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Isolated sarcoidosis of the hypothalamic-pituitary system is a very rare form of neurosarcoidosis. A high index of suspicion is required for diagnosis and the choice of therapy embodies another challenge due to lack of standardized protocols. Glucocorticoids are the mainstay of initial treatment, whereas the second and third-line therapy include immunomodulators and cytotoxic drugs, in addition to monoclonal antibodies. This report presents an unusual case of panhypopituitarism in a 32-year-old previously healthy male patient due to isolated hypothalamo-pituitary sarcoidosis confirmed histologically, refractory to pulse-dose glucocorticoids and then successfully treated by methotrexate. Based on our report, in patients requiring additional therapy usage of the methotrexate as the second line agent should be considered, however the time frame and the dosing schedule of methotrexate are still unknown and deserve further investigation.

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Some modifications of the simple asexual Penna model, enriched by epigenetic contributions, are presented. The standard bit-string Penna model of biological aging and population evolution is based on an inherited DNA structure which defines the future life of a newly born individuals, when genes are activated by the biological clock, and the predefined genetic death is fully controlled by the number of defected genes. Epigenomes allow to introduce additional mechanism of gene activation or silencing without affecting the DNA genome itself. It may be either inherited or may reflect external, environmental factors. In the presented model, information read from the introduced epigenome may alter gene expression that may be stopped or re-activated. We concentrate on the influence of epigenetics on the age a distribution of genetic mortality m(a). Changes in m(a) are strong for the case of inherited epigenetic contribution with nearly perfect inheritance and 'positive' epigenome that partly ignores the 'bad' mutations. We conclude that the epigenetic contribution may influence population structure m(a) and could be, at least partly, responsible for deviation of m(a) distribution from the Gompertz law. In short, we claim that proposed epigenetic contribution may be seen as a candidate for possible explanation of observed deviation from the Gompertz law, also among senior members of society. A very simple model was used in this paper and many crucial mechanisms of biological aging were omitted. Therefore, further work based on a more realistic models is necessary.

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In this paper we present Green function technique applied to calculations of spin-spin correlations in systems governed by Ising Hamiltonian. This offers approximate yet reasonably accurate analytical results, as an alternative approach to direct computer simulation. Local spin operators are represented in terms of particle operators for fermions. Chain of Green functions for local magnetization on given site involves nearest neighbors and it is decoupled at the next-nearest-neighbors level. Therefore, still accounts at the lowest level for magnetic correlations between nearest neighbors. This technique was applied to binary alloy A x B 1-x with given atomic short range order. Calculations for stoichiometric x=1/2 composition show how temperature dependence of magnetization and spin-spin correlations are modified when atomic order parameter changes. We scanned this parameter from the case of ordered binary alloy, via random alloy, to clusterlike structure. In model calculations we (a) confirm characteristic λ -like shape of the magnetic specific heat near Curie temperature and (b) recover essential results of exact, two-dimensional Ising model. This supports our claim of usefulness of such analytical approach, which is easy and flexible to describe different geometries (clusters, thin films) and conditions imposed on spins located on specific atoms (spins partly pinned on the surface atoms).

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In this paper we present results of numerical calculation of the Penna bit-string model of biological aging, modified for the case of a -dependent mutation rate m(a), where a is the parent's age. The mutation rate m(a) is the probability per bit of an extra bad mutation introduced in offspring inherited genome. We assume that m(a) increases with age a. As compared with the reference case of the standard Penna model based on a constant mutation rate m , the dynamics of the population growth shows distinct changes in age distribution of the population. Here we concentrate on mortality q(a), a fraction of items eliminated from the population when we go from age (a) to (a+1) in simulated transition from time (t) to next time (t+1). The experimentally observed q(a) dependence essentially follows the Gompertz exponential law for a above the minimum reproduction age. Deviation from the Gompertz law is however observed for the very old items, close to the maximal age. This effect may also result from an increase in mutation rate m with age a discussed in this paper. The numerical calculations are based on analytical solution of the Penna model, presented in a series of papers by Coe et al. [J. B. Coe, Y. Mao, and M. E. Cates, Phys. Rev. Lett. 89, 288103 (2002)]. Results of the numerical calculations are supported by the data obtained from computer simulation based on the solution by Coe et al.

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Brain histamine plays a regulatory role in feeding behaviour, acting as an inhibitory modulator. Portocaval anastomosis (PCA) is associated with cerebral aminergic systems alterations, including high histamine accumulation and release from neurons. Despite that, the rats with PCA eat significantly more, their body mass being lower than sham-operated animals. To disclose underlying regulatory mechanisms, food intake was measured before and after treatment with antagonists of histamine H(1) and H(2), orexin type 1 (OX(1)) and cannabinoid type 1 (CB(1)) receptors in adult male Lewis rats 6 months following the end-to-side PCA or sham operation. Hypothalamic concentrations of orexin A and histamine as well as serum concentrations of leptin, insulin and cholecystokinin (CCK) were analysed. PCA rats with body mass lower by 30%, have consumed more feed and water 150% and 200%, respectively. The modifying effects of pyrilamine, ranitidine, SB 334867 and rimonabant were less pronounced in PCA compared with sham-operated rats. Hypothalamic orexin A and histamine concentrations were higher in PCA rats than in the control group with intact portocaval system. In PCA rats, serum concentrations of CCK were higher, leptin concentrations lower, while there were no differences between the groups in insulin levels. In conclusion, the adaptive mechanisms efficiently render PCA rats less sensitive to peripheral and central anorexigenic signals. Orexin A appears to be involved in the counteracting mechanisms preventing further body mass loss in PCA rats.

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There are some analytical solutions of the Penna model of biological aging; here, we discuss the approach by Coe et al. (Phys. Rev. Lett. 89, 288103, 2002), based on the concept of self-consistent solution of a master equation representing the Penna model. The equation describes transition of the population distribution at time t to next time step (t + 1). For the steady state, the population n(a, l, t) at age a and for given genome length l becomes time-independent. In this paper we discuss the stability of the analytical solution at various ranges of the model parameters--the birth rate b or mutation rate m. The map for the transition from n(a, l, t) to the next time step population distribution n(a + 1, l, t + 1) is constructed. Then the fix point (the steady state solution) brings recovery of Coe et al. results. From the analysis of the stability matrix, the Lyapunov coefficients, indicative of the stability of the solutions, are extracted. The results lead to phase diagram of the stable solutions in the space of model parameters (b, m, h), where h is the hunt rate. With increasing birth rate b, we observe critical b (0) below which population is extinct, followed by non-zero stable single solution. Further increase in b leads to typical series of bifurcations with the cycle doubling until the chaos is reached at some b (c). Limiting cases such as those leading to the logistic model are also discussed.

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Allograft ischemia and cellular degradation accompanying rejection favor graft colonization by translocated microorganisms. Bacterial colonization adds to the graft destruction. The dendritic cells (DC) of allograft recipients engage in allogeneic and antibacterial reactions; they process and present to lymphocytes 2 types of antigens. This may lead to overstimulation of DCs that may nonspecifically intensify the rejection process. We investigated the effects of allogeneic and bacterial antigens on splenic DCs phenotypes. In vitro stimulation of a spleen DC-enriched population by E. coli, LPS, and CpG DNA brought about an increase in expression of OX6(+) (MHC class II) from 47.4% in the control cells to 65% in the E. coli-stimulated group (P < .05) and 85% in the LPS and CpGDNA groups (P < .05). Interestingly, a significant drop in the frequency of OX62(+) DC was observed after incubation with LPS. Allogeneic heart transplants brought about an increase of OX6(+) in DCs to 100% and a decrease of ED1(+) monocyte frequency. Simultaneously, an increase in expression of W3/13(+) T cells in DC-enriched splenic cells was observed. There was no significant change in the frequency of OX62(+) expression. Both types of antigens evoked splenic DC response; however, there were differences in the frequency of phenotype expression. Allogeneic but not bacterial antigens increased W3/13 antigen expression; the frequency of OX62(+) in cells decreased after LPS but not after bacterial stimulation.

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Experimental studies on allogeneic transplantation have shown that recipient dendritic cells (DC) play a role in peripheral tolerance as well as in rejection of allografts. It is not known whether DCs exert their tolerogenic function in the graft or in recipient lymphoid tissue. To answer this question we created a chimeric heart model deprived of its own DCs and repopulated with recipient DCs. The rationale for this model was to observe whether recipient mature and immature DCs located in the graft attenuate recruitment and stimulation of recipient lymphocytes, subsequently prolonging graft survival. Vascularized bone marrow transplants from the prospective recipient to the lethally irradiated heart donor, which function for a period of 14 days, were used to replace donor DCs with prospective recipient either mature or immature DCs. Replacement of the donor heart with either of these cells did not prolong graft survival. The intragraft microchimerism did not mitigate the allogeneic rejection reaction.

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Warm and cold ischemia as well as rejection of the transplanted organ or tissue cause destructive changes in the graft parenchyma. Fragments of disintegrated cellular organelles are phagocytized and digested by recipient scavenger cells in lymph nodes, spleen, and liver. Some fragments engulfed by dendritic cells are processed including donor DNA present in the ingested cellular debris. The question arises as to whether the DNA from the disintegrated cells may be used as a measure of graft damage. In this study we provide evidence that both syngeneic and allogeneic organ transplantation followed by "seeding" of donor DNA from graft cells is internalized in recipient macrophages and dendritic cells in lymphoid organs. The kinetics of accumulation of donor DNA in recipient tissues reflected the degree of ischemic and immune graft damage. Immunosuppression with cyclosporine or tacrolimus did not significantly attenuate the DNA release. Measurements of the concentration of donor DNA gives insight into the kinetics of allograft rejection. Real-time polymerase chain reaction for donor DNA in recipient serum and blood leukocytes that have engulfed donor cell debris may be useful for clinical diagnostic application.

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Microchimerism after allogeneic organ transplantation has been widely documented using DNA identification techniques. However, the question as to whether the detected donor DNA is present in the surviving donor passenger cells, recipient macrophages phagocytizing rejected donor cells, or dendritic cells (DC) internalizing donor apoptotic bodies or cell fragments has not been answered. We provide evidence that allogeneic organ transplantation is followed not only by cellular microchimerism caused by release of graft passenger cells but also dissemination of donor DNA from the ischemic rejecting graft cells and its internalization in recipient DC. The high levels of donor DNA at the time of heart rejection were inversely proportional to the concentration of donor passenger cells detected with use of flow cytometry. Depending on the type of graft, the kinetics of DNA distribution in recipient tissues were different. Immunosuppressive drugs attenuated the rejection reaction and release of DNA from grafts. Allogeneic but not syngeneic donor DNA fragments were found in recipient splenic DC-enriched population. Interestingly, that donor DNA fragments could be detected in recipient tissue at high levels on day 30. This challenges the notion that fragments of DNA are immediately cleaved by cell plasmatic enzymes. The biologic significance of our findings is not clear. We speculate that donor DNA fragments in recipient DC may play a, so far unknown, role in the immunization/tolerance process to allogeneic antigens.

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Experimental studies on allogeneic transplantation have shown that recipient dendritic cells (DC) play a role in peripheral tolerance as well as in rejection of allografts. It is not known whether DC exert their tolerogenic function in recipient lymphoid tissue, and whether they process shed alloantigen in the graft itself. To answer this question we created a chimeric heart model deprived of its own DC and repopulated by recipient DC. The rationale for this model was to observe whether recipient DC located in the graft attenuate recruitment and stimulation of recipient lymphocytes, subsequently prolonging graft survival. Vascularized bone marrow transplants (VBMTx) from the prospective recipient to the lethally irradiated heart donor, which function for a period of 14 days, were used to replace donor DC with prospective recipient DC. Hearts from chimeric LEW rats (with BN DC) were transplanted to untreated BN rats. Also, hearts from chimeric LEW rats (with BN DC) were returned to untreated LEW rats. Replacement of the donor heart with recipient DC did not prolong graft survival. Rather, it initiated a rejection reaction that was already present in the donor. Recipient DC retained their immunogenic properties also when the graft was returned back to a donor strain animal.

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The dendritic cells (DC) of an allograft recipients become engaged not only in an allogeneic but also antibacterial reaction. They react to the alloantigens and microorganisms which colonize the rejecting grafts. This leads to overstimulation of DCs what may non-specifically intensity the rejection process. We investigated the effects of allogeneic and bacterial antigens on splenic DCs phenotypes. In vitro stimulation of spleen DC-enriched population by E. coli, LPS and CpG DNA brought about an increase in expression of OX6 (MHC class II) from 47.4% in the control population to 65% in the E. coli stimulated group (p < 0.05) and to 85% in the LPS and CpGDNA groups (p < 0.05). Interestingly, a significant drop in the frequency of OX62+ antigen was observed after incubation with LPS. Allogeneic heart transplants brought about an increase of OX6+ (MHC class II) DCs to 100% and a decrease of EDI+ cells. Simultaneously, an increase in expression of W3/13 on DC-enriched splenic cells was observed. There was no significant change in the frequency of OX62+ expression in conclusion, both bacterial and alloantigens strongly activate splenic DCs what may add to the intensity of the rejection process.

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Rejecting tissue and organ grafts shed cellular debris from damaged cells. Cellular debris contains fragments of nuclei with their genetic material. The question arises what is the fate of donor DNA in recipient fluids and tissues. Is it enzymatically disintegrated and becomes a waste product or it is utilized by recipient cells. We have shown, using sex-mismatched transplants and the Sry-gene fragment PCR detection method, that at the time of rejection recipient tissue contain donor DNA. The concentration of donor DNA did not parallel the concentration of live donor passenger cells. There were differences in donor DNA concentration depending on whether heart, skin or BMC were transplanted. Moreover, there was more donor DNA in recipient tissues than in control syngeneic transplants. Interestingly, a relatively high donor DNA concentration was detected in syngeneic recipients reflecting the extent of non-immune pre-transplantation ischemic damage of the graft.

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Cyclosporin A (CsA) changes the distribution of the circulating pool of lymphocytes and decreases their traffic to organ allograft. The mechanism of this process is complex and includes, among others, inhibition of induction of nuclear factor of activated T cells and suppression of GM CSF and E-selectin expression. We studied the expression adhesion molecules CD11a, CD18, CD44, CD54 and CD62L on the thoracic duct lymphocytes of rats treated with CsA. The 7-day administration of CsA evidently decreased the expression of CD62L but did not affect the other adhesion molecules. Lower concentration of CD62L molecules on the surface of circulating lymphocytes may influence their migration to allograft and distribution in host lymphoid tissues.

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