[Optimization of modern conservative therapy of micropenis in hypogonadal men].

The study was aimed to the optimization of conservative therapy of micropenis in hypogonadal men using combination of traction therapy and androgen replacment therapy (ART) with injections of prolonged testosterone undecanoate (Nebido) and to evaluatiom of the safety of ART in terms of the risk of prostate cancer against the background of combined treatment of micropenis by both methods within 12 months. The study included 16 men aged 22-62 years with micropenis and hypogonadism. 10 men were diagnosed with primary hypogonadism, 6 men were diagnosed with secondary hypogonadism without reserve gonadal function; therefore, all 16 patients were treated with testosterone undecanoate 1000 mg intramuscularly according to the scheme: the second injection 6 weeks after the first injection, then each injection once a 12 weeks, the course of 12 months. During the first 3 months of ART, hypogonadism in all men was eliminated, but only at 6 month of ART, the length of the penis in the flaccid state at maximum extension increased from 5.8±1.2 to 8.3±1.2 cm (p<0.05), and the length of the erect penis - from 6.8±1.1 to 11.8±0.9 (p<0,05). At the next stage, from the 6th to the 12th month of ART, traction therapy was simultaneously carried out. At the end of the treatment, the length of the penis in the flaccid state at maximum extension increased by 58% of the original length, and in a state of erection - by 114% (p<0.05). During the 12 months of treatment, prostate volume in all men increased from 3.4±1.2 to 16.3±1.2 (p<0.05), which corresponds to the size of the prostate in healthy men. Total blood PSA level increased from 0.72±0.03 to 1.4±0.05 ng/ml (p<0.05), but it was in the acceptable range of reference values for healthy men during whole period of ART in all patients. Start therapy with prolonged testosterone undecanoate for 6 months significantly increases the efficiency of traction therapy in men with hypogonadism and micropenis, but for maintenance of the effect, ART should be continued during all period of treatment.

[Human cellular immunity and space flights]. / Kletochnyi immunitet cheloveka i kosmicheskii polet.

Results of studying cellular immunity of crew members of long-term space missions, data of an experiment with extended head-down tilting of human subjects (HDT), and data obtained in the course of adapting immunologic test methods for the use in microgravity are summarized. Disorders in immunologic reactivity were shown to occur under the conditions of space flight. They included decreases in both quantitative and functional indices of cellular immunity, and emergence of signs of sensibilization to different allergens. The modified tests were evaluated by efficacy of determination of the proliferative activity of lymphocytes in minimal volumes of capillary blood inside one-piece syringes with a medium containing PHA and the Cytodex-1 suspension, evaluation of natural cytotoxicity on the level of an effector cell (number of peripheral blood lymphocytes capable of producing conjugates with fixed target cells). Sensibilization to allergens of normal human microflora was tested in analogs of routine hematocrit capillaries used for examination of healthy donors under ordinary rest-work regimen. No significant differences between the standard and modified tests were revealed. The proposed test modifications are quite simple in use and require minimum of equipment.

[The possibility of performing artificial selection in vivo for a change in the mutability level in populations of mouse bone marrow stem cells]. / O vozmozhnosti provedeniia iskusstvennogo otbora in vivo na izmenenie urovnia mutabil'nosti v populiatsiiakh stvolovykh kostnomozgovykh kletok myshei.

Bone marrow cells of CBA males were transplanted to irradiated syngeneic females and after 13 days the mean frequency of blood erythrocytes with micronuclei, cloning efficiency of haemopoietic stem cells (HSC), and variability range of frequency of cells with micronuclei in spleen colonies were studied in 44 primary recipients. A wide range of variability has been shown for the indicators of mutability and cloning efficiency (0.1-1.8% for frequency of erythrocytes with micronuclei, 200-300-1500 for cloning efficiency, 0.1-0.5% for frequency of cells with micronuclei in spleen colonies of individual transplants). A weak negative correlation between the frequency of erythrocytes with micronuclei and the cloning efficiency was observed. We conclude that the difference in frequency of erythrocytes with micronuclei between HSC subpopulations is sufficiently high to carry out an artificial selection for high and low mutability in the course of transplantations. The cloning efficiency can be increased when spleen colonies are studied by micronuclear analysis. Data on the importance of such a selection in studying the behavior of "mutability" and "cloning efficiency" characters, immortalization, "aging", and death of HSC populations of CBA mice have been reported.

[Immune resistance of humans during extended isolation]. / Immunologicheskaia rezistentnost' cheloveka pri dlitel'noi izoliatsii.

Analyzed were parameters of the immune reactivity and allergological status of participants in the 135-day chamber experiment with periods of induced psychoemotional strain. Stressful situations gave rise to shifts in the antibody system, i.e. decreased blood levels of ImgA, ImgM, and ImgG, decline in the functional activity of T-lymphocytes, suppression of the cytokinetic activity of lymphocytes-natural killers, and sensibilization to various allergens. Totality of these shifts resembles the ones which are typically seen during initial readaptation to the Earth's conditions on after long-term space mission.

Effect of space flight on cytokine production and other immunologic parameters of rhesus monkeys.

During a recent flight of a Russian satellite (Cosmos #2229), initial experiments examining the effects of space flight on immunologic responses of rhesus monkeys were performed to gain insight into the effect of space flight on resistance to infection. Experiments were performed on tissue samples taken from the monkeys before and immediately after flight. Additional samples were obtained approximately 1 month after flight for a postflight restraint study. Two types of experiments were carried out throughout this study. The first experiment determined the ability of leukocytes to produce interleukin-1 and to express interleukin-2 receptors. The second experiment examined the responsiveness of rhesus bone marrow cells to recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Human reagents that cross-reacted with monkey tissue were utilized for the bulk of the studies. Results from both studies indicated that there were changes in immunologic function attributable to space flight. Interleukin-1 production and the expression of interleukin-2 receptors was decreased after space flight. Bone marrow cells from flight monkeys showed a significant decrease in their response to GM-CSF compared with the response of bone marrow cells from nonflight control monkeys. These results suggest that the rhesus monkey may be a useful surrogate for humans in future studies that examine the effect of space flight on immune response, particularly when conditions do not readily permit human study.

Natural killer cells after ALTAIR mission.

Reduced in vitro NK cytotoxic activity have routinely been observed after both prolonged and short-term space flights. This study investigated the effects of space flight on NK cell functions, NK cell counts and the production of IL-2 and TNF by lymphocytes of French-Russian crew members. In the French cosmonaut, after 21 days space flight, the cytotoxic activity of NK cells, the capacity the NK cells to bind and lyse the individual target cells and the percentage of NK cells were decreased. In this cosmonaut a twofold reduction TNF production in cultures of lymphocytes stimulated with PMA and with the mixture of PHA and PMA was observed on the first day after landing. However, the activity of the production of TNF in 48-hour PHA-cultures of lymphocytes was unchanged and the biological activity of IL-2 was not reduced. The immunological examination did not detect any substantial deviations from the norm in both russian cosmonauts after 197 days space flight. Various explanations for decreased cytotoxicity in cosmonauts after space flight can be proposed, and these include the defective function of NK cells and reduced numbers of circulating effector cells.

Immune changes during long-duration missions.

Immune changes during space flights in excess of two weeks have been almost exclusively studied by Russian investigators. Most of these studies have compared postflight values with those obtained before flight. In a very few cases, analyses have also been attempted during flight or with samples collected during flight. Studies of cosmonauts during spaceflight have shown that IgG levels were unchanged, whereas IgA and IgM levels were sometimes increased. Additionally, inflight delayed type hypersensitivity testing demonstrated a decrease below the warning level in 1/3 of the cosmonauts tested. Pre- vs. postflight analyses have often revealed a postflight decrease in: PHA-triggered lymphocyte blast transformation; the proliferation index of T-lymphocytes in the xenogeneic graft versus host reaction; the mitogen-induced production of interleukin-2; the presence of certain leukocyte sub sets; and cytotoxic activity of natural killer cells. Other factors that either did not change, or changed in an apparently random manner after flight included: production of alpha and gamma interferon; autoimmune tests; and globulin classes.

Effect of spaceflight on lymphocyte proliferation and interleukin-2 production.

Studies of peripheral blood lymphocytes from astronauts indicate that microgravity depresses T-cell responsiveness. However, this effect has not been examined in cells of peripheral lymphatic tissue, where most lymphocytes are located. In this study, inguinal lymph node lymphocytes from rats flown on the COSMOS 2044 mission were tested for proliferation and interleukin-2 (IL-2) production. Cells cultured with mitogenic lectins, phorbol ester, and calcium ionophore, or T-cell mitogen and lymphokine, were assayed for DNA synthesis by [3H]thymidine incorporation. Lymphocytes incubated with a T-cell mitogen alone also were tested for IL-2 production. Proliferation of lymphocytes from flight rats was not significantly different from controls for any of the mitogens tested. Furthermore, lymph node lymphocytes from flight rats was not significantly different from controls for any of the mitogens tested. Furthermore, lymph node lymphocytes from control and flown rats produced similar amounts of IL-2. Thus microgravity may act on lymphocytes in a tissue-specific manner, a new finding that could impact on the evaluation of spaceflight effects on immunocompetence.

Spaceflight alters immune cell function and distribution.

Experiments were carried out aboard COSMOS 2044 to determine the effects of spaceflight on immunologically important cell function and distribution. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. In one experiment, rat bone marrow cells were examined in Moscow, for their response to recombinant murine granulocyte/monocyte colony-stimulating factor (GM-CSF). In another experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States for analysis on a flow cytometer. Bone marrow cells from flown and suspended rats showed a decreased response to granulocyte/monocyte colony-stimulating factor compared with bone marrow cells from control rats. Of the spleen cell subpopulations examined from flown rats, only those cells expressing markers for suppressor-cytotoxic T- and helper T-cells showed an increased percentage of stained cells. Bone marrow cells showed an increase in the percentage of cells expressing markers for helper T-cells in the myelogenous population and increased percentages of anti-asialo granulocyte/monocyte-1-bearing interleukin-2 receptor-bearing pan T- and helper T-cells in the lymphocytic population. Cell populations from rats suspended antiorthostatically did not follow the same pattern of distribution of leukocytes as cell populations for flown rats. The results from COSMOS 2044 are similar, but not identical, to earlier results from COSMOS 1887 and confirm that spaceflight can have profound effects on immune system components and activities.

Effect of spaceflight on natural killer cell activity.

The effects of spaceflight on immune cell function were determined in rats flown on COSMOS 2044. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. The ability of natural killer cells to lyse two different target cell lines was determined. Spleen and bone marrow cells obtained from flight rats showed significantly inhibited cytotoxicity for YAC-1 target cells compared with cells from synchronous control rats. This could have been due to exposure of the rats to microgravity. Antiorthostatic suspension did not affect the level of cytotoxicity from spleen cells of suspended rats for YAC-1 cells. On the other hand, cells from rats flown in space showed no significant differences from vivarium and synchronous control rats in cytotoxicity for K-562 target cells. Binding of natural killer cells to K-562 target cells was unaffected by spaceflight. Antiorthostatic suspension resulted in higher levels of cytotoxicity from spleen cells for 51Cr-labeled K-562 cells. The results indicate differential effects of spaceflight on function of natural killer cells. This shows that spaceflight has selective effects on the immune response.

Immune resistance of man in space flights.

The immune system of 72 cosmonauts was studied after their flights on board Salyut 6, 7 and Mir orbital stations. PHA lymphocyte reactivity, T helper activity and NK capacity to recognize and kill the target were decreased on 1-7 days after prolonged (3-11 months) space flights. Certain alterations were found in the ultrastructure of the NK secretory and locomotor apparatuses. Decrement of IL 2 production was shown using the biological test. However immunoenzymatic analysis did not reveal a decrease in IL 2 synthesis. Production of a alpha-interferon remained unchanged while that of gamma-interferon either rose or was diminished. Several cosmonauts displayed a trend towards increased OAF production. The observed decrease in immune system functioning may increase the risk of various diseases during prolonged space flights.

Effects of spaceflight on levels and activity of immune cells.

Experiments were carried out on cells from rats that had been flown on Soviet Biosputnik Cosmos 1887 to explore the effects of spaceflight on immune responses. Rat bone marrow cells were examined for their response to colony stimulating factor-M. Rat spleen and bone marrow cells were stained with antibodies directed against cell surface antigenic markers. The results of the studies indicate that bone marrow cells from flown rats showed a decreased response to colony stimulating factor. There was a higher percentage of spleen cells from flown rats staining positively for pan-T-cell, suppressor-T-cell and interleukin-2 receptor cell surface antigens. A small increase in the percentage of cells staining positively for helper-T-cell antigens was also noted. In addition, a higher percentage of cells that appeared to be part of the myelogenous population of bone marrow cells from flown rats stained positively for surface immunoglobulin.

[Immunologic mechanisms of regulating calcium metabolism in human bone tissue (production of osteoclast-activating factor) during long-term anti-orthostatic hypokinesia]. / Immunologicheskie mekhanizmy reguliatsii obmena kal'tsiia v kostnoi tkani cheloveka (produktsiia osteoklastaktiviruiushchego faktora) pri dlitel'noi antiortostaticheskoi gipokinezii.

During 370 days 10 healthy male subjects were exposed to antiorthostatic hypokinesia. The exposure enhanced the production of the osteoclast-activating factor (OAF) by blood mononuclear cells. The enhancement began after the 2nd month of hypokinesia and continued to increase thereafter. The index of resorption was: prior to hypokinesia--1.15 +/- 0.156, 8 months after onset--2.05 +/- 0.129, and 11.5 months after onset--2.37 +/- 0.296, the upper normal limit being 1.54. The changes were correlated with a greater amount of active T-lymphocytes in blood and a progressive increase of calcium negative balance. This investigation lends support to the previously formulated hypothesis (I. V. Konstantinova, 1986) that immunological mechanisms associated with the OAF production contribute to calcium metabolism disorders in human bone during prolonged space flights.

Immunocompetent cells producing humoral mediators of bone tissue mineral metabolism during space flight simulation.

During 120-day and 370 day hypokinesia the possibility has been shown of manifestation of mechanism of immunological regulation of osteoclast functions. Supernatants of mononuclear peripheral blood cells which were in vitro nitrogen-stimulated, had an increased potential for resorption in 45Ca-labelled mice fetus long bone organ cultures. Resorbing activity was increased in mononuclear supernatants from some of the subjects exposed to 120-day hypokinesia and from all subjects exposed to 370-day hypokinesia. This variable returned to base-line values after completion of the bed-rest period. Lymphocyte in vitro proliferative activity decreased at the end of hypokinesia and during the initial days of recovery, and the number of active T-rosetting cells was, on the contrary increased. This suggested a possible activation of part of immunocompetent cell population potentially producing humoral regulators of bone cell functions in vivo. A study of a group of healthy males performing their routine daily activity and of patients with local osteoporosis (paradontitis) showed significant differences between normal subjects and patients, confirming the informative value of the method used and allowed to establish approximate limits of physiological variations of the values.