Effects of zinc-fortified drinking skim milk (as functional food) on cytokine release and thymic hormone activity in very old persons: a pilot study.

Zinc is a relevant nutritional factor for the whole life of an organism because it affects the inflammatory/immune response and antioxidant activity, leading to a healthy state. Despite its important function, the dietary intake of zinc is inadequate in elderly. Possible interventions include food fortification because it does not require changes in dietary patterns, the cost is low and it can reach a large portion of the elderly population, including very old subjects. Studies evaluating the impact of Zn-fortified foods on functional parameters in elderly, in particular, in very old individuals, are missing. The objective of this study was to evaluate the efficacy of consumption of a zinc-fortified drinking skim milk (Zn-FMilk) for a period of 2 months in comparison to standard non-fortified milk (No-FMilk) on some biochemical parameters, zinc status, inflammatory/immune response and on a key parameter of the T cell-mediated immunity (thymulin hormone) in healthy very old subjects. The treatment with zinc-fortified milk (Zn-FMilk) is a good omen to increase the cell-mediated immunity in very old age represented by thymulin activity and some cytokine (IL-12p70, IFN-γ) release. At clinical level, a good healthy state occurs in 70 % of the subjects with no hospitalization after 1 year of the follow-up in comparison to very old control subjects that did not participate to crossover design. In conclusion, the Zn-FMilk can be considered a good functional food for elderly, including older people. It might be a good replacement to the zinc tablets or lozenges taking into account the attitude of old people to uptake milk as a preferential food.

Antigen-induced changes in the endocrine function of the thymus in CBA mice during aging: role of peptide factors released by the pineal gland.

The titer of thymic serum factor was measured in adult and old CBA females 15, 30, and 60 min, 24, 48, 72, and 96 h after injection of 3% suspension of sheep erythrocytes and changes of this parameter under the effect of epithalamin were studied in old immunized mice. The titer of thymic serum factor increased appreciably in adult mice virtually at all periods of the study after immunization (a drop was observed only 72 h after immunization). In old mice the titer of thymic serum factor virtually did not change after injection of sheep erythrocytes, while immunization of old mice preinjected with epithalamin significantly increased this parameter. Not only the values, but their dynamics in old mice injected with epithalamin corresponded to those in immunized adult animals.

The effects of dietary vitamin E and selenium deficiencies on plasma thyroid and thymic hormone concentrations in the chicken.

Beginning at hatching, male Cornell K strain single comb white leghorn chickens were fed a basal diet, with or without vitamin E (100 IU/kg) and/or selenium (Se, 0.2 ppm). After 3 weeks of treatment, animals fed either the Se-deficient or basal diet had significantly reduced plasma Se-dependent glutathione peroxidase activities when compared to those fed a vitamin E and Se-supplemented diet. Similarly, animals fed the vitamin E-deficient or basal diet had significantly reduced plasma alpha-tocopherol levels. The effect of these treatments on plasma concentrations of thyroid hormones (T(3)/T(4)), growth hormone (GH), and thymic hormone (thymulin) was determined using radioimmunoassay and ELISA. A deficiency in Se, but not in vitamin E, resulted in an increase in plasma T(4) concentrations while plasma T(3) concentrations were decreased. Plasma GH levels showed some fluctuation as a result of the dietary treatments but there was no significant correlation between plasma GH levels and any of the other variables. A significant decrease in plasma thymulin levels was observed in Se-deficient birds compared to those receiving adequate Se in the diet. A vitamin E deficiency had no measurable effect on plasma thymulin levels. From these studies, we conclude that plasma thymulin concentrations directly correlate with plasma T(3) concentrations which are negatively affected by a Se deficiency.

[Endocrine function of the thymus and ionizing radiation]. / Endokrinnaia funktsiia timusa i ioniziruiushchaia radiatsiia.

It is shown that external as well as incorporated radiation inhibit the endocrine function of the thymus in the result of the direct and indirect effects. Postradiation deficiency of thymic hormones plays a significant role in pathogenesis of functional disorders in the immunity system. Immunocorrection with thymic agents is the most effective method when the mechanism of inhibition of thymic hormonal function are taken into account.

[Serum levels of thymus hormones and autoantibodies to the thymus epithelium in inhabitants of regions contaminated with radionuclides]. / Soderzhanie gormonov timusa i autoantitel k épiteliiu timusa v syvorotke krovi zhitelei raionov, zagriaznennykh radionuklidami.

Increased level of serum thymic activity and normal serum concentration of alpha-1-thymosin were revealed in inhabitants of region polluted by radionuclides after Chernobyl accident (settlement Vyshkov, Bryansk region). In the same population the serum level of autoantibodies, reacting with thymic epithelial cell line was elevated. Similar but less prominent alterations were found in population of radiologically pure region (settlement Potchep). Revealed autoantibodies had mainly IgM isotype. The negative correlation exists between levels of autoantibodies and serum thymic activity. Sera of persons from the control group and one half of Vyshkov inhabitants reacted with thymic epithelial cells of both human and mouse origin; in other half of Vyshkov inhabitants species-specific autoantibodies were revealed. We propose that correlated increase of antithymic autoantibody level and decrease of serum thymic activity are the consequence and indicators of unfavorable ecological conditions; however the contribution of radiation factor to their induction can not be estimated on the basis of presented data.

Zinc supplementation restores plasma concentrations of zinc and thymulin in patients with Crohn's disease.

The aim of this work was to evaluate whether oral supplementation with zinc sulphate (ZnSO4) could restore thymic endocrine function in patients with Crohn's disease who showed decreased plasma concentrations of zinc and active thymulin, a zinc-dependent thymic hormone. Twenty-seven patients in clinical remission were randomly assigned to receive, for 3 months, one of the following treatments: 60 mg/day ZnSO4; 200 mg/day ZnSO4 or placebo. Plasma thymulin activity and zinc concentrations significantly increased only in patients treated with 200 mg/day ZnSO4. Lymphocyte subpopulations, within the range of normality before zinc supplementation, were unaffected by any of the administered treatments. In conclusion, low plasma concentrations of zinc and thymulin in Crohn's disease patients were restored by the administration of high doses of zinc.

Late T cell deficiency in victims of the Chernobyl radiation accident: possible mechanisms of induction.

T cell number, serum concentrations of thymic hormones and anti-epithelial autoantibodies were studied in people affected at Chernobyl NPP. Group 1 took part in the clearing-up operation and had no clinical manifestations of acute radiation sickness. Group 2 worked at the NPP during the accident; they survived acute radiation sickness (degree I-II, subgroup 2a; degree III-IV, subgroup 2b). The total doses of external radiation were 0.1-0.5 Gy in group 1, up to 4 Gy in subgroup 2a and up to 9 Gy in subgroup 2b. Total T cell number, serum thymic activity and alpha 1-thymosin concentration were decreased in all groups of affected persons. CD8+ cell number decreased only in group 1; CD4+ cell number in subgroup 2b. A decrease in thymic hormone level was most prominent in subgroup 2b. The titres of anti-epithelial antibodies were increased in all groups of affected persons independently of radiation dose. The titres were higher in patients with subnormal levels of alpha 1-thymosin. It has been proposed that radiation alters the function of thymic epithelial cells by direct action and/or through indirect mechanisms including participation of autoantibodies. The observed complex of alterations is similar to that in the normal process of immunological ageing.

Malignant thymoma associated with T-cell lymphocytosis. A case report with immunophenotypic and gene rearrangement analysis.

Patients with malignant thymoma rarely may also have a peripheral T-cell lymphocytosis. "Lymphocyte spillover" from the thymus into the peripheral blood as well as a second, associated neoplasm (ie, T-cell chronic lymphocytic leukemia) are two hypotheses that have been proposed to explain this clinical phenomenon. We describe another patient with a lymphocyte-rich malignant thymoma associated with peripheral T-cell lymphocytosis. At the time of initial diagnosis, the patient's complete blood cell count was unremarkable. However, subsequent to the development of pulmonary metastases, the patient developed persistent lymphocytosis. The total leukocyte count ranged from 20 to 30 x 10(9)/L, 80% of these cells being lymphocytes. Immunophenotypic analysis of peripheral blood specimens from this patient proved that the circulating cells were mature, polyclonal T cells. The cells expressed the alpha/beta T-cell receptor and the pan-T-cell antigens CD2, CD3, CD5, and CD7, and were negative for both terminal deoxynucleotidyl transferase (TdT) and the CD1 antigen. A mixture of T-helper (CD4+) and T-suppressor (CD8+) cells were present in a ratio of 1:1.6. Gene rearrangement studies revealed that the T-cell receptor beta chain and the immunoglobulin heavy-chain genes were in the germline configuration. Serum samples from this patient were also analyzed for thymic hormones; the level of thymosin alpha 1 was markedly elevated, while that of thymosin beta 4 was decreased. These results effectively exclude the hypothesis that the lymphocytosis represents a second, associated neoplasm. The lymphocyte spillover hypothesis also seems unlikely (although not excluded), since the lymphocytes in lymphocyte-rich thymomas usually have an immature thymic cortical immunophenotype. Furthermore, one might expect nonspecific elevation of all thymic hormone levels with lymphocyte spillover. Thus, we suggest that the lymphocytosis results from a poorly defined immunoregulatory disorder, related to the presence of thymoma, and perhaps secondary thymic hormone imbalance.

[Changes in the neuroendocrine and immune state of adaptational homeostasis in normal pregnancy]. / Izmeneniia v neiroéndokrinnom i immunnom zveníakh adaptatsionnogo gomeostata pri fiziologicheski protekaiushchei beremennosti.

43 women with physiologically proceeding pregnancy have been examined during 1st, 2nd and 3d terms. The control group consists of 28 practically healthy non-pregnant women. It is stated that during pregnancy essential changes in the function of endocrine glands of mother take place. the appearance of placenta, a new gland of internal secretion, producing choriogonadotropin (CG) as well as the great amount of other hormones of the steroid and protein nature causes essential changes in the regulatory mechanisms underlying the physiological activity of internal secretion glands in mother. The development and early functioning of the internal secretion glands of a fetus promote the hormonal shifts. With the pregnancy development the number of estrogen increases hundred times, relative to their production in non-pregnant women secretion of progesterone and prolactin increase ten times. The functional activity of anterior lobe of the hypophysis, manifesting itself in hypersecretion of adrenocorticotropic hormone inhibition of follicule-stimulating hormone production changes as well. Changes in the functional state of the adrenal gland cortex: cortisole secretion is high are found.

Zinc and thymic hormone-dependent immunity in normal ageing and in patients with senile dementia of the Alzheimer type.

Plasma zinc levels were measured in young controls, aged controls, patients with dementia of the Alzheimer type and patients with non-Alzheimer type dementia. Zinc levels decreased with age; however, no difference was found between patients with dementia and age-matched controls. Plasma levels of active or inactive thymulin, a nonapeptide produced and released by the thymus gland, were also determined in young controls, aged controls, patients with dementia of the Alzheimer type and patients with non-Alzheimer type dementia. Basal levels of active thymulin were decreased in aged controls and in patients with dementia. In vitro reactivation of thymulin after zinc addition to plasma samples was decreased in aged controls. A further impairment of thymulin reactivation was present in patients with dementia. A significant age-dependent decrease in lymphocyte proliferation after mitogen stimulation was found; however, no difference was present between aged controls and patients with dementia of the Alzheimer type. Interleukin-2-induced cell activation and its effect on mitogen-induced proliferation were also measured; once again only an age-associated decrease was found. The endocrine function of the thymus of patients with dementia appears to be more compromised than that from aged controls.

Changes in circulating levels of neuroendocrine and thymic hormones during aging in rats: a correlation study.

It is well established that during early life the thymus gland and the neuroendocrine system influence each other's maturation. Furthermore, there is a growing body of evidence indicating that the immune and neuroendocrine systems also function as a bidirectional network during adult life. In order to assess possible changes in the thymic-neuroendocrine network during aging, we undertook to measure and correlate the circulating levels of several neuroendocrine and thymic hormones in young (3 month) and old (26 month) male Sprague-Dawley rats. Sequential plasma samples were obtained from chronically cannulated, nonstressed animals every 30 min for 5 h. Two days later rats were killed between 11:30 a.m. and 1:30 p.m. and trunk serum was obtained. All hormones were measured by radioimmunoassay. Growth hormone (GH), prolactin (PRL), thyrotropin (TSH) and corticosterone were measured in plasma, whereas thyroxine (T4), triiodothyronine (T3), thymosin alpha 1 (T alpha 1) and thymosin beta 4 (T beta 4) were determined in trunk serum. The circulating levels of T3, PRL, corticosterone and T beta 4 did not show significant differences between young and old rats, whereas GH, T4, T alpha 1, and thymus weight showed a significant age-related reduction. The anterior pituitary (AP) weight and plasma TSH were significantly higher in old than in young rats. Three pairs of parameters showed highly significant levels of linear correlation: AP weight vs. T alpha 1; thymus weight vs. T4 and T alpha 1 vs. T4 (p less than 0.01, p less than 0.001 and p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of low thymic hormone levels in cancer patients by lysine-arginine combination.

Thymic hormones are required for maturation and maintenance of the immune efficiency. It has been previously demonstrated that with advancing age there occurs a progressive reduction of the plasma level of one of the best known thymic peptides, i.e. thymulin, and that the administration of an amino acid combination (lysine-arginine, as present in the commercial preparation Lysargin, Baldacci, Italy) to elderly individuals is able to increase the synthesis and/or release of thymulin to values comparable to those recorded in young subjects. In the present paper we report evidence that cancer patients show much lower thymulin values than those recorded in healthy age-matched individuals and that the oral administration of the amino acid preparation is able to significantly increase thymulin levels even over the values of age-matched controls and to increase the number of peripheral T-cell subsets. It is suggested that such an effect is mediated through the known secretagogue activity of the amino acids on the pituitary release of growth hormone, which has a modulating effect on the thymic endocrine activity.

[The pathogenesis of congenital thymus hyperplasia in children with immune defects]. / Zur Pathogenese der angeborenen Thymushyperplasie (ATH) bei Kindern mit Immundefekten.

Complex clinical and morphological studies were conducted into conditions of the thymus as well as of the lymphatic and neuro-endocrine systems in stillbirths and children up to five years of age. Thymic hormones in blood and thymic tissue were determined, as well. CTH, in most of these cases, was found to reflect dysfunction of the hypothalamic-hypophyseal system which eventually resulted in development of polyglandular endocrinopathy and congenital immune deficiency, primarily in the T-system. CTH has proved quite often to be associated with congenital malformations.

[Blood thymus hormone content in different types of neoplastic process and its changes as a result of chemotherapy and surgical removal of tumors]. / Soderzhanie gormonov timusa v krovi pri razlichnykh tipakh opukholevogo protsessa i ego izmenenie v rezul'tate khimioterapii i khirurgicheskogo udaleniia opukholi.

Levels of thymic hormones in blood serum were found to decrease during the development of Guerin's carcinoma, methylcholanthrene- and DMBA-induced carcinogenesis, soft tissue sarcomas, mammary cancer, in children with tumors of the urinary-genital tract, that evidences for the suppression of the thymic endocrine function in neoplastic processes. A decrease in the level of substances, active in the test under study is not revealed in patients with different forms of leukemias. The tumour elimination normalizes the thymic endocrine function, while multiagent chemotherapy increases the insufficiency. The data obtained suggest the immunotherapy for malignant neoplasms with thymic hormones.

Effect of oral zinc administration on prolactin and thymulin circulating levels in patients with chronic renal failure.

High serum PRL and low zinc (Zn) levels are common findings in patients with chronic renal failure (CRF); in such patients serum Zn concentrations have been reported to be inversely correlated to serum PRL levels. Moreover, Zn regulates both thymus growth and the biological activity of the thymic hormone thymulin, and PRL-thymic interrelationships have been described. To determine whether hypozincemia alters serum PRL and plasma thymulin concentrations in CRF, 9 men with CRF treated by chronic hemodialysis were given 400 mg/day Zn sulfate, orally (4.96 meq/day Zn), for 6 months. Before treatment, serum PRL levels were significantly higher (P less than 0.001) in these patients than in normal men [mean, 28.7 +/- 20.7 (+/-SD) vs. 7.5 +/- 3.7 micrograms/L], and their serum PRL response to TRH (200 micrograms, iv) was impaired (mean maximal percent increase, 38.2 +/- 10.9 vs. 641 +/- 335; P less than 0.001). The plasma Zn-bound bioactive thymulin titer (1.3 +/- 0.7 1/log2), total thymulin titer (Zn-bound plus Zn-unbound forms, 2.1 +/- 0.8 1/log2), and serum Zn (13.1 +/- 2.4 mumol/L) were lower (P less than 0.001) in men with CRF than in normal men. Zn therapy did not induce any significant change in basal and TRH-stimulated serum PRL levels, while serum Zn levels significantly increased, reaching the normal range after the first week of treatment (17.8 +/- 6.3 mumol/L). Plasma total thymulin increased rapidly, reaching normal levels after 1 week, but Zn-bound thymulin increased modestly during the first month of treatment and more after 3 and 6 months of treatment. There was no age-related difference in plasma thymulin levels during therapy. We conclude that oral Zn administration in patients with CRF significantly increases both total and Zn-bound thymulin, but does not modify basal and TRH-stimulated serum PRL levels. The observation that Zn supplementation markedly increased plasma thymulin levels in uremic patients suggests that Zn is a potent stimulus for thymic hormone synthesis, and it can reverse the age-related diminution of thymic activity in CRF patients.

Degradation of thymopentin by human lymphocytes: evidence for aminopeptidase activity.

Thymopentin (Arg-Lys-Asp-Val-Tyr) was shown to be degraded in vitro by human lymphocytes into two main fragments; the tetrapeptide Lys-Asp-Val-Tyr and the tripeptide Asp-Val-Tyr. Degradation products were identified by HPLC and amino-acid analysis. Analysis of the time-course of degradation revealed a 'stepwise' degradative event beginning at the N-terminal. The degradation of thymopentin after the first 10 min, as well as the formation of the tetrapeptide (5-30 min) were essentially curvilinear. Degradation of the tripeptide, was linear. Upon screening a panel of compounds that inhibit enzymatic activity, bestatin, amastatin and 1,10-phenanthroline were shown to be the most effective. Bestatin and amastatin caused an 85-90% inhibition of thymopentin degrading activity with IC50 values of 7.1 x 10(-6) M and 4.5 x 10(-9) M, respectively. 1,10-Phenanthroline completely inhibited the degradative process with an IC50 of 2 x 10(-4) M. When the tetrapeptide Lys-Asp-Val-Tyr was used as the starting substrate, similar IC50 values were seen for amastatin, bestatin and 1,10-phenanthroline. The importance of divalent metal ions in the degradative event was demonstrated not only by the effect of 1,10-phenanthroline, but also by the ability of Zn2+ and Co2+ to reverse the inhibition of 1,10-phenanthroline (at its IC50) to activities near control values (no inhibitor). These data strongly suggest that an aminopeptidase(s) is responsible for the degradative activity.

Involution of thymic epithelium and low serum thymulin bioactivity in weanling mice subjected to severe food intake restriction or severe protein deficiency.

The volume of epithelium in the cortex and in the medulla of the thymus was compared in four groups of weanling male and female CBA/J mice. Well-nourished controls (C), food intake restricted (R), and animals given a low-protein diet ad libitum (LP) were fed from 23 to 37 days of age. Baseline controls (B) were studied at 23 days of age. Epithelial volume fraction was estimated for each group by point-counting morphometry on electron micrographs. Other mice were used to obtain group mean estimates of thymic index (mg/g live weight) and volume fraction of cortex and medulla (light microscope-level point-counting morphometry). Cortical and medullary epithelial volumes were calculated for each animal examined by electron microscopy by obtaining the live weight and applying, in sequence, the group mean thymic index, an assumed thymic density of 1.0 mm3/mg, the group mean cortical or medullary volume fraction, and the measured cortical or medullary volume fraction for that animal. Serum thymulin bioactivity was also measured in C, R, and LP mice. The results reveal thymic epithelial involution in the two most common rodent models of malnutrition, and suggest that this may contribute to the low serum thymulin levels found in malnourished experimental animals and humans.

Thymulin (Zn-FTS) activity in protein-energy malnutrition: new evidence for interaction between malnutrition and infection on thymic function.

The combined effects of protein-energy malnutrition (PEM) and infection on thymic function evaluated by specific plasma thymulin activity were studied in Senegalese children: 29 hospitalized in Dakar for severe malnutrition and various diseases; 9 infected without sign of severe PEM, living in Dakar; 13 apparently healthy, uninfected, living in Dakar; and 7 apparently healthy, uninfected, living in Paris. Most of the free-living children in Dakar suffered from mild to moderate PEM. The specific thymulin activity (total plasma activity minus the activity recorded after adsorption of the plasma with a monoclonal antithymulin antibody) was almost undetectable in the infected children and was normal only in the children living in Paris. Such activity might be decreased by moderate and severe PEM and severe malnutrition may not be the only underlying cause of depressed level of thymulin in malnourished children from the Third World. Concurrent infections are important factors.