were to confirm thymic involution during suspension, and determine if involution correlated with increased GC receptor concentration. Seven days of antiorthostatic (AO) suspension of rats produced a significant (P<0.001) reduction in thymic wet weight not associated with an alteration of % water content. GC receptor concentration (pmol/mg protein) decreased 20% (P<0.025) in thymus glands from 7 day AO suspended rats. Suspension, therefore, is associated with involution of the thymus but this is not dependent upon AO positioning. Thymus GC receptor concentrations were depressed in 7 day suspended rats, in contrast with previous observations on skeletal muscle, suggesting that different mechanisms may underlie these responses.

Animals↗

[Estrogen receptors in rabbit thymus].

The estrogen receptors presence or absence in the thymus gland represents the basic element to assert or to exclude any estrogenic action in the thymus. Now we have measured the presence of cytoplasmatic estrogen receptors in the female rabbits thymus, using some methods (sucrose gradient, protamine sulphate, dextran-coated charcoal). Finally, we have investigated, using the sucrose gradient assay, the nuclear ER presence in 1000g thymic pellet. The results exclude high levels of estrogen-binding proteins while don't suggest their total absence in the female rabbit thymus.

Animals↗

Tissue distribution and subcellular localization of retinol-binding protein in normal and vitamin A-deficient rats.

Levels of retinol-binding (RBP), the plasma transport protein for vitamin A, were measured by radioimmunoassay in sera and in a large number of tissues from both normal and vitamin A-deficient rats. The tissues included liver, kidney, fat, muscle, brain, eye, salivary gland, thymus, lung, heart, intestine, spleen, adrenal, testes, thyroid, and red blood cells. The RBP levels in tissues other than serum, liver, and kidneys varied from 12 mug/g of tissue for normal spleen to an undetectable level in red blood cells. Much of the RBP in the tissues with low levels may have been due to residual serum in the samples. In general, except for liver, RBP levels were lower in tissues from vitamin A-deficient rats than in those from normal rats. In normal rats, the liver, kidney, and serum levels were 30 plus or minus 4 (mean plus orminus SEM), 151 plus or minus 22, and 44 plus or minus 3 mug/g, respectively. In vitamin A-deficient rats, the liver RBP level was about three times the normal level whereas the kidney and serum levels were about one-fifth the normal values. When normal liver homogenates were fractionated by centrifugation, 67% of the RBP was recovered in the microsomal fraction and only 9% was found in the soluble 105,000 g supernate. In contrast, 76% of the RBP in homogenates of normal kidneys was in the soluble fraction. Similar results were obtained with deficient livers and kidneys. Incubation with deoxycholate released the liver RBP into the soluble fraction. RBP is produced in the liver and removed from the blood by the kidneys. The levels of RBP in normal and deficient liver, serum, and kidney appear to reflect the relative rates of RBP secretion and turnover.

Adipose Tissue↗

[The role of immunological mechanisms in the development of the late sequelae of nuclear disasters].

Effects, both specific and non-specific, were analysed of ionizing radiation in a comparative evaluation of medical sequels of the Chernobyl disaster and of the Semipalatinsk Range nuclear test. A hypothesis is advanced assuming that development of all major bodily morbid conditions is directly related to the dysfunction of certain complex of organs, the thyroid gland in the first place, the thymus gland known to be a central organ of systemic immunogenesis. A breach in the thymus link triggers harmful cascade reactions of neuroimmunoendocrinological regulation, appeared to be responsible for the pathogenesis of practically all pathologies disclosed.

Gene Expression Regulation↗

The role of the endocrine thymus in female reproduction.

Neonatal thymectomy in mice induces ovarian disturbances, indicating some relationship between the thymus and the ovaries. The mechanism of the relationship, however, is not fully understood. One approach to elucidating the complex relationship has been to measure circulating hormone levels in thymectomized animals and those with small thymus glands, and compare these levels with those found in control animals. The data indicate that a thymus-pituitary-ovarian axis exists and that thymus disturbances may hasten the aging processes of the ovaries.

Animals↗

The effect of 5-hydroxytryptamine on the cotton pellet local inflammatory response in the rat.

The cotton pellet technique was used to evaluate the effect of 5-HT and certain related compounds on granuloma formation in the rat. 5-HT (10 mg/kg) significantly decreased granuloma formation, significantly increased adrenal weight, and significantly decreased thymus weight in normal rats, and significantly decreased granuloma formation and thymus weight in sham-operated rats. On the other hand, 5-HT (10 mg/kg) significantly increased granuloma weight in adrenalectomized rats. Methysergide (1 mg/kg) blocked the inhibitory effect of 5-HT on granuloma formation as well as the changes in weight of adrenal and thymus glands. 5-HIAA (11 mg/kg) and 5-HTP (13 mg/kg) failed to alter granuloma formation.

5-Hydroxytryptophan↗

The thymic findings in stillborns with neural tube defects.

Neural tube defects are among the most common congenital anomalies causing perinatal deaths. Other organ system anomalies may be associated with neural tube defects: for instance, various types of thymus pathology have been reported in these patients. In this study thymic changes were investigated in 30 stillborns with neural tube defects seen between January 1988 and June 1989. Thymic weights were significantly reduced in 14 cases and increased in 7. One patient had a double thymus, and in two cases no thymus tissue could be found. These findings suggest a primary developmental defect of the neural crest, affecting the orderly development of the thymus gland.

Female↗

Normal development of thymus in male and female mice requires estrogen/estrogen receptor-alpha signaling pathway.

Estrogen receptors (ERs) are expressed in the thymus of both males and females, but their role in thymic development and function is unclear. To determine whether ERalpha plays a role in thymic function of either males or females, we compared thymuses of male and female wild-type (WT) and ERalpha knockout (alphaERKO) mice from birth to adulthood. Although thymic size was similar in both male and female WT and alphaERKO mice at birth (d 0), by postnatal d 5 and at all subsequent ages, both male and female alphaERKO mice had significant (30-55%) reductions in thymic weight. Morphometric analysis revealed a reduction in thymic medullary areas in adult alphaERKO mice compared with age-matched WT controls that paralleled thymic involution. There were changes in relative percentages of CD4+ and CD4+CD8+ T-cells, and large decreases (70-80%) in overall absolute numbers of CD4+ and CD4+CD8+ T-cells. Serum corticosterone and testosterone levels were not different in either neonatal or adult male WT or alphaERKO mice, and serum levels of 17beta-estradiol (E2) were similar in neonatal WT and alphaERKO males, indicating that increases in these thymolytic hormones are not responsible for the decreased thymic weight in alphaERKO males. Additionally, delayed-type hypersensitivity was significantly increased in male alphaERKO mice compared with WT mice. In summary, ERalpha deficiency does not inhibit initial differentiation or fetal thymic development, but the absence of ERalpha results in marked decreases in thymic size in both sexes during the postnatal period. These results are the first direct demonstration that the E2/ERalpha signaling system is necessary for maintenance of normal postnatal function of the female thymus gland. The similar results obtained in males demonstrate a role for the E2/ERalpha signaling system in the male thymus and emphasize that estrogens play a more critical role in the male than previously realized.

Animals↗

Myocardial infarction in young vs old male rats: pathophysiologic changes.

Young (90 days) and old (15 months) male, Sprague-Dawley rats were subjected to an acute and massive myocardial infarct by giving them two injections of a large dose of isoproterenol. The animals were autopsied at sequential time intervals to ascertain the similarities or dissimilarities in the pathophysiologic events which attend acute myocardial infarction and repair in young vs old rats. Although the signs and severity of hypotensive shock appeared to be equal, mortality was higher in the old rats, especially during the acute necrosis phase. The older rats also manifested more severe and persistent congestive heart failure, i.e., hydrothorax. Serum enzymes (CPK, SGOT, SGPT, and LDH), lipids (triglycerides, free fatty acids, and cholesterol), glucose, and BUN levels manifested a dynamic rise and fall concomitant with the induced myocardial necrosis and repair phases with distinct differences in these metabolic changes between young and old rats. Despite initially higher circulating levels of corticosterone in the old vs young rats, the older animals manifested little or no increase in circulating corticosterone levels during the acute stress of myocardial infarction. This apparent lack of adrenocortical responsiveness was accentuated by the concomitant finding of greatly hypertrophied, hemorrhagic, and lipid-depleted adrenal glands in the old rats vs a dynamic increase in circulating corticosterone levels and alterations in the weight of adrenal and thymus glands of the young rats. During the myocardial repair phase, the young rats manifested extensive endocardial fibrosis whereas the old rats displayed little or no endocardial fibrosis but copous and persistent myocardial edema and ground substance in keeping with their higher concentration of cardiac hexosamine. The pathophysiologic course of events which attends myocardial necrosis and repair is quite different in young vs old rats and may be related to the degree of responsiveness of the pituitary-adrenal axis which changes with age.

Adrenal Glands↗

Effects of patulin on thymus capillary of rats.

Patulin is a mycotoxin that is produced by species of Penicillum, Aspergillus, and Byssochylamys molds that may grow on a variety of foods including fruit, grains and cheese. Patulin, at a dose of 0.1 mg kg(-1) bw day(-1) was administered orally to growing male rats aged 5-6 weeks for a period of 60 or 90 days. The dose of patulin used in the present study was based on estimated human exposure levels. At the end of these periods, the thymus glands of patulin-treated and control Wistar rats were removed and ultrastructural changes in capillary cells of the thymus of patulin-treated Wistar rats were determined by electron microscopy. The walls of thymus capillaries of the 60-day patulin-treated rat groups (P-60) exhibited degeneration observable in electron microscopic sections. For example, loss of cytoplasm and mitochondrial cristae of cells, swollen endothelial cells, increased thickness of the basement membrane, closed lumen of capillaries, accumulation of fibrous material at the periphery of the capillaries and nuclear anomalies were seen in these sections. Such degeneration and changes were also observed in sections of capillaries of the 90-day patulin-treated rat groups (P-90). The levels of degeneration of endothelial cell nucleus of P-90 were greater than those of P-60. This study demonstrated the ultrastructural degeneration of thymus capillary cells of patulin-treated rats. The results obtained from this study may provide a guide to research dealing with the toxic effects of patulin on tissue and organ ultrastructure.

Administration, Oral↗

Ultrastructural changes in the adult rat thymus after estradiol benzoate treatment.

Although numerous authors have correlated high levels of circulating estrogens with thymic involution, a systematic analysis to date on the histological changes affecting the thymus gland in that situation is lacking. In the present study we report both histological and ultrastructural changes occurring in the thymus of adult Wistar rats which received a single dose either of 100 micrograms or 500 micrograms of estradiol benzoate. Both doses induced thymic involution which correlated well with histological changes observed in the lymphoid populations but also with profound modifications in the thymic epithelial component. Moreover, intrathymic erythro-and granulopoiesis, increased numbers of both macrophages and plasma cells, and important variations in the thymic vascular permeability occurred in estradiol benzoate treated rats. These results are discussed from the perspective that changes in both the non-lymphoid cell components of thymic microenvironments and vascular permeability are essential to understand the general effects of sex steroids on the immune system.

Animals↗

Pineal influence on intermale aggression in adult house mice.

Previously isolated, adult male mice of a wild-derived strain were sham-operated or pinealectomized (pinx) and 14 days later were paired for 15 min, then grouped three per cage for 7 days. During 15 min pairings, mean latency to initiation of fighting was increased twofold and duration of fighting was reduced 35 to 41 percent in pairs comprised of one or both pinx animals. Although pinealectomy failed to influence which pair member initiated fighting, sham males were ranked as dominant in 75 percent of sham-pinx pairs. Pinealectomy reduced adrenal gland weights among isolated animals and increased in general the effects of social subordination in grouped males. Compared to sham subordinates, pinx subordinates experienced adrenal enlargment and twofold greater wounding and had lighter thymus glands and final body weights. Additionally, however, pinealectomy prevented atrophy of seminal vesicles among subordinates. Thus, present results suggest a role of the pineal gland in influencing intermale aggression and linking social stimuli with testis dysfunction in adult house mice.

Adrenal Glands↗

The differentiation of T lymphocytes. Density characterisation of thymic and peripheral T cells responding in syngeneic and allogenic mixed lymphocyte reactions.

Equilibrium density separation on continuous albumin gradients was used to separate and characterise the T cells responding by proliferation to both syngeneic and allogeneic stimulating cells in the one-way mixed leucocyte reactions (MLR). In CBA mouse spleen both light and dense T cells were capable of responding in an allogeneic MLR. No T cells responding to stimulation be syngeneic B lymphocytes could be isolated from adult or 7-day CBA mouse spleen. In adult CBA mouse thymus, cells responding to allogeneic stimuli were enriched in the light density region, along with the low theta subpopulation. Self-reactive cells, responding with proliferation when cultured with syngeneic adult CBA splenic lymphocytes, and found in adult and 4-day CBA mouse thymus, were also enriched in the light density zones. However, in adult thymus syngeneic MLR reactivity was also found in the dense zones, and the density distribution profiles of total syngeneic MLR responding cells revealed a series of peaks extending over the whole density range. It was suggested that these syngeneic MLR responders undergo a complete maturation process, including progressive density increases, within the thymus gland. Such a sterile differentiation pathway could be a censorship process, leading to death of self-reactive cells within the thymus.

Animals↗

Rat mutant (NZNU) showing "nude" characteristics.

A new rat mutant (nznu) is described which shows characteristics similar to those of the nude mouse. The mutant is an autosomal recessive. Homozygotes are essentially hairless (except for stunted vibriassae) and show deficient thymus gland development. Under conventional breeding conditions the mutants are difficult to raise and few survive weaning. The absence of functional thymus-derived lymphocytes in the nude rat is implied by (1) acceptance of histoincompatible skin grafts, (2) lack of response to the T cell mitogens phytohaemagglutinin and concanvalin A, and (3) absence of cells sensitive to alloantiserum directed against rat thymus-derived lymphocytes. Although total blood leukocytes from the nude rat were within the normal range, differential counting of leukocytes showed a 4-fold elevation of neutrophils and a 2.5-fold reduction of lymphocytes, compared with normal rats. Phenotypically normal heterozygotes gave values intermediate between nude and normal rats.

Animals↗

B-lymphocyte colony-forming cells in the SJL/J mouse thymus graft repopulation: independence on host thymus and graft genotype.

We have studied the development of B-lymphocyte colony-forming cells (BL-CFC) in SJL and A.SW mouse thymus grafts transplanted into lethally irradiated A.SW mice protected with SJL mouse bone marrow (A.SW-SJL bone marrow chimaeras). The chimaeric state was confirmed by Ly allotype analysis. High incidence of BL-CJC was found in both the A.SW and the SJL thymus grafts, indicating that SJL bone marrow generates BL-CFC, or cells capable of generating BL-CFC, with a high affinity for homing in the thymus irrespective of the genotype of the thymus reticulum. The incidence of BL-CFC in the SJL thymus grafts, however, was approximately 20 times higher than the incidence of BK-CFC in the A.SW thymus grafts. Thus, the extensive infiltration of ageing SJL thymus glands by BL-CFC demonstrated recently is caused not only by SJL bone marrow B cells with a high affinity for thymus homing but also by the specific property of the SJL thymus environment. The extensive infiltration of syngeneic thymus grafts by BL-CFC observed in ageing SJL mice was found to occur independent of an intact host thymus function, indicating the extrathymic origin of these cells.

Animals↗

Autosensitization of lymphocytes against thymus reticulum cells.

Lymph nodes of normal rats contain lymphocytes that can be induced in vitro to mediate a specific cellular immune reaction against reticulum cells derived from syngeneic adult thymus glands. It is likely that these lymphocytes had access to reticulum cell antigens during the period in which they developed immunocompetence within the thymus. This suggests that contact with self-antigens during development may not eliminate self-reactive lymphocytes. These findings are in conflict with the theory that natural tolerance to self-antigens depends upon elimination of lymphocyte clones.

Animals↗