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Sample records for late phase immunity

  1. Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae

    PubMed Central

    Smith, Ryan C.; Barillas-Mury, Carolina; Jacobs-Lorena, Marcelo

    2015-01-01

    Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNFα transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete-to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of a wound-healing response. LL3 silencing abrogates the ability of mosquito hemocytes to differentiate and respond to parasite infection, implicating hemocytes as critical modulators of the late-phase immune response. PMID:26080400

  2. Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae.

    PubMed

    Smith, Ryan C; Barillas-Mury, Carolina; Jacobs-Lorena, Marcelo

    2015-06-30

    Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNFα transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete-to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of a wound-healing response. LL3 silencing abrogates the ability of mosquito hemocytes to differentiate and respond to parasite infection, implicating hemocytes as critical modulators of the late-phase immune response. PMID:26080400

  3. The STAT pathway mediates late phase immunity against Plasmodium in the mosquito Anopheles gambiae

    PubMed Central

    Gupta, Lalita; Molina-Cruz, Alvaro; Kumar, Sanjeev; Rodrigues, Janneth; Dixit, Rajnikant; Zamora, Rodolfo E.; Barillas-Mury, Carolina

    2009-01-01

    The STAT family of transcription factors activate expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late phase anti-plasmodial response that reduces oocyst survival in An. gambiae. PMID:19454353

  4. The STAT pathway mediates late-phase immunity against Plasmodium in the mosquito Anopheles gambiae.

    PubMed

    Gupta, Lalita; Molina-Cruz, Alvaro; Kumar, Sanjeev; Rodrigues, Janneth; Dixit, Rajnikant; Zamora, Rodolfo E; Barillas-Mury, Carolina

    2009-05-01

    The STAT family of transcription factors activates expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late-phase antiplasmodial response that reduces oocyst survival in A. gambiae. PMID:19454353

  5. Inhibitory effect of hot-water extract of quince (Cydonia oblonga) on immunoglobulin E-dependent late-phase immune reactions of mast cells.

    PubMed

    Kawahara, Takeshi; Iizuka, Tatsuhiro

    2011-03-01

    We evaluated the effect of a crude hot-water extract (HW) of quince (Cydonia oblonga Miller) fruit on immunoglobulin E (IgE)-dependent late-phase immune reactions of mast cells using in vitro system. Mast cell-like RBL-2H3 cells were treated with quince HW and late-phase reaction was then induced by stimulation with IgE + Antigen. Quince HW reduced the elevation of interleukin-13 and tumor necrosis factor-α expression level. Furthermore, quince HW suppressed these cytokine expressions of mouse bone marrow-derived mast cells (BMMCs), a normal mast cell model. Leukotriene C(4) and prostaglandin D(2) production in BMMCs after 1 and 6 h of stimulation, respectively, were also reduced by treating the cells with quince HW. We found that the induction of intracellular cyclooxygenase (COX)-2 expression but not COX-1 expression in BMMCs was reduced by quince HW. These results suggest that quince HW has an inhibitory effect on broad range of the late-phase immune reactions of mast cells. PMID:21264509

  6. Late-time cosmological phase transitions

    NASA Technical Reports Server (NTRS)

    Schramm, David N.

    1991-01-01

    It is shown that the potential galaxy formation and large scale structure problems of objects existing at high redshifts (Z approx. greater than 5), structures existing on scales of 100 M pc as well as velocity flows on such scales, and minimal microwave anisotropies ((Delta)T/T) (approx. less than 10(exp -5)) can be solved if the seeds needed to generate structure form in a vacuum phase transition after decoupling. It is argued that the basic physics of such a phase transition is no more exotic than that utilized in the more traditional GUT scale phase transitions, and that, just as in the GUT case, significant random Gaussian fluctuations and/or topological defects can form. Scale lengths of approx. 100 M pc for large scale structure as well as approx. 1 M pc for galaxy formation occur naturally. Possible support for new physics that might be associated with such a late-time transition comes from the preliminary results of the SAGE solar neutrino experiment, implying neutrino flavor mixing with values similar to those required for a late-time transition. It is also noted that a see-saw model for the neutrino masses might also imply a tau neutrino mass that is an ideal hot dark matter candidate. However, in general either hot or cold dark matter can be consistent with a late-time transition.

  7. Late-time cosmological phase transitions

    SciTech Connect

    Schramm, D.N. Fermi National Accelerator Lab., Batavia, IL )

    1990-11-01

    It is shown that the potential galaxy formation and large-scale structure problems of objects existing at high redshifts (Z {approx gt} 5), structures existing on scales of 100M pc as well as velocity flows on such scales, and minimal microwave anisotropies ({Delta}T/T) {approx lt} 10{sup {minus}5} can be solved if the seeds needed to generate structure form in a vacuum phase transition after decoupling. It is argued that the basic physics of such a phase transition is no more exotic than that utilized in the more traditional GUT scale phase transitions, and that, just as in the GUT case, significant random gaussian fluctuations and/or topological defects can form. Scale lengths of {approximately}100M pc for large-scale structure as well as {approximately}1 M pc for galaxy formation occur naturally. Possible support for new physics that might be associated with such a late-time transition comes from the preliminary results of the SAGE solar neutrino experiment, implying neutrino flavor mixing with values similar to those required for a late-time transition. It is also noted that a see-saw model for the neutrino masses might also imply a tau neutrino mass that is an ideal hot dark matter candidate. However, in general either hot or cold dark matter can be consistent with a late-time transition. 47 refs., 2 figs.

  8. Extended evaluation of a Phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late stage colorectal cancer

    PubMed Central

    Balint, Joseph P.; Gabitzsch, Elizabeth S.; Rice, Adrian; Latchman, Yvette; Xu, Younong; Messerschmidt, Gerald L.; Chaudhry, Arvind; Morse, Michael A.; Jones, Frank R.

    2015-01-01

    A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T-regulatory (Treg) to T-effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMC), and determination of HLA-A2 status. An overall survival of 20% (median survival of 11 months) was observed during long-term follow-up and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA) specific CMI activity decreased from their peak values during follow-up in 5 patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed and samples from 3 of 5 patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations. PMID:25956394

  9. Phase-dependent immune evasion of herpesviruses.

    PubMed

    Vider-Shalit, Tal; Fishbain, Vered; Raffaeli, Shai; Louzoun, Yoram

    2007-09-01

    Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development

  10. SDO Sees Late Phase in Solar Flares

    NASA Video Gallery

    On May 5, 2010, shortly after the Solar Dynamics Observatory (SDO) began normal operation, the sun erupted with numerous coronal loops and flares. Many of these showed a previously unseen "late pha...

  11. Cytokine expression during early and late phase of acute Puumala hantavirus infection

    PubMed Central

    2011-01-01

    Background Hantaviruses of the family Bunyaviridae are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. An immune-mediated pathogenesis is discussed for both syndromes. The aim of our study was to investigate cytokine expression during the course of acute Puumala hantavirus infection. Results We retrospectively studied 64 patients hospitalised with acute Puumala hantavirus infection in 2010 during a hantavirus epidemic in Germany. Hantavirus infection was confirmed by positive anti-hantavirus IgG/IgM. Cytokine expression of IL-2, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF-α and TGF-β1 was analysed by ELISA during the early and late phase of acute hantavirus infection (average 6 and 12 days after onset of symptoms, respectively). A detailed description of the demographic and clinical presentation of severe hantavirus infection requiring hospitalization during the 2010 hantavirus epidemic in Germany is given. Acute hantavirus infection was characterized by significantly elevated levels of IL-2, IL-6, IL-8, TGF-β1 and TNF-α in both early and late phase compared to healthy controls. From early to late phase of disease, IL-6, IL-10 and TNF-α significantly decreased whereas TGF-β1 levels increased. Disease severity characterized by elevated creatinine and low platelet counts was correlated with high pro-inflammatory IL-6 and TNF-α but low immunosuppressive TGF-β1 levels and vice versa . Conclusion High expression of cytokines activating T-lymphocytes, monocytes and macrophages in the early phase of disease supports the hypothesis of an immune-mediated pathogenesis. In the late phase of disease, immunosuppressive TGF-β1 level increase significantly. We suggest that delayed induction of a protective immune mechanism to downregulate a massive early pro-inflammatory immune response might contribute to the pathologies characteristic of human hantavirus infection

  12. Escherichia coli produces linoleic acid during late stationary phase.

    PubMed Central

    Rabinowitch, H D; Sklan, D; Chace, D H; Stevens, R D; Fridovich, I

    1993-01-01

    Escherichia coli produces linoleic acid in the late stationary phase. This was the case whether the cultures were grown aerobically or anaerobically on a supplemented glucose-salts medium. The linoleic acid was detected by thin-layer chromatography and was measured as the methyl ester by gas chromatography. The linoleic acid methyl ester was identified by its mass spectrum. Lipids extracted from late-stationary-phase cells generated thiobarbituric acid-reactive carbonyl products when incubated with a free radical initiator. In contrast, extracts from log-phase or early-stationary-phase cells failed to do so, in accordance with the presence of polyunsaturated fatty acid only in the stationary-phase cells. PMID:8366020

  13. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications.

    PubMed

    Reymann, Klaus G; Frey, Julietta U

    2007-01-01

    Our review focuses on the mechanisms which enable the late maintenance of hippocampal long-term potentiation (LTP; >3h), a phenomenon which is thought to underlie prolonged memory. About 20 years ago we showed for the first time that the maintenance of LTP - like memory storage--depends on intact protein synthesis and thus, consists of at least two temporal phases. Here we concentrate on mechanisms required for the induction of the transient early-LTP and of the protein synthesis-dependent late-LTP. Our group has shown that the induction of late-LTP requires the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory, reinforcing inputs within specific, effective time windows. The induction of late-LTP is characterized by novel, late-associative properties such as 'synaptic tagging' and 'late-associative reinforcement'. Both phenomena require the associative setting of synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. 'Synaptic tagging' guarantees input specificity and thus the specific processing of afferent signals for the establishment of late-LTP. 'Late-associative reinforcement' describes a process where early-LTP by the co-activation of modulatory inputs can be transformed into late-LTP in activated synapses where a tag is set. Recent evidence from behavioral experiments, which studied processes of emotional and cognitive reinforcement of LTP, point to the physiological relevance of the above mechanisms during cellular and system's memory formation. PMID:16919684

  14. Timing of the Late Vistulian (Weichselian) glacial phases in Poland

    NASA Astrophysics Data System (ADS)

    Marks, Leszek

    2012-06-01

    The Lower Vistula Region in northern Poland is a stratotype area for the Vistulian (Weichselian) glaciation and during Last Glacial Maximum (LGM) the southernmost extension of the Scandinavian ice sheet occurred in western Poland and in eastern Germany. Reinterpretation of the available geochronological data (radiocarbon, 36Cl and 10Be ages), supplied with new field geological evidence, mostly for the Late Vistulian ice sheet limits and movement directions, was focused in three key regions in Poland. During the late Middle Vistulian there was one or two ice sheet advances in the Lower Vistula region. The Late Vistulian maximum ice sheet limit in Poland was time-transgressive and occurred at 24-19 kyrs BP (generally, the younger to the east). Ice sheet limits during the Leszno Phase occurred at 24 cal/10Be/36Cl kyrs, the Poznań Phase ice sheet limit was dated to 19 10Be/36Cl kyrs and the Pomeranian Phase ice sheet limit about 16-17 10Be/36Cl kyrs. Every Late Vistulian glacial phase in Poland was preceded by an ice sheet retreat.

  15. Domain wall formation in late-time phase transitions

    NASA Technical Reports Server (NTRS)

    Kolb, Edward W.; Wang, Yun

    1992-01-01

    We examine domain wall formulation in late time phase transitions. We find that in the invisible axion domain wall phenomenon, thermal effects alone are insufficient to drive different parts of the disconnected vacuum manifold. This suggests that domain walls do not form unless either there is some supplemental (but perhaps not unreasonable) dynamics to localize the scalar field responsible for the phase transition to the low temperature maximum (to an extraordinary precision) before the onset of the phase transition, or there is some non-thermal mechanism to produce large fluctuations in the scalar field. The fact that domain wall production is not a robust prediction of late time transitions may suggest future directions in model building.

  16. The acute phase protein haptoglobin regulates host immunity

    PubMed Central

    Huntoon, Kristin M.; Wang, Yanping; Eppolito, Cheryl A.; Barbour, Karen W.; Berger, Franklin G.; Shrikant, Protul A.; Baumann, Heinz

    2008-01-01

    The contribution of acute phase plasma proteins to host immune responses remains poorly characterized. To better understand the role of the acute phase reactant and major hemoglobin-binding protein haptoglobin (Hp) on the function of immune cells, we generated Hp-deficient C57BL/6J mice. These mice exhibit stunted development of lymphoid organs associated with lower counts of mature T and B cells in the blood and secondary lymphoid compartments. Moreover, these mice show markedly reduced adaptive immune responses as represented by reduced accumulation of IgG antibody after immunization with adjuvant and nominal antigen, abrogation of Th1-dominated delayed-type hypersensitivity reaction, loss of mitogenic responses mounted by T cells, and reduced T cell responses conveyed by APCs. Collectively, these defects are in agreement with the observations that Hp-deficient mice are not capable of generating a recall response or deterring a Salmonella infection as well as failing to generate tumor antigen-specific responses. The administration of Hp to lymphocytes in tissue culture partially ameliorates these functional defects, lending further support to our contention that the acute phase response protein Hp has the ability to regulate immune cell responses and host immunity. The phenotype of Hp-deficient mice suggests a major regulatory activity for Hp in supporting proliferation and functional differentiation of B and T cells as part of homeostasis and in response to antigen stimulation. PMID:18436583

  17. Phase-Dependent Immune Evasion of Herpesviruses▿ †

    PubMed Central

    Vider-Shalit, Tal; Fishbain, Vered; Raffaeli, Shai; Louzoun, Yoram

    2007-01-01

    Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development

  18. Acute brief heat stress in late gestation alters neonatal calf innate immune functions.

    PubMed

    Strong, R A; Silva, E B; Cheng, H W; Eicher, S D

    2015-11-01

    Heat stress, as one of the environmental stressors affecting the dairy industry, compromises the cow milk production, immune function, and reproductive system. However, few studies have looked at how prenatal heat stress (HS) affects the offspring. The objective of this study was to evaluate the effect of HS during late gestation on calf immunity. Calves were born to cows exposed to evaporative cooling (CT) or HS (cyclic 23-35°C) for 1 wk at 3 wk before calving. Both bull and heifer calves (CT, n=10; HS, n=10) were housed in similar environmental temperatures after birth. Both CT and HS calves received 3.78 L of pooled colostrum within 12 h after birth and were fed the same diet throughout the study. In addition to tumor necrosis factor α, IL-1β, IL-1 receptor antagonist (IL-1RA), and toll-like receptor (TLR)2, and TLR4 mRNA expression, the expression of CD14(+) and CD18(+) cells, and DEC205(+) dendritic cells were determined in whole blood samples at d 0, 3, 7, 14, 21, and 28. The neutrophil to lymphocyte ratio, differential cell counts, and the hematocrit were also determined. During late gestation, the HS cows had greater respiration rates, rectal temperatures, and tended to spend more time standing compared with the CT cows. The HS calves had less expression of tumor necrosis factor-α and TLR2 and greater levels of IL-1β, IL-1RA, and TLR4 compared with CT calves. The HS calves also had a greater percentage of CD18(+) cells compared with the CT calves. Additionally, a greater percentage of neutrophils and lesser percentage of lymphocytes were in the HS calves compared with the CT calves. The results indicate that biomarkers of calves' immunity are affected in the first several weeks after birth by HS in the dam during late gestation. PMID:26298746

  19. Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.

    PubMed

    Balint, Joseph P; Gabitzsch, Elizabeth S; Rice, Adrian; Latchman, Yvette; Xu, Younong; Messerschmidt, Gerald L; Chaudhry, Arvind; Morse, Michael A; Jones, Frank R

    2015-08-01

    A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations. PMID:25956394

  20. PRR11 regulates late-S to G2/M phase progression and induces premature chromatin condensation (PCC)

    SciTech Connect

    Zhang, Chundong; Zhang, Ying; Li, Yi; Zhu, Huifang; Wang, Yitao; Cai, Wei; Zhu, Jiang; Ozaki, Toshinori; Bu, Youquan

    2015-03-13

    Recently, we have demonstrated that proline-rich protein 11 (PRR11) is a novel tumor-related gene product likely implicated in the regulation of cell cycle progression as well as lung cancer development. However, its precise role in cell cycle progression remains unclear. In the present study, we have further investigated the expression pattern and functional implication of PRR11 during cell cycle in detail in human lung carcinoma-derived H1299 cells. According to our immunofluorescence study, PRR11 was expressed largely in cytoplasm, the amount of PRR11 started to increase in the late S phase, and was retained until just before mitotic telophase. Consistent with those observations, siRNA-mediated knockdown of PRR11 caused a significant cell cycle arrest in the late S phase. Intriguingly, the treatment with dNTPs further augmented PRR11 silencing-mediated S phase arrest. Moreover, knockdown of PRR11 also resulted in a remarkable retardation of G2/M progression, and PRR11-knockdown cells subsequently underwent G2 phase cell cycle arrest accompanied by obvious mitotic defects such as multipolar spindles and multiple nuclei. In addition, forced expression of PRR11 promoted the premature Chromatin condensation (PCC), and then proliferation of PRR11-expressing cells was massively attenuated and induced apoptosis. Taken together, our current observations strongly suggest that PRR11, which is strictly regulated during cell cycle progression, plays a pivotal role in the regulation of accurate cell cycle progression through the late S phase to mitosis. - Highlights: • PRR11 started to increase in the late S phase and was retained until just before mitotic telophase. • PRR11-knockdown caused a significant cell cycle arrest in the late S phase and G2 phase. • The treatment with dNTPs further augmented PRR11 silencing-mediated S phase arrest. • PRR11-knockdown led to multipolar spindles and multiple nuclei. • Forced expression of PRR11 promoted the PCC and inhibited

  1. Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

    PubMed Central

    Baurhoo, Bushansingh; Ferket, Peter; Ashwell, Chris M.; de Oliviera, Jean; Zhao, Xin

    2012-01-01

    Background Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. Methods and Principal Findings Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy

  2. Effects of late-gestation heat stress on immunity and performance of calves.

    PubMed

    Dahl, G E; Tao, S; Monteiro, A P A

    2016-04-01

    Lactating cows that experience heat stress will have reduced dry matter intake and milk yield and shift metabolism, which ultimately reduces the efficiency of milk production. Dry cows that are heat stressed similarly experience lower intake, reduced mammary growth, and compromised immune function that ultimately results in a poorer transition into lactation and lower milk yield in the next lactation. A recent focus in our laboratory is on the effects of late gestation, in utero heat stress on calf survival and performance. We have completed a series of studies to examine preweaning growth and health, and later reproductive and productive responses, in an attempt to quantify acute and persistent effects of in utero heat strain. Late gestation heat stress results in calves with lower body weight at birth, shorter stature at weaning, and failure to achieve the same weight or height at 12 mo of age observed in calves from dams that are cooled when dry. A portion of the reduced growth may result from the lower immune status observed in calves heat stressed in utero, which begins with poorer apparent efficiency of immunoglobulin absorption and extends to lower survival rates through puberty. Heat-stressed calves, however, have permanent shifts in metabolism that are consistent with greater peripheral accumulation of energy and less lean growth relative to those from cooled dams. Comparing reproductive performance in calves heat stressed versus those cooled in utero, we observe that the cooled heifers require fewer services to attain pregnancy and become pregnant at an earlier age. Tracking the milk production in calves that were heat stressed in utero versus those cooled in late gestation revealed a significant reduction of yield in the first lactation, approximately 5 kg/d through 35 wk of lactation, despite similar body weight and condition score at calving. These observations indicate that a relatively brief period of heat stress in late gestation dramatically alters

  3. On the nature of the extreme-ultraviolet late phase of solar flares

    SciTech Connect

    Li, Y.; Ding, M. D.; Guo, Y.; Dai, Y.

    2014-10-01

    The extreme-ultraviolet (EUV) late phase of solar flares is a second peak of warm coronal emissions (e.g., Fe XVI) for many minutes to a few hours after the GOES soft X-ray peak. It was first observed by the EUV Variability Experiment on board the Solar Dynamics Observatory (SDO). The late-phase emission originates from a second set of longer loops (late-phase loops) that are higher than the main flaring loops. It is suggested to be caused by either additional heating or long-lasting cooling. In this paper, we study the role of long-lasting cooling and additional heating in producing the EUV late phase using the enthalpy based thermal evolution of loops model. We find that a long cooling process in late-phase loops can well explain the presence of the EUV late-phase emission, but we cannot exclude the possibility of additional heating in the decay phase. Moreover, we provide two preliminary methods based on the UV and EUV emissions from the Atmospheric Imaging Assembly on board SDO to determine whether or not additional heating plays a role in the late-phase emission. Using nonlinear force-free field modeling, we study the magnetic configuration of the EUV late phase. It is found that the late phase can be generated either in hot spine field lines associated with a magnetic null point or in large-scale magnetic loops of multipolar magnetic fields. In this paper, we also discuss why the EUV late phase is usually observed in warm coronal emissions and why the majority of flares do not exhibit an EUV late phase.

  4. Late onset of cryptococcal cervical lymphadenitis following immune reconstitution inflammatory syndrome in a patient with AIDS.

    PubMed

    Sethupathi, Meenakshi; Yoganathan, Kathir

    2015-01-01

    A 32-year-old woman was diagnosed HIV positive with disseminated cryptococcal infection in May 2006. Her initial CD4 was 7 cells/µL and she had a right supraclavicular nodal mass, which was biopsied and shown to be consistent with cryptococcal lymphadenitis. She was treated for disseminated cryptococcal infection and was started on antiretroviral medications subsequently. Two years later, she developed a left supraclavicular mass. Her CD4 count was 320 cells/µL and HIV RNA level was undetectable. Investigations and biopsy results were consistent with a late presentation of cryptococcal immune reconstitution inflammatory syndrome (IRIS). She was treated with oral corticosteroids and her symptoms resolved completely. IRIS is a recognised complication of HIV treatment and occurs in a significant percentage of patients within the first 3 months of starting antiretroviral therapy. This case report illustrates the importance of recognising late presentations of IRIS. It is vital to differentiate true cryptococcal lymphadenitis from IRIS-induced cryptococcal lymphadenitis. PMID:25564633

  5. On the Importance of the Flare's Late Phase for the Solar Extreme Ultraviolet Irradiance

    NASA Technical Reports Server (NTRS)

    Woods, Thomas N.; Eparvier, Frank; Jones, Andrew R.; Hock, Rachel; Chamberlin, Phillip C.; Klimchuk, James A.; Didkovsky, Leonid; Judge, Darrell; Mariska, John; Bailey, Scott; Tobiska, W. Kent; Schrijver, Carolus J.; Webb, David F.; Warren, Harry

    2011-01-01

    The new solar extreme ultraviolet (EUV) irradiance observations from NASA Solar Dynamics Observatory (SDO) have revealed a new class of solar flares that are referred to as late phase flares. These flares are characterized by the hot 2-5 MK coronal emissions (e.g., Fe XVI 33.5 nm) showing large secondary peaks that appear many minutes to hours after an eruptive flare event. In contrast, the cool 0.7-1.5 MK coronal emissions (e.g., Fe IX 17.1 nm) usually dim immediately after the flare onset and do not recover until after the delayed second peak of the hot coronal emissions. We refer to this period of 1-5 hours after the fl amrea sin phase as the late phase, and this late phase is uniquely different than long duration flares associated with 2-ribbon flares or large filament eruptions. Our analysis of the late phase flare events indicates that the late phase involves hot coronal loops near the flaring region, not directly related to the original flaring loop system but rather with the higher post-eruption fields. Another finding is that space weather applications concerning Earth s ionosphere and thermosphere need to consider these late phase flares because they can enhance the total EUV irradiance flare variation by a factor of 2 when the late phase contribution is included.

  6. PRR11 regulates late-S to G2/M phase progression and induces premature chromatin condensation (PCC).

    PubMed

    Zhang, Chundong; Zhang, Ying; Li, Yi; Zhu, Huifang; Wang, Yitao; Cai, Wei; Zhu, Jiang; Ozaki, Toshinori; Bu, Youquan

    2015-03-13

    Recently, we have demonstrated that proline-rich protein 11 (PRR11) is a novel tumor-related gene product likely implicated in the regulation of cell cycle progression as well as lung cancer development. However, its precise role in cell cycle progression remains unclear. In the present study, we have further investigated the expression pattern and functional implication of PRR11 during cell cycle in detail in human lung carcinoma-derived H1299 cells. According to our immunofluorescence study, PRR11 was expressed largely in cytoplasm, the amount of PRR11 started to increase in the late S phase, and was retained until just before mitotic telophase. Consistent with those observations, siRNA-mediated knockdown of PRR11 caused a significant cell cycle arrest in the late S phase. Intriguingly, the treatment with dNTPs further augmented PRR11 silencing-mediated S phase arrest. Moreover, knockdown of PRR11 also resulted in a remarkable retardation of G2/M progression, and PRR11-knockdown cells subsequently underwent G2 phase cell cycle arrest accompanied by obvious mitotic defects such as multipolar spindles and multiple nuclei. In addition, forced expression of PRR11 promoted the premature Chromatin condensation (PCC), and then proliferation of PRR11-expressing cells was massively attenuated and induced apoptosis. Taken together, our current observations strongly suggest that PRR11, which is strictly regulated during cell cycle progression, plays a pivotal role in the regulation of accurate cell cycle progression through the late S phase to mitosis. PMID:25666944

  7. ON THE ORIGIN OF THE EXTREME-ULTRAVIOLET LATE PHASE OF SOLAR FLARES

    SciTech Connect

    Liu Kai; Wang Yuming; Zhang Jie; Cheng Xin

    2013-05-10

    Solar flares typically have an impulsive phase that is followed by a gradual phase as best seen in soft X-ray emissions. A recent discovery based on the EUV Variability Experiment observations on board the Solar Dynamics Observatory (SDO) reveals that some flares exhibit a second large peak separated from the first main phase peak by tens of minutes to hours, which is coined as the flare's EUV late phase. In this paper, we address the origin of the EUV late phase by analyzing in detail two late phase flares, an M2.9 flare on 2010 October 16 and an M1.4 flare on 2011 February 18, using multi-passband imaging observations from the Atmospheric Imaging Assembly on board SDO. We find that (1) the late phase emission originates from a different magnetic loop system, which is much larger and higher than the main phase loop system. (2) The two loop systems have different thermal evolution. While the late phase loop arcade reaches its peak brightness progressively at a later time spanning for more than one hour from high to low temperatures, the main phase loop arcade reaches its peak brightness at almost the same time (within several minutes) in all temperatures. (3) Nevertheless, the two loop systems seem to be connected magnetically, forming an asymmetric magnetic quadruple configuration. (4) Further, the footpoint brightenings in UV wavelengths show a systematic delay of about one minute from the main flare region to the remote footpoint of the late phase arcade system. We argue that the EUV late phase is the result of a long-lasting cooling process in the larger magnetic arcade system.

  8. The stance phase of walking during late pregnancy: temporospatial and ground reaction force variables.

    PubMed

    Lymbery, Janelle K; Gilleard, Wendy

    2005-01-01

    The purpose of this study was to investigate temporospatial and ground reaction force variables in the stance phase of walking during late pregnancy. An eight-camera motion-analysis system was used to record 13 pregnant women at 38 weeks' gestation and again 8 weeks after birth. In late pregnancy, there was a wider step width, and mediolateral ground reaction force tended to be increased in a medial direction. The center of pressure moved more medially initially and less anteriorly at 100% of stance in late pregnancy. The differences suggest that women may adapt their gait to maximize stability in the stance phase of walking and to control mediolateral motion. PMID:15901811

  9. Mechanisms of Stage-Transcending Protection Following Immunization of Mice with Late Liver Stage-Arresting Genetically Attenuated Malaria Parasites

    PubMed Central

    Sack, Brandon K.; Keitany, Gladys J.; Vaughan, Ashley M.; Miller, Jessica L.; Wang, Ruobing; Kappe, Stefan H. I.

    2015-01-01

    Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP) that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s) targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine. PMID:25974076

  10. Ultrastructure of Pseudomonas saccharophila at early and late log phase of growth.

    NASA Technical Reports Server (NTRS)

    Young, H. L.; Chao, F.-C.; Turnbill, C.; Philpott, D. E.

    1972-01-01

    Description of the fine structure of Pseudomonas saccarophila at the early log phase and the late log phase of growth, such as shown by electron microscopy with the aid of various techniques of preparation. The observations reported suggested that, under the experimental conditions applied, P. saccharophila multiplies by the method of constrictive division.

  11. Crossover design and its application in late-phase diabetes studies.

    PubMed

    Wang, Tao; Malone, James; Fu, Haoda; Heilmann, Cory; Qu, Yongming; Huster, William J

    2016-09-01

    Crossover design has been widely used in late-phase clinical studies, as well as in pharmacokinetic and pharmacodynamic, bioequivalence, and medical device studies; however, its interpretability and applicability continue to be debated. Herein we provide discussions around a crossover design's scientific benefit, applicability, and how it can be implemented in late-phase diabetes studies by properly handling key issues: carryover effect, washout period, and baseline selection. Specifically, detailed considerations are provided about the validity and situations of having appropriate length of study duration to deal with carryover effects so that a washout period may not be needed. A simulation study and data mining results on 12 crossover late-phase insulin clinical trials are presented to examine the discussion points and proposals. PMID:27100270

  12. Early and late B cell immune responses in lethal and self-cured rodent malaria.

    PubMed

    Azcárate, Isabel G; Marín-García, Patricia; Pérez-Benavente, Susana; Diez, Amalia; Puyet, Antonio; Bautista, José M

    2015-05-01

    ICR mice have heterogeneous susceptibility to lethal Plasmodium yoelii yoelii 17XL from the first days of experimental infection as evidenced by the different parasitemia levels and clinical outcomes. This mouse model has revealed specific immune responses on peripheral blood correlating with the infection fate of the animals. To search for immune-markers linked to parasitemia we examined B lymphocytes in organs of the immune system as key effectors of rodent immunity against malaria. To determine changes in immune cellularity fostered by the different prognostic parasitemia we examined B cell subsets in low (<15%) and high (>50%) parasitized mice during the first days of the infection. In the case of surviving mice, we studied the preservation of memory immune response 500 days after the primary P. yoelii challenge. Correlating with the parasitemia level, it was observed an increase in total cellularity of spleen during the first week of infection which remained after 16 months of the infection in surviving animals. B cell subsets were also modified across the different infection fates. Subpopulation as follicular B cells and B-1 cells proportions behaved differently depending on the parasitemia kinetics. In addition, peritoneal cavity cells proliferated in response to high parasitemia. More significantly, P. yoelii -specific memory B cells remained in the spleen 500 days after the primo-infection. This study demonstrates that B cell kinetics is influenced by the different parasitemia courses which are naturally developed within a same strain of untreated mice. We show that high levels of parasitemia at the beginning of infection promote an extremely fast and exacerbate response of several cell populations in spleen and peritoneal cavity that, in addition, do not follow the kinetics observed in peripheral blood. Furthermore, our results describe the longest persistence of memory B cells long time upon a single malaria infection in mice. PMID:25466589

  13. Lower Pre-Treatment T Cell Activation in Early- and Late-Onset Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

    PubMed Central

    Goovaerts, Odin; Jennes, Wim; Massinga-Loembé, Marguerite; Ondoa, Pascale; Ceulemans, Ann; Vereecken, Chris; Worodria, William; Mayanja-Kizza, Harriet; Colebunders, Robert; Kestens, Luc

    2015-01-01

    Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The role of disturbed T cell reconstitution in TB-IRIS is not well understood. We investigated T cell activation and maturation profiles in patients who developed TB-IRIS at different intervals during ART. Methods Twenty-two HIV-TB patients who developed early-onset TB-IRIS and 10 who developed late-onset TB-IRIS were matched for age, sex and CD4 count to equal numbers of HIV-TB patients who did not develop TB-IRIS. Flow cytometry analysis was performed on fresh blood, drawn before and after ART initiation and during TB-IRIS events. T cell activation and maturation was measured on CD4+ and CD8+ T cells using CD45RO, CD38, HLA-DR, CCR7 and CD27 antibodies. Results CD8+ T cell activation before ART was decreased in both early-onset (77% vs. 82%, p = 0.014) and late-onset (71% vs. 83%, p = 0.012) TB-IRIS patients compared to non-IRIS controls. After ART initiation, the observed differences in T cell activation disappeared. During late-onset, but not early-onset TB-IRIS, we observed a skewing from memory to terminal effector CD4+ and CD8+ T cell populations (p≤0.028). Conclusion Our data provide evidence of reduced CD8+ T cell activation before ART as a common predisposing factor of early- and late-onset TB-IRIS. The occurrence of TB-IRIS itself was not marked by an over-activated CD8+ T cell compartment. Late- but not early-onset TB-IRIS was characterized by a more terminally differentiated T cell phenotype. PMID:26208109

  14. Liver protein kinase A activity is decreased during the late hypoglycemic phase of sepsis.

    PubMed

    Hsu, C; Hsu, H K; Yang, S L; Jao, H C; Liu, M S

    1999-10-01

    Changes in protein kinase A (PKA, or cAMP-dependent protein kinase) activity in the rat liver during different metabolic phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into 3 groups: control, early sepsis, and late sepsis. Early and late sepsis refer to those animals killed at 9 and 18 h, respectively, after CLP. Hepatic PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and diethylaminoethyl (DEAE)-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined on the basis of the rate of incorporation of [gamma-32-P]ATP into histone. The results show that during early sepsis, both type I and type II PKA activities remained unchanged. During late sepsis, type I PKA activity was decreased by 40.7-53.6%, whereas type II PKA activity was unaffected. Kinetic analysis of the data on type I PKA during the late phase of sepsis reveals that the Vmax (maximal velocity) values for ATP, cAMP, and histone were decreased by 40.7, 53.6, and 47.3%, respectively whereas the Km (substrate concentration required for half-maximal enzymatic activity) values for ATP, cAMP, and histone were unaltered. These data indicate that type I PKA was inactivated during the late hypoglycemic phase of sepsis in the rat liver. Because PKA-mediated phosphorylation plays an important role in the regulation of hepatic glucose metabolism, an inactivation of PKA may contribute to the development of hypoglycemia during the late phase of sepsis. PMID:10509629

  15. Models and correlations of the DEBRIS Late-Phase Melt Progression Model

    SciTech Connect

    Schmidt, R.C.; Gasser, R.D.

    1997-09-01

    The DEBRIS Late Phase Melt Progression Model is an assembly of models, embodied in a computer code, which is designed to treat late-phase melt progression in dry rubble (or debris) regions that can form as a consequence of a severe core uncover accident in a commercial light water nuclear reactor. The approach is fully two-dimensional, and incorporates a porous medium modeling framework together with conservation and constitutive relationships to simulate the time-dependent evolution of such regions as various physical processes act upon the materials. The objective of the code is to accurately model these processes so that the late-phase melt progression that would occur in different hypothetical severe nuclear reactor accidents can be better understood and characterized. In this report the models and correlations incorporated and used within the current version of DEBRIS are described. These include the global conservation equations solved, heat transfer and fission heating models, melting and refreezing models (including material interactions), liquid and solid relocation models, gas flow and pressure field models, and the temperature and compositionally dependent material properties employed. The specific models described here have been used in the experiment design analysis of the Phebus FPT-4 debris-bed fission-product release experiment. An earlier DEBRIS code version was used to analyze the MP-1 and MP-2 late-phase melt progression experiments conducted at Sandia National Laboratories for the US Nuclear Regulatory Commission.

  16. Frequency of wet brewers grains supplementation during late gestation of beef cows and its effects on offspring postnatal growth and immunity.

    PubMed

    Moriel, P; Artioli, L F A; Piccolo, M B; Marques, R S; Poore, M H; Cooke, R F

    2016-06-01

    Our objectives were to evaluate postnatal growth and measurements of innate and humoral immunity of beef calves born to dams fed wet brewers grains (WBG) daily or 3 times weekly during late gestation. On d 0 (approximately 60 d before calving), 28 multiparous, spring-calving Angus cows (BW = 578 ± 19 kg; age = 4.7 ± 0.65 yr; BCS = 7.0 ± 0.18) were stratified by sire, age, BW, and BCS and then randomly allocated into 1 of 14 drylot pens (2 cows/pen; 18 by 3 m; 27 m/cow). Cows were offered ground tall fescue hay ad libitum and received similar weekly WBG supplementation (DMI = 0.5% of BW multiplied by 7 d). Treatments were randomly assigned to pens (7 pens/treatment) and consisted of cows receiving WBG supplementation daily (S7; weekly DMI of WBG divided by 7 d) or 3 times weekly (S3; weekly DMI of WBG divided by 3 d; Mondays, Wednesdays, and Fridays) from d 0 until calving. Cow-calf pairs were managed as a single group on tall fescue pastures from calving to weaning (d 226). Calves were immediately submitted to a preconditioning period from d 226 to 266 and vaccinated against infectious bovine rhinotracheitis, bovine viral diarrhea virus, , and on d 231 and 245. Decreasing the frequency of WBG supplementation did not impact ( ≥ 0.21) precalving intake of total DM, CP, and TDN; BW and BCS change; overall plasma cortisol concentrations; and postcalving growth and pregnancy rate of cows. Overall plasma concentrations of glucose and insulin did not differ ( ≥ 0.28) between S3 and S7 cows, whereas S3 cows had greater ( = 0.002) plasma glucose concentrations and tended ( = 0.06) to have greater plasma insulin concentrations on days they were not fed WBG vs. days of WBG supplementation. Calf plasma concentrations of haptoglobin and cortisol at birth but not serum IgG ( = 0.63) tended ( = 0.10) to be greater for S3 vs. S7 calves. However, additional calf growth and immunity variables obtained during pre- and postweaning phases did not differ between S3 and S7 calves

  17. Acute brief heat stress in late gestation alters neonatal calf innate immune functions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heat stress (HS), as one of the environmental stressors affecting the dairy industry, compromises the cow's milk production, immune function, and reproductive system. However, few studies have looked at how prenatal HS affects the offspring. The objective of this study was to evaluate the effect of ...

  18. Effect of vitamin E on the immune system of ewes during late pregnancy and lactation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present experiment was designed to determine the effects of a regimen of repeated, intramuscular (i.m.) injections of vitamin E (VE) on innate and humoral components of the immune response of pregnant and lactating ewes. Pregnant ewes were randomly assigned to two treatments consisting of i.m. i...

  19. Phenotypic characterisation of the cellular immune infiltrate in placentas of cattle following experimental inoculation with Neospora caninum in late gestation

    PubMed Central

    2013-01-01

    Despite Neospora caninum being a major cause of bovine abortion worldwide, its pathogenesis is not completely understood. Neospora infection stimulates host cell-mediated immune responses, which may be responsible for the placental damage leading to abortion. The aim of the current study was to characterize the placental immune response following an experimental inoculation of pregnant cattle with N. caninum tachyzoites at day 210 of gestation. Cows were culled at 14, 28, 42 and 56 days post inoculation (dpi). Placentomes were examined by immunohistochemistry using antibodies against macrophages, T-cell subsets (CD4, CD8 and γδ), NK cells and B cells. Macrophages were detected mainly at 14 days post inoculation. Inflammation was generally mild and mainly characterized by CD3+, CD4+ and γδ T-cells; whereas CD8+ and NK cells were less numerous. The immune cell repertoire observed in this study was similar to those seen in pregnant cattle challenged with N. caninum at early gestation. However, cellular infiltrates were less severe than those seen during first trimester Neospora infections. This may explain the milder clinical outcome observed when animals are infected late in gestation. PMID:23876124

  20. IRAK-M regulates the inhibition of TLR-mediated macrophage immune response during late in vitro Leishmania donovani infection.

    PubMed

    Srivastav, Supriya; Saha, Amrita; Barua, Jayita; Ukil, Anindita; Das, Pijush K

    2015-10-01

    Intramacrophage protozoan parasite Leishmania donovani, causative agent of visceral leishmaniasis, escapes Toll-like receptor (TLR) dependent early host immune response by inducing the deubiquitinating enzyme A20, which is sustained up to 6 h postinfection only. Therefore, Leishmania must apply other means to deactivate late host responses. Here, we elucidated the role of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR signaling, in downregulating macrophage proinflammatory response during late hours of in vitro infection. Our data reveal a sharp decline in IRAK1 and IRAK4 phosphorylation at 24 h postinfection along with markedly reduced association of IRAK1-TNF receptor associated factor 6, which is mandatory for TLR activation. In contrast, IRAK-M was induced after A20 levels decreased and reached a maximum at 24 h postinfection. IRAK-M induction coincided with increased stimulation of TGF-β, a hallmark cytokine of visceral infection. TGF-β-dependent signaling-mediated induction of SMAD family of proteins, 2, 3, and 4 plays important roles in transcriptional upregulation of IRAK-M. In infected macrophages, siRNA-mediated silencing of IRAK-M displayed enhanced IRAK1 and IRAK4 phosphorylation with a concomitant increase in downstream NF-κB activity and reduced parasite survival. Taken together, the results suggest that IRAK-M may be targeted by L. donovani to inhibit TLR-mediated proinflammatory response late during in vitro infection. PMID:26140693

  1. Protein kinase a activity is increased in rat heart during late hypodynamic phase of sepsis.

    PubMed

    Yang, S L; Hsu, C; Lue, S I; Hsu, H K; Liu, M S

    1997-07-01

    Changes in the activities of protein kinase A (PKA, or cAMP-dependent protein kinase) in rat heart during different cardiodynamic phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture. Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals killed at 9 and 18 h, respectively, after cecal ligation and puncture. Cardiac PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and DEAE-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined based on the rate of incorporation of [gamma-32P]ATP into histone. Results obtained show that during early sepsis, both type I and type II PKA activities were unaffected. During late sepsis, type I PKA activities were stimulated by 66.7-97.7%, while type II PKA activities remained constant. Kinetic analysis of the data on type I PKA during late sepsis reveals that the Vmax values for ATP, cAMP, and histone were increased by 84.7, 66.7, and 97.7%, respectively; while the Km values for ATP, cAMP, and histone were unaltered. These data indicate that type I PKA is activated in rat heart during late hypodynamic phase of sepsis. Since kinase-mediated phosphorylation plays an important role in regulating myocardial function and metabolism, an activation of type I PKA during late sepsis may contribute to the development of altered myocardial function during hypodynamic phase of sepsis. PMID:9249915

  2. Effects of laser immunotherapy on late-stage, metastatic breast cancer patients in a Phase II clinical trial

    NASA Astrophysics Data System (ADS)

    Ferrel, Gabriela L.; Zhou, Feifan; Li, Xiaosong; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Chen, Wei R.

    2014-03-01

    Laser immunotherapy (LIT), a novel technique with a local intervention to induce systemic antitumor effects, was developed to treat metastatic cancers. The pre-clinical studies of LIT have shown its unique characteristics in generating a specific antitumor immunity in treating metastatic tumors in rats and mice. For late-stage, metastatic breast cancer patients, who were considered to be out of other available treatment options, we conducted a small Phase II clinical trial using LIT starting in 2009 in Lima, Peru. This Phase II study was closed in December of 2012, as acknowldged by the Ministry of Health (MOH) of Peur letter 438-2014-OGITT/INS dated March 5th, 2014. Ten patients were enrolled and received LIT in one or multiple 4-week treatment cycles. At the study closing date, four patients were alive and two of them remained cancer free. Here, following the successful conclusion of our Phase II study, we report the clinical effects of LIT on metastatic breast cancer patients. Specifically, we present the overall status of all the patients three years after the treatment and also the outcomes of two long-term surviving patients.

  3. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  4. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  5. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  6. Fluid phase recognition molecules in neutrophil-dependent immune responses.

    PubMed

    Jaillon, Sébastien; Ponzetta, Andrea; Magrini, Elena; Barajon, Isabella; Barbagallo, Marialuisa; Garlanda, Cecilia; Mantovani, Alberto

    2016-04-01

    The innate immune system comprises both a cellular and a humoral arm. Neutrophils are key effector cells of the immune and inflammatory responses and have emerged as a major source of humoral pattern recognition molecules (PRMs). These molecules, which include collectins, ficolins, and pentraxins, are specialised in the discrimination of self versus non-self and modified-self and share basic multifunctional properties including recognition and opsonisation of pathogens and apoptotic cells, activation and regulation of the complement cascade and tuning of inflammation. Neutrophils act as a reservoir of ready-made soluble PRMs, such as the long pentraxin PTX3, the peptidoglycan recognition protein PGRP-S, properdin and M-ficolin, which are stored in neutrophil granules and are involved in neutrophil effector functions. In addition, other soluble PRMs, such as members of the collectin family, are not expressed in neutrophils but can modulate neutrophil-dependent immune responses. Therefore, soluble PRMs are an essential part of the innate immune response and retain antibody-like effector functions. Here, we will review the expression and general function of soluble PRMs, focusing our attention on molecules involved in neutrophil effector functions. PMID:27021644

  7. Role of mast cell in the late phase of contact hypersensitivity induced by trimellitic anhydride

    PubMed Central

    Chai, Ok Hee

    2015-01-01

    Mast cells are known as effector cells of IgE-mediated allergic responses, but role of mast cells in contact hypersensitivity (CHS) has been considered controversial. In this study, we investigated role of mast cell in trimellitic anhydride (TMA)-induced CHS. The mice were sensitized to TMA on the back and repeatedly challenged with TMA on the left ear at 1-week intervals. The ear after challenge showed biphasic responses. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of early and late phase reactions in proportion to the frequency of TMA challenges in C57BL/6 mice. In late phase reaction, peak of ear response by single challenge showed at 24 hours after challenge, but the peak by repeat challenges at 8 hours after the last challenge. Number of mast cells and eosinophils per unit area increased in proportion to frequency of TMA challenges. However, mast cell-deficient WBB6F1/J-KitW/KitW-v mice developed the late phase reaction without the early phase reaction. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of ear response and the infiltration of eosinophils. The magnitude of these responses observed according to the frequency of the TMA challenge in mast cell-deficient WBB6F1/J-KitW/KitW-v mice was significantly lower than that in C57BL/6 mice. Also TMA elicited mast cell degranulation and histamine release from rat peritoneal mast cells in a concentration-dependent manner. Conclusively, TMA induces the early and late phase reactions in CHS, and mast cells may be required for TMA-induced CHS. PMID:26770872

  8. Cosmic ray anisotropies observed late in the decay phase of solar flare events

    NASA Technical Reports Server (NTRS)

    Allum, F. R.; Palmeira, R. A. R.; Mccracken, K. G.; Rao, U. R.; Fairfield, D. H.; Gleeson, L. J.

    1974-01-01

    Data was obtained from instrumentation on Explorers 34 and 41 on cosmic-ray anisotropy and magnetic field vectors during five solar flare events. The analysis was conducted in the energy range from 0.7 to 7.6 MeV, of the late decay phase, to evaluate the dependence of net cosmic-ray anisotropy vector amplitude and direction on the magnetic field azimuth. Results showed that in the late decay phase the direction of the net cosmic-ray anisotropy vector was invariant in relation to the direction of the magnetic field, particle energy, and species. Within the statistical error of the available data the invariant direction was perpendicular to the mean magnetic field direction.

  9. Phase Relationship between Alternans of Early and Late Phases of Ventricular Action Potentials

    PubMed Central

    Jing, Linyuan; Agarwal, Anuj; Chourasia, Sonam; Patwardhan, Abhijit

    2012-01-01

    Background: Alternans of early phase and of duration of action potential (AP) critically affect dispersion of refractoriness through their influence on conduction and repolarization. We investigated the phase relationship between the two alternans and its effect on conduction. Methods and Results: Transmembrane potentials recorded from ventricles of eight swine and three canines during paced activation intervals of ≤300 ms were used to quantify alternans of maximum rate of depolarization (|dv/dt|max) and of action potential duration (APD). Incidence of APD alternans was 62 and 76% in swine and canines. Alternans of APD was frequently accompanied with alternans of |dv/dt|max. Of these, 4 and 26% were out of phase in swine and canines, i.e., low |dv/dt|max preceded long APD. Computer simulations show that out of phase alternans attenuate variation of wavelength and thus minimize formation of spatially discordant alternans. Conclusion: The spontaneous switching of phase relationship between alternans of depolarization and repolarization suggests that mechanisms underlying these alternans may operate independent of each other. The phase between these alternans can critically impact spatial dispersion of refractoriness and thus stability of conduction, with the in phase relation promoting transition from concord to discord while out of phase preventing formation of discord. PMID:22701104

  10. The immediate early gene of canine herpesvirus is transcribed through early and late phases.

    PubMed

    Miyoshi, Masahiro; Okazaki, Katsunori; Takiguchi, Mitsuyoshi; Kida, Hiroshi; Hashimoto, Akira

    2002-07-01

    The immediate early (IE) gene of canine herpesvirus (CHV), homologue of the infected cell protein 4 (ICP4) gene of herpes simplex virus 1, is transcribed as a 4.9kb mRNA during IE phase. The IE gene was further transcribed as a 4.8kb mRNA through early (E) and late (L) phases of productive infection. Transcription of the 4.8kb mRNA initiated from downstream of the TATA box in an intron which was spliced out during IE phase. The reverse transcription-polymerase chain reaction revealed that the IE promoter was turned off during L phase at a permissive temperature. We, thus, propose to redesignate the IE gene of CHV as CICP4 gene. PMID:12185320

  11. Protein kinases paralleling late-phase LTP formation in dorsal hippocampus in the rat.

    PubMed

    Li, Lin; Wan, Jia; Sase, Sunetra; Gröger, Marion; Pollak, Arnold; Korz, Volker; Lubec, Gert

    2014-10-01

    Hippocampal long term potentiation (LTP), representing a cellular model for learning and memory formation, can be dissociated into at least two phases: a protein-synthesis-independent early phase, lasting about 4h and a protein-synthesis-dependent late phase LTP lasting 6h or longer, or even days. A large series of protein kinases have been shown to be involved and herein, a distinct set of protein kinases proposed to be involved in memory retrieval in previous work was tested in dorsal hippocampus of the rat following induction of late-phase LTP. A bipolar stimulation electrode was chronically implanted into the perforant path, while two monopolar recording electrodes were implanted into the dentate gyrus of the dorsal hippocampus. The recording electrode was measuring extracellular excitatory postsynaptic potentials, while the other one measured population spikes. Protein kinases were determined by immunoblotting and immunoflourescence on hippocampal areas showed the distribution pattern of protein kinases PKN1 and NEK7. Induction of LTP was proven, elevated levels for protein kinases PKN1, RPS6KB1, STK4, CDC42BPB, PRKG, TLK, BMX and decreased levels for NEK7, MAK14 and PLK1 were observed. A remarkable overlap of protein kinases observed in spatial memory processes with those proposed in LTP formation was demonstrated. The findings may be relevant for design of future studies on protein kinases and for the interpretation of previous work. PMID:24911953

  12. Two phase deglaciation incorporating a late-stage readvance in the Brunswick, Maine area

    SciTech Connect

    Borelli, C.; Smity, P. . Dept. of Geoscience)

    1993-03-01

    Reinterpretation of late Wisconsinan glacial deposits indicate that retreat of the Laurentide ice margin occurred west of the marine limit in the Brunswick area. Marine transgression deposited the overlying Presumpscot Formation which locally contains organic rich, silty sand. A regionally extensive readvance deformed and truncated the uppermost glaciomarine sediments during the oceanic highstand. Striations and other ice flow indicators which are found underlying the Presumpscot Formation consistently trend NW-SE, while those found on exposed outcrops above the Presumpscot Formation dominantly trend NE-SW. These otherwise anomalous directional flow indicators support a late stage readvance of the ice sheet. Areally extensive, stratified, and locally imbricated outwash caps the glaciomarine sediments. Mineral composition of the basal outwash differs from the upper outwash sequences, supporting the readvance model by indicating different source areas. Multi-phase emergence characterized by terraced landforms caused a reworking and redeposition of sediment in a fluvial, tidally influenced environment. Localized eolian deposits record a late phase reworking of sediment.

  13. Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement

    PubMed Central

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F.; Escobar, Martha L.

    2011-01-01

    It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

  14. Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement.

    PubMed

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

    2011-01-01

    It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

  15. Late time cosmological phase transitions 1: Particle physics models and cosmic evolution

    NASA Technical Reports Server (NTRS)

    Frieman, Joshua A.; Hill, Christopher T.; Watkins, Richard

    1991-01-01

    We described a natural particle physics basis for late-time phase transitions in the universe. Such a transition can seed the formation of large-scale structure while leaving a minimal imprint upon the microwave background anisotropy. The key ingredient is an ultra-light pseudo-Nambu-Goldstone boson with an astronomically large (O(kpc-Mpc)) Compton wavelength. We analyze the cosmological signatures of and constraints upon a wide class of scenarios which do not involve domain walls. In addition to seeding structure, coherent ultra-light bosons may also provide unclustered dark matter in a spatially flat universe, omega sub phi approx. = 1.

  16. Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

    PubMed Central

    Joubert, Marisa K.; Hokom, Martha; Eakin, Catherine; Zhou, Lei; Deshpande, Meghana; Baker, Matthew P.; Goletz, Theresa J.; Kerwin, Bruce A.; Chirmule, Naren; Narhi, Linda O.; Jawa, Vibha

    2012-01-01

    Aggregation of biotherapeutics has the potential to induce an immunogenic response. Here, we show that aggregated therapeutic antibodies, previously generated and determined to contain a variety of attributes (Joubert, M. K., Luo, Q., Nashed-Samuel, Y., Wypych, J., and Narhi, L. O. (2011) J. Biol. Chem. 286, 25118–25133), can enhance the in vitro innate immune response of a population of naive human peripheral blood mononuclear cells. This response depended on the aggregate type, inherent immunogenicity of the monomer, and donor responsiveness, and required a high number of particles, well above that detected in marketed drug products, at least in this in vitro system. We propose a cytokine signature as a potential biomarker of the in vitro peripheral blood mononuclear cell response to aggregates. The cytokines include IL-1β, IL-6, IL-10, MCP-1, MIP-1α, MIP-1β, MMP-2, and TNF-α. IL-6 and IL-10 might have an immunosuppressive effect on the long term immune response. Aggregates made by stirring induced the highest response compared with aggregates made by other methods. Particle size in the 2–10 μm range and the retention of some folded structure were associated with an increased response. The mechanism of aggregate activation at the innate phase was found to occur through specific cell surface receptors (the toll-like receptors TLR-2 and TLR-4, FcγRs, and the complement system). The innate signal was shown to progress to an adaptive T-cell response characterized by T-cell proliferation and secretion of T-cell cytokines. Investigating the ability of aggregates to induce cytokine signatures as biomarkers of immune responses is essential for determining their risk of immunogenicity. PMID:22584577

  17. Eosinophil infiltration into human skin is antigen-dependent in the late-phase reaction.

    PubMed

    Litchfield, T M; Smith, C H; Atkinson, B A; Norris, P G; Elliott, P; Haskard, D O; Lee, T H

    1996-06-01

    Eosinophils play a critical role in late-phase reaction allergic inflammatory responses, although the factors responsible for selective tissue eosinophilia are currently ill-defined. To determine whether recruitment of eosinophils is allergen-specific, or a feature of inflammation in allergic individuals, we have examined cutaneous cell infiltrates and endothelial cell adhesion molecule expression in atopic subjects 6 h (n = 8) and 24 h (n = 7) following ultraviolet-B (UVB) irradiation, or intradermal injection of late-phase reaction allergens or diluent control, using standard immunohistochemical techniques. The numbers of eosinophils were increased significantly, when compared to controls, at both 6 h (P < 0.01) and 24 h (P < 0.05), following intradermal allergen challenge, whereas no significant increase in eosinophils was observed following UVB irradiation. UVB and allergen both induced significant increases in neutrophils, monocytes and T cells at 24 h compared to control sites. An increased expression of endothelial cell adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1), was observed in both models of inflammation. Vascular cell adhesion molecule-1 (VCAM-1) was induced weakly on some biopsies following allergen, and not at all following UVB. These data indicate that eosinophil infiltration in susceptible individuals is a specific property of allergen. Although this study would support the postulated role of VCAM-1 in selective eosinophil recruitment, given its variable and weak expression, additional factors are likely to be involved. PMID:8763415

  18. Adenovirus Induction of an Interferon-Regulatory Factor during Entry into the Late Phase of Infection

    PubMed Central

    Feigenblum, David; Walker, Robert; Schneider, Robert J.

    1998-01-01

    Virus infection of animal cells can induce intracellular antiviral responses mediated by the induction of interferon-regulatory transcription factors (IRFs), which bind to and control genes directed by the interferon-stimulated response element (ISRE). The purpose of this study was to determine whether adenovirus (Ad) induces IRFs during infection, because they might play a role in promoting viral pathogenesis. Here we show that after the late phase of infection, Ad induces a transcription factor related to the IRF family of factors. The IRF is induced shortly after Ad entry into late phase and is shown to stimulate ISRE-directed transcription, to require activation by protein tyrosine kinase signalling, and to be induced several hours prior to the inhibition of cell protein synthesis. Inhibition of tyrosine kinase activity blocks Ad induction and activation of the IRF. Attempts to identify the Ad-induced factor immunologically and by photo-UV cross-linking indicate that it is likely a novel member of the IRF family. Finally, several independent lines of evidence also suggest that Ad induction of the IRF might correlate with the ability of the virus to block host cell protein synthesis later during infection. PMID:9765473

  19. Immunizations.

    PubMed

    Sanford, Christopher A; Jong, Elaine C

    2016-03-01

    Vaccinations are a cornerstone of the pretravel consultation. The pretravel provider should assess a traveler's past medical history, planned itinerary, activities, mode of travel, and duration of stay and make appropriate vaccine recommendations. Given that domestic vaccine-preventable illnesses are more common in international travelers than are exotic or low-income nation-associated vaccine-preventable illnesses, clinicians should first ensure that travelers are current regarding routine immunizations. Additional immunizations may be indicated in some travelers. Familiarity with geographic distribution and seasonality of infectious diseases is essential. Clinicians should be cognizant of which vaccines are live, as there exist contraindications for live vaccines. PMID:26900111

  20. The Adenovirus L4 33-Kilodalton Protein Binds to Intragenic Sequences of the Major Late Promoter Required for Late Phase-Specific Stimulation of Transcription▿

    PubMed Central

    Ali, Humayra; LeRoy, Gary; Bridge, Gemma; Flint, S. J.

    2007-01-01

    The adenovirus late IVa2 protein is required for maximally efficient transcription from the viral major late (ML) promoter, and hence, the synthesis of the majority of viral late proteins. This protein is a sequence-specific DNA-binding protein that also promotes the assembly of progeny virus particles. Previous studies have established that a IVa2 protein dimer (DEF-B) binds specifically to an intragenic ML promoter sequence necessary for late phase-specific stimulation of ML transcription. However, activation of transcription from the ML promoter correlates with binding of at least one additional infected-cell-specific protein, termed DEF-A, to the promoter. Using an assay for the DNA-binding activity of DEF-A, we identified the unknown protein by using conventional purification methods, purification of FLAG-tagged IVa2-protein-containing complexes, and transient synthesis of viral late proteins. The results of these experiments established that the viral L4 33-kDa protein is the only component of DEF-A: the IVa2 and L4 33-kDa proteins are necessary and sufficient for formation of all previously described complexes in the intragenic control region of the ML promoter. Furthermore, the L4 33-kDa protein binds to the promoter with the specificity characteristic of DEF-A and stimulates transcription from the ML promoter in transient-expression assays. PMID:17093188

  1. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  2. The Late Gradual Phase of Large Flares: The Case of November 3, 2003

    NASA Astrophysics Data System (ADS)

    Auraß, H.

    2014-12-01

    The hard X-ray time profiles of most solar eruptive events begin with an impulsive phase that may be followed by a late gradual phase. In a recent article (Aurass et al. in Astron. Astrophys. 555, A40, 2013), we analyzed the impulsive phase of the solar eruptive event on November 3, 2003 in radio and X-ray emission. We found evidence of magnetic breakout reconnection using the radio diagnostic of the common effect of the flare current sheet and, at heights of ±0.4 R⊙, of a coronal breakout current sheet (a source site that we called X). In this article we investigate the radio emission during the late gradual phase of the previously analyzed event. The work is based on 40-400 MHz dynamic spectra (Radio Spectrograph Observatorium Tremsdorf, Leibniz Institut für Astrophysik Potsdam, AIP) combined with radio images obtained by the French Nançay Multifrequency Radio Heliograph (NRH) of the Observatoire de Paris, Meudon. Additionally we use Ramaty High Energy Solar Spectroscopic Imager (RHESSI) hard X-ray (HXR) flux records, and Solar and Heliospheric Observatory (SOHO) Large Angle and Spectrometric Coronagraph (LASCO) and Extreme ultraviolet Imaging Telescope (EIT) images. The analysis shows that the late gradual phase is subdivided into two distinct stages. Stage 1 (here lasting five minutes) is restricted to reoccurring radio emission at source site X. We observe plasma emission and an azimuthally moving source (from X toward the NE; speed ∼1200 kms) at levels radially ordered against the undisturbed coronal density gradient. These radio sources mark the lower boundary of an overdense region with a huge azimuthal extent. By the end of its motion, the source decays and reappears at point X. This is the onset of stage 2 traced here during its first 13 minutes. By this time, NRH sources observed at frequencies ≤236.6 MHz radially lift off with a speed of ∼400 kms (one third of the front speed of the coronal mass ejection (CME)) as one slowly decaying

  3. Therapeutic Immunization In HIV Infected Ugandans Receiving Stable Antiretroviral Treatment: A Phase I Safety Study4

    PubMed Central

    Kityo, Cissy; Bousheri, Stephanie; Akao, Juliette; Ssali, Francis; Byaruhanga, Rose; Ssewanyana, Isaac; Muloma, Prossy; Myalo, Sula; Magala, Rose; Lu, Yichen; Mugyenyi, Peter; Cao, Huyen

    2011-01-01

    Therapeutic immunizations in HIV infection may boost immunity during antiretroviral treatment. We report on the first therapeutic vaccine trial in Uganda, Africa. This open label Phase I trial was designed to assess the safety, tolerability and immunogenicity of a therapeutic HIV-1 vaccine candidate. Thirty HIV positive volunteers receiving a stable regimen of antiretroviral therapy with CD4 counts > 400 were recruited for the safety evaluation of LFn-p24C, a detoxified anthrax-derived polypeptide fused to the subtype C HIV gag protein p24. The vaccine was well tolerated and HIV RNA levels remained undetectable following three immunizations. CD4 counts in vaccine recipients were significantly higher compared to the control individuals after 12 months. HIV-specific responses were associated with higher gain in CD4 counts following LFn-p24C immunizations. Volunteers were subsequently asked to undergo a 30-day period of observed treatment interruption. 8/24 (30%) individuals showed no evidence of viral rebound during treatment interruption. All demonstrated prompt suppression of viral load following resumption of ART. Our data demonstrates the safety of LFn-p24C and suggests that adjunct therapeutic immunization may benefit select individuals in further boosting an immune response. PMID:21211581

  4. A conceptual framework: the early and late phases of skeletal muscle dysfunction in the acute respiratory distress syndrome.

    PubMed

    Files, D Clark; Sanchez, Michael A; Morris, Peter E

    2015-01-01

    Patients with acute respiratory distress syndrome (ARDS) often develop severe diaphragmatic and limb skeletal muscle dysfunction. Impaired muscle function in ARDS is associated with increased mortality, increased duration of mechanical ventilation, and functional disability in survivors. In this review, we propose that muscle dysfunction in ARDS can be categorized into an early and a late phase. These early and late phases are based on the timing in relationship to lung injury and the underlying mechanisms. The early phase occurs temporally with the onset of lung injury, is driven by inflammation and disuse, and is marked predominantly by muscle atrophy from increased protein degradation. The ubiquitin-proteasome, autophagy, and calpain-caspase pathways have all been implicated in early-phase muscle dysfunction. Late-phase muscle weakness persists in many patients despite resolution of lung injury and cessation of ongoing acute inflammation-driven muscle atrophy. The clinical characteristics and mechanisms underlying late-phase muscle dysfunction do not involve the massive protein degradation and atrophy of the early phase and may reflect a failure of the musculoskeletal system to regain homeostatic balance. Owing to these underlying mechanistic differences, therapeutic interventions for treating muscle dysfunction in ARDS may differ during the early and late phases. Here, we review clinical and translational investigations of muscle dysfunction in ARDS, placing them in the conceptual framework of the early and late phases. We hypothesize that this conceptual model will aid in the design of future mechanistic and clinical investigations of the skeletal muscle system in ARDS and other critical illnesses. PMID:26134116

  5. Evaporative cooling in late-gestation Murrah buffaloes potentiates immunity around transition period and overcomes reproductive disorders.

    PubMed

    Aarif, Ovais; Aggarwal, Anjali

    2015-10-15

    The objective of the study was to observe the effect of evaporative cooling during late gestation on immunity around the transition period and the probable outcome on reproductive disorders in Murrah buffaloes. Sixteen pregnant dry Murrah buffaloes at 60 days prepartum were selected and divided into two groups of eight animals each. Group 1 buffaloes remained without the provision of cooling, whereas the second group of buffaloes was managed under fans and mist cooling during the dry period. After parturition, all the animals were managed under evaporative cooling. Dry matter intake was significantly (P < 0.05) higher in cooled relative to noncooled animals at -15, 0, and +20 days of parturition. Cortisol and prolactin levels were significantly (P < 0.05) higher in noncooled relative to cooled animals at -15 and 0 days of parturition. However, prolactin was significantly (P < 0.05) higher in cooled animals at +20 days. Messenger RNA expression of prolactin receptor gene (PRL-R) was upregulated and suppressor of cytokine signaling gene 1 (SOCS-1) was downregulated in cooled animals at -20, 0, and +20 days of parturition. Tumor necrosis factor α and interleukin 4 levels remained significantly (P < 0.05) higher in cooled animals at -20, 0, and +20 days of parturition. Interleukin 6 was significantly (P < 0.05) lower in cooled animals at -20 and 0 days. Interferon γ levels were significantly higher at -20 and +20 days of parturition in cooled relative to noncooled animals. The reproductive disorders such as retention of placenta, metritis, and endometritis occurred at the rate of 37.25%, 25%, and 12.25% in the noncooled group, whereas only retention of placenta was observed in the cooled (12.5%) group. PMID:26211430

  6. TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

    PubMed Central

    Ferri, Federica; Parcelier, Aude; Petit, Vanessa; Gallouet, Anne-Sophie; Lewandowski, Daniel; Dalloz, Marion; van den Heuvel, Anita; Kolovos, Petros; Soler, Eric; Squadrito, Mario Leonardo; De Palma, Michele; Davidson, Irwin; Rousselet, Germain; Romeo, Paul-Henri

    2015-01-01

    Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown. PMID:26592194

  7. Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

    PubMed Central

    Gundel, R H; Wegner, C D; Torcellini, C A; Clarke, C C; Haynes, N; Rothlein, R; Smith, C W; Letts, L G

    1991-01-01

    This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma. Images PMID:1717514

  8. Dynamics of cellular immune responses in the acute phase of dengue virus infection.

    PubMed

    Yoshida, Tomoyuki; Omatsu, Tsutomu; Saito, Akatsuki; Katakai, Yuko; Iwasaki, Yuki; Kurosawa, Terue; Hamano, Masataka; Higashino, Atsunori; Nakamura, Shinichiro; Takasaki, Tomohiko; Yasutomi, Yasuhiro; Kurane, Ichiro; Akari, Hirofumi

    2013-06-01

    In this study, we examined the dynamics of cellular immune responses in the acute phase of dengue virus (DENV) infection in a marmoset model. Here, we found that DENV infection in marmosets greatly induced responses of CD4/CD8 central memory T and NKT cells. Interestingly, the strength of the immune response was greater in animals infected with a dengue fever strain than in those infected with a dengue hemorrhagic fever strain of DENV. In contrast, when animals were re-challenged with the same DENV strain used for primary infection, the neutralizing antibody induced appeared to play a critical role in sterilizing inhibition against viral replication, resulting in strong but delayed responses of CD4/CD8 central memory T and NKT cells. The results in this study may help to better understand the dynamics of cellular and humoral immune responses in the control of DENV infection. PMID:23381396

  9. Late-phase melt progression experiment: MP-2. Results and analysis

    SciTech Connect

    Gasser, R.D.; Gauntt, R.O.; Bourcier, S.C.

    1997-05-01

    In-pile experiments addressing late-phase processes in Light Water Reactors (LWRs) were performed in the Annular Core Research Reactor (ACRR) at Sandia National Laboratories. Melt Progression (MP) experiments were designed to provide information to develop and verify computer models for analysis of LWR core damage in severe accidents. Experiments examine the formation and motion of ceramic molten pools in disrupted reactor core regions. The MP-2 experiment assembly consisted of: (1) a rubble bed of enriched UO{sub 2} and ZrO{sub 2} simulating severely disrupted reactor core regions, (2) a ceramic/metallic crust representing blockage formed by early phase melting, relocation, and refreezing of core components, and (3) an intact rod stub region that remained in place below the blockage region. The test assembly was fission heated in the central cavity of the ACRR at an average rate of about 0.2 KA, reaching a peak molten pool temperature around 3400 K. Melting of the debris bed ceramic components was initiated near the center of the bed. The molten material relocated downward, refreezing to form a ceramic crust near the bottom of the rubble bed. As power levels were increased, the crust gradually remelted and reformed at progressively lower positions in the bed until late in the experiment when it penetrated into and attacked the ceramic/metallic blockage. The metallic components of the blockage region melted and relocated to the bottom of the intact rod stub region before the ceramic melt penetrated the blockage region from above. The ceramic pool penetrated halfway into the blockage region by the end of the experiment. Measurements of thermal response and material relocation are compared to the results of the computer simulations. Postexperiment examination of the assembly with the associated material interactions and metallurgy are also discussed in detail with the analyses and interpretation of results. 16 refs., 206 figs., 24 tabs.

  10. On the thermal stability of late blooming phases in reactor pressure vessel steels: An atomistic study

    NASA Astrophysics Data System (ADS)

    Bonny, G.; Terentyev, D.; Bakaev, A.; Zhurkin, E. E.; Hou, M.; Van Neck, D.; Malerba, L.

    2013-11-01

    Radiation-induced embrittlement of bainitic steels is the lifetime limiting factor of reactor pressure vessels in existing nuclear light water reactors. The primary mechanism of embrittlement is the obstruction of dislocation motion produced by nanometric defect structures that develop in the bulk of the material due to irradiation. In view of improving the predictive capability of existing models it is necessary to understand better the mechanisms leading to the formation of these defects, amongst which the so-called "late blooming phases". In this work we study the stability of the latter by means of density functional theory (DFT) calculations and Monte Carlo simulations based on a here developed quaternary FeCuNiMn interatomic potential. The potential is based on extensive DFT and experimental data. The reference DFT data on solute-solute interaction reveal that, while Mn-Ni pairs and triplets are unstable, larger clusters are kept together by attractive binding energy. The NiMnCu synergy is found to increase the temperature range of stability of solute atom precipitates in Fe significantly as compared to binary FeNi and FeMn alloys. This allows for thermodynamically stable phases close to reactor temperature, the range of stability being, however, very sensitive to composition.

  11. What was the phase relationship between precession and sedimentation in the Mediterranean during the Late Miocene?

    NASA Astrophysics Data System (ADS)

    Marzocchi, Alice; Flecker, Rachel; Lunt, Dan; Gladstone, Rupert; Hilgen, Frits; Krijgsman, Wout; Sierro, Francisco; Ivanovic, Ruza

    2014-05-01

    The Messinian Salinity Crisis (MSC) drastically modified the environment of the Mediterranean Sea. The large signal-noise ratio preserved in the geological record for this extreme event makes it a perfect target for exploring the biogeochemical processes involved through palaeoclimate modelling. In addition, Late Miocene sequences in the Mediterranean have been astronomically tuned, providing a very high-resolution age model that resolves sediment data on a millennial timescale or shorter. Consequently it is possible to carry out robust model-data comparison where the precise orbital phasing is equivalent. Sequences of laminated sapropelitic beds interbedded within homogeneous marls are frequently found in Late Miocene sections in the Mediterranean and have been associated with orbitally-driven climate responses. In fact, the deposition of these sediments has been linked to freshwater input causing both stratification of the water column and increased surface productivity, at times of high summer insolation. Most of the hypotheses relating the phasing of the sedimentary record to the orbital forcing are, however, still untested. Insight can therefore be gained by investigating the impact of varying orbital parameters on the Mediterranean's hydrologic budget using global climate models. A series of 22 fully coupled atmosphere-ocean-vegetation snap-shot simulations have been run at evenly spaced intervals (1kyr) through an entire precession cycle during the pre-evaporite stage of the MSC (~6.5 Ma). In our simulations, the Mediterranean Sea's hydrologic budget exhibits high seasonal variability. Model results can be directly compared with high-resolution geological data that is available for our selected time slice; for instance, cyclic changes in microfaunal assemblages that have a strong seasonal bias can be compared with our model output. This allows us to test the biogeochemical phasing of Mediterranean successions in relation to orbital forcing. Our simulations

  12. Theta Frequency Stimulation Induces a Local Form of Late Phase LTP in the CA1 Region of the Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2005-01-01

    The late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation. This form of LTP requires activation of transcription and translation and results in the cell-wide distribution of gene products that can be captured by other marked synapses. Here we report that theta frequency stimulation (5 Hz, 30 sec) applied to the…

  13. Proteasome Inhibition Enhances the Induction and Impairs the Maintenance of Late-Phase Long-Term Potentiation

    ERIC Educational Resources Information Center

    Dong, Chenghai; Upadhya, Sudarshan C.; Ding, Lan; Smith, Thuy K.; Hegde, Ashok N.

    2008-01-01

    Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity.…

  14. Swimming Exercise in the Acute or Late Phase after Sciatic Nerve Crush Accelerates Nerve Regeneration

    PubMed Central

    Teodori, Rosana Macher; Betini, Joice; de Oliveira, Larissa Salgado; Sobral, Luciane Lobato; Takeda, Sibele Yoko Mattozo; Montebelo, Maria Imaculada de Lima

    2011-01-01

    There is no consensus about the best time to start exercise after peripheral nerve injury. We evaluated the morphological and functional characteristics of the sciatic nerves of rats that began to swim immediately after crush nerve injury (CS1), those that began to swim 14 days after injury (CS14), injured rats not submitted to swimming (C), and uninjured rats submitted to swimming (S). After 30 days the number of axons in CS1 and CS14 was lower than in C (P < 0.01). The diameter of axons and nerve fibers was larger in CS1 (P < 0.01) and CS14 (P < 0.05) than in C, and myelin sheath thickness was lower in all crushed groups (P < 0.05). There was no functional difference between CS1 and CS14 (P > 0.05). Swimming exercise applied during the acute or late phase of nerve injury accelerated nerve regeneration and synaptic elimination after axonotmesis, suggesting that exercise may be initiated immediately after injury. PMID:21876821

  15. Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory

    PubMed Central

    Nagy, Vanja; Bozdagi, Ozlem; Matynia, Anna; Balcerzyk, Marcin; Okulski, Pawel; Dzwonek, Joanna; Costa, Rui M.; Silva, Alcino J.; Kaczmarek, Leszek; Huntley, George W.

    2015-01-01

    Matrix metalloproteinases (MMPs) are extracellular proteases that have well recognized roles in cell signaling and remodeling in many tissues. In the brain, their activation and function are customarily associated with injury or pathology. Here, we demonstrate a novel role for MMP-9 in hippocampal synaptic physiology, plasticity, and memory. MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late-phase long-term potentiation (L-LTP) in area CA1. Such regulation requires NMDA receptors and protein synthesis. Blockade of MMP-9 pharmacologically prevents induction of L-LTP selectively; MMP-9 plays no role in, nor is regulated during, other forms of short-term synaptic potentiation or long-lasting synaptic depression. Similarly, in slices from MMP-9 null-mutant mice, hippocampal LTP, but not long-term depression, is impaired in magnitude and duration; adding recombinant active MMP-9 to null-mutant slices restores the magnitude and duration of LTP to wild-type levels. Activated MMP-9 localizes in part to synapses and modulates hippocampal synaptic physiology through integrin receptors, because integrin function-blocking reagents prevent an MMP-9-mediated potentiation of synaptic signal strength. The fundamental importance of MMP-9 function in modulating hippocampal synaptic physiology and plasticity is underscored by behavioral impairments in hippocampal-dependent memory displayed by MMP-9 null-mutant mice. Together, these data reveal new functions for MMPs in synaptic and behavioral plasticity. PMID:16481424

  16. Dissociation of cutaneous vascular permeability and the development of cutaneous late-phase allergic reactions

    SciTech Connect

    Keahey, T.M.; Indrisano, J.; Kaliner, M.A.

    1989-03-01

    Cutaneous late-phase allergic reactions (LPR) are characterized by an early, immediate hypersensitivity whealing reaction followed by persistent, localized induration that peaks 6 to 8 hours later. In this study we used rodents to examine the relationship between vascular permeability (VP) and induration during LPR. Efflux of macromolecular tracers from the vasculature into skin was measured with the use of radiolabeled albumin and neutral dextran tracers having large molecular radii. To induce LPR immunologically, we used either intradermal injections of antirat IgE or passive cutaneous sensitization with IgE antidinitrophenyl followed 24 hours later by intravenous injection of albumin-dinitrophenyl. (/sup 125/I)albumin and (/sup 3/H)dextran tracers were injected intravenously before and at various intervals after the induction of LPR. Although a marked increase in VP occurred within the first 30 minutes after induction of mast cell degranulation, analysis of radiolabeled tracer accumulation at 2, 4, 8, and 24 hours failed to demonstrate any further increase in VP. These findings indicate that the induration observed in rodent LPR is not associated with increased VP beyond the immediate hypersensitivity stage and suggest that impairment of lymphatic drainage, cellular infiltration, and/or fibrin deposition are contributing factors.

  17. Azadirachta indica (neem) leaf dietary effects on the immunity response and disease resistance of Asian seabass, Lates calcarifer challenged with Vibrio harveyi.

    PubMed

    Talpur, Allah Dad; Ikhwanuddin, Mhd

    2013-01-01

    The present study was aimed to address the possible evaluation of Azadirachta indica (neem) leaf-supplemented diets on innate immune response in Asian seabass, Lates calcarifer fingerlings against Vibrio harveyi infection. Fish were fed for two weeks diets containing six graded levels of neem leaf at 0 g, 1 g, 2 g, 3 g, 4 g and 5 g per kg feed. Fish fed neem leaf-supplemented diet displayed significant differences (p < 0.05) in weight gain, specific growth rate (SGR) and feed conversion ratio (FCR) compared to the control group fed without neem leaf-supplemented diet. Various innate immune parameters were examined pre-challenge and post-challenge. Fish was injected intraperitoneally with a lethal dose of V. harveyi containing 10(8) cells mL(-1). Supplementation of neem leaf diet significantly increased phagocytic activity, superoxide anion production, serum lysozyme, serum bactericidal activity, serum anti-protease activity throughout the experimental period when compared with the control group. Dietary doses of neem leaf diet significantly influenced the immune parameters, haematological parameters and blood biochemical indices of treated fish. The results suggested that fish fed neem leaf-supplemented diet improved the immune system and increased survival rate in L. calcarifer fingerlings against V. harveyi infection. PMID:23178500

  18. Properties of the adenovirus IVa2 gene product, an effector of late-phase-dependent activation of the major late promoter.

    PubMed Central

    Lutz, P; Kedinger, C

    1996-01-01

    The adenovirus major late promoter is strongly activated after the onset of viral DNA replication. Sequence elements located downstream of the major later promoter start site have previously been shown to be essential for this activation. Two proteins (DEF-A and DEF-B) bind to these elements in a late-phase-dependent manner. DEF-B has been identified as the product of adenovirus intermediate gene IVa2 (pIVa2) (C. Tribouley, P. Lutz, A. Staub, and C. Kedinger, J. Virol. 68:4450-4457, 1994). Here we show that pIVa2, while monomeric in solution, binds to its recognition sequence as a dimer and that two 20-residue amphipathic alpha helices play an essential role in this DNA-binding activity. Attempts to purify DEF-A have failed, but its chromatographic behavior, together with its immunological properties, established that pIVa2 is also a component of this heteromeric protein. In addition, the time course of pIVa2 synthesis during infection correlated with simultaneous detection of the binding of both DEF-A and DEF-B complexes to the downstream elements. Finally, as revealed by immunomicroscopy, pIVa2 is targeted to the nucleus, where it distributes to restricted locations in the nucleoplasm, as well as to the nucleoli. Altogether, these results demonstrate that pIVa2 plays a critical role in the transition from the early to the late phase of the lytic cycle. Furthermore, pIVa2 may serve additional functions yet to be uncovered, as suggested by its presence within the cell nucleolus. PMID:8627656

  19. Decision making for late-phase recovery from nuclear or radiological incidents.

    PubMed

    Chen, S Y

    2015-02-01

    Much of the effort on radiological emergency preparedness has focused on the initial responses to an event (e.g., rescuing or triaging missions), while guidance on the more complex issues (e.g., radiological remediation or population resettlement) of long-term recovery has been lacking. The recent major nuclear accidents at Chernobyl, Ukraine, in 1986 and Fukushima, Japan, in 2011 have clearly shown that radiological effects can spread over extended areas and last for a long period of time, thus making planning for long-term recovery an essential extension to the overall response. Similar challenges may be encountered in the aftermath of malicious acts involving devices such as radiological dispersal devices or improvised nuclear devices. Given the potentially unprecedented nature of the impact, the affected communities would have to face a series of daunting tasks in attempting to return to normality. To achieve this objective, a top priority is to conduct an effective and timely remediation of the contaminated areas. In contrast to emergency responses, the late-stage recovery effort is necessarily community focused and therefore will be driven by stakeholders. However, given the nature of the contamination and the widespread impact, cleanup in the aftermath of a major incident could involve a rather complex decision-making process for which the requisite experiences may not be readily available. To this end, the National Council on Radiation Protection and Measurements (NCRP) established a scientific committee to prepare a comprehensive study that develops a framework and recommends an approach to optimizing decision making in late-phase recovery in the wake of major nuclear or radiological incidents. This study, published as NCRP Report No. 175, addresses all relevant dimensions in decision making for long-term recovery. The report describes optimization as a flexible, graded, and iterative process that consists of a series of steps, all of which involve

  20. Characterization of immune cells and cytokine localization in the rat utero-placental unit mid- to late gestation.

    PubMed

    Tessier, Daniel R; Raha, Sandeep; Holloway, Alison C; Yockell-Lelièvre, Julien; Tayade, Chandrakant; Gruslin, Andrée

    2015-08-01

    The success of pregnancy is dependent on the precise regulation of the immune response within the utero-placental environment. Rats are beginning to be widely used as a model for human immune-related pregnancy complications. However, our knowledge of immune cells and cytokine localization in the rat utero-placental tissue is limited. The current study aimed to localize the immune cell populations, including uterine natural killer (uNK) cells, neutrophils, and macrophages within the rat utero-placental unit at two crucial gestational ages, gestational days 15.5 and 18.5. In addition, we characterized the distribution of the cytokines TNFα, IFNγ, and IL-10 in the utero-placental regions at both the above-mentioned gestational ages. Our study has demonstrated co-localization TNFα and IFNγ with uNK cells in perivascular regions of the rat mesometrial triangle at both gestational ages. Neutrophils and IL-10-positive cells were localized at the maternal-fetal interface and in the spiral artery lumen of the rat mesometrial triangle at both gestational ages. TNFα and IL-10 demonstrated a temporal change in the localization from GD15.5 to GD18.5, which coincides with the leading edge of trophoblast invasion into the mesometrial triangle. The current study furthers our knowledge of the localization of uterine immune cells and relevant cytokines, and provides a base from which to research the function of these immune cells and cytokines during rat pregnancy as a model to study human immune-related pregnancy complications. PMID:25725501

  1. Reversal of the late phase of spike frequency adaptation in cat spinal motoneurons during fictive locomotion.

    PubMed

    Brownstone, Robert M; Krawitz, Sherry; Jordan, Larry M

    2011-03-01

    In spinal motoneurons, late spike frequency adaptation (SFA) is defined as the slowing of the firing rate over tens of seconds and can be seen during sustained or intermittent current injection. Although the function of late SFA is not known, it may result in a decrease in force production over time, or muscle fatigue. Because locomotion can persist for long periods of time without fatigue, late SFA was studied using intracellular recordings from adult cat motoneurons during fictive locomotion. Of eight lumbar motoneurons studied, all showed late adaptation during control conditions, but none demonstrated late adaptation during locomotor activity. The most consistent properties that correlated with the presence or absence of late SFA were those related to availability of fast, inactivating sodium channels, particularly action potential rate of rise. Evidence of the reversal of late SFA during locomotion was present for several minutes following locomotor trials, consistent with the suggestion that SFA is modulated through slow metabotropic pathways. The abolition of late adaptation in spinal motoneurons during fictive locomotion is an example of a state-dependent change in the "intrinsic" properties of mammalian motoneurons. This change contributes to increased excitability of motoneurons during locomotion and results in robust firing during sustained locomotion. PMID:21177992

  2. Too little but not too late: Results of a literature review to improve routine immunization programs in developing countries

    PubMed Central

    Ryman, Tove K; Dietz, Vance; Cairns, K Lisa

    2008-01-01

    Background Globally, immunization services have been the center of renewed interest with increased funding to improve services, acceleration of the introduction of new vaccines, and the development of a health systems approach to improve vaccine delivery. Much of the credit for the increased attention is due to the work of the GAVI Alliance and to new funding streams. If routine immunization programs are to take full advantage of the newly available resources, managers need to understand the range of proven strategies and approaches to deliver vaccines to reduce the incidence of diseases. In this paper, we present strategies that may be used at the sub-national level to improve routine immunization programs. Methods We conducted a systematic review of studies and projects reported in the published and gray literature. Each paper that met our inclusion criteria was rated based on methodological rigor and data were systematically abstracted. Routine-immunization – specific papers with a methodological rigor rating of greater than 60% and with conclusive results were reported. Results Greater than 11,000 papers were identified, of which 60 met our inclusion criteria and 25 papers were reported. Papers were grouped into four strategy approaches: bringing immunizations closer to communities (n = 11), using information dissemination to increase demand for vaccination (n = 3), changing practices in fixed sites (n = 4), and using innovative management practices (n = 7). Conclusion Immunization programs are at a historical crossroads in terms of developing new funding streams, introducing new vaccines, and responding to the global interest in the health systems approach to improving immunization delivery. However, to complement this, actual service delivery needs to be strengthened and program managers must be aware of proven strategies. Much was learned from the 25 papers, such as the use of non-health workers to provide numerous services at the community level. However

  3. Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response.

    PubMed

    Franciszkiewicz, Katarzyna; Boissonnas, Alexandre; Boutet, Marie; Combadière, Christophe; Mami-Chouaib, Fathia

    2012-12-15

    Immune system-mediated eradication of neoplastic cells requires induction of a strong long-lasting antitumor T-cell response. However, generation of tumor-specific effector T cells does not necessarily result in tumor clearance. CTL must first be able to migrate to the tumor site, infiltrate the tumor tissue, and interact with the target to finally trigger effector functions indispensable for tumor destruction. Chemokines are involved in circulation, homing, retention, and activation of immunocompetent cells. Although some of them are known to contribute to tumor growth and metastasis, others are responsible for changes in the tumor microenvironment that lead to extensive infiltration of lymphocytes, resulting in tumor eradication. Given their chemoattractive and activating properties, a role for chemokines in the development of the effector phase of the antitumor immune response has been suggested. Here, we emphasize the role of the chemokine-chemokine receptor network at multiple levels of the T-cell-mediated antitumor immune response. The identification of chemokine-dependent molecular mechanisms implicated in tumor-specific CTL trafficking, retention, and regulation of their in situ effector functions may offer new perspectives for development of innovative immunotherapeutic approaches to cancer treatment. PMID:23222302

  4. Hot spine loops and the nature of a late-phase solar flare

    SciTech Connect

    Sun, Xudong; Todd Hoeksema, J.; Liu, Yang; Aulanier, Guillaume; Su, Yingna; Hannah, Iain G.; Hock, Rachel A.

    2013-12-01

    The fan-spine magnetic topology is believed to be responsible for many curious features in solar explosive events. A spine field line links distinct flux domains, but direct observation of such a feature has been rare. Here we report a unique event observed by the Solar Dynamic Observatory where a set of hot coronal loops (over 10 MK) connected to a quasi-circular chromospheric ribbon at one end and a remote brightening at the other. Magnetic field extrapolation suggests that these loops are partly tracers of the evolving spine field line. Continuous slipping- and null-point-type reconnections were likely at work, energizing the loop plasma and transferring magnetic flux within and across the fan quasi-separatrix layer. We argue that the initial reconnection is of the 'breakout' type, which then transitioned to a more violent flare reconnection with an eruption from the fan dome. Significant magnetic field changes are expected and indeed ensued. This event also features an extreme-ultraviolet (EUV) late phase, i.e., a delayed secondary emission peak in warm EUV lines (about 2-7 MK). We show that this peak comes from the cooling of large post-reconnection loops beside and above the compact fan, a direct product of eruption in such topological settings. The long cooling time of the large arcades contributes to the long delay; additional heating may also be required. Our result demonstrates the critical nature of cross-scale magnetic coupling—topological change in a sub-system may lead to explosions on a much larger scale.

  5. A multi-slice recording system for stable late phase hippocampal long-term potentiation experiments.

    PubMed

    Kroker, Katja Sabine; Rosenbrock, Holger; Rast, Georg

    2011-01-15

    A major challenge in neuroscience is identifying the cellular and molecular processes underlying learning and memory formation. In the past decades, significant progress has been made in understanding cellular and synaptic mechanisms underlying hippocampal learning and memory using long-term potentiation (LTP) experiments in brain slices as a model system. To expedite LTP measurements it is helpful to further optimize such recording systems. Here, we describe a modification of a multi-slice recording system (SliceMaster, Scientifica Limited, East Sussex, UK) that allows absolutely stable measurements of field excitatory postsynaptic potentials (fEPSPs) for up to 8 h in up to eight slices simultaneously. The software Notocord(®) was used for on-line data acquisition and to control the digital pattern generator which can generate different patterns for slice stimulation, inducing different types of LTP. Moreover, in contrast to common gravity-driven perfusion systems, a Pumped Perfusion System was employed to recycle drug solutions applied to the hippocampal slice. In addition, slices were positioned on two stacked grids for optimal recording of fEPSPs. These two stacked grids were placed in the measuring chambers allowing recordings for several hours without any perturbances. In summary, this modified slice-recording system improves throughput and allows for better statistical design, increases number of used slices per animal and enables very robust LTP measurements for up to 7 h. Hence, this system is suitable not only to investigate molecular mechanisms underlying the late phase of LTP, but also to screen candidate compounds in the context of drug discovery. PMID:21087635

  6. Endothelial gaps and adherent leukocytes in allergen-induced early- and late-phase plasma leakage in rat airways.

    PubMed Central

    Baluk, P.; Bolton, P.; Hirata, A.; Thurston, G.; McDonald, D. M.

    1998-01-01

    Exposure of sensitized individuals to antigen can induce allergic responses in the respiratory tract, manifested by early and late phases of vasodilatation, plasma leakage, leukocyte influx, and bronchoconstriction. Similar responses can occur in the skin, eye, and gastrointestinal tract. The early-phase response involves mast cell mediators and the late-phase response is leukocyte dependent, but the mechanism of leakage is not understood. We sought to identify the leaky blood vessels, to determine whether these vessels contained endothelial gaps, and to analyze the relationship of the gaps to adherent leukocytes, using biotinylated lectins or silver nitrate to stain the cells in situ and Monastral blue as a tracer to quantify plasma leakage. Most of the leakage occurred in postcapillary venules (< 40-microns diameter), whereas most of the leukocyte migration (predominantly neutrophils) occurred in collecting venules. Capillaries and arterioles did not leak. Endothelial gaps were found in the leaky venules, both by silver nitrate staining and by scanning electron microscopy, and 94% of the gaps were distinct from sites of leukocyte adhesion or migration. We conclude that endothelial gaps contribute to both early and late phases of plasma leakage induced by antigen, but most leakage occurs upstream to sites of leukocyte adhesion. Images Figure 3 Figure 5 Figure 6 Figure 7 PMID:9626051

  7. Endothelial gaps and adherent leukocytes in allergen-induced early- and late-phase plasma leakage in rat airways.

    PubMed

    Baluk, P; Bolton, P; Hirata, A; Thurston, G; McDonald, D M

    1998-06-01

    Exposure of sensitized individuals to antigen can induce allergic responses in the respiratory tract, manifested by early and late phases of vasodilatation, plasma leakage, leukocyte influx, and bronchoconstriction. Similar responses can occur in the skin, eye, and gastrointestinal tract. The early-phase response involves mast cell mediators and the late-phase response is leukocyte dependent, but the mechanism of leakage is not understood. We sought to identify the leaky blood vessels, to determine whether these vessels contained endothelial gaps, and to analyze the relationship of the gaps to adherent leukocytes, using biotinylated lectins or silver nitrate to stain the cells in situ and Monastral blue as a tracer to quantify plasma leakage. Most of the leakage occurred in postcapillary venules (< 40-microns diameter), whereas most of the leukocyte migration (predominantly neutrophils) occurred in collecting venules. Capillaries and arterioles did not leak. Endothelial gaps were found in the leaky venules, both by silver nitrate staining and by scanning electron microscopy, and 94% of the gaps were distinct from sites of leukocyte adhesion or migration. We conclude that endothelial gaps contribute to both early and late phases of plasma leakage induced by antigen, but most leakage occurs upstream to sites of leukocyte adhesion. PMID:9626051

  8. Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103(+) dendritic cells in late-stage ovarian cancer.

    PubMed

    Flies, Dallas B; Higuchi, Tomoe; Harris, Jaryse C; Jha, Vibha; Gimotty, Phyllis A; Adams, Sarah F

    2016-08-01

    Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment. CD11c+CD11b(-)CD103(+) dendritic cells are absent in the peritoneal cavity of healthy mice but comprise up to 40% of dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity in advanced disease. Among CD11c+CD11b+ cells, Lair-1 expression distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) immunoregulatory dendritic cells, and may contribute to local tumor antigen-specific T cell dysfunction. Using an adoptive transfer model, we find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to promote disease clearance. These data demonstrate that antitumor immune capacity is maintained among local dendritic cell subpopulations in the tumor environment with cancer progression. Similar dendritic cell subsets are present in malignant ascites from women with ovarian cancer, supporting the translational relevance of these results. PMID:27622059

  9. Effects of hirami lemon, Citrus depressa Hayata, leaf meal in diets on the immune response and disease resistance of juvenile barramundi, Lates calcarifer (bloch), against Aeromonas hydrophila.

    PubMed

    Shiu, Ya-Li; Lin, Hsueh-Li; Chi, Chia-Chun; Yeh, Shinn-Pyng; Liu, Chun-Hung

    2016-08-01

    The present study was conducted to evaluate the dietary supplementation of leaf meal from Citrus depressa Hayata on the growth, innate immune response, and disease resistance of juvenile barramundi, Lates calcarifer. Four diets were formulated to contain 0% (control), 1% (C1), 3% (C3), and 5% (C5) leaf meal, respectively. During a 56 d feeding trial, fish survival, growth performance, and feed efficiency were not significantly different among all groups. For immune response, respiratory burst, superoxide dismutase and lysozyme activities were not significantly different among all groups. However, fish fed the C5 diet for 56 d had significantly higher phagocytic activity. Also, fish fed C3 and C5 diets had significantly higher Mx gene expressions in spleens and head kidneys with nerve necrosis virus injections after 24 h. Disease resistance against Aeromonas hydrophila was increased by the C5 diet. In this study, barramundi fed on a diet containing 5% C. depressa Hayata leaf meal had significantly better innate immune response and disease resistance against A. hydrophila. PMID:27265807

  10. Phase diagram and critical behavior of a forest-fire model in a gradient of immunity

    NASA Astrophysics Data System (ADS)

    Guisoni, Nara; Loscar, Ernesto S.; Albano, Ezequiel V.

    2011-01-01

    The forest-fire model with immune trees (FFMIT) is a cellular automaton early proposed by Drossel and Schwabl [Physica APHYADX0378-437110.1016/0378-4371(93)90001-K 199, 183 (1993)], in which each site of a lattice can be in three possible states: occupied by a tree, empty, or occupied by a burning tree (fire). The trees grow at empty sites with probability p, healthy trees catch fire from adjacent burning trees with probability (1-g), where g is the immunity, and a burning tree becomes an empty site spontaneously. In this paper we study the FFMIT by means of the recently proposed gradient method (GM), considering the immunity as a uniform gradient along the horizontal axis of the lattice. The GM allows the simultaneous treatment of both the active and the inactive phases of the model in the same simulation. In this way, the study of a single-valued interface gives the critical point of the active-absorbing transition, whereas the study of a multivalued interface brings the percolation threshold into the active phase. Therefore we present a complete phase diagram for the FFMIT, for all range of p, where, besides the usual active-absorbing transition of the model, we locate a transition between the active percolating and the active nonpercolating phases. The average location and the width of both interfaces, as well as the absorbing and percolating cluster densities, obey a scaling behavior that is governed by the exponent α=1/(1+ν), where ν is the suitable correlation length exponent (ν⊥ for the directed percolation transition and ν for the standard percolation transition). We also show that the GM allows us to calculate the critical exponents associated with both the order parameter of the absorbing transition and the number of particles in the multivalued interface. Besides, we show that by using the gradient method, the collapse in a single curve of cluster densities obtained for samples of different side is a very sensitive method in order to obtain the

  11. Phase diagram and critical behavior of a forest-fire model in a gradient of immunity.

    PubMed

    Guisoni, Nara; Loscar, Ernesto S; Albano, Ezequiel V

    2011-01-01

    The forest-fire model with immune trees (FFMIT) is a cellular automaton early proposed by Drossel and Schwabl [Physica A 199, 183 (1993)], in which each site of a lattice can be in three possible states: occupied by a tree, empty, or occupied by a burning tree (fire). The trees grow at empty sites with probability p, healthy trees catch fire from adjacent burning trees with probability (1-g), where g is the immunity, and a burning tree becomes an empty site spontaneously. In this paper we study the FFMIT by means of the recently proposed gradient method (GM), considering the immunity as a uniform gradient along the horizontal axis of the lattice. The GM allows the simultaneous treatment of both the active and the inactive phases of the model in the same simulation. In this way, the study of a single-valued interface gives the critical point of the active-absorbing transition, whereas the study of a multivalued interface brings the percolation threshold into the active phase. Therefore we present a complete phase diagram for the FFMIT, for all range of p, where, besides the usual active-absorbing transition of the model, we locate a transition between the active percolating and the active nonpercolating phases. The average location and the width of both interfaces, as well as the absorbing and percolating cluster densities, obey a scaling behavior that is governed by the exponent α=1/(1+ν), where ν is the suitable correlation length exponent (ν(⊥) for the directed percolation transition and ν for the standard percolation transition). We also show that the GM allows us to calculate the critical exponents associated with both the order parameter of the absorbing transition and the number of particles in the multivalued interface. Besides, we show that by using the gradient method, the collapse in a single curve of cluster densities obtained for samples of different side is a very sensitive method in order to obtain the critical points and the percolation

  12. Transforming growth factor-β1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection.

    PubMed

    Bhaskaran, N; Quigley, C; Weinberg, A; Huang, A; Popkin, D; Pandiyan, P

    2016-07-01

    As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to T cell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing α-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-β1 (TGF-β1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-β1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-β1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections. PMID:26530137

  13. Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy.

    PubMed

    Santoni, Matteo; Buti, Sebastiano; Conti, Alessandro; Porta, Camillo; Procopio, Giuseppe; Sternberg, Cora N; Bracarda, Sergio; Basso, Umberto; De Giorgi, Ugo; Rizzo, Mimma; Derosa, Lisa; Ortega, Cinzia; Massari, Francesco; Milella, Michele; Bersanelli, Melissa; Cerbone, Linda; Muzzonigro, Giovanni; Burattini, Luciano; Montironi, Rodolfo; Santini, Daniele; Cascinu, Stefano

    2015-12-01

    We aimed to assess the prognostic role of pretreatment neutrophilia, lymphocytopenia, and neutrophil to lymphocyte ratio (NLR) in patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) for late relapsing (>5 years) metastatic renal cell carcinoma (mRCC). Data were collected from 13 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as >5 years after initial radical nephrectomy. One hundred fifty-one patients were included in this analysis. Among them, MSKCC risk score was favorable in 68 %, intermediate in 29 %, and poor in 3 %. Fifty-six patients (37 %) had NLR ≥3 at the start of VEGFR-TKI therapy (group A), while 95 had lower NLR (63 %, group B). The median overall survival (OS) was 28.8 months in group A and 68.7 months (95 % confidence interval (CI) 45.3-NA) in group B (p < 0.001). The median progression-free survival (PFS) was 15.8 months in group A and 25.1 months in group B (p = 0.03). At multivariate analysis, MSKCC risk group and NLR were independent prognostic factors for both OS and PFS. Pretreatment NLR is an independent prognostic factor for patients with late relapsing mRCC treated with first-line VEGFR-TKIs. A better characterization of baseline immunological impairment may optimize the management of this RCC subpopulation. PMID:25559290

  14. Serum amyloid A in marine bivalves: An acute phase and innate immunity protein.

    PubMed

    Rosani, U; Domeneghetti, S; Gerdol, M; Franzoi, M; Pallavicini, A; Venier, P

    2016-06-01

    Serum amyloid A (SAA) is among the most potent acute phase proteins (APP) in vertebrates. After injury, its early expression can dramatically increase to promote the recruitment of immuno-competent cells, expression of pro-inflammatory proteins and the activation of the innate immune defences. Although APP have been studied in many vertebrates, only recently their search was extended to invertebrates and the finding of SAA-like molecules has opened new questions on the immune-regulatory functions of these soluble proteins in the animal kingdom. Taking advantage of the considerable amount of genomic and transcriptomic data currently available, we retrieved 51 SAA-like proteins in several protostome taxa comprising 21 marine bivalve species and basal metazoans. In addition to vertebrate-like SAAs, we identified a second protein type with peculiar features. In the bivalves Crassostrea gigas and Mytilus galloprovincialis, both digital expression analysis and qPCR data indicated an induction of the classical SAA after bacterial challenge. PMID:26828389

  15. Impact on red blood cell immunity patterns in postoperative phase following total hip arthroplasty

    PubMed Central

    Yu, Defu; Fu, Changma; Yu, Runze

    2014-01-01

    Objective In this study, we aimed to measure changes in red blood cell (RBC) immunity and cytokine levels after performing total hip replacement surgery. Material and methods Twenty patients receiving total hip arthroplasty were investigated by measuring presurgical and postoperative RBC natural tumor erythrocyte rosette rate (NTERR), RBC C3b receptor rosette rate (RC3bRR), RBC membrane CD35, CD58 and CD59 expression and cytokine levels [including tumor necrosis factor α (TNF-α), interleukin 2 (IL-2), interferon γ (IFN-γ), interleukin 10 (IL-10) and prostaglandin E2 (PGE2)]. Blood samples were collected on the day before surgery and on the first day after hip arthroplasty. Results Postoperative NTERR and RC3bRR were significantly lower than presurgical levels (p < 0.05). The RBC membrane CD35, CD58 and CD59 expressions were significantly decreased in the postoperative phase compared to pre-operative levels. Importantly, RBC promoting lymphocyte proliferation rates were significantly reduced after surgery. In addition, postoperative TNF-α, IL-2 and IFN-γ levels in RBC and lymphocyte culture fluid were lower than those pre-operation, whereas IL-10 and PGE2 were significantly increased compared to presurgical levels (p < 0.05). Conclusions The modification of RBC immune function may be involved in the occurrence and development of the infection following hip arthroplasty, and this suggests a novel strategy to prevent such infection. PMID:26155151

  16. Marek's disease virus influences the core gut microbiome of the chicken during the early and late phases of viral replication.

    PubMed

    Perumbakkam, Sudeep; Hunt, Henry D; Cheng, Hans H

    2014-10-01

    Marek's disease (MD) is an important neoplastic disease of chickens caused by the Marek's disease virus (MDV), an oncogenic alphaherpesvirus. In this study, dysbiosis induced by MDV on the core gut flora of chicken was assessed using next generation sequence (NGS) analysis. Total fecal and cecum-derived samples from individual birds were used to estimate the influence of MDV infection on the gut microbiome of chicken. Our analysis shows that MDV infection alters the core gut flora in the total fecal samples relatively early after infection (2-7 days) and in the late phase of viral infection (28-35 days) in cecal samples, corresponding well with the life cycle of MDV. Principle component analyses of total fecal and cecal samples showed clustering at the early and late time points, respectively. The genus Lactobacillus was exclusively present in the infected samples in both total fecal and cecal bird samples. The community colonization of core gut flora was altered by viral infection, which manifested in the enrichment of several genera during the early and late phases of MDV replication. The results suggest a relationship between viral infection and microbial composition of the intestinal tract that may influence inflammation and immunosuppression of T and B cells in the host. PMID:25065611

  17. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase.

    PubMed

    Fang, H; Liu, A; Dahmen, U; Dirsch, O

    2013-01-01

    The anti-malaria drug chloroquine is well known as autophagy inhibitor. Chloroquine has also been used as anti-inflammatory drugs to treat inflammatory diseases. We hypothesized that chloroquine could have a dual effect in liver ischemia/reperfusion (I/R) injury: chloroquine on the one hand could protect the liver against I/R injury via inhibition of inflammatory response, but on the other hand could aggravate liver I/R injury through inhibition of autophagy. Rats (n=6 per group) were pre-treated with chloroquine (60 mg/kg, i.p.) 1 h before warm ischemia, and they were continuously subjected to a daily chloroquine injection for up to 2 days. Rats were killed 0.5, 6, 24 and 48 h after reperfusion. At the early phase (i.e., 0-6 h after reperfusion), chloroquine treatment ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines and fewer histopathologic changes. In contrast, chloroquine worsened liver injury at the late phase of reperfusion (i.e., 24-48 h after reperfusion). The mechanism of protective action of chloroquine appeared to involve its ability to modulate mitogen-activated protein kinase activation, reduce high-mobility group box 1 release and inflammatory cytokines production, whereas chloroquine worsened liver injury via inhibition of autophagy and induction of hepatic apoptosis at the late phase. In conclusion, chloroquine prevents ischemic liver damage at the early phase, but aggravates liver damage at the late phase in liver I/R injury. This dual role of chloroquine should be considered when using chloroquine as an inhibitor of inflammation or autophagy in I/R injury. PMID:23807223

  18. The fallacy of coverage: uncovering disparities to improve immunization rates through evidence. Results from the Canadian International Immunization Initiative Phase 2 - Operational Research Grants.

    PubMed

    Mhatre, Sharmila L; Schryer-Roy, Anne-Marie

    2009-01-01

    Immunization can and does save lives. However, the presence of vaccines does not easily translate into every child being vaccinated, and this is what the studies in this journal supplement reveal. From South Asia to West Africa,the evidence presented here reveals what we are calling the fallacy of coverage, going beyond uncovering the real vaccination rates to providing evidence on the reasons for the lack of effective coverage.The evidence for the fallacy of coverage is part of an operational research program entitled the Canadian International Immunization Initiative Phase 2 (CIII2). Through a competitive peer review process, six research grants were awarded to increase access to and enhance immunization services. This journal supplement provides a forum for the presentation of the results of five of the six studies.The story of the fallacy of coverage is made up of five theme areas of evidence - timeliness of immunization, social and gender inequities, vaccine efficacy, understanding demand side issues to tailor interventions, and national data sets masking actual district level coverage rates - that reveal the discrepancies in immunization coverage rates and the reasons behind these discrepancies. As part of the story, and to turn around the fallacy of coverage, the studies also provide proof of effective and locally relevant solutions.Policies and funding, while keeping an eye on future diseases, clearly need to maintain and increase support to address existing vaccine-preventable diseases to increase coverage such that by 2015 we can achieve 90% national vaccination coverage and reach the MDG of reducing mortality rates among children under five by two-thirds.The results from the operational research grants of the CIII2 offer some answers on how to reach this goal by demonstrating how locally generated evidence can inform immunization strategies to ensure that children who need to get vaccinated will get vaccinated, and vaccinated on time. PMID:19828053

  19. Pain relief induces dopamine release in the rat nucleus accumbens during the early but not late phase of neuropathic pain.

    PubMed

    Kato, Takahiro; Ide, Soichiro; Minami, Masabumi

    2016-08-26

    Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications. PMID:27369326

  20. Mathematical model reveals how regulating the three phases of T-cell response could counteract immune evasion.

    PubMed

    Lorenzi, Tommaso; Chisholm, Rebecca H; Melensi, Matteo; Lorz, Alexander; Delitala, Marcello

    2015-10-01

    T cells are key players in immune action against the invasion of target cells expressing non-self antigens. During an immune response, antigen-specific T cells dynamically sculpt the antigenic distribution of target cells, and target cells concurrently shape the host's repertoire of antigen-specific T cells. The succession of these reciprocal selective sweeps can result in 'chase-and-escape' dynamics and lead to immune evasion. It has been proposed that immune evasion can be countered by immunotherapy strategies aimed at regulating the three phases of the immune response orchestrated by antigen-specific T cells: expansion, contraction and memory. Here, we test this hypothesis with a mathematical model that considers the immune response as a selection contest between T cells and target cells. The outcomes of our model suggest that shortening the duration of the contraction phase and stabilizing as many T cells as possible inside the long-lived memory reservoir, using dual immunotherapies based on the cytokines interleukin-7 and/or interleukin-15 in combination with molecular factors that can keep the immunomodulatory action of these interleukins under control, should be an important focus of future immunotherapy research. PMID:26119966

  1. Systemic and local immune responses in sheep after Neospora caninum experimental infection at early, mid and late gestation.

    PubMed

    Arranz-Solís, David; Benavides, Julio; Regidor-Cerrillo, Javier; Horcajo, Pilar; Castaño, Pablo; del Carmen Ferreras, María; Jiménez-Pelayo, Laura; Collantes-Fernández, Esther; Ferre, Ignacio; Hemphill, Andrew; Pérez, Valentín; Ortega-Mora, Luis Miguel

    2016-01-01

    Besides its importance in cattle, Neospora caninum may also pose a high risk as abortifacient for small ruminants. We have recently demonstrated that the outcome of experimental infection of pregnant sheep with 10(6) Nc-Spain7 tachyzoites is strongly dependent on the time of gestation. In the current study, we assessed peripheral and local immune response in those animals. Serological analysis revealed earlier and higher IFN-γ and IgG responses in ewes infected at early (G1) and mid (G2) gestation, when abortion occurred. IL-4 was not detected in sera from any sheep. Inflammatory infiltrates in the placenta mainly consisted of CD8+ and, to a lesser extent, CD4+ T cells and macrophages (CD163+). The infiltrate was more intense in sheep infected at mid-gestation. In the foetal mesenchyme, mostly free tachyzoites were found in animals infected at G1, while those infected in G2 displayed predominantly particulate antigen, and parasitophorous vacuoles were detected in sheep infected at G3. A similar pattern of placental cytokine mRNA expression was found in all groups, displaying a strengthened upregulation of IFN-γ and IL-4 and milder increases of TNF-α and IL-10, reminiscent of a mixed Th1 and Th2 response. IL-12 and IL-6 were only slightly upregulated in G2, and TGF-β was downregulated in G1 and G2, suggestive of limited T regulatory (Treg) cell activity. No significant expression of TLR2 or TLR4 could be detected. In summary, this study confirms the pivotal role of systemic and local immune responses at different times of gestation during N. caninum infection in sheep. PMID:26739099

  2. Age-Related Enhancement of a Protein Synthesis-Dependent Late Phase of LTP Induced by Low Frequency Paired-Pulse Stimulation in Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2006-01-01

    Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by…

  3. PRODUCTION OF THE EXTREME-ULTRAVIOLET LATE PHASE OF AN X CLASS FLARE IN A THREE-STAGE MAGNETIC RECONNECTION PROCESS

    SciTech Connect

    Dai, Y.; Ding, M. D.; Guo, Y.

    2013-08-20

    We report on observations of an X class flare on 2011 September 6 by the instruments on board the Solar Dynamics Observatory. The flare occurs in a complex active region with multiple polarities. The Extreme-Ultraviolet (EUV) Variability Experiment observations in the warm coronal emission reveal three enhancements, the third of which corresponds to an EUV late phase. The three enhancements have a one-to-one correspondence to the three stages in flare evolution identified by the spatially resolved Atmospheric Imaging Assembly observations, which are characterized by a flux rope eruption, a moderate filament ejection, and the appearance of EUV late phase loops, respectively. The EUV late phase loops are spatially and morphologically distinct from the main flare loops. Multi-channel analysis suggests the presence of a continuous but fragmented energy injection during the EUV late phase resulting in the warm corona nature of the late phase loops. Based on these observational facts, we propose a three-stage magnetic reconnection scenario to explain the flare evolution. Reconnections in different stages involve different magnetic fields but show a casual relationship between them. The EUV late phase loops are mainly produced by the least energetic magnetic reconnection in the last stage.

  4. Deformed phase space Kaluza-Klein cosmology and late time acceleration

    NASA Astrophysics Data System (ADS)

    Sabido, M.; Yee-Romero, C.

    2016-06-01

    The effects of phase space deformations on Kaluza-Klein cosmology are studied. The deformation is introduced by modifying the symplectic structure of the minisuperspace variables. In the deformed model, we find an accelerating scale factor and therefore infer the existence of an effective cosmological constant from the phase space deformation parameter β.

  5. The Relationship between AMH and AMHR2 Polymorphisms and the Follicular Phase in Late Reproductive Stage Women

    PubMed Central

    Jurczak, Anna; Szkup, Małgorzata; Grzywacz, Anna; Safranow, Krzysztof; Grochans, Elżbieta

    2016-01-01

    The objective of this work was the analysis of the relationships between the genotypes of the AMH and AMH receptor type 2 genes, hormone levels and the menstrual cycle in a group of Polish women in the late reproductive stage. The study was conducted using a measurement-based method (body weight and height), laboratory method (serum hormone levels AMH, FSH and E2), and genetic analysis (DNA isolated from whole blood by a salting-out method). The study involved 345 healthy, late-reproductive-stage women from Poland, aged 42.3 ± 4.5 years. The analysis demonstrated that neither the T/T and G/T+G/G genotypes of the AMH Ile49Ser polymorphism (rs10407022), nor the A/A and the G/A + G/G genotypes of the AMHR2 2482 A > G polymorphism (rs2002555), nor the C/C and C/T + T/T genotypes of the AMH polymorphism (rs11170547) were statistically significantly related (p > 0.05) to such factors as age, BMI, hormone (FSH and E2) levels and ovarian parameters (AMH) in the follicular phase. No relationships were found between ovarian parameters (FSH, E2, AMH) and genetic variants of AMH (rs10407022) and AMHR2 (rs11170547, rs2002555) in healthy women in the late reproductive stage. PMID:26848671

  6. Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses

    PubMed Central

    Dérian, Nicolas; Bellier, Bertrand; Pham, Hang Phuong; Tsitoura, Eliza; Kazazi, Dorothea; Huret, Christophe; Mavromara, Penelope; Klatzmann, David; Six, Adrien

    2016-01-01

    Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standardized staining with tetramer, we first quantified antigen-specific T-cell expansion 5 to 10 days after vaccination with one of a set of 41 different vaccine vectors all expressing the same antigen. Hierarchical clustering of the responses defined sets of high and low T cell response inducers. We then compared these responses with the transcriptome of splenic dendritic cells obtained 6 hours after vaccination with the same vectors and produced a random forest model capable of predicting the quality of the later antigen-specific T-cell expansion. The model also successfully predicted vector classification as low or strong T-cell response inducers of a novel set of vaccine vectors, based on the early transcriptome results obtained from spleen dendritic cells, whole spleen and even peripheral blood mononuclear cells. Finally, our model developed with mouse datasets also accurately predicted vaccine efficacy from literature-mined human datasets. PMID:26998760

  7. Factors influencing the late phase of recovery after bone mineral density loss in allogeneic stem cell transplantation survivors.

    PubMed

    Anandi, P; Jain, N A; Tian, X; Wu, C O; Pophali, P A; Koklanaris, E; Ito, S; Savani, B N; Barrett, J; Battiwalla, M

    2016-08-01

    Accelerated bone mineral density loss (BMDL) occurs early after allogeneic stem cell transplantation (SCT) and is related to factors such as steroids and chronic GvHD. In order to understand the natural history of BMDL of SCT in the longer term, we evaluated a longitudinal cohort of 148 survivors with a median follow-up of 12 years (range 3-22 years). All women received hormone replacement therapy, and routine calcium/vitamin D supplementation was recommended but ∼50% of patients still had suboptimal vitamin D levels and bisphosphonates were rarely utilized. BMD significantly improved from 5 to 20+ years but the femoral neck and forearm remained vulnerable sites. Younger age, higher pretransplant body mass index (BMI) and increment in BMI post transplant were significantly associated with increased BMD and protected against osteopenia/osteoporosis. These findings support consideration of BMD loss in SCT survivors in two phases, an early phase of BMD loss (3-5 years) followed by a later phase of BMD recovery, with different protective and aggravating factors. Treatment- and transplant-related factors (such as steroids, immunosuppressives, chronic GvHD, vitamin D) are known to impact the early phase of BMD loss but age and BMI are more influential in the late phase of BMD recovery. PMID:27042843

  8. Short-term energy restriction during late gestation of beef cows decreases postweaning calf humoral immune response to vaccination.

    PubMed

    Moriel, P; Piccolo, M B; Artioli, L F A; Marques, R S; Poore, M H; Cooke, R F

    2016-06-01

    Our objectives were to evaluate the pre- and postweaning growth and measurements of innate and humoral immune response of beef calves born to cows fed 70 or 100% of NEm requirements during the last 40 d of gestation. On d 0 (approximately 40 d before calving), 30 multiparous Angus cows pregnant to embryo transfer (BW = 631 ± 15 kg; age = 5.2 ± 0.98 yr; BCS = 6.3 ± 0.12) were randomly allocated into 1 of 10 drylot pens (3 cows/pen). Treatments were randomly assigned to pens (5 pens/treatment) and consisted of cows limit-fed (d 0 to calving) isonitrogenous, total-mixed diets formulated to provide 100 (CTRL) or 70% (REST) of daily NEm requirements of a 630-kg beef cow at 8 mo of gestation. Immediately after calving, all cow-calf pairs were combined into a single management group and rotationally grazed on tall fescue pastures (6 pastures; 22 ha/pasture) until weaning (d 266). All calves were assigned to a 40-d preconditioning period in a drylot from d 266 to 306 and vaccinated against infectious bovine rhinotracheitis, bovine viral diarrhea virus (BVDV), , and spp. on d 273 and 287. Blood samples from jugular vein were collected from cows on d 0, 17, and 35 and from calves within 12 h of birth and on d 266, 273, 274, 276, 279, and 287. By design, REST cows consumed less ( ≤ 0.002) total DMI, TDN, and NEm but had similar CP intake ( = 0.67), which tended ( = 0.06) to increase BW loss from d 0 to calving, than CTRL cows (-1.09 vs. -0.70 ± 0.14 kg/d, respectively). However, gestational NEm intake did not affect ( ≥ 0.30) plasma concentrations of cortisol, insulin, and glucose during gestation and BCS at calving as well as postcalving pregnancy rate, BW, and BCS change of cows. Calf serum IgG concentrations and plasma concentrations of haptoglobin and cortisol at birth as well as calf pre- and postweaning BW and ADG did not differ ( ≥ 0.15) between calves born to REST and CTRL cows. However, calf postweaning overall plasma concentrations of cortisol; plasma

  9. Refractory Ascites with Liver Fibrosis Developed in Late Phase Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Patients

    PubMed Central

    Hosoi, Hiroki; Warigaya, Kenji; Murata, Shogo; Mushino, Toshiki; Kuriyama, Kodai; Nishikawa, Akinori; Tamura, Shinobu; Hatanaka, Kazuo; Hanaoka, Nobuyoshi; Muragaki, Yasuteru; Murata, Shinichi; Nakakuma, Hideki; Sonoki, Takashi

    2016-01-01

    We report cases of three patients of refractory ascites without other fluid retention that occurred around five months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). All three patients expired and postmortem examinations revealed unexpected liver fibrosis lacking histological evidences of graft-versus-host-disease (GVHD). The three patients showed normal hepatic function and size before transplantation. During their clinical courses, serum biochemistry test showed no elevation of hepatic enzymes and bilirubin; however, imaging studies demonstrated hepatic atrophy at the onset of ascites. One of the liver specimens showed bile obstruction, which could be seen in hepatic damage by GVHD. Although ascites resulting from venoocclusive disease in early phase allo-HSCT is well documented, ascites associated with hepatic fibrosis in late phase allo-HCST has not been reported. Further clinico-pathological studies on similar patients should be required to ascertain refractory ascites associated with liver fibrosis after allo-HSCT. PMID:27499838

  10. Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era

    PubMed Central

    Habermann, Thomas M.; Wang, Sophia S.; Maurer, Matthew J.; Morton, Lindsay M.; Lynch, Charles F.; Ansell, Stephen M.; Hartge, Patricia; Severson, Richard K.; Rothman, Nathaniel; Davis, Scott; Geyer, Susan M.; Cozen, Wendy; Chanock, Stephen J.

    2008-01-01

    To evaluate the hypothesis that host germ line variation in immune genes is associated with overall survival in diffuse large B-cell lymphoma (DLBCL), we genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate genes in 365 DLBCL patients diagnosed from 1998 to 2000. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of SNPs with survival after adjusting for clinical factors. During follow-up, 96 (26%) patients died, and the median follow-up was 57 months for surviving patients. The observed survival of this cohort was consistent with population-based estimates conditioned on surviving 12 months. An IL10 haplotype (global P = .03) and SNPs in IL8RB (rs1126580; HRAG/GG = 2.11; CI, 1.28-3.50), IL1A (rs1800587; HRCT/TT = 1.90; CI, 1.26-2.87), TNF (rs1800629; HRAG/GG = 1.44; CI, 0.95-2.18), and IL4R (rs2107356; HRCC/CT = 1.97; CI, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter 4 SNPs with clinical factors was strongly associated with survival in a Cox model (P = 6.0 × 10−11). Kaplan-Meier 5-year survival estimates for low, intermediate-low, intermediate-high, and high-risk patients were 94%, 79%, 60%, and 48%, respectively. These data support a role for germ line variation in immune genes, particularly genes associated with a proinflammatory state, as predictors of late survival in DLBCL. PMID:18633131

  11. Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants.

    PubMed

    Kaminski, H; Couzi, L; Garrigue, I; Moreau, J-F; Déchanet-Merville, J; Merville, P

    2016-08-01

    Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2-negative (Vδ2(neg) ) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2(neg) γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD. PMID:26953216

  12. Evidence for platelet-activating factor as a late-phase mediator of chronic pancreatitis in the rat.

    PubMed Central

    Zhou, W. G.; Chao, W.; Levine, B. A.; Olson, M. S.

    1990-01-01

    The role of platelet-activating factor (PAF) as a mediator of pancreatic inflammation was examined in the rat pancreatic duct ligation model of obstructive pancreatitis. Pancreatic generation of PAF, as measured by bioassay (ie, platelet [3H]serotonin secretion), was determined at various times after induction of inflammation. Tissue levels of PAF in the normal pancreas averaged 600 +/- 49 pg/g, but PAF was not detectable during the initial 24 hours of pancreatitis, a time when the inflammatory reaction would be considered acute, that is, during the period of maximal serum amylase release and the development of interstitial edema. However a substantial increase in pancreatic PAF levels (12 times control levels) was observed 7 to 14 days after duct ligation during the late-phase response interval similar to the situation characteristic of chronic pancreatitis in which parenchymal atrophy, fibrosis, and pancreatic insufficiency evolve. One week after duct ligation when PAF levels peaked, an evaluation was made of the effects of PAF antagonists (BN52021 and WEB2170) on pancreatic lesions using Evan's blue extravasation, pancreatic myeloperoxidase (MPO) activity, and acid phosphatase activity in peritoneal lavage fluid. BN52021 or WEB2170 treatment was shown to reduce pancreatic damage and inflammation significantly. Long-term in vivo administration of exogenous PAF (20 micrograms/kg/hr for 7 days) exhibited a reduction of [3H]thymidine uptake into and amylase release from pancreatic acini in vitro. Our observations 1) that pancreatic PAF levels increased significantly during the chronic phase of obstructive pancreatitis induced by duct ligation; 2) that inhibition of the action of PAF, through specific receptor antagonism, caused an attenuation of pancreatic lesions; and 3) that chronic administration of PAF resulted in decreased pancreatic regeneration and exocrine function are consistent with a pivotal role for PAF as a late-phase inflammatory mediator in chronic

  13. The Toqua site, 40MR6: A late Mississippian, Dallas phase town

    SciTech Connect

    Chapman, J.; Polhemus, R.R.

    1987-01-01

    Archaeological work in the Little Tennessee River Valley was very much affected by the fluctuations in the Tellico Reservoir scheduling and funding. Stated project goals were: ''Questions regarding Cherokee origins, culture change and acculturation, and the length of time during which the valley was inhabited by man will be among the major ones to be considered.'' From the project inception, the principal research commitment was to the eighteenth century Overhill Cherokee occupation of the valley. By 1967, the inundation date was set for 1971. Four main research problems were identified: (1) a complete survey of the reservoir area to locate all prehistoric and historic sites that will be inundated; (2) a thorough testing of the eighteenth century Cherokee towns to determine the effects of acculturation; (3) to determine how long the Overhill Cherokee have occupied the Little Tennessee Valley by excavating a late prehistoric Mississippian village or an early Historic Cherokee village to discover by (sic) continuities between the prehistoric Mississippian complexes and the Historic Cherokee; and (4) to test intensively occupied sites in depth to find earlier Woodland and Archaic complexes in stratigraphic succession (Guthe, 1967). This report describes the results of these investigations.

  14. NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Persistent Immune Deficiency in Pediatric Transplant Survivors

    PubMed Central

    Bunin, Nancy; Small, Trudy; Szabolcs, Paul; Baker, K. Scott; Pulsipher, Michael A.; Torgerson, Troy

    2011-01-01

    Defective immune reconstitution is a major barrier to successful hematopoietic cell transplantation (HCT), and has important implications in the pediatric population. There are many factors which affect immune recovery, including stem cell source and GVHD. Complete assessment of immune recovery, including T and B lymphocyte evaluation, innate immunity and response to neoantigens, may provide insight as to infection risk and optimal time for immunizations. The increasing use of cord blood grafts requires additional study regarding early reconstitution and impact upon survival. Immunization schedules may require modification based upon stem cell source and immune reconstitution, and this is of particular importance as many children have been incompletely immunized, or not at all, prior to school entry. Additional studies are needed in children post HCT to evaluate the impact of differing stem cell sources upon immune reconstitution, infectious risks and immunization responses. PMID:22100979

  15. Opposing regulation of the late phase TNF response by mTORC1-IL-10 signaling and hypoxia in human macrophages

    PubMed Central

    Huynh, Linda; Kusnadi, Anthony; Park, Sung Ho; Murata, Koichi; Park-Min, Kyung-Hyun; Ivashkiv, Lionel B.

    2016-01-01

    Tumor necrosis factor (TNF) is best known for inducing a rapid but transient NF-κB-mediated inflammatory response. We investigated later phases of TNF signaling, after the initial transient induction of inflammatory genes has subsided, in primary human macrophages. TNF signaling induced expression of late response genes, including inhibitors of NF-κB and TLR signaling, with delayed and sustained kinetics 6–24 hr after TNF stimulation. A subset of late phase genes was expressed in rheumatoid arthritis synovial macrophages, confirming their expression under chronic inflammatory conditions in vivo. Expression of a subset of late phase genes was mediated by autocrine IL-10, which activated STAT3 with delayed kinetics. Hypoxia, which occurs at sites of infection or inflammation where TNF is expressed, suppressed this IL-10-STAT3 autocrine loop and expression of late phase genes. TNF-induced expression of IL-10 and downstream genes was also dependent on signaling by mTORC1, which senses the metabolic state of cells and is modulated by hypoxia. These results reveal an mTORC1-dependent IL-10-mediated late phase response to TNF by primary human macrophages, and identify suppression of IL-10 responses as a new mechanism by which hypoxia can promote inflammation. Thus, hypoxic and metabolic pathways may modulate TNF responses during chronic inflammation. PMID:27558590

  16. Oscillation Phase Locking and Late ERP Components of Intracranial Hippocampal Recordings Correlate to Patient Performance in a Working Memory Task

    PubMed Central

    Kleen, Jonathan K.; Testorf, Markus E.; Roberts, David W.; Scott, Rod C.; Jobst, Barbara J.; Holmes, Gregory L.; Lenck-Santini, Pierre-Pascal

    2016-01-01

    In working memory tasks, stimulus presentation induces a resetting of intracranial temporal lobe oscillations in multiple frequency bands. To further understand the functional relevance of this phenomenon, we investigated whether working memory performance depends on the phase precision of ongoing oscillations in the hippocampus. We recorded intra-hippocampal local field potentials in individuals performing a working memory task. Two types of trials were administered. For high memory trials presentation of a list of four letters (“List”) was followed by a single letter memory probe (“Test”). Low memory load trials, consisting of four identical letters (AAAA) followed by a probe with the same letter (A), were interspersed. Significant phase locking of ongoing oscillations across trials, estimated by the Pairwise Phase Consistency Index (PPCI) was observed in delta (0.5–4 Hz), theta (5–7 Hz), and alpha (8–12 Hz) bands during stimulus presentation and recall but was increased in low memory load trials. Across patients however, higher delta PPCIs during recall in the left hippocampus were associated with faster reaction times. Because phase locking could also be interpreted as a consequence of a stimulus evoked potential, we performed event related potential analysis (ERP) and examined the relationship of ERP components with performance. We found that both amplitude and latency of late ERP components correlated with both reaction time and accuracy. We propose that, in the Sternberg task, phase locking of oscillations, or alternatively its ERP correlate, synchronizes networks within the hippocampus and connected structures that are involved in working memory. PMID:27378885

  17. Parameters of immunity acute phase reaction in men in relation to exposure duration to mercury vapours.

    PubMed

    Moszczynski, P; Moszczynski, P; Słowinski, S; Bem, S; Bartus, R

    1991-01-01

    The study was carried out in 89 men aged 21 to 57 years with a history of exposure to mercury vapour from 2 to 26 years during occupational work involving chlorine production by the method of mercury electrolysis. The workers were divided into three groups depending on the duration of occupational exposure: 1) 32 workers with a short history of exposure 2-10 years, 2) 37 workers with medium-long exposure - 11-20 years, and 3) 20 workers with a history of long exposure - 21-26 years. The urinary concentrations of mercury in these individuals was 73 +/- 60 microliters x 1(-1), and in blood this concentration was not exceeding 50 microliters x 1(-1). The control group comprised 40 men aged 17 to 52 years. They had not had any occupational exposure to chemicals, or harmful physical factors. On the basis of clinical, haematological and biochemical studies 89 workers with occupational exposure to mercury vapour were regarded as clinically healthy. None of them had any symptoms and signs of the complete neurasthenic syndrome or organic brain injury. Increased nervous excitability was the complaint of 24 workers, 9 had headaches, sleep disturbances were reported by 5, and a feeling of tiredness and apathy was mentioned by 5 men. EEG recording demonstrated 81 normal tracings, and moderately pathological records in 8 men. The parameters of immunity and proteins acute phase reaction were determined, measuring the concentration of immunoglobulins, lysozyme, C3c, C4, alpha 1-acid glycoprotein, haptoglobin and ceruloplasmin in serum. A lower level of IgA, IgG and lysozyme was only noted in individuals with occupational exposure exceeding 20 years.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1725175

  18. Phasic Contractions of the Mouse Vagina and Cervix at Different Phases of the Estrus Cycle and during Late Pregnancy

    PubMed Central

    Gravina, Fernanda S.; van Helden, Dirk F.; Kerr, Karen P.; de Oliveira, Ramatis B.; Jobling, Phillip

    2014-01-01

    Background/Aims The pacemaker mechanisms activating phasic contractions of vaginal and cervical smooth muscle remain poorly understood. Here, we investigate properties of pacemaking in vaginal and cervical tissues by determining whether: 1) functional pacemaking is dependent on the phase of the estrus cycle or pregnancy; 2) pacemaking involves Ca2+ release from sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) -dependent intracellular Ca2+ stores; and 3) c-Kit and/or vimentin immunoreactive ICs have a role in pacemaking. Methodology/Principal Findings Vaginal and cervical contractions were measured in vitro, as was the distribution of c-Kit and vimentin positive interstitial cells (ICs). Cervical smooth muscle was spontaneously active in estrus and metestrus but quiescent during proestrus and diestrus. Vaginal smooth muscle was normally quiescent but exhibited phasic contractions in the presence of oxytocin or the K+ channel blocker tetraethylammonium (TEA) chloride. Spontaneous contractions in the cervix and TEA-induced phasic contractions in the vagina persisted in the presence of cyclopiazonic acid (CPA), a blocker of the SERCA that refills intracellular SR Ca2+ stores, but were inhibited in low Ca2+ solution or in the presence of nifedipine, an inhibitor of L-type Ca2+channels. ICs were found in small numbers in the mouse cervix but not in the vagina. Conclusions/Significance Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips were normally quiescent but could be induced to exhibit phasic contractions independent on phase of the estrus cycle or late pregnancy. Spontaneous cervical or TEA-induced vaginal phasic contractions were not mediated by ICs or intracellular Ca2+ stores. Given that vaginal smooth muscle is normally quiescent then it is likely that increases in hormones such as oxytocin, as might occur through sexual stimulation, enhance the

  19. MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice

    PubMed Central

    Sorkin, Linda S; Boyle, David; Hammaker, Deepa; Herman, David; Vail, Emily; Firestein, Gary S

    2009-01-01

    Spinal p38 MAP kinase plays a key role in chronic pain behavior. However, clinical development of p38 inhibitors has been hindered by significant toxicity. To evaluate alternative strategies of p38 regulation, we determined if known upstream activators of p38 (MKK3 and MKK6), are involved in development and maintenance of pain and spinal p38 phosphorylation. Acute pain behaviors were not altered in MKK3 or MKK6 deficient mice. The phase 2 formalin response was delayed in MKK3−/− mice, but unchanged in magnitude, while the response remained normal in MKK6−/− mice. More striking, late formalin allodynia (3 to 18 days post-injection) was prominent in wild type and MKK6−/− mice, but was delayed for several days in MKK3−/− mice. In wild type, but not MKK3−/− mice, intraplantar formalin elicited increases in ipsilateral spinal MKK3/6 phosphorylation acutely and again at 9 days post injection. Phosphorylation of MKK3/6 correlated with phase 2 formalin behavior. Wild type and MKK3−/− mice both expressed increases in spinal phosphorylated p38, however in WT mice this response began several days earlier, and was of higher magnitude and duration than in MKK3−/− mice. This phosphorylation correlated with the late allodynia. Phosphorylated MKK3/6 was detected only in astrocytes, given that P-p38 is usually not seen in astrocytes this argues for astrocytic release of soluble mediators that affect p38 phosphorylation in microglia. Taking these data together, MKK3, but not MKK6, is necessary for normal development of chronic pain behavior and phosphorylation of spinal p38. PMID:19427893

  20. Global and local current sheet thickness estimates during the late growth phase

    NASA Technical Reports Server (NTRS)

    Pulkkinen, T. I.; Baker, D. N.; Mitchell, D. G.; Mcpherron, Robert L.; Huang, C. Y.; Frank, L. A.

    1992-01-01

    The thinning and intensification of the cross tail current sheet during the substorm growth phase are analyzed during the CDAW 6 substorm (22 Mar. 1979) using two complementary methods. The magnetic field and current sheet development are determined using data from two spacecraft and a global magnetic field model with several free parameters. These results are compared with the local calculation of the current sheet location and structure previously done by McPherron et al. Both methods lead to the conclusion that an extremely thin current sheet existed prior to the substorm onset, and the thicknesses estimated by the two methods at substorm onset agree relatively well. The plasma data from the ISEE 1 spacecraft at 13 R(sub E) show an anisotropy in the low energy electrons during the growth phase which disappears just before the substorm onset. The global magnetic model results suggest that the field is sufficiently stretched to scatter such low energy electrons. The strong stretching may improve the conditions for the growth of the ion tearing instability in the near Earth tail at substorm onset.

  1. The Fulong coastal area in northeast Taiwan: Late Holocene sedimentary phases including destruction and aggradation

    NASA Astrophysics Data System (ADS)

    Boese, Margot; Luethgens, Christopher; Bauersachs, Marc

    2014-05-01

    Coastal areas are often subject to rapid morphological transformations owing to varying processes such as sea level changes, tectonic uplift, and geomorphological changes by catastrophic storm events, followed by phases of resilience. The study sites in northeast Taiwan at Fulong beach and adjacent areas, situated close to a nuclear power plant construction site, give evidence of an aggradational phase, a destructive phase, and resilience by a second aggradational phase. According to OSL data, a first aeolian accumulation started on top of marine and peri-marine/fluvial sediments at about 3 ka and lasted about 1500 years, interrupted by one palaeosoil. These data refer to an outcrop at a meander bluff at the southern bank of the Shuangsi river, not far from its present-day mouth. According to the morphological situation, this sand accumulation is only the remnant of a former greater dune system that has been eroded in its northern part. The former course of the Shuangsi and the location of its mouth are not known. The top of the outcrop is represented by two sand layers which are definitely younger than the lower sands as their deposition started about max. 630 years ago. The present-day dune system to the north of the river shows at least four dune ridges and the seaward aggradation is still continuing. The oldest dune ridge was sampled close to its top and dated to about 600 years ago (Dörschner et al. 2012). About 3 km upstream, a sedimentary sequence at the river bank has been studied, comprising a lower silty deposit with organic remnants and layered tree trunks at its top. This deposit is considered to be of marine origin, probably a peri-marine situation. This fine-grained sediment is covered by coarse fluvial gravels, indicating one or several catastrophic events in this morphological environment. Above the gravels, another fine-grained sediment related to flood events with low energy has been found. Radiocarbon analyses of organic material in both fine

  2. Climate-driven sediment aggradation and incision phases since the Late Pleistocene in the NW Himalaya, India

    NASA Astrophysics Data System (ADS)

    Dey, Saptarshi; Thiede, Rasmus C.; Schildgen, Taylor F.; Wittmann, Hella; Bookhagen, Bodo; Scherler, Dirk; Jain, Vikrant; Strecker, Manfred R.

    2016-04-01

    Deciphering the response of sediment routing systems to climatic forcing is fundamental for understanding the impacts of climate change on landscape evolution and depositional systems. In the Sub-Himalaya, late Pleistocene to Holocene alluvial fills and fluvial terraces record periodic fluctuations of sediment supply and transport capacity on timescale of 103 to 105 years, most likely related to past climatic fluctuations. To evaluate the climatic control on sediment supply and transport capacity, we analyze remnant alluvial fans and terraces in the Kangra Basin of the northwestern Sub-Himalaya. Based on field observations and OSL and CRN-dating, we recognized two sedimentary cycles with major sediment aggradation and subsequent re-incision phases. The large one developed over the entire last glacial period with ˜200 m high alluvial fan (AF1) and the second one during the latest Pleistocene/Holocene with ˜50 m alluvial fan (AF2) and its re-incision . Surface-exposure dating of six terrace levels with in-situ cosmogenic nuclides (10Be) indicates the onset of channel abandonment and ensuing incision phases. Two terrace surfaces from the highest level (T1) sculpted into the oldest-preserved AF1 dates back to 48.9 ± 4.1 ka and 42.1 ± 2.7 ka (2σ error). T2 surfaces sculpted into the remnants of AF1 have exposure ages of 16.8 ± 2 ka and 14.1 ± 0.9 ka, while terraces sculpted into the late Pleistocene- Holocene fan (AF2) provide ages of 8.4± 0.8 ka, 6.6± 0.7 ka, 4.9± 0.4 ka and 3.1± 0.3 ka. Together with previously-published ages on the timing of aggradation, we find a correlation between variations in sediment transport with oxygen-isotope records from regions affected by Indian Summer Monsoon. During stronger monsoon phases and post-LGM glacial retreat manifested by increased sediment delivery (moraines and hillslope-derived) to the trunk streams, causing aggradation in the basin; whereas, weakened monsoon phases characterized by reduced sediment

  3. Immune Regulatory Mechanisms in Allergic Conjunctivitis

    PubMed Central

    Niederkorn, Jerry Y.

    2008-01-01

    Purpose of review This review highlights recent findings regarding the immune regulation of allergic conjunctivitis (AC). Mouse models have facilitated prospective studies that have not been possible in patients. The availability of gene knockout mice and the wealth of monoclonal antibodies have permitted exquisite dissection of the pathophysiology and immune regulation of AC. Recent findings New insights have emerged in three areas: a) role of costimulatory molecules in the induction of Th2 immune responses; b) crucial role of interferon-γ (IFN-γ) in the expression of AC; and c) the function of T regulatory cells in shaping conjunctival inflammation once the immune response has been initiated. Summary Allergic conjunctivitis involves early phase and late phase reactions. The early phase reaction (EPR) is IgE antibody-dependent, while the late phase reaction (LPR) is IgE-independent and is mediated by inflammatory cells, especially eosinophils. Recent studies in mouse models of AC have provided important insights into the immune regulation of both the EPR and LPR of AC. Mounting evidence suggests that IFN-γ is crucial for optimum expression of AC. Costimulatory molecules influence the induction of Th2 immune responses and the EPR while regulatory T cells shape the expression of the LPR of AC. PMID:18769204

  4. BCR-ABL transcript variations in chronic phase chronic myelogenous leukemia patients on imatinib first-line: Possible role of the autologous immune system.

    PubMed

    Clapp, Geoffrey D; Lepoutre, Thomas; Nicolini, Franck E; Levy, Doron

    2016-05-01

    Many chronic myelogenous leukemia (CML) patients in chronic phase who respond well to imatinib therapy show fluctuations in their leukemic loads in the long-term. We developed a mathematical model of CML that incorporates the intervention of an autologous immune response. Our results suggest that the patient's immune system plays a crucial role in imatinib therapy in maintaining disease control over time. The observed BCR-ABL/ABL oscillations in such patients provide a signature of the autologous immune response. PMID:27467931

  5. CFD modeling of debris melting phenomena during late phase Candu 6 severe accident

    SciTech Connect

    Nicolici, S.; Dupleac, D.; Prisecaru, I.

    2012-07-01

    The objective of this paper was to study the phase change of the debris formed on the Candu 6 calandria bottom in a postulated accident sequence. The molten pool and crust formation were studied employing the Ansys-Fluent code. The 3D model using Large Eddy Simulation (LES) predicts the conjugate, radiative and convective heat transfer inside and from the corium pool. LES simulations require a very fine grid to capture the crust formation and the free convection flow. This aspect (fine mesh requirement) correlated with the long transient has imposed the use of a slice from the 3D calandria geometry in order not to exceed the computing resources. The preliminary results include heat transfer coefficients, temperature profiles and heat fluxes through calandria wall. From the safety point of view it is very important to maintain a heat flux through the wall below the CHF assuring the integrity of the calandria vessel. This can be achieved by proper cooling of the tank water which contains the vessel. Also, transient duration can be estimated being important in developing guidelines for severe accidents management. The debris physical structure and material properties have large uncertainties in the temperature range of interest. Thus, further sensitivity studies should be carried out in order to better understand the influence of these parameters on this complex phenomenon. (authors)

  6. Late Quaternary landscape development at the margin of the Pomeranian phase (MIS 2) near Lake Wygonin (Northern Poland)

    NASA Astrophysics Data System (ADS)

    Hirsch, Florian; Schneider, Anna; Nicolay, Alexander; Błaszkiewicz, Mirosław; Kordowski, Jarosław; Noryskiewicz, Agnieszka M.; Tyszkowski, Sebastian; Raab, Alexandra; Raab, Thomas

    2015-04-01

    In Central Europe, Late Quaternary landscapes experienced multiple phases of geomorphologic activity. In this study,we used a combined geomorphological, pedological, sedimentological and palynological approach to characterize landscape development after the Last Glacial Maximum (LGM) near Lake Wygonin in Northern Poland. The pedostratigraphical findings from soil pits and drillings were extrapolated using ground-penetrating radar (GPR) and electric resistivity tomography (ERT). During the Pomeranian phase, glacial and fluvioglacial processes dominated the landscape near Lake Wygonin. At the end of the glacial period, periglacial processes became relevant and caused the formation of ventifacts and coversands containing coated sand grains. At approximately 15,290-14,800 cal yr BP, a small pond formed in a kettle hole (profile BWI2). The lacustrine sediments lack eolian sand components and therefore indicate the decline of eolian processes during that time. The increase of Juniperus and rock-rose (Helianthemum) in the pollen diagram is a prominent marker of the Younger Dryas. At the end of the Younger Dryas, a partial reshaping of the landscape is indicated by abundant charcoal fragments in disturbed lake sediments. No geomorphologic activity since the beginning of the Holocene is documented in the terrestrial and wetland archives. The anthropogenic impact is reflected in the pollen diagram by the occurrence of rye pollen grains (Cerealia type, Secale cereale) and translocated soil sediments dated to 1560-1410 cal yr BP, proving agricultural use of the immediate vicinity. With the onset of land use, gully incision and the accumulation of colluvial fans reshaped the landscape locally. Since 540-460 cal yr BP, further gully incision in the steep forest tracks has been associated with the intensification of forestry. Outside of the gully catchments, the weakly podzolized Rubic Brunic Arenosols show no features of Holocene soil erosion. Reprinted from CATENA, Volume 124

  7. Babesia divergens apical membrane antigen-1 (BdAMA-1): A poorly polymorphic protein that induces a weak and late immune response.

    PubMed

    Moreau, E; Bonsergent, C; Al Dybiat, I; Gonzalez, L M; Lobo, C A; Montero, E; Malandrin, L

    2015-08-01

    Babesiosis is an important veterinary and zoonotic tick borne disease caused by the hemoprotozoan Babesia spp. which infects red blood cell of its vertebrate host. In order to control the infection, vaccination that targets molecules involved in the invasion process of red blood cells could provide a good alternative to chemotherapy. Among these molecules, Apical Membrane Antigen-1 (AMA-1) has been described as an excellent vaccine candidate in Plasmodium spp. In this paper, we have investigated AMA-1 of Babesia divergens (BdAMA-1) as vaccine candidate by evaluating its polymorphism and by studying the humoral response against BdAMA-1 of sheep experimentally infected with B. divergens. Polymorphism of BdAMA-1 was investigated by sequencing the corresponding gene of 9 B. divergens isolates from different geographical areas in France. Two Bdama-1 haplotypes (A and B) could be defined based on 2 non-synonymous point mutations. In silico prediction of linear epitopes revealed that the antigenicity of the 2 haplotypes is very similar. Antibody production against the extracellular domain of BdAMA-1 is weak and late, between 1 and 5 months after the inoculation of parasites. Both IgG1 and IgG2 are components of the anti-BdAMA-1 response. These results indicate that while BdAMA-1 may not be an immuno-dominant antigen, it could induce a mixed type 1 and type 2 immune response. In light of these results, the potential of BdAMA-1 as vaccine candidate is discussed. PMID:25956948

  8. MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase

    PubMed Central

    Wang, Huafeng; Hung, Chiung Yu; Sinha, Meenal; Lee, Linda M.; Wiesner, Darin L.; LeBert, Vanessa; Lerksuthirat, Tassanee; Suresh, Marulasiddappa; DeFranco, Anthony L.; Lowell, Clifford A.; Klein, Bruce S.; Wüthrich, Marcel

    2016-01-01

    Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells. The poor survival of activated T cells in Myd88-/- mice is linked to increased caspase3-mediated apoptosis, but not to Fas- or Bim-dependent apoptotic pathways, nor to reduced expression of the anti-apoptotic molecules Bcl-2 or Bcl-xL. Moreover, TLR3, 7, and/or 9, but not TLR2 or 4, also were required extrinsically for MyD88-dependent Th17 cell responses and vaccine immunity. Similar MyD88 requirements governed the survival of virus primed T cells. Our data identify unappreciated new requirements for eliciting adaptive immunity and have implications for designing vaccines. PMID:27542117

  9. Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial

    PubMed Central

    2013-01-01

    Background The Montpellier cancer institute phase II trial started in 2004 and evaluated the feasibility of intraoperative radiotherapy (IORT) technique given as a sole radiation treatment for patients with an excellent prognostic and very low recurrence risk. Methods Forty-two patients were included between 2004 and 2007. Inclusion criteria were patients ≥ 65 years old, T0-T1, N0, ductal invasive unifocal carcinoma, free-margin > 2 mm. IORT was delivered using dedicated linear accelerator. One fraction of 21 Gy was prescribed and specified at the 90% isodose using electrons. In vivo dosimetry was performed for all patients. Primary end-point was the quality index. Secondary endpoints were quality of life, local recurrences, cosmetic results, specific and overall survival. Results At inclusion, median age was 72 years (range, 66–80). Median tumor diameter was 10 mm. All patients received the total prescribed dose. No acute grade 3 toxicities were observed. Late cosmetic results were good at 5 years despite the poor agreement of accuracy assessment between patients and physicians. Four patients (9.5%) experienced a local failure and underwent salvage mastectomy. The 5 year-disease free survival is 92.7% (range 79.1−97.6). All patients are still alive with a median follow-up of 72 months (range 66–74). Conclusion Our results confirm with a long-term follow-up that exclusive partial breast IORT is feasible for early-breast cancer in selected patients. IORT provides good late cosmetics results and should be considered as a safe and very comfortable “one-step” treatment procedure. Nevertheless, patient assessments are essential for long-term quality results. PMID:23902825

  10. Disease Severity Is Associated with Differential Gene Expression at the Early and Late Phases of Infection in Nonhuman Primates Infected with Different H5N1 Highly Pathogenic Avian Influenza Viruses

    PubMed Central

    Muramoto, Yukiko; Shoemaker, Jason E.; Le, Mai Quynh; Itoh, Yasushi; Tamura, Daisuke; Sakai-Tagawa, Yuko; Imai, Hirotaka; Uraki, Ryuta; Takano, Ryo; Kawakami, Eiryo; Ito, Mutsumi; Okamoto, Kiyoko; Ishigaki, Hirohito; Mimuro, Hitomi; Sasakawa, Chihiro; Matsuoka, Yukiko; Noda, Takeshi; Fukuyama, Satoshi; Ogasawara, Kazumasa; Kitano, Hiroaki

    2014-01-01

    ABSTRACT Occasional transmission of highly pathogenic avian H5N1 influenza viruses to humans causes severe pneumonia with high mortality. To better understand the mechanisms via which H5N1 viruses induce severe disease in humans, we infected cynomolgus macaques with six different H5N1 strains isolated from human patients and compared their pathogenicity and the global host responses to the virus infection. Although all H5N1 viruses replicated in the respiratory tract, there was substantial heterogeneity in their replicative ability and in the disease severity induced, which ranged from asymptomatic to fatal. A comparison of global gene expression between severe and mild disease cases indicated that interferon-induced upregulation of genes related to innate immunity, apoptosis, and antigen processing/presentation in the early phase of infection was limited in severe disease cases, although interferon expression was upregulated in both severe and mild cases. Furthermore, coexpression analysis of microarray data, which reveals the dynamics of host responses during the infection, demonstrated that the limited expression of these genes early in infection led to a failure to suppress virus replication and to the hyperinduction of genes related to immunity, inflammation, coagulation, and homeostasis in the late phase of infection, resulting in a more severe disease. Our data suggest that the attenuated interferon-induced activation of innate immunity, apoptosis, and antigen presentation in the early phase of H5N1 virus infection leads to subsequent severe disease outcome. IMPORTANCE Highly pathogenic avian H5N1 influenza viruses sometimes transmit to humans and cause severe pneumonia with ca. 60% lethality. The continued circulation of these viruses poses a pandemic threat; however, their pathogenesis in mammals is not fully understood. We, therefore, investigated the pathogenicity of six H5N1 viruses and compared the host responses of cynomolgus macaques to the virus

  11. CHARACTERIZATION OF IMMEDIATE AND LATE PHASE AIRWAY RESPONSES TO HOUSE DUST MITE CHALLENGE IN BROWN NORWAY RATS AND CORRELATIONS AMONG PHYSIOLOGICAL MEDIATORS

    EPA Science Inventory

    CHARACTERIZATION OF IMMEDIATE AND LATE PHASE AIRWAY RESPONSES TO HOUSE DUST MITE CHALLENGE IN BROWN NORWAY RATS AND CORRELATIONS AMONG PATHOPHYSIOLOGICAL MEDIATORS (P.
    SinghI, D.W. Winsett2, M.J. Daniels2, J. Richards2, K. Crissman2, D.L. Doerfler2 and M.I. Gilmour2, 1NCSU, Ra...

  12. HSP70.1 AND -70.3 ARE REQUIRED FOR LATE-PHASE PROTECTION INDUCED BY ISCHEMIC PRECONDITIONING OF MOUSE HEARTS

    EPA Science Inventory

    Heat-Shock Proteins 70.1 and 70.3 Are Required for Late-phase Protection
    Induced by Ischemic Preconditioning of the Mouse Heart
    Craig R. Hampton 1 , Akira Shimamoto 1 , Christine L. Rothnie 1 , Jeaneatte Griscavage-Ennis 1 ,
    Albert Chong 1 , David J. Dix 2 , Edward D. Ve...

  13. The Late S-Phase Transcription Factor Hcm1 Is Regulated through Phosphorylation by the Cell Wall Integrity Checkpoint

    PubMed Central

    Negishi, Takahiro; Veis, Jiri; Hollenstein, David; Sekiya, Mizuho; Ammerer, Gustav

    2016-01-01

    The cell wall integrity (CWI) checkpoint in the budding yeast Saccharomyces cerevisiae coordinates cell wall construction and cell cycle progression. In this study, we showed that the regulation of Hcm1, a late-S-phase transcription factor, arrests the cell cycle via the cell wall integrity checkpoint. Although the HCM1 mRNA level remained unaffected when the cell wall integrity checkpoint was induced, the protein level decreased. The overproduction of Hcm1 resulted in the failure of the cell wall integrity checkpoint. We identified 39 Hcm1 phosphorylation sites, including 26 novel sites, by tandem mass spectrometry analysis. A mutational analysis revealed that phosphorylation of Hcm1 at S61, S65, and S66 is required for the proper onset of the cell wall integrity checkpoint by regulating the timely decrease in its protein level. Hyperactivation of the CWI mitogen-activated protein kinase (MAPK) signaling pathway significantly reduced the Hcm1 protein level, and the deletion of CWI MAPK Slt2 resulted in a failure to decrease Hcm1 protein levels in response to stress, suggesting that phosphorylation is regulated by CWI MAPK. In conclusion, we suggest that Hcm1 is regulated negatively by the cell wall integrity checkpoint through timely phosphorylation and degradation under stress to properly control budding yeast proliferation. PMID:26729465

  14. Subarachnoid hemorrhage in the rat: cerebral blood flow and glucose metabolism during the late phase of cerebral vasospasm

    SciTech Connect

    Delgado, T.J.; Arbab, M.A.; Diemer, N.H.; Svendgaard, N.A.

    1986-10-01

    A double-isotope technique for the simultaneous measurement of CBF and CMRglu was applied to a subarachnoid hemorrhage (SAH) model in the rat. Cisternal injection of 0.07 ml blood caused a rather uniform 20% reduction in CBF together with an increase in glucose utilization of 30% during the late phase of vasospasm. In one-third of the SAH animals, there were focal areas where the flow was lowered to 30% of the control values and the glucose uptake increased to approximately 250% of control. We suggest that blood in the subarachnoid space via a neural mechanism induces the global flow and metabolic changes, and that the foci are caused by vasospasm superimposed on the global flow and metabolic changes. In the double-isotope autoradiographic technique, (/sup 14/C)iodoantipyrine and (/sup 3/H)deoxyglucose were used for CBF and CMRglu measurements, respectively, in the same animal. In half of the sections, the (/sup 14/C)iodoantipyrine was extracted using 2,2-dimethoxypropane before the section was placed on a /sup 3/H- and /sup 14/C-sensitive film. The other sections were placed on x-ray film with an emulsion insensitive to /sup 3/H. The validity of the double-isotope method was tested by comparing the data with those obtained in animals receiving a single isotope. The CBF and metabolic values obtained in the two groups were similar.

  15. MELCOR 1.8.2 assessment: The MP-1 and MP-2 late phase melt progression experiments

    SciTech Connect

    Tautges, T.J.

    1994-05-01

    MELCOR is a fully integrated, engineering-level computer code being developed at Sandia National Laboratories for the USNRC, that models the entire spectrum of severe accident phenomena in a unified framework for both BWRs and PWRs. As a part of an ongoing assessment program, MELCOR has been used to model the MP-1 and MP-2 experiments, which provided data for late-phase melt progression in PWR geometries. Core temperature predicted by MELCOR were within 250--500 K of measured data in both MP-1 and MP-2. Relocation in the debris bed and metallic crust regions of MP-2 was predicted accurately compared to PIE data. Temperature gradients in lower portions of the test bundle were not predicted well in both MP-1 and MP-2, due to the lack of modeling of the heat transfer path to the cooling jacket in those portions of the test bundles. Fifteen sensitivity studies were run on various core (COR), control volume hydrodynamics (CVH) and heat structures (HS) package parameters. No unexpected sensitivities were found, and in particular there were no sensitivities to reduced time step, finer nodalization or to computer platform. Calculations performed by the DEBRIS and TAC2D codes for MP-1 and MP-2 showed better agreement with measured data than those performed by MELCOR. This was expected, through, due to the fully 2-dimensional modeling used in the other codes.

  16. Status Update on the NCRP Scientific Committee SC 5-1 Report: Decision Making for Late-Phase Recovery from Nuclear or Radiological Incidents - 13450

    SciTech Connect

    Chen, S.Y.

    2013-07-01

    In August 2008, the U.S. Department of Homeland Security (DHS) issued its final Protective Action Guide (PAG) for radiological dispersal device (RDD) and improvised nuclear device (IND) incidents. This document specifies protective actions for public health during the early and intermediate phases and cleanup guidance for the late phase of RDD or IND incidents, and it discusses approaches to implementing the necessary actions. However, while the PAG provides specific guidance for the early and intermediate phases, it prescribes no equivalent guidance for the late-phase cleanup actions. Instead, the PAG offers a general description of a complex process using a site-specific optimization approach. This approach does not predetermine cleanup levels but approaches the problem from the factors that would bear on the final agreed-on cleanup levels. Based on this approach, the decision-making process involves multifaceted considerations including public health, the environment, and the economy, as well as socio-political factors. In an effort to fully define the process and approach to be used in optimizing late-phase recovery and site restoration following an RDD or IND incident, DHS has tasked the NCRP with preparing a comprehensive report addressing all aspects of the optimization process. Preparation of the NCRP report is a three-year (2010-2013) project assigned to a scientific committee, the Scientific Committee (SC) 5-1; the report was initially titled, Approach to Optimizing Decision Making for Late- Phase Recovery from Nuclear or Radiological Terrorism Incidents. Members of SC 5-1 represent a broad range of expertise, including homeland security, health physics, risk and decision analysis, economics, environmental remediation and radioactive waste management, and communication. In the wake of the Fukushima nuclear accident of 2011, and guided by a recent process led by the White House through a Principal Level Exercise (PLE), the optimization approach has since

  17. A quantitative histological study of strain-dependent differences in the effects of irradiation on mouse lung during the intermediate and late phases

    SciTech Connect

    Sharplin, J.; Franko, A.J. )

    1989-07-01

    Strain differences in the intermediate and late phases of the radiation response of mouse lung were investigated histologically. The proportion of lung impairment in mice at 28 and 52 weeks postirradiation and in mice dying of respiratory insufficiency was assessed by scoring lung acini as nonfunctional due to lesions which obstructed airflow, or open and presumably functional. The nine strains tested were divided into three groups on the basis of the late fibrotic response. Group 1 mice, three C57 strains, developed extensive contracted fibrosis and usually showed enough damage to explain late deaths. Group 2, SWR, A, and BALB/c strains, developed foci of contracted fibrosis. Group 3, CBA and two C3H strains, did not form fibrotic scars. Mice in Groups 2 and 3 that died with no pleural effusions appeared to have insufficient late lung damage to account for respiratory distress. Problems with pulmonary blood flow were indicated by evidence of loss of fine vasculature and right ventricular hypertrophy. In nondistressed, late-stage mice in Groups 2 and 3, loss of capillary perfusion in lung parenchyma free of obvious lesions was demonstrated by infusion of colloidal carbon. In one strain, A, an estimate of the proportion of nonperfused lung was made on distressed late-stage mice. Almost 50% of lung acini were nonfunctional as a result of nonperfusion, and an additional 9% of acini were nonfunctional due to lesions obstructing ventilation. It is suggested that nonperfusion of apparently normal lung acini is a major factor in late-phase deaths in those mouse strains which show little or no fibrosis.

  18. An injectable, low-toxicity phospholipid-based phase separation gel that induces strong and persistent immune responses in mice.

    PubMed

    Han, Lu; Xue, Jiao; Wang, Luyao; Peng, Ke; Zhang, Zhirong; Gong, Tao; Sun, Xun

    2016-10-01

    Sustained antigen delivery using incomplete Freund's adjuvant (IFA) can induce strong, long-term immune response, but it can also cause severe side effects. Here we describe an injectable, phospholipid-based phase separation gel (PPSG) that readily transforms in situ into a drug depot. PPSG loaded with the model antigen ovalbumin (OVA) supported sustained OVA release in mice that lasted nearly one month. Immunizing mice with a single injection of PPSG/OVA elicited a strong and persistent increase in titers of OVA-specific IgG, IgG1 and IgG2a. Co-administering CpG-ODN further increased antibody titers. Such co-administration recruited dendritic cells to injection sites and activated dendritic cells in the draining lymph nodes. Moreover, immunization with PPSG/OVA/CpG resulted in potent memory antibody responses and high frequency of memory T cells. Remarkably, PPSG/OVA/CpG was associated with much lower toxicity at injection sites than IFA/OVA/CpG, and it showed no systemic toxicity such as to lymph nodes or spleen. These findings illustrate the potential of injectable PPSG for sustained, minimally toxic delivery of antigens and adjuvants. PMID:27522253

  19. Differential signaling circuits in regulation of ultraviolet C light-induced early- and late-phase activation of NF-κB.

    PubMed

    Wu, Shiyong; Tong, Lingying

    2010-01-01

    Ultraviolet C light (UVC) induces nuclear factor-kappa B (NF-κB) activation via a complex network. In the early phase (4-12 h) of irradiation, NF-κB activation is accompanied with IκBα reduction via a translation inhibition pathway. In the late phase of UVC-induced NF-κB activation (16-24 h), the IκBα depletion is a combined result of regulation at both transcriptional and translational levels. However, the NF-κB activation appears to be independent of the level of IκBα. In this review, we will discuss the multiple signaling circuits that regulate NF-κB activation during the early and late phases of UVC irradiation. PMID:20553411

  20. Simultaneous phase-shifting interferometry: immune to azimuth error of fast-axes in retarder array.

    PubMed

    Zheng, Donghui; Chen, Lei; Li, Jinpeng; Gu, Chenfeng; Zhu, Wenhua; Han, Zhigang

    2015-11-20

    Simultaneous phase-shifting interferometry based on a 2×2 retarder array with random fast-axes (RARF-SPSI) is proposed for real-time wavefront measurements. The retarder array is used as the phase-shift component, where the phase retardances are π/2, π, 3π/2, and 2π and the four fast-axes of the four retarders can be somewhat random. In this paper, the mathematical model of RARF-SPSI is built by using a Stokes vector and a Mueller matrix, the phase demodulation method through solving equations is derived, and the coefficient matrix of the equations that is associated with the azimuth of the fast-axes is calculated by Fourier analysis. Then the corresponding simulation analysis is executed. In the experiment, four simultaneous phase-shifting interferograms are captured and the phase distribution under test is demodulated through the proposed method. Compared with the four-bucket phase-shifting algorithm adopted in traditional simultaneous phase-shifting interferometry, the ripple error is suppressed well. The advantage of the proposed RARF-SPSI is that there is no need to calibrate the fast-axes of the phase-shift component before measuring; in other words, the phase demodulation error caused by the azimuth error of fast-axes is eliminated. PMID:26836541

  1. Post lung-stage schistosomula of Schistosoma mansoni exhibit transient susceptibility to macrophage-mediated cytotoxicity in vitro that may relate to late phase killing in vivo.

    PubMed

    Pearce, E J; James, S L

    1986-09-01

    Studies of protective immunity against Schistosoma mansoni in immunized mice suggest that a proportion of challenge parasites may be eliminated after they have passed through the lungs of the host several days after infection; however, no potential immune effector mechanism of resistance against this stage of the parasite has yet been identified, since schistosomes have been shown to rapidly become resistant to antibody-dependent killing mechanisms. In this study, different development stages of S. mansoni were examined for their susceptibility to in vitro cytotoxicity by lymphokine-activated macrophages. As previously shown, newly transformed larvae were readily killed by lymphokine-treated peritoneal macrophages or the macrophage cell line IC-21 (80% mortality over 48 h in vitro), whereas 7 and 10 day old lung-stage parasites had become refractory to macrophage effects. However, after 2 to 2 1/2 weeks of development in vivo, juvenile parasites recovered from the liver were again susceptible to activated macrophage-mediated cytotoxicity (25-65% mortality). Ultrastructural studies of 2 1/2 week old parasites co-cultured with activated IC-21 cells revealed that damage was largely restricted to the areas beneath the parasite surface and gut syncitia; surface membrane disruption was not evident. This late stage of susceptibility was transient and by 4 to 6 weeks liver-stage worms had again become refractory to macrophage killing. The interaction of post lung-stage parasites with activated macrophages was antibody independent. Furthermore, schistosomes isolated from the portal circulation 2 1/2 weeks after infection showed no evidence of surface-bound immunoglobulin in a quantitative immunofluorescence assay, nor did antisera from chronically infected mice (CIS) or mice vaccinated with irradiated cercariae (VS) react with the surface of these parasites in vitro, making the possibility of direct antibody-dependent killing mechanisms unlikely. However, both CIS and VS

  2. Distinguishing Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion from Prolonged Febrile Seizures by Acute Phase EEG Spectrum Analysis

    PubMed Central

    Oguri, Masayoshi; Saito, Yoshiaki; Fukuda, Chisako; Kishi, Kazuko; Yokoyama, Atsushi; Lee, Sooyoung; Torisu, Hiroyuki; Toyoshima, Mitsuo; Sejima, Hitoshi; Kaji, Shunsaku; Hamano, Shin-ichiro; Okanishi, Toru; Tomita, Yutaka; Maegaki, Yoshihiro

    2016-01-01

    Background To differentiate the features of electroencephalography (EEG) after status epileptics in febrile children with final diagnosis of either febrile seizure (FS) or acute encephalopathy for an early diagnosis. Methods We retrospectively collected data from 68 children who had status epilepticus and for whom EEGs were recorded within 120 h. These included subjects with a final diagnosis of FS (n = 20), epileptic status (ES; n = 11), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 18), mild encephalopathy with a reversible splenial lesion (MERS; n = 7), other febrile encephalopathies (n = 10), hypoxic-ischemic encephalopathy (n = 1), and intracranial bleeding (n = 1). Initially, all EEGs were visually assessed and graded, and correlation with outcome was explored. Representative EEG epochs were then selected for quantitative analyses. Furthermore, data from AESD (n = 7) and FS (n = 16) patients for whom EEG was recorded within 24 h were also compared. Results Although milder and most severe grades of EEG correlated with neurological outcome, the outcome of moderate EEG severity group was variable and was not predictable from usual inspection. Frequency band analysis revealed that solid delta power was not significantly different among the five groups (AESD, MERS, FS, ES and control), and that MERS group showed the highest theta band power. The ratios of delta/alpha and (delta + theta)/(alpha + beta) band powers were significantly higher in the AESD group than in other groups. The alpha and beta band powers in EEGs within 24 h from onset were significantly lower in the AESD group. The band powers and their ratios showed earlier improvement towards 24 h in FS than in AESD. Conclusion Sequential EEG recording up to 24 h from onset appeared to be helpful for distinction of AESD from FS before emergence of the second phase of AESD. PMID:27046946

  3. The Human Cytomegalovirus-Specific UL1 Gene Encodes a Late-Phase Glycoprotein Incorporated in the Virion Envelope

    PubMed Central

    Shikhagaie, Medya; Mercé-Maldonado, Eva; Isern, Elena; Muntasell, Aura; Albà, M. Mar; López-Botet, Miguel; Hengel, Hartmut

    2012-01-01

    We have investigated the previously uncharacterized human cytomegalovirus (HCMV) UL1 open reading frame (ORF), a member of the rapidly evolving HCMV RL11 family. UL1 is HCMV specific; the absence of UL1 in chimpanzee cytomegalovirus (CCMV) and sequence analysis studies suggest that UL1 may have originated by the duplication of an ancestor gene from the RL11-TRL cluster (TRL11, TRL12, and TRL13). Sequence similarity searches against human immunoglobulin (Ig)-containing proteins revealed that HCMV pUL1 shows significant similarity to the cellular carcinoembryonic antigen-related (CEA) protein family N-terminal Ig domain, which is responsible for CEA ligand recognition. Northern blot analysis revealed that UL1 is transcribed during the late phase of the viral replication cycle in both fibroblast-adapted and endotheliotropic strains of HCMV. We characterized the protein encoded by hemagglutinin (HA)-tagged UL1 in the AD169-derived HB5 background. UL1 is expressed as a 224-amino-acid type I transmembrane glycoprotein which becomes detectable at 48 h postinfection. In infected human fibroblasts, pUL1 colocalized at the cytoplasmic site of virion assembly and secondary envelopment together with TGN-46, a marker for the trans-Golgi network, and viral structural proteins, including the envelope glycoprotein gB and the tegument phosphoprotein pp28. Furthermore, analyses of highly purified AD169 UL1-HA epitope-tagged virions revealed that pUL1 is a novel constituent of the HCMV envelope. Importantly, the deletion of UL1 in HCMV TB40/E resulted in reduced growth in a cell type-specific manner, suggesting that pUL1 may be implicated in regulating HCMV cell tropism. PMID:22345456

  4. Immune cells in the female reproductive tract.

    PubMed

    Lee, Sung Ki; Kim, Chul Jung; Kim, Dong-Jae; Kang, Jee-Hyun

    2015-02-01

    The female reproductive tract has two main functions: protection against microbial challenge and maintenance of pregnancy to term. The upper reproductive tract comprises the fallopian tubes and the uterus, including the endocervix, and the lower tract consists of the ectocervix and the vagina. Immune cells residing in the reproductive tract play contradictory roles: they maintain immunity against vaginal pathogens in the lower tract and establish immune tolerance for sperm and an embryo/fetus in the upper tract. The immune system is significantly influenced by sex steroid hormones, although leukocytes in the reproductive tract lack receptors for estrogen and progesterone. The leukocytes in the reproductive tract are distributed in either an aggregated or a dispersed form in the epithelial layer, lamina propria, and stroma. Even though immune cells are differentially distributed in each organ of the reproductive tract, the predominant immune cells are T cells, macrophages/dendritic cells, natural killer (NK) cells, neutrophils, and mast cells. B cells are rare in the female reproductive tract. NK cells in the endometrium significantly expand in the late secretory phase and further increase their number during early pregnancy. It is evident that NK cells and regulatory T (Treg) cells are extremely important in decidual angiogenesis, trophoblast migration, and immune tolerance during pregnancy. Dysregulation of endometrial/decidual immune cells is strongly related to infertility, miscarriage, and other obstetric complications. Understanding the immune system of the female reproductive tract will significantly contribute to women's health and to success in pregnancy. PMID:25713505

  5. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials.

    PubMed

    Galipeau, Jacques; Krampera, Mauro; Barrett, John; Dazzi, Francesco; Deans, Robert J; DeBruijn, Joost; Dominici, Massimo; Fibbe, Willem E; Gee, Adrian P; Gimble, Jeffery M; Hematti, Peiman; Koh, Mickey B C; LeBlanc, Katarina; Martin, Ivan; McNiece, Ian K; Mendicino, Michael; Oh, Steve; Ortiz, Luis; Phinney, Donald G; Planat, Valerie; Shi, Yufang; Stroncek, David F; Viswanathan, Sowmya; Weiss, Daniel J; Sensebe, Luc

    2016-02-01

    Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an "open-access" manner, such as through publication or database collection. PMID:26724220

  6. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials

    PubMed Central

    Galipeau, Jacques; Krampera, Mauro; Barrett, John; Dazzi, Francesco; Deans, Robert J.; Debruijn, Joost; Dominici, Massimo; Fibbe, Willem E.; Gee, Adrian P.; Gimble, Jeffery M.; Hematti, Peiman; Koh, Mickey B.C.; Leblanc, Katarina; Martin, Ivan; Mcniece, Ian K.; Mendicino, Michael; Oh, Steve; Ortiz, Luis; Phinney, Donald G.; Planat, Valerie; Shi, Yufang; Stroncek, David F.; Viswanathan, Sowmya; Weiss, Daniel J.; Sensebe, Luc

    2016-01-01

    Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an “open-access” manner, such as through publication or database collection. PMID:26724220

  7. Peripheral therapeutic ultrasound stimulation alters the distribution of spinal C-fos immunoreactivity induced by early or late phase of inflammation.

    PubMed

    Hsieh, Yueh-Ling

    2008-03-01

    The purpose of this investigation was to examine the central modulated effects of therapeutic ultrasound (US) on neuronal activity in the spinal cord on early and late phases of inflammation. In this study, induction of c-Fos protein, which reflects neuronal activation (particularly inflammatory nociception), was investigated in the lumbar spinal cord with immunohistochemistry. Inflammatory monoarthritis was induced in 20 male Wistar rats (weighing 250-300 g) via intra-articular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. Two phases of arthritis, early phase (18 h after adjuvant injection) and late phase (7 d after adjuvant injection), were studied in the rats. Pulsed-mode US (1 MHz, the spatial average temporal average intensity [I(SATA)] = 0.5 W/cm(2), 50% duty cycle) was applied for 5 min. The effects of US and sham treatments against these phases of arthritis were demonstrated by spinal c-Fos-like immunoreactivity (c-Fos-LI). All data were evaluated statistically with the paired t-test or analysis of variance with Bonferroni corrections. c-Fos-LI neurons were abundant (average 264.2 +/- 11.9) in the L3 and L4 neurons of the spinal cord in areas ipsilateral to the CFA-induced arthritic leg in the early phase, but few were present (average 40.4 +/- 4.5) in the late phase in sham-treated animals. Bonferroni corrections to the alpha level were used to check the group differences in spinal c-Fos expression, and significance was reached when p < 0.025. In the early inflammatory phase, US treatment significantly suppressed the increased number of c-Fos-LI neurons associated with CFA-induced arthritis in superficial laminae, nucleus proprius, deep laminae and ventral horn of the spinal cord. However, during the late inflammatory phase, US significantly triggered c-Fos expression in most laminae, particularly in the nucleus proprius, deep laminae and ventral horn of the spinal cord. The results of our study suggest that administration of US

  8. Differential effects of early- and late-life access to carotenoids on adult immune function and ornamentation in mallard ducks (Anas platyrhynchos).

    PubMed

    Butler, Michael W; McGraw, Kevin J

    2012-01-01

    Environmental conditions early in life can affect an organism's phenotype at adulthood, which may be tuned to perform optimally in conditions that mimic those experienced during development (Environmental Matching hypothesis), or may be generally superior when conditions during development were of higher quality (Silver Spoon hypothesis). Here, we tested these hypotheses by examining how diet during development interacted with diet during adulthood to affect adult sexually selected ornamentation and immune function in male mallard ducks (Anas platyrhynchos). Mallards have yellow, carotenoid-pigmented beaks that are used in mate choice, and the degree of beak coloration has been linked to adult immune function. Using a 2 × 2 factorial experimental design, we reared mallards on diets containing either low or high levels of carotenoids (nutrients that cannot be synthesized de novo) throughout the period of growth, and then provided adults with one of these two diets while simultaneously quantifying beak coloration and response to a variety of immune challenges. We found that both developmental and adult carotenoid supplementation increased circulating carotenoid levels during dietary treatment, but that birds that received low-carotenoid diets during development maintained relatively higher circulating carotenoid levels during an adult immune challenge. Individuals that received low levels of carotenoids during development had larger phytohemagglutinin (PHA)-induced cutaneous immune responses at adulthood; however, dietary treatment during development and adulthood did not affect antibody response to a novel antigen, nitric oxide production, natural antibody levels, hemolytic capacity of the plasma, or beak coloration. However, beak coloration prior to immune challenges positively predicted PHA response, and strong PHA responses were correlated with losses in carotenoid-pigmented coloration. In sum, we did not find consistent support for either the Environmental

  9. Exercise-induced stress inhibits both the induction and elicitation phases of in vivo T-cell-mediated immune responses in humans.

    PubMed

    Harper Smith, Adam D; Coakley, Sarah L; Ward, Mark D; Macfarlane, Andrew W; Friedmann, Peter S; Walsh, Neil P

    2011-08-01

    Little is known about the influence of exercise on induction and elicitation phases of in vivo immunity in humans. We used experimental contact-hypersensitivity, a clinically relevant in vivo measure of T cell-mediated immunity, to investigate the effects of exercise on induction and elicitation phases of immune responses to a novel antigen. The effects of 2 h-moderate-intensity-exercise upon the induction (Study One) and elicitation of in vivo immune memory (Study Two) to diphenylcyclopropenone (DPCP) were examined. Study One: matched, healthy males were randomly-assigned to exercise (N=16) or control (N=16) and received a primary DPCP exposure (sensitization), 20 min after either 2 h running at 60% V O(2peak) (EX) or 2 h seated rest (CON). Four weeks later, participants received a low, dose-series DPCP challenge (elicitation) on their upper inner arm, which was read at 24 and 48 h as clinical score, oedema (skinfold thickness) and redness (erythema). Study Two: pilot; 13 healthy males were sensitized to DPCP. Elicitation challenges were repeated every 4 weeks until responses reached a reproducible plateau. Then, N=9 from the pilot study completed both EX and CON trials in a randomized order. Elicitation challenges were applied and evaluated as in Study One. Results demonstrate that exercise-induced stress significantly impairs both the induction (oedema -53% at 48 h; P<0.001) and elicitation (oedema -19% at 48 h; P<0.05) phases of the in vivo T-cell-mediated immune response. These findings demonstrate that prolonged moderate-intensity exercise impairs the induction and elicitation phases of in vivo T-cell-mediated immunity. Moreover, the induction component of new immune responses appears more sensitive to systemic-stress-induced modulation than the elicitation component. PMID:21362469

  10. Staphylococcus Coagulase-Positive Skin Inflammation Associated with Epidermal Growth Factor Receptor-Targeted Therapy: An Early and a Late Phase of Papulopustular Eruptions

    PubMed Central

    David, Michael; Stemmer, Salomon M.

    2010-01-01

    Objective. Cutaneous eruptions, mainly papulopustular, are the most common associated side effects of epidermal growth factor receptor inhibitors (EGFRIs). This study investigated the possible role of bacterial infection in EGFRI-induced eruptions and its relation to clinical morphology. Patients and Methods. The study group consisted of all 29 patients referred for dermatologic evaluation of side effects of cetuximab or erlotinib from March 2008 to November 2009. Specimens were taken for bacterial culture from pustules in patients with grade >1 papulopustular rash and from periungual secretions in patients with paronychia. Results. Twenty-four of 29 patients had a papulopustular reaction; five of 29 had paronychia/xerosis. Of the papulopustular eruption patients, time to rash appearance yielded two distinct groups: early-phase, median 8 days after drug initiation, located mainly on the face (n = 17) and late-phase, median ∼200 days after drug initiation, located mainly on the trunk (n = 7). Bacterial culture grew Staphylococcus aureus (SA) in seven of 13 early-phase patients tested and in all late-phase patients. Treatment consisted of topical steroids with or without topical/systemic antibiotics. All patients had a clear improvement in their cutaneous symptoms within a few days. Dose reduction or temporary discontinuation of the EGFRI was necessary in only four of 29 patients. Conclusions. As described in the literature, EGFRI-induced papulopustular eruption may appear early and probably is an inflammatory process with or without SA secondary infection. The papulopustular eruption may also appear as a late phase, described here for the first time, which is an infectious process with all patients being SA+. The >50% overall incidence of SA infection in our study highlights the need for routine bacterial cultures from EGFRI-induced eruption. PMID:20709888

  11. Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

    PubMed

    Kim, Joung Min; Jeong, Seong Wook; Yang, Jihoon; Lee, Seong Heon; Kim, Woon Mo; Jeong, Seongtae; Bae, Hong Beom; Yoon, Myung Ha; Choi, Jeong Il

    2015-07-23

    Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation. PMID:26037417

  12. Cellular immune response in intraventricular experimental neurocysticercosis.

    PubMed

    Moura, Vania B L; Lima, Sarah B; Matos-Silva, Hidelberto; Vinaud, Marina C; Loyola, Patricia R A N; Lino, Ruy S

    2016-03-01

    Neurocysticercosis (NCC) is considered a neglected parasitic infection of the human central nervous system. Its pathogenesis is due to the host immune response, stage of evolution and location of the parasite. The aim of this study was to evaluate the in situ and systemic immune response through cytokines dosage (IL-4, IL-10, IL-17 and IFN-γ) as well as the local inflammatory response of the experimental NCC with Taenia crassiceps. The in situ and systemic cellular and inflammatory immune response were evaluated through the cytokines quantification at 7, 30, 60 and 90 days after inoculation and histopathological analysis. All cysticerci were found within the cerebral ventricles. There was a discrete intensity of inflammatory cells of mixed immune profile, polymorphonuclear and mononuclear cells, at the beginning of the infection and predominance of mononuclear cells at the end. The systemic immune response showed a significant increase in all the analysed cytokines and predominance of the Th2 immune profile cytokines at the end of the infection. These results indicate that the location of the cysticerci may lead to ventriculomegaly. The acute phase of the infection showed a mixed Th1/Th17 profile accompanied by high levels of IL-10 while the late phase showed a Th2 immune profile. PMID:26626017

  13. Immune response

    MedlinePlus

    Innate immunity; Humoral immunity; Cellular immunity; Immunity; Inflammatory response; Acquired (adaptive) immunity ... and usually does not react against them. INNATE IMMUNITY Innate, or nonspecific, immunity is the defense system ...

  14. Comparative Solar Wind Properties at 9AU between the maximum and late declining phases of the Solar Cycle and possible implications for the magnetospheric dynamics of Saturn

    NASA Astrophysics Data System (ADS)

    Went, D. R.; Jackman, C. M.; Forsyth, R. J.; Dougherty, M. K.; Crary, F. J.

    2009-04-01

    We compare and contrast the general plasma and magnetic field properties of the solar wind upstream of Saturn (8.5-9.5 AU) at solar maximum (Pioneer-11 encounter) and the late-declining (Cassini approach) phase of the solar cycle. In both cases we find a highly structured solar wind dominated by co-rotating interaction regions (CIRs), merged interaction regions (MIRs) and Interplanetary Coronal Mass Ejections (ICMEs) that temporarily disrupt an otherwise clear two sector interplanetary magnetic field structure. Solar rotations generally contain two CIR compressions with embedded crossings of the heliospheric current sheet. There is no conclusive evidence for (persistent) departures from the Parker Spiral IMF model in this region of the heliosphere at either phase of the solar cycle, consistent with previous analyses (Thomas and Smith 1980, Jackman et al. 2008). However it is clear that average plasma properties vary significantly between the maximum and late declining phases of the cycle and there are a number of small but notable deviations. In particular, the average dynamic pressure of the solar wind varies by a factor of roughly two between solar maximum and solar minimum with potentially important consequences for the dynamics of Saturn's magnetosphere. These consequences should become apparent as Cassini enters its extended Equinox Mission which should encompass the rising phase and eventually maximum of Solar Cycle 24. They will be discussed and predictions will be made for future Cassini observations.

  15. The ontogeny of immunity in the honey bee, Apis mellifera L. following an immune challenge.

    PubMed

    Laughton, Alice M; Boots, Michael; Siva-Jothy, Michael T

    2011-07-01

    The honey bee, Apis mellifera, is an ideal system for investigating ontogenetic changes in the immune system, because it combines holometabolous development within a eusocial caste system. As adults, male and female bees are subject to differing selective pressures: worker bees (females) exhibit temporal polyethism, while the male drones invest in mating. They are further influenced by changes in the threat of pathogen infection at different life stages. We investigated the immune response of workers and drones at all developmental phases, from larvae through to late stage adults, assaying both a constitutive (phenoloxidase, PO activity) and induced (antimicrobial peptide, AMP) immune response. We found that larval bees have low levels of PO activity. Adult workers produced stronger immune responses than drones, and a greater plasticity in immune investment. Immune challenge resulted in lower levels of PO activity in adult workers, which may be due to the rapid utilisation and a subsequent failure to replenish the constitutive phenoloxidase. Both adult workers and drones responded to an immune challenge by producing higher titres of AMPs, suggesting that the cost of this response prohibits its constant maintenance. Both castes showed signs of senescence in immune investment in the AMP response. Different sexes and life stages therefore alter their immune system management based on the combined factors of disease risk and life history. PMID:21570403

  16. Community Immunity (Herd Immunity)

    MedlinePlus

    ... Content Marketing Share this: Main Content Area ​Community Immunity ("Herd" Immunity) Vaccines can prevent outbreaks of disease and save ... disease is contained. This is known as "community immunity." In the illustration below, the top box depicts ...

  17. A phase trial of the oral Lactobacillus casei vaccine polarizes Th2 cell immunity against transmissible gastroenteritis coronavirus infection.

    PubMed

    Jiang, Xinpeng; Hou, Xingyu; Tang, Lijie; Jiang, Yanping; Ma, Guangpeng; Li, Yijing

    2016-09-01

    Transmissible gastroenteritis coronavirus (TGEV) is a member of the genus Coronavirus, family Coronaviridae, order Nidovirales. TGEV is an enteropathogenic coronavirus that causes highly fatal acute diarrhoea in newborn pigs. An oral Lactobacillus casei (L. casei) vaccine against anti-transmissible gastroenteritis virus developed in our laboratory was used to study mucosal immune responses. In this L. casei vaccine, repetitive peptides expressed by L. casei (specifically the MDP and tuftsin fusion protein (MT)) were repeated 20 times and the D antigenic site of the TGEV spike (S) protein was repeated 6 times. Immunization with recombinant Lactobacillus is crucial for investigations of the effect of immunization, such as the first immunization time and dose. The first immunization is more important than the last immunization in the series. The recombinant Lactobacillus elicited specific systemic and mucosal immune responses. Recombinant L. casei had a strong potentiating effect on the cellular immunity induced by the oral L. casei vaccine. However, during TGEV infection, the systemic and local immune responses switched from Th1 to Th2-based immune responses. The systemic humoral immune response was stronger than the cellular immune response after TGEV infection. We found that the recombinant Lactobacillus stimulated IL-17 expression in both the systemic and mucosal immune responses against TGEV infection. Furthermore, the Lactobacillus vaccine stimulated an anti-TGEV infection Th17 pathway. The histopathological examination showed tremendous potential for recombinant Lactobacillus to enable rapid and effective treatment for TGEV with an intestinal tropism in piglets. The TGEV immune protection was primarily dependent on mucosal immunity. PMID:27020282

  18. Contribution of the phase transition of Pacific Decadal Oscillation to the late 1990s' shift in East China summer rainfall

    NASA Astrophysics Data System (ADS)

    zhu, yali

    2016-04-01

    Based on our previous study, the interdecadal changes in summer rainfall over East China in the late 1990s are further explored here. The increased local rising motion is implicated as the dominant factor of increased rainfall in the lower Huang-Huai River valley (LHR). Both the observation and numerical experiments using Community Atmosphere Model, version 4 suggest that the negative Pacific Decadal Oscillation (PDO) mode can result in rising anomalies and thus more rainfall in the LHR. The East Asian westerly jet stream (EAWJS) is suggested as a bridge to link the Pacific sea surface temperature anomalies and East Asian summer rainfall. Model results reveal that the negative PDO mode can lead to significant easterly anomalies over East Asia. As a result, the EAWJS is weakened and shifts poleward, which coincides with observed changes in EAWJS after the late 1990s. In addition, weakened and poleward shifted EAWJS can result in an anomalous ascending motion to its south (in the LHR) by modulating the jet-related secondary meridional-vertical circulation. Consequently, rainfall increased in the LHR after the late 1990s. Besides, the positive Atlantic Meridional Oscillation can only induce insignificant changes over East Asia and partly counteract the negative PDO effect there.

  19. A Scoping Analysis Of The Impact Of SiC Cladding On Late-Phase Accident Progression Involving Core–Concrete Interaction

    SciTech Connect

    Farmer, M. T.

    2015-11-01

    The overall objective of the current work is to carry out a scoping analysis to determine the impact of ATF on late phase accident progression; in particular, the molten core-concrete interaction portion of the sequence that occurs after the core debris fails the reactor vessel and relocates into containment. This additional study augments previous work by including kinetic effects that govern chemical reaction rates during core-concrete interaction. The specific ATF considered as part of this study is SiC-clad UO2.

  20. InCVAX - A novel strategy for treatment of late-stage, metastatic cancers through photoimmunotherapy induced tumor-specific immunity

    PubMed Central

    Zhou, Feifan; Li, Xiaosong; Naylor, Mark F.; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel S.K.; Du, Nan; Shi, Lei; Wang, Xiuli; Chen, Wei R.

    2015-01-01

    A novel, promising potential cancer vaccine strategy was proposed to use a two-injection procedure for solid tumors to prompt the immune system to identify and systemically eliminate the primary and metastatic cancers. The two-injection procedure consists of local photothermal application on a selected tumor intended to liberate whole cell tumor antigens, followed by a local injection of an immunoadjuvant that consists of a semi-synthetic functionalized glucosamine polymer, N-dihydro-galacto-chitosan (GC), which is intended to activate antigen presenting cells and facilitate an increased uptake of tumor antigens. This strategy is thus proposed as an in situ autologous cancer vaccine (inCVAX) that may activate antigen presenting cells and expose them to tumor antigens in situ, with the intention of inducing a systemic tumor specific T-cell response. Here, the development of inCVAX for the treatment of metastatic cancers in the past decades are systematically reviewed. The antitumor immune responses of local photothermal treatment and immunological stimulation with GC are also discussed. This treatment approach is also commonly referred to as laser immunotherapy (LIT). PMID:25633839

  1. Late regulation of immune genes and microRNAs in circulating leukocytes in a pig model of influenza A (H1N2) infection

    PubMed Central

    Brogaard, Louise; Heegaard, Peter M. H.; Larsen, Lars E.; Mortensen, Shila; Schlegel, Michael; Dürrwald, Ralf; Skovgaard, Kerstin

    2016-01-01

    MicroRNAs (miRNAs) are a class of short regulatory RNA molecules which are implicated in modulating gene expression. Levels of circulating, cell-associated miRNAs in response to influenza A virus (IAV) infection has received limited attention so far. To further understand the temporal dynamics and biological implications of miRNA regulation in circulating leukocytes, we collected blood samples before and after (1, 3, and 14 days) IAV challenge of pigs. Differential expression of miRNAs and innate immune factor mRNA transcripts was analysed using RT-qPCR. A total of 20 miRNAs were regulated after IAV challenge, with the highest number of regulated miRNAs seen on day 14 after infection at which time the infection was cleared. Targets of the regulated miRNAs included genes involved in apoptosis and cell cycle regulation. Significant regulation of both miRNAs and mRNA transcripts at 14 days after challenge points to a protracted effect of IAV infection, potentially affecting the host’s ability to respond to secondary infections. In conclusion, experimental IAV infection of pigs demonstrated the dynamic nature of miRNA and mRNA regulation in circulating leukocytes during and after infection, and revealed the need for further investigation of the potential immunosuppressing effect of miRNA and innate immune signaling after IAV infection. PMID:26893019

  2. A Hectochelle Radial Velocity Survey of Cep OB3b: An ONC like cluster at late gas dispersal phase

    NASA Astrophysics Data System (ADS)

    Karnath, Nicole; Allen, Thomas; Prchlik, Jakub; Gutermuth, Robert A.; Megeath, Samuel Thomas; Pipher, Judith; Wolk, Scott J.

    2016-01-01

    Cep OB3b is a young (~3-5 Myr), late gas dispersal cluster of roughly 3000 members broken into two sub-clusters (Eastern and Western) at a distance of 700pc; it is a rare example of nearby cluster in the late stages of gas dispersal and appears to be a more evolved analog to the Orion Nebular Cluster. As part of an ongoing multi wavelength study, we focus on Hectochelle data from the MMT to measure the radial velocities of 499 stars. After removing binaries, outliers, and imposing a minimum R value to the cross correlation, we obtain radial velocities of 57 previously identified members, with an average error of 1.7 km/s. There is no observed variation in radial velocity across the cluster in right ascension or declination. The preferred mechanism for this type of kinematic evolution is that any initial kinematic structure from formation may have been erased and that minimal or no rotation is present in the cluster. However, the Eastern sub-cluster, containing the most massive star in the field, an O7 star, has a higher velocity dispersion than the Western sub-cluster, which contains several B stars. We will compare these results to CO maps of the residual gas in the cluster and discuss possible reasons for this difference. Finally, we will assess whether the cluster is bound or in a state of expansion.

  3. Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts.

    PubMed Central

    Takuwa, N; Takuwa, Y

    1997-01-01

    It is well documented that Ras functions as a molecular switch for reentry into the cell cycle at the border between G0 and G1 by transducing extracellular growth stimuli into early G1 mitogenic signals. In the present study, we investigated the role of Ras during the late stage of the G1 phase by using NIH 3T3 (M17) fibroblasts in which the expression of a dominant negative Ras mutant, p21(Ha-Ras[Asn17]), is induced in response to dexamethasone treatment. We found that delaying the expression of Ras(Asn17) until late in the G1 phase by introducing dexamethasone 3 h after the addition of epidermal growth factor (EGF) abolished the downregulation of the p27kip1 cyclin-dependent kinase (CDK) inhibitor which normally occurred during this period, with resultant suppression of cyclin Ds/CDK4 and cyclin E/CDK2 and G1 arrest. The immunodepletion of p27kip1 completely eliminated the CDK inhibitor activity from EGF-stimulated, dexamethasone-treated cell lysate. The failure of p27kip1 downregulation and G1 arrest was also observed in cells in which Ras(Asn17) was induced after growth stimulation with a phorbol ester or alpha-thrombin and was mimicked by the addition late in the G1 phase of inhibitors for phosphatidylinositol-3-kinase. Ras-mediated downregulation of p27kip1 involved both the suppression of synthesis and the stimulation of the degradation of the protein. Unlike the earlier expression of Ras(Asn17) at the border between G0 and G1, its delayed expression did not compromise the EGF-stimulated transient activation of extracellular signal-regulated kinases or inhibit the stimulated expression of a principal D-type cyclin, cyclin D1, until close to the border between G1 and S. We conclude that Ras plays temporally distinct, phase-specific roles throughout the G1 phase and that Ras function late in G1 is required for p27kip1 downregulation and passage through the restriction point, a prerequisite for entry into the S phase. PMID:9271412

  4. γδ T Cell Immune Manipulation during Chronic Phase of Simian HIV Infection Confers Immunological Benefits1

    PubMed Central

    Ali, Zahida; Yan, Lin; Plagman, Nicholas; Reichenberg, Armin; Hintz, Martin; Jomaa, Hassan; Villinger, Francois; Chen, Zheng W.

    2010-01-01

    Vγ2Vδ2 T cells, a major human γδ T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vγ2Vδ2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vγ2Vδ2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vγ2Vδ2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vγ2Vδ2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-γ, TNF-α, IL-4, and IL-10 during peak expansion of Vγ2Vδ2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vγ2Vδ2 T cells and CD4+ and CD8+ αβ T cells producing antimicrobial cytokines. Thus, HMBPP/Vγ2Vδ2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV

  5. Crystallization and X-ray diffraction analysis of a novel immune-type receptor from Ictalurus punctatus and phasing by selenium anomalous dispersion methods

    SciTech Connect

    Ostrov, David A. Hernández Prada, José A.; Haire, Robert N.; Magis, Andrew T.; Bailey, Kate; Litman, Gary W.

    2007-12-01

    A highly diversified novel immune-type receptor from catfish, NITR10, was crystallized to reveal novel mechanisms of immune recognition. X-ray diffraction data from crystals of a novel immune-type receptor (NITR10 from the catfish Ictalurus punctatus) were collected to 1.65 Å resolution and reduced to the primitive hexagonal lattice. Native and selenomethionine derivatives of NITR10 crystallized under different conditions yielded P3{sub 1}21 crystals. SeMet NITR10 was phased to a correlation coefficient of 0.77 by SAD methods and experimental electron-density maps were calculated to 1.65 Å. Five NITR10 molecules are predicted to be present in the asymmetric unit based on the Matthews coefficient.

  6. Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans

    PubMed Central

    Borgogni, Erica; Zedda, Luisanna; Cantisani, Rocco; Chiappini, Nico; Schiavetti, Francesca; Rosa, Domenico; Castellino, Flora; Montomoli, Emanuele; Bodinham, Caroline L.; Lewis, David J.; Medini, Duccio; Bertholet, Sylvie; Del Giudice, Giuseppe

    2016-01-01

    CD4+ T follicular helper cells (TFH) have been identified as the T-cell subset specialized in providing help to B cells for optimal activation and production of high affinity antibody. We recently demonstrated that the expansion of peripheral blood influenza-specific CD4+IL-21+ICOS1+ T helper (TH) cells, three weeks after vaccination, associated with and predicted the rise of protective neutralizing antibodies to avian H5N1. In this study, healthy adults were vaccinated with plain seasonal trivalent inactivated influenza vaccine (TIIV), MF59®-adjuvanted TIIV (ATIIV), or saline placebo. Frequencies of circulating CD4+ TFH1 ICOS+ TFH cells and H1N1-specific CD4+IL-21+ICOS+ CXCR5+ TFH and CXCR5- TH cell subsets were determined at various time points after vaccination and were then correlated with hemagglutination inhibition (HI) titers. All three CD4+ T cell subsets expanded in response to TIIV and ATIIV, and peaked 7 days after vaccination. To demonstrate that these TFH cell subsets correlated with functional antibody titers, we defined an alternative endpoint metric, decorrelated HI (DHI), which removed any correlation between day 28/day 168 and day 0 HI titers, to control for the effect of preexisting immunity to influenza vaccine strains. The numbers of total circulating CD4+ TFH1 ICOS+ cells and of H1N1-specific CD4+IL-21+ICOS+ CXCR5+, measured at day 7, were significantly associated with day 28, and day 28 and 168 DHI titers, respectively. Altogether, our results show that CD4+ TFH subsets may represent valuable biomarkers of vaccine-induced long-term functional immunity. Trial Registration ClinicalTrials.gov NCT01771367 PMID:27336786

  7. Neuroendocrine, metabolic, and immune functions during the acute phase response of inflammatory stress in monosodium L-glutamate-damaged, hyperadipose male rat.

    PubMed

    Castrogiovanni, Daniel; Gaillard, Rolf C; Giovambattista, Andrés; Spinedi, Eduardo

    2008-01-01

    In rats, neonatal treatment with monosodium L-glutamate (MSG) induces several metabolic and neuroendocrine abnormalities, which result in hyperadiposity. No data exist, however, regarding neuroendocrine, immune and metabolic responses to acute endotoxemia in the MSG-damaged rat. We studied the consequences of MSG treatment during the acute phase response of inflammatory stress. Neonatal male rats were treated with MSG or vehicle (controls, CTR) and studied at age 90 days. Pituitary, adrenal, adipo-insular axis, immune, metabolic and gonadal functions were explored before and up to 5 h after single sub-lethal i.p. injection of bacterial lipopolysaccharide (LPS; 150 microg/kg). Our results showed that, during the acute phase response of inflammatory stress in MSG rats: (1) the corticotrope-adrenal, leptin, insulin and triglyceride responses were higher than in CTR rats, (2) pro-inflammatory (TNFalpha) cytokine response was impaired and anti-inflammatory (IL-10) cytokine response was normal, and (3) changes in peripheral estradiol and testosterone levels after LPS varied as in CTR rats. These data indicate that metabolic and neroendocrine-immune functions are altered in MSG-damaged rats. Our study also suggests that the enhanced corticotrope-corticoadrenal activity in MSG animals could be responsible, at least in part, for the immune and metabolic derangements characterizing hypothalamic obesity. PMID:18382067

  8. Pharmacological characterization of the late phase reduction in lung functions and correlations with microvascular leakage and lung edema in allergen-challenged Brown Norway rats.

    PubMed

    Mauser, Peter J; House, Aileen; Jones, Howard; Correll, Craig; Boyce, Christopher; Chapman, Richard W

    2013-12-01

    Late phase airflow obstruction and reduction in forced vital capacity are characteristic features of human asthma. Airway microvascular leakage and lung edema are also present in the inflammatory phase of asthma, but the impact of this vascular response on lung functions has not been precisely defined. This study was designed to evaluate the role of increased lung microvascular leakage and edema on the late phase changes in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats using pharmacological inhibitors of the allergic inflammatory response. Rats were sensitized and challenged with ovalbumin aerosol and forced expiratory lung functions (FVC, PEF) and wet and dry lung weights were measured 48 h after antigen challenge. Ovalbumin challenge reduced FVC (63% reduction) and PEF (33% reduction) and increased wet (65% increase) and dry (51% increase) lung weights. The antigen-induced reduction in FVC and PEF was completely inhibited by oral treatment with betamethasone and partially attenuated by inhibitors of arachidonic acid metabolism including indomethacin (cyclooxygenase inhibitor), 7-TM and MK-7246 (CRTH2 antagonists) and montelukast (CysLT1 receptor antagonist). Antagonists of histamine H1 receptors (mepyramine) and 5-HT receptors (methysergide) had no significant effects indicating that these pre-formed mast cell mediators were not involved. There was a highly significant (P < 0.005) correlation for the inhibition of FVC reduction and increase in wet and dry lung weights by these pharmacological agents. These results strongly support the hypothesis that lung microvascular leakage and the associated lung edema contribute to the reduction in forced expiratory lung functions in antigen-challenged Brown Norway rats and identify an important role for the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in these responses. PMID:23523662

  9. Solar Wind Sources in the Late Declining Phase of Cycle 23: Effects of the Weak Solar Polar Field on High Speed Streams

    NASA Astrophysics Data System (ADS)

    Luhmann, J. G.; Lee, C. O.; Li, Yan; Arge, C. N.; Galvin, A. B.; Simunac, K.; Russell, C. T.; Howard, R. A.; Petrie, G.

    2009-05-01

    The declining phases of solar cycles are known for their high speed solar wind streams that dominate the geomagnetic responses during this period. Outstanding questions about these streams, which can provide the fastest winds of the solar cycle, concern their solar origins, persistence, and predictability. The declining phase of cycle 23 has lasted significantly longer than the corresponding phases of the previous two cycles. Solar magnetograph observations suggest that the solar polar magnetic field is also ˜ 2 - 3 times weaker. The launch of STEREO in late 2006 provided additional incentive to examine the origins of what is observed at 1 AU in the recent cycle, with the OMNI data base at the NSSDC available as an Earth/L1 baseline for comparisons. Here we focus on the year 2007 when the solar corona exhibited large, long-lived mid-to-low latitude coronal holes and polar hole extensions observed by both SOHO and STEREO imagers. STEREO provides in situ measurements consistent with rigidly corotating solar wind stream structure at up to ˜ 45° heliolongitude separation by late 2007. This stability justifies the use of magnetogram-based steady 3D solar wind models to map the observed high speed winds back to their coronal sources. We apply the WSA solar wind model currently running at the NOAA Space Weather Prediction Center with the expectation that it should perform its best at this quiet time. The model comparisons confirm the origins of the observed high speed streams expected from the solar images, but also reveal uncertainties in the solar wind source mapping associated with this cycle’s weaker solar polar fields. Overall, the results illustrate the importance of having accurate polar fields in synoptic maps used in solar wind forecast models. At the most fundamental level, they demonstrate the control of the solar polar fields over the high speed wind sources, and thus one specific connection between the solar dynamo and the solar wind character.

  10. Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: A phase III randomized study

    SciTech Connect

    Zhao Kuaile; Shi Xuehui; Jiang Guoliang . E-mail: jianggl@21cn.com; Yao Weiqiang; Guo Xiaomao; Wu Gendi; Zhu Longxiang

    2005-07-15

    Purpose: Late course accelerated hyperfractionated (LCAF) radiotherapy (RT) is as effective as standard chemoradiotherapy for nonsurgical management of locally advanced esophageal squamous cell carcinoma (SCC). We have evaluated further the efficacy of concurrent LCAF RT and chemotherapy. Methods and Materials: In all, 111 eligible patients with esophageal SCC were randomized to receive LCAF alone (LCAF) or concurrent LCAF and chemotherapy (LCAT+CT) between March 1998 and July 2000. All patients received conventional fractionation irradiation of 1.8 Gy per day, to a dose of 41.4 Gy/23 fractions in 4-5 weeks, followed by accelerated hyperfractionated irradiation using reduced fields, 1.5 Gy/fractions twice a day, to a dose of 27 Gy in 18 days. Thus, the total dose was 68.4 Gy/41 fractions in 44 days. Fifty-four patients in the LCAF+CT arm had an additional four cycles of chemotherapy using cisplatin 25 mg/m{sup 2} daily and fluorouracil (5-FU) 600 mg/m{sup 2} daily on Days 1-3 every 4 weeks starting on the same day that LCAF was delivered. Results: The median survival was 23.9 months (95% confidence [CI], 20.1-27.7) for the LCAF arm and 30.8 months (95% CI, 17.6-44.1) for the LCAF+CT arm, respectively. Survival rates at 1, 3, and 5 years of the LCAF arm were 77%, 39%, and 28%, respectively, while those of the LCAF+CT arm were 67%, 44%, and 40%, respectively (p = 0.310). Grades 3 and 4 acute toxicities occurred in 46% and 25% of the patients in the LCAF arm and the LCAF+CT arm, respectively; 6% of the patients in the combined arm had Grade 5 acute toxicities, whereas none was noted in the LCAF alone arm. Conclusions: Late course accelerated hyperfractionation was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received intensified treatment with concurrent chemotherapy. Further randomized studies with a larger number of patients should be carried out, but additional measures must be taken to reduce the higher

  11. Late circadian phase in adults and children is correlated with use of high color temperature light at home at night.

    PubMed

    Higuchi, Shigekazu; Lee, Sang-Il; Kozaki, Tomoaki; Harada, Tetsuo; Tanaka, Ikuo

    2016-01-01

    Light is the strongest synchronizer of human circadian rhythms, and exposure to residential light at night reportedly causes a delay of circadian rhythms. The present study was conducted to investigate the association between color temperature of light at home and circadian phase of salivary melatonin in adults and children. Twenty healthy children (mean age: 9.7 year) and 17 of their parents (mean age: 41.9 years) participated in the experiment. Circadian phase assessments were made with dim light melatonin onset (DLMO). There were large individual variations in DLMO both in adults and children. The average DLMO in adults and in children were 21:50 ± 1:12 and 20:55 ± 0:44, respectively. The average illuminance and color temperature of light at eye level were 139.6 ± 82.7 lx and 3862.0 ± 965.6 K, respectively. There were significant correlations between color temperature of light and DLMO in adults (r = 0.735, p < 0.01) and children (r = 0.479, p < 0.05), although no significant correlations were found between illuminance level and DLMO. The results suggest that high color temperature light at home might be a cause of the delay of circadian phase in adults and children. PMID:27010525

  12. Menstrual cycle phase and carbohydrate ingestion alter immune response following endurance exercise and high intensity time trial performance test under hot conditions

    PubMed Central

    2014-01-01

    Background Sex hormones are known to regulate some responses during exercise. Evaluation of the differences in exercise response with regard to menstrual cycle will help understand the menstrual cycle phase specific adaptations to exercise and athletic performance. Methods We investigated the effects of menstrual cycle phase and carbohydrate (CHO) ingestion on immune response during endurance exercise at 30°C. Six healthy women completed 4 trials comprising 90 min of cycling at 50% peak aerobic power V˙O2peak and a high intensity time trial performance test (POST). They ingested a placebo- or CHO-containing beverage during the trials, which were performed during both the follicular and luteal phases of the menstrual cycle. In all trials, thermoregulatory, cardiorespiratory, and immune responses were measured during exercise and after POST. Results Although the thermoregulatory responses differed between the menstrual cycle phases, the cardiorespiratory responses were not different. After placebo ingestion, leukocyte concentration (cells/μL) at POST (15.9 × 103) in the luteal phase was significantly higher than that in the follicular phase (12.9 × 103). The rise in leukocyte concentration was attenuated upon CHO ingestion, and the difference between menstrual cycle phases disappeared. A significant positive correlation was found between leukocyte concentration and serum free fatty acid concentrations. Interleukin-6, calprotectin, and myeloperoxidase concentrations significantly increased at POST in all trials, but no significant differences were observed between menstrual cycle phase or beverage type. Concentrations of other cytokines did not change during exercise in any of the 4 trials. Menstrual cycle phase and beverage type had no significant effect on the POST outcome. Thus, differences in leukocyte mobilization between menstrual cycle phases could result from the effect of sex hormones on substrate utilization. Conclusions The menstrual cycle

  13. An important role of increase in tetrahydrobiopterin via H2O2-JAK2 signalling pathway in late phase of ischaemic preconditioning.

    PubMed

    Hiroi, Toshihito; Wajima, Teruaki; Kaneko, Yuji; Kiuchi, Yuji; Shimizu, Shunichi

    2010-05-01

    The goal of this study was to elucidate whether there is an increase in myocardial tetrahydrobiopterin (BH4), which is a cofactor for nitric oxide synthase, during the late phase of ischaemic preconditioning (IPC) leading to cardioprotection against myocardial infarction and, if so, to examine the induction mechanisms of BH4 synthesis. Rats were preconditioned with four cycles of 3 min left main coronary artery (LCA) occlusion followed by 10 min reperfusion. Twenty-four hours later, the rats were subjected to 20 min ischaemia by LCA ligation and 2 h reperfusion, and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. The IPC protocol reduced the infarct size, and increased the BH4 content and expression of GTP-cyclohydrolase I (GTPCH), which is the rate-limiting enzyme for BH4 synthesis. Administration of a GTPCH inhibitor attenuated both the reduction in infarct size and the increase in BH4 levels. Moreover, the increase in BH4 content was reduced by administration of catalase or a Janus tyrosine kinase-2 (JAK2) inhibitor. These observations suggest that upregulation of BH4 synthesis in the heart contributes to an acquisition of ischaemic tolerance in late IPC, and the increase in myocardial BH4 content seems to be mediated by the induction of GTPCH via the H(2)O(2)-JAK2 pathway. PMID:20139166

  14. Altered Phase-Relationship between Peripheral Oscillators and Environmental Time in Cry1 or Cry2 Deficient Mouse Models for Early and Late Chronotypes

    PubMed Central

    Destici, Eugin; Jacobs, Edwin H.; Tamanini, Filippo; Loos, Maarten; van der Horst, Gijsbertus T. J.; Oklejewicz, Małgorzata

    2013-01-01

    The mammalian circadian system is composed of a light-entrainable central clock in the suprachiasmatic nuclei (SCN) of the brain and peripheral clocks in virtually any other tissue. It allows the organism to optimally adjust metabolic, physiological and behavioral functions to the physiological needs it will have at specific time of the day. According to the resonance theory, such rhythms are only advantageous to an organism when in tune with the environment, which is illustrated by the adverse health effects originating from chronic circadian disruption by jetlag and shift work. Using short-period Cry1 and long-period Cry2 deficient mice as models for morningness and eveningness, respectively, we explored the effect of chronotype on the phase relationship between the central SCN clock and peripheral clocks in other organs. Whereas the behavioral activity patterns and circadian gene expression in the SCN of light-entrained Cry1-/- and Cry2-/- mice largely overlapped with that of wild type mice, expression of clock and clock controlled genes in liver, kidney, small intestine, and skin was shown to be markedly phase-advanced or phase-delayed, respectively. Likewise, circadian rhythms in urinary corticosterone were shown to display a significantly altered phase relationship similar to that of gene expression in peripheral tissues. We show that the daily dissonance between peripheral clocks and the environment did not affect the lifespan of Cry1-/- or Cry2-/- mice. Nonetheless, the phase-shifted peripheral clocks in light-entrained mice with morningness and eveningness-like phenotypes may have implications for personalized preventive and therapeutic (i.e. chronomodulation-based) health care for people with early and late chronotypes. PMID:24386234

  15. Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self antigens in cancer patients

    PubMed Central

    Morse, Michael A.; Chapman, Robert; Powderly, John; Blackwell, Kimberly; Keler, Tibor; Green, Jennifer; Riggs, Renee; He, Li-Zhen; Ramakrishna, Venky; Vitale, Laura; Zhao, Biwei; Butler, Stephen A.; Hobeika, Amy; Osada, Takuya; Davis, Thomas; Clay, Timothy; Lyerly, H. Kim

    2011-01-01

    Purpose The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity. Experimental Design Two phase I studies were performed with CDX-1307, a vaccine composed of human chorionic gonadotropin beta chain (hCG-β) fused to a MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose-escalation of single agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with GM-CSF and the Toll-like receptor (TLR)-3 agonist poly-ICLC and TLR7/8 agonist resiquimod to activate the APC. Results CDX-1307 induced consistent humoral and T cell responses to hCG-β when co-administered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and non-elevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions. Conclusions APC targeting and activation induce adaptive immunity against poorly immunogenic self antigens which has implications for enhancing the efficacy of cancer immunotherapy. PMID:21632857

  16. Characterization of Leptospiral Outer Membrane Lipoprotein LipL36: Downregulation Associated with Late-Log-Phase Growth and Mammalian Infection

    PubMed Central

    Haake, David A.; Martinich, Carleen; Summers, Theresa A.; Shang, Ellen S.; Pruetz, Jay D.; McCoy, Adam M.; Mazel, Mary K.; Bolin, Carole A.

    1998-01-01

    We report the cloning of the gene encoding a 36-kDa leptospiral outer membrane lipoprotein, designated LipL36. We obtained the N-terminal amino acid sequence of a staphylococcal V8 proteolytic-digest fragment in order to design an oligonucleotide probe. A Lambda-Zap II library containing EcoRI fragments of Leptospira kirschneri DNA was screened, and a 2.3-kb DNA fragment which contained the entire structural lipL36 gene was identified. Several lines of evidence indicate that LipL36 is lipid modified in a manner similar to that of LipL41, a leptospiral outer membrane lipoprotein we described in a previous study (E. S. Shang, T. A. Summers, and D. A. Haake, Infect. Immun. 64:2322–2330, 1996). The deduced amino acid sequence of LipL36 would constitute a 364-amino-acid polypeptide with a 20-amino-acid signal peptide, followed by an L-X-Y-C lipoprotein signal peptidase cleavage site. LipL36 is solubilized by Triton X-114 extraction of L. kirschneri; phase separation results in partitioning of LipL36 exclusively into the hydrophobic, detergent phase. LipL36 is intrinsically labeled during incubation of L. kirschneri in media containing [3H]palmitate. Processing of LipL36 is inhibited by globomycin, a selective inhibitor of lipoprotein signal peptidase. After processing, LipL36 is exported to the outer membrane along with LipL41 and lipopolysaccharide. Unlike LipL41, there appears to be differential expression of LipL36. In early-log-phase cultures, LipL36 is one of the most abundant L. kirschneri proteins. However, LipL36 levels drop considerably beginning in mid-log phase. LipL36 expression in vivo was evaluated by examining the humoral immune response to leptospiral antigens in the hamster model of leptospirosis. Hamsters surviving challenge with culture-adapted virulent L. kirschneri generate a strong antibody response to LipL36. In contrast, sera from hamsters surviving challenge with host-adapted L. kirschneri do not recognize LipL36. These findings suggest that

  17. Randomized phase 2 trial of NP001–a novel immune regulator: Safety and early efficacy in ALS

    PubMed Central

    Block, Gilbert; Katz, Jonathan S.; Barohn, Richard J.; Gopalakrishnan, Vidhya; Cudkowicz, Merit; Zhang, Jane R.; McGrath, Michael S.; Ludington, Elizabeth; Appel, Stan H.; Azhir, Ari

    2015-01-01

    Objective: To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS). Methods: This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity ≥70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months. Safety, tolerability, and inflammatory biomarkers were assessed throughout the study. Preliminary efficacy was evaluated using the ALS Functional Rating Scale-Revised (ALSFRS-R) slope and change from baseline, with and without matched historical placebo controls, after 6 months of treatment. A post hoc analysis of the percentage of patients (“responders”) whose ALSFRS-R did not change from baseline was also conducted. Results: NP001 was generally safe and well-tolerated, except for infusion site pain and dizziness. No significant slowing of decline in the primary or secondary measures was observed. However, slowing of progression was observed in the high-dose group in patients with greater inflammation (wide range C-reactive protein). Moreover, NP001 may have dose dependently halted symptom progression in a subset of patients. More than 2 times as many patients on high-dose NP001 (25%) did not progress during 6 months of treatment compared with those on placebo (11%). Most “responders” had an elevated biomarker of inflammation, interleukin-18, and were positive for lipopolysaccharide at baseline, which decreased after treatment with NP001. Conclusion: The arresting of progression of ALS symptoms by NP001 in a subset of patients with marked neuroinflammation, as observed here, will represent a novel therapeutic approach for patients with ALS, if confirmed. Classification of evidence: This study provides Class I evidence that for patients with ALS, NP001 is safe and did not significantly slow progression of the

  18. Single Phase 40Ar/39Ar Dating of Rajahmundry Trap Basalts Contemporaneous With Late Stage Deccan Trap Volcanism

    NASA Astrophysics Data System (ADS)

    Knight, K. B.; Knight, K. B.; Renne, P. R.; Renne, P. R.; Halkett, A.; White, N.

    2001-12-01

    The Rajahmundry Traps of eastern peninsular India, often considered to be outliers of the Deccan Traps, occupy ~35 km2 centered on the Krishna-Godavari Basin and extending offshore in the sub-surface. Onshore exposures average 60m in thickness, including a laterally continuous sedimentary interlayer of laterite, limestone and shale ( ~2m thick, total) separating `upper' flows from `lower' flows. 40Ar/39Ar CO2 laser incremental heating analysis of twelve plagioclase separates from Rajahmundry Trap basalts reveal an age of ~64.6 Ma for the entire sequence based on the FCs standard at 28.02 Ma. Flows chosen for dating include 8 sites spanning both the `upper' and `lower' flow sequences. Paleontological studies of sediments adjacent to the basalt at depth in Krishna-Godavari Basin, e.g. Jaiprakash et al. (1993), suggest that the period of time covered by the two flows and intertrappean sediments is up to ca. 6 myr. Dates obtained for this study, however, show that ages for both upper and lower flows are indistinguishable within 2σ error from one another, and span ~2 Ma at most, pointing to a substantial hiatus in the sedimentary record at the top of the upper basalt flows. Extremely high Ca/K ratios (up to ~400) in several samples limits precision due to error propagation attending the large correction necessary for reactor produced 36Ar from Ca. However, plateau ages as precise as 64.8 +/- 0.4 and 65.5 +/- 0.8 from above and below (respectively, 2σ errors) the sedimentary interlayer have been obtained. Samples with both high and low Ca/K ratios confirm rapid eruption of the entire Rajahmundry Trap sequence. A petrogenetic link between these basalts and the Deccan Trap basalts (the remains of which lie over 300 km from the nearest exposure of Rajahmundry Trap) has been suggested but has yet to be substantiated. These new data clearly place the eruption of the Rajahmundry Traps temporally close to the K-T boundary, coincident with late stage Deccan volcanism and

  19. Identical M sub r 70,000 S6 kinase is activated biphasically by epidermal growth factor: A phosphopeptide that characterizes the late phase

    SciTech Connect

    Susa, M.; Thomas, G. )

    1990-09-01

    Mitogenic stimulation of quiescent mouse 3T3 cells with epidermal growth factor leads to biphasic S6 kinase activation. The kinases present in both phases of the response have been purified from {sup 32}P-labeled cells and shown to contain a phosphoprotein of equivalent M{sub r} 70,000. Chromatographic analysis of the purified S6 kinases on a Mono Q column reveals that (1) all {sup 32}P-labeled protein coelutes with S6 kinase activity, (2) only those fractions containing S6 kinase autophosphorylate, (3) autophosphorylation is restricted to a single M{sub r} 70,000 protein, and (4) the extent of autophosphorylation directly parallels the degree of S6 kinase activation. Analysis of the two autophosphorylated S6 kinases by two-dimensional tryptic phosphopeptide mapping indicates that they are the same protein. Both in vivo {sup 32}P-labeled S6 kinase contain phosphoserine and phosphothreonine but no detectable phosphotyrosine. Two-dimensional tryptic peptide maps of the in vivo {sup 32}P-labeled S6 kinases are essentially identical, except for a single qualitative change in the late-phase S6 kinase.

  20. Endometrial gene expression in high- and low-fertility heifers in the late luteal phase of the estrous cycle and a comparison with midluteal gene expression.

    PubMed

    Killeen, Aideen P; Diskin, Michael G; Morris, Dermot G; Kenny, David A; Waters, Sinéad M

    2016-04-01

    Embryonic mortality is a major constraint to improving reproductive efficiency and profitability in livestock enterprises. We previously reported differential expression of genes with identified roles in cellular growth and proliferation, lipid metabolism, endometrial remodeling, inflammation, angiogenesis, and metabolic exchange in endometrial tissue on day 7 of the estrous cycle (D7), between heifers ranked as either high (HF) or low (LF) for fertility. The aim of the current study was to further elucidate the underlying molecular mechanisms contributing to early embryo loss by examining differential endometrial gene expression in HF or LF heifers at a later stage of the estrous cycle;day 14(D14). A second objective was to compare these expression profiles with those from midluteal HF and LF endometrium. Using the same animal model as employed in the previous study, we slaughtered HF and LF animals on D14, harvested endometrial tissue, and carried out global gene expression analysis using the Affymetrix Bovine GeneChip. Microarray analysis detected 430 differentially expressed genes (DEG) between HF and LF animals. Ingenuity Pathway Analysis revealed enrichment for a host of biological pathways including lipid metabolism, molecular transport, immune response, cell morphology and development, and cell growth and proliferation. Important DEG includedALB, BMPR2, CCL28, COL4A3/4, FADS1, ITGA6, LDLR, PLCB3, PPARG, PTGS2, and SLC27A4 Furthermore, DEG expressed on both D7 and D14 included:PCCB,SLC25A24,DAP, and COL4A4 This study highlights some of the pathways and mechanisms underpinning late luteal bovine endometrial physiology and endometrial-related conception rate variance. PMID:26850042

  1. Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A.

    PubMed

    Sperk, Elena; Welzel, Grit; Keller, Anke; Kraus-Tiefenbacher, Uta; Gerhardt, Axel; Sütterlin, Marc; Wenz, Frederik

    2012-08-01

    The randomized phase III trial TARGIT A showed non-inferiority regarding local control after intraoperative radiotherapy (IORT 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only) in comparison to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. This is the first analysis of long-term toxicities in the setting of TARGIT. Between 02/2002 and 12/2008, 305 patients were treated within TARGIT A (Arm A: n = 34 IORT, n = 20 IORT + WBRT for risk factors; Arm B WBRT: n = 55) or received IORT as a planned boost (control group: n = 196) at a single center. Toxicity was assessed according to the LENT SOMA scales. No significant differences were seen between Arm A and Arm B regarding fibrosis, breast edema, retraction, ulceration, lymphedema, hyperpigmentation, and pain. Arm A had significantly less telangiectases compared to Arm B (p = 0.049). In the subanalysis (Arm A IORT vs. Arm A IORT + WBRT vs. Arm B), fibrosis had a cumulative rate of 5.9 versus 37.5 versus 18.4 %, respectively (38.2 % IORT boost control group), at 3 years. No telangiectases were seen after IORT alone (0 % Arm A IORT vs. 17.5 % Arm A IORT + WBRT vs. 17.7 % Arm B). The hazard ratio of higher grade toxicity as first event was 0.46 (95 % CI, 0.26-0.83) for Arm A IORT as compared to Arm B (p = 0.010). No recurrences were seen after a median follow-up of 40 months (Arm A) and 42 months (Arm B). With its very low chronic skin toxicity rates and outstanding long-term results regarding toxicity and local control, IORT with 50 kV X-rays is a safe and effective method for treatment of selected breast cancer patients. PMID:22842984

  2. Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

    PubMed Central

    Goldman, John M.; Majhail, Navneet S.; Klein, John P.; Wang, Zhiwei; Sobocinski, Kathleen A.; Arora, Mukta; Horowitz, Mary M.; Rizzo, J. Douglas

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. Patients and Methods Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. Results Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). Conclusion Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population. PMID:20212247

  3. Adenylyl cyclase subtype 1 is essential for late-phase long term potentiation and spatial propagation of synaptic responses in the anterior cingulate cortex of adult mice.

    PubMed

    Chen, Tao; O'Den, Gerile; Song, Qian; Koga, Kohei; Zhang, Ming-Ming; Zhuo, Min

    2014-01-01

    Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain. PMID:25304256

  4. Immune System

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immune System KidsHealth > For Teens > Immune System Print A A ... could put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  5. MicroRNA Expression Profile in Bovine Granulosa Cells of Preovulatory Dominant and Subordinate Follicles during the Late Follicular Phase of the Estrous Cycle

    PubMed Central

    Gebremedhn, Samuel; Salilew-Wondim, Dessie; Ahmad, Ijaz; Sahadevan, Sudeep; Hossain, Md Munir; Hoelker, Michael; Rings, Franca; Neuhoff, Christiane; Tholen, Ernst; Looft, Christian; Schellander, Karl; Tesfaye, Dawit

    2015-01-01

    In bovine, ovarian follicles grow in a wave-like fashion with commonly 2 or 3 follicular waves emerging per estrous cycle. The dominant follicle of the follicular wave which coincides with the LH-surge becomes ovulatory, leaving the subordinate follicles to undergo atresia. These physiological processes are controlled by timely and spatially expressed genes and gene products, which in turn are regulated by post-transcriptional regulators. MicroRNAs, a class of short non-coding RNA molecules, are one of the important posttranscriptional regulators of genes associated with various cellular processes. Here we investigated the expression pattern of miRNAs in granulosa cells of bovine preovulatory dominant and subordinate follicles during the late follicular phase of bovine estrous cycle using Illumina miRNA deep sequencing. In addition to 11 putative novel miRNAs, a total of 315 and 323 known miRNAs were detected in preovulatory dominant and subordinate follicles, respectively. Moreover, in comparison with the subordinate follicles, a total of 64 miRNAs were found to be differentially expressed in preovulatory dominant follicles, of which 34 miRNAs including the miR-132 and miR-183 clusters were significantly enriched, and 30 miRNAs including the miR-17-92 cluster, bta-miR-409a and bta-miR-378 were significantly down regulated in preovulatory dominant follicles. In-silico pathway analysis revealed that canonical pathways related to oncogenesis, cell adhesion, cell proliferation, apoptosis and metabolism were significantly enriched by the predicted target genes of differentially expressed miRNAs. Furthermore, Luciferase reporter assay analysis showed that one of the differentially regulated miRNAs, the miR-183 cluster miRNAs, were validated to target the 3´-UTR of FOXO1 gene. Moreover FOXO1 was highly enriched in granulosa cells of subordinate follicles in comparison with the preovulatory dominant follicles demonstrating reciprocal expression pattern with miR-183

  6. Ontogeny of Early Life Immunity

    PubMed Central

    Dowling, David J.; Levy, Ofer

    2014-01-01

    The human immune system is comprised of cellular and molecular components designed to coordinately prevent infection while avoiding potentially harmful inflammation and auto-immunity. Immunity varies with age, reflecting unique age-dependent challenges including fetal gestation, the neonatal phase and infancy. Herein, we review novel mechanistic insights into early life immunity, with emphasis on emerging models of human immune ontogeny, which may inform age-specific translational development of novel anti-infectives, immunomodulators and vaccines. PMID:24880460

  7. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis

    PubMed Central

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M.; Lucas, Megan; Spencer, John S.; Amara, Rama Rao; Plikaytis, Bonnie B.; Posey, James E.; Sable, Suraj B.

    2016-01-01

    Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32–52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime–Apa-subunit-boost strategy compared to Apa-subunit-prime–BCG-boost approach. However, parenteral BCG-prime–Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime–boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime–boost regimens against tuberculosis in humans. PMID:27173443

  8. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

    PubMed

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M; Lucas, Megan; Spencer, John S; Amara, Rama Rao; Plikaytis, Bonnie B; Posey, James E; Sable, Suraj B

    2016-01-01

    Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans. PMID:27173443

  9. A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens

    PubMed Central

    Gilbert, Peter B.; Grove, Douglas; Gabriel, Erin; Huang, Ying; Gray, Glenda; Hammer, Scott M.; Buchbinder, Susan P.; Kublin, James; Corey, Lawrence; Self, Steven G.

    2012-01-01

    Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection. PMID:23181167

  10. Human Folliculin Delays Cell Cycle Progression through Late S and G2/M-Phases: Effect of Phosphorylation and Tumor Associated Mutations

    PubMed Central

    Laviolette, Laura A.; Wilson, Jonas; Koller, Julia; Neil, Christopher; Hulick, Peter; Rejtar, Tomas; Karger, Barry; Teh, Bin Tean; Iliopoulos, Othon

    2013-01-01

    The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN), and is characterized by clinical features including fibrofolliculomas, lung cysts and multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn–/– mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcnflox/flox). The reintroduction of tumor-associated FLCN mutants (FLCN ΔF157, FLCN 1–469 or FLCN K508R) fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73) fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms. PMID:23874397

  11. Inflammatory cytokine and acute phase protein concentrations in the peripheral blood and uterine washings of cows with subclinical endometritis in the late postpartum period.

    PubMed

    Brodzki, Piotr; Kostro, Krzysztof; Krakowski, Leszek; Marczuk, Jan

    2015-06-01

    The aim of the study was to evaluate the concentrations of proinflammatory cytokines: tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), anti-inflammatory cytokine interleukin-10 (IL-10), and acute phase proteins (APPs)--haptoglobin (Hp) and serum amyloid A (SAA) in serum and uterine washings of cows with subclinical endometritis, and compare them to healthy animals. The study was performed on 24 cows on day 60 after delivery. The cows were divided into two groups based on the results of cytological tests: 12 cows with subclinical endometritis and 12 healthy cows. Experimental material consisted of blood serum and uterine washings. The levels of the following cytokines in the study material were determined with ELISA: TNF-α, IL-6, IL-10 and APPs - Hp and SAA. The results show that the levels of TNF-α (p < 0.01), IL-6, IL-10 as well as SAA and Hp were significantly higher in the serum of cows with subclinical endometritis compared to the controls (p < 0.001). Uterine washings had significantly higher levels of IL-6, IL-10, and Hp in the experimental cows compared to the controls (p < 0.001). The demonstrated differences in the concentration of cytokines and APP between cows with subclinical endometritis and healthy cows, in both the serum and uterine washings, may suggest the usefulness of these parameters in the diagnosis of subclinical endometritis in cows in the late postpartum period. PMID:25846950

  12. Caffeine treatment prevents rapid eye movement sleep deprivation-induced impairment of late-phase long-term potentiation in the dentate gyrus.

    PubMed

    Alhaider, Ibrahim A; Alkadhi, Karim A

    2015-11-01

    The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus, but they differ in various respects, including their reactions to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late-phase long-term potentiation (L-LTP) and its signalling cascade in the DG area of the hippocampus of rapid eye movement sleep-deprived rats. Rats were chronically treated with caffeine (300 mg/L drinking water) for 4 weeks, after which they were sleep-deprived for 24 h. L-LTP was induced in in anaesthetized rats, and extracellular field potentials from the DG area were recorded in vivo. The levels of L-LTP-related signalling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L-LTP magnitude, and basal levels of total cAMP response element-binding protein (CREB), phosphorylated CREB (P-CREB), and calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented the reductions in the basal levels of P-CREB, total CREB and CaMKIV in sleep-deprived rats. Furthermore, caffeine prevented post-L-LTP sleep deprivation-induced downregulation of P-CREB and brain-derived neurotrophic factor in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation-induced deficits in brain function. PMID:26449851

  13. Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors

    PubMed Central

    2013-01-01

    Background DNA electroporation has been demonstrated in preclinical models to be a promising strategy to improve cancer immunity, especially when combined with other genetic vaccines in heterologous prime-boost protocols. We report the results of 2 multicenter phase 1 trials involving adult cancer patients (n=33) with stage II-IV disease. Methods Patients were vaccinated with V930 alone, a DNA vaccine containing equal amounts of plasmids expressing the extracellular and trans-membrane domains of human HER2, and a plasmid expressing CEA fused to the B subunit of Escherichia coli heat labile toxin (Study 1), or a heterologous prime-boost vaccination approach with V930 followed by V932, a dicistronic adenovirus subtype-6 viral vector vaccine coding for the same antigens (Study 2). Results The use of the V930 vaccination with electroporation alone or in combination with V932 was well-tolerated without any serious adverse events. In both studies, the most common vaccine-related side effects were injection site reactions and arthralgias. No measurable cell-mediated immune response (CMI) to CEA or HER2 was detected in patients by ELISPOT; however, a significant increase of both cell-mediated immunity and antibody titer against the bacterial heat labile toxin were observed upon vaccination. Conclusion V930 vaccination alone or in combination with V932 was well tolerated without any vaccine-related serious adverse effects, and was able to induce measurable immune responses against bacterial antigen. However, the prime-boost strategy did not appear to augment any detectable CMI responses against either CEA or HER2. Trial registration Study 1 – ClinicalTrials.gov, NCT00250419; Study 2 – ClinicalTrials.gov, NCT00647114. PMID:23497415

  14. Late paternities.

    PubMed

    Cohen, Jean

    2007-06-01

    Late paternities are frequent. Very often these couples ask for medically assisted procreation. In general, it is considered that the couple should not be treated differently from the couple where the father is younger. Recent studies show a certain number of specific risks linked to the late paternities. Doctors and society do not act in the same way towards men and women: a 'sensible age' for women to no longer attempt pregnancy has been set in many countries at 42 years of age, whereas men aged 80 can benefit from IVF attempts and be reimbursed by the state or insurance companies. This is an obvious inequity. PMID:17579995

  15. Immune Restoration

    MedlinePlus

    ... marrow cells immune to HIV infection. Letting the immune system repair itself: CD4 counts have increased for many ... have taken ART. Some scientists believe that the immune system might be able to heal and repair itself ...

  16. Immune response

    MedlinePlus Videos and Cool Tools

    ... cells. T cells are responsible for cell-mediated immunity. This type of immunity becomes deficient in persons with HIV, the virus ... blood. B lymphocytes provide the body with humoral immunity as they circulate in the fluids in search ...

  17. Escherichia coli sec mutants accumulate a processed immature form of maltose-binding protein (MBP), a late-phase intermediate in MBP export.

    PubMed

    Ueguchi, C; Ito, K

    1990-10-01

    Protein translocation across the Escherichia coli cytoplasmic membrane may consist of several temporally or topographically distinct steps. Although early events in the translocation pathway have been characterized to some extent, the mechanisms responsible for the trans-bilayer movement of a polypeptide are only poorly understood. This article reports on our attempts to dissect the translocation pathway in vivo. A processed form of maltose-binding protein (MBP) was detected in the spheroplasts of secY and secA temperature-sensitive mutant cells that had been pulse-labeled at the permissive temperature (30 degrees C). This species of molecule was found to have an electrophoretic mobility identical to that of the mature MBP, but a considerable fraction of it was inaccessible to externally added protease. It had not attained the protease-resistant conformation characteristically observed for the exported mature protein. The radioactivity associated with this species decreased during chase and was presumably converted into the exported mature form, a process that required energy, probably the proton motive force, as demonstrated by its inhibition by an energy uncoupler. The spheroplast-associated processed form was more predominantly observed in the presence of a low concentration of chloramphenicol. A similar intermediate was also detected for beta-lactamase in wild-type cells. These results suggest that in a late phase of translocation, the bulk of the polypeptide chain can move through the membrane in the absence of the covalently attached leader peptide, and the secA-secY gene products are somehow involved in this process. We termed the processed intermediates processed immature forms. PMID:2211501

  18. Effects of Organic and Inorganic Forms of Manganese, Zinc, Copper, and Chromium on Bioavailability of These Minerals and Calcium in Late-Phase Laying Hens.

    PubMed

    Yenice, Engin; Mızrak, Cengizhan; Gültekin, Meltem; Atik, Zafer; Tunca, Muhammet

    2015-10-01

    In the present study, the effects of dietary supplementation of organic and inorganic Mn, Zn, Cu, and Cr mixtures using two different levels (80, 60, 5, and 0.15 mg/kg and 40, 30, 2.5, and 0.07 mg/kg, respectively) on the bioavailability of these trace minerals and Ca in late-phase laying hens were evaluated. Three hundred and sixty laying hens (Barred Rock) at 50 weeks of age were used, and the duration of study was 16 weeks. Each of the four dietary regimes was randomly assigned to six replicates, which included 15 hens each. Organic trace minerals were provided as methionine chelates; inorganic Mn, Zn, and Cr were provided as oxides; and Cu was provided as sulfate. The organic form significantly increased the concentrations of serum Mn, Zn, Cu, and Ca; egg Mn, Zn, Cu, and Cr; and eggshell Zn and Cr compared with the inorganic form. However, the form of trace minerals did not affect the concentrations of serum Cr and eggshell Mn, Cu, and Ca. High-level addition of trace minerals significantly increased serum Mn and Zn; egg Mn, Zn, Cu, and Cr; and eggshell Mn, Zn, and Cu concentrations compared with low-level addition but did not affect serum Cu, Cr, and Ca or eggshell Cr and Ca concentrations. While the organic form reduced the excretion of Mn, Zn, Cu, Cr, and Ca, the high-level supplement increased Mn, Zn, and Cu excretion. The addition level did not affect Cr and Ca excretion. These results demonstrate that dietary supplementation of an organic Mn, Zn, Cu, and Cr mixture increases the bioavailability of Mn, Zn, Cu, Cr, and Ca compared with inorganic sources and that a lower level of trace mineral supplementation results in lower mineral excretion, particularly in an organic form. PMID:25800653

  19. Absence of the Yeast Hsp31 Chaperones of the DJ-1 Superfamily Perturbs Cytoplasmic Protein Quality Control in Late Growth Phase

    PubMed Central

    Amm, Ingo; Norell, Derrick; Wolf, Dieter H.

    2015-01-01

    The Saccharomyces cerevisiae heat shock proteins Hsp31, Hsp32, Hsp33 and Hsp34 belong to the DJ-1/ThiJ/PfpI superfamily which includes the human protein DJ-1 (PARK7) as the most prominent member. Mutations in the DJ-1 gene are directly linked to autosomal recessive, early-onset Parkinson’s disease. DJ-1 acts as an oxidative stress-induced chaperone preventing aggregation and fibrillation of α-synuclein, a critical factor in the development of the disease. In vivo assays in Saccharomyces cerevisiae using the model substrate ΔssCPY*Leu2myc (ΔssCL*myc) as an aggregation-prone misfolded cytoplasmic protein revealed an influence of the Hsp31 chaperone family on the steady state level of this substrate. In contrast to the ubiquitin ligase of the N-end rule pathway Ubr1, which is known to be prominently involved in the degradation process of misfolded cytoplasmic proteins, the absence of the Hsp31 chaperone family does not impair the degradation of newly synthesized misfolded substrate. Also degradation of substrates with strong affinity to Ubr1 like those containing the type 1 N-degron arginine is not affected by the absence of the Hsp31 chaperone family. Epistasis analysis indicates that one function of the Hsp31 chaperone family resides in a pathway overlapping with the Ubr1-dependent degradation of misfolded cytoplasmic proteins. This pathway gains relevance in late growth phase under conditions of nutrient limitation. Additionally, the Hsp31 chaperones seem to be important for maintaining the cellular Ssa Hsp70 activity which is important for Ubr1-dependent degradation. PMID:26466368

  20. Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.

    PubMed

    Zagaar, Munder A; Dao, An T; Alhaider, Ibrahim A; Alkadhi, Karim A

    2016-07-01

    The dentate gyrus (DG) and CA1 regions of the hippocampus are intimately related physically and functionally, yet they react differently to insults. The purpose of this study was to determine the protective effects of regular treadmill exercise on late phase long-term potentiation (L-LTP) and its signaling cascade in the DG region of the hippocampus of rapid eye movement (REM) sleep-deprived rats. Adult Wistar rats ran on treadmills for 4 weeks then were acutely sleep deprived for 24 h using the modified multiple platform method. After sleep deprivation, the rats were anesthetized and L-LTP was induced in the DG region. Extracellular field potentials from the DG were recorded in vivo, and levels of L-LTP-related signaling proteins were assessed both before and after L-LTP expression using immunoblot analysis. Sleep deprivation reduced the basal levels of phosphorylated cAMP response element-binding protein (P-CREB) as well as other upstream modulators including calcium/calmodulin kinase IV (CaMKIV) and brain-derived neurotrophic factor (BDNF) in the DG of the hippocampus. Regular exercise prevented impairment of the basal levels of P-CREB and total CREB as well as those of CaMKIV in sleep-deprived animals. Furthermore, regular exercise prevented sleep deprivation-induced inhibition of L-LTP and post-L-LTP downregulation of P-CREB and BDNF levels in the DG. The current findings show that our exercise regimen prevents sleep deprivation-induced deficits in L-LTP as well as the basal and poststimulation levels of key signaling molecules. PMID:25902862

  1. Focal Transient CNS Vessel Leak Provides a Tissue Niche for Sequential Immune Cell Accumulation during the Asymptomatic Phase of EAE Induction

    PubMed Central

    Barkauskas, Deborah S.; Dorand, R. Dixon; Myers, Jay T.; Evans, Teresa A.; Barkauskas, Kestutis J.; Askew, David; Purgert, Robert; Huang, Alex Y.

    2015-01-01

    Peripheral immune cells are critical to the pathogenesis of neurodegenerative diseases including multiple sclerosis (MS) (Hendriks et al., 2005; Kasper and Shoemaker, 2010). However, the precise sequence of tissue events during the early asymptomatic induction phase of experimental autoimmune encephalomyelitis (EAE) pathogenesis remains poorly defined. Due to the spatial-temporal constrains of traditional methods used to study this disease, most studies had been performed in the spine during peak clinical disease; thus the debate continues as to whether tissue changes such as vessel disruption represents a cause or a byproduct of EAE pathophysiology in the cortex. Here, we provide dynamic, high-resolution information on the evolving structural and cellular processes within the grey matter of the mouse cortex during the first 12 asymptomatic days of EAE induction. We observed that transient focal vessel disruptions precede microglia activation, followed by infiltration of and directed interaction between circulating dendritic cells and T cells. Histamine antagonist minimizes but not completely ameliorates blood vessel leak. Histamine H1 receptor blockade prevents early microglia function, resulting in subsequent reduction in immune cell accumulation, disease incidence and clinical severity. PMID:25708987

  2. Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

    PubMed Central

    Arnold, Kelly B.; Novak, Richard M.; McCorrister, Stuart; Shaw, Souradet; Westmacott, Garrett R.; Ball, Terry B.; Lauffenburger, Douglas A.; Burgener, Adam

    2015-01-01

    ABSTRACT The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and ex vivo human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (n = 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (P < 0.05, ≥2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway, P = 1.41E–5) and extravasation proteins (P = 5.62E–4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4+ T cell and neutrophil gene set signatures with the luteal phase (P < 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV. IMPORTANCE Recent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for

  3. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study.

    PubMed

    Newland, Adrian; Godeau, Bertrand; Priego, Victor; Viallard, Jean-Francois; López Fernández, María F; Orejudos, Amelia; Eisen, Melissa

    2016-01-01

    In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (≥50 × 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration ≤6 months who were treated with romiplostim for ≤12 months. The starting dose of romiplostim was 1 μg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts ≥50 × 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count ≥50 × 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435). PMID:26537623

  4. A preliminary fMRI study of a novel self-paced written fluency task: observation of left-hemispheric activation, and increased frontal activation in late vs. early task phases

    PubMed Central

    Golestanirad, Laleh; Das, Sunit; Schweizer, Tom A.; Graham, Simon J.

    2015-01-01

    Neuropsychological tests of verbal fluency are very widely used to characterize impaired cognitive function. For clinical neuroscience studies and potential medical applications, measuring the brain activity that underlies such tests with functional magnetic resonance imaging (fMRI) is of significant interest—but a challenging proposition because overt speech can cause signal artifacts, which tend to worsen as the duration of speech tasks becomes longer. In a novel approach, we present the group brain activity of 12 subjects who performed a self-paced written version of phonemic fluency using fMRI-compatible tablet technology that recorded responses and provided task-related feedback on a projection screen display, over long-duration task blocks (60 s). As predicted, we observed robust activation in the left anterior inferior and medial frontal gyri, consistent with previously reported results of verbal fluency tasks which established the role of these areas in strategic word retrieval. In addition, the number of words produced in the late phase (last 30 s) of written phonemic fluency was significantly less (p < 0.05) than the number produced in the early phase (first 30 s). Activation during the late phase vs. the early phase was also assessed from the first 20 s and last 20 s of task performance, which eliminated the possibility that the sluggish hemodynamic response from the early phase would affect the activation estimates of the late phase. The last 20 s produced greater activation maps covering extended areas in bilateral precuneus, cuneus, middle temporal gyrus, insula, middle frontal gyrus and cingulate gyrus. Among these areas, greater activation was observed in the bilateral middle frontal gyrus (Brodmann area BA 9) and cingulate gyrus (BA 24, 32) likely as part of the initiation, maintenance, and shifting of attentional resources. Consistent with previous pertinent fMRI literature involving overt and covert verbal responses, these findings highlight

  5. Integrated Immune

    NASA Technical Reports Server (NTRS)

    Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarnece

    2010-01-01

    This slide presentation reviews the program to replace several recent studies about astronaut immune systems with one comprehensive study that will include in-flight sampling. The study will address lack of in-flight data to determine the inflight status of immune systems, physiological stress, viral immunity, to determine the clinical risk related to immune dysregulation for exploration class spaceflight, and to determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

  6. Identification of mRNAs differentially expressed in quiescence or in late G1 phase of the cell cycle in human breast cancer cells by using the differential display method.

    PubMed Central

    Alpan, R. S.; Sparvero, S.; Pardee, A. B.

    1996-01-01

    BACKGROUND: The decision for a cell to enter the DNA synthesis (S) phase of the cell cycle or to arrest in quiescence is likely to be determined by genes expressed in the late G1 phase, at the restriction point. Loss of restriction point control is associated with malignant cellular transformation and cancer. For this reason, identifying genes that are differentially expressed in late G1 phase versus quiescence is important for understanding the molecular basis of normal and malignant growth. MATERIALS AND METHODS: The differential display (DD) method detects mRNA species that are different between sets of mammalian cells, allowing their recovery and cloning of the corresponding cDNAs. Using this technique, we compared mRNAs from synchronized human breast cancer cells (21 PT) in quiescence and in late G1. RESULTS: Six mRNAs differentially expressed in late G1 or in quiescence were identified. One mRNA expressed 10 hr after serum induction showed 99% homology to a peptide transporter involved in antigen presentation of the class I major histocompatibility complex (TAP-1) mRNA. Another mRNA expressed specifically in quiescence and down-regulated 2 hr following serum induction showed 98% homology to human NADP+ -dependent cytoplasmic malic enzyme (EC1.1.1.40) mRNA, which is an important enzyme in fatty acid synthesis and lipogenesis. Three others showed high homology to different mRNAs in the GeneBank, corresponding to genes having unknown functions. Finally, one mRNA revealed no significant homology to known genes in the GeneBank. CONCLUSIONS: We conclude that DD is an efficient and powerful method for the identification of growth-related genes which may have a role in cancer development. Images FIG. 2 FIG. 3 PMID:8827717

  7. Nutritional content and a phase-I safety clinical trial of a herbal-nutritional supplement (IMUNITI) with putative immune-modulating properties.

    PubMed

    Matsabisa, M G; Sekhoacha, M P; Ibrahim, O; Moodley, P; Faber, M

    2012-01-01

    The relationship between HIV and AIDS and poor nutrition has been well established. Poor nutrition hastens the progression of HIV infection to AIDS. The rising pandemic of HIV and AIDS and high toxicity associated with anti-retroviral use are major factors that have compelled research to explore traditional herbal medicines as potential alternatives or supplements to anti-retroviral agents. A Phase I clinical trial was conducted on IMUNITI Wellness Pack, a herbal product with putative immune-modulating properties. The product is a combination of 7 herbal preparations, minerals, vitamins, and a specially formulated soya-maize meal porridge and a bottle of water purifier. The aim was to evaluate the safety and tolerability of IMUNITI, with a purpose of developing it for use in HIV-infected patients. The phase I study was conducted at the MRC clinic in Botha's hill and the study lasted 5 weeks from date of participant dosing. The study was a randomised blinded placebo-controlled phase I clinical trial conducted on 48 healthy males. The participants were randomly divided into 4 groups of 12. The 3 groups received different escalating doses of IMUNITI while the forth group received placebo tablets. Participants consumed IMUNITI daily for a period of 5 weeks. Assessments were done at baseline, week 1 and week 5 to determine the safety parameters in all participants. In this study, IMUNITI did not show any safety concerns. In all study participants, there were no significant changes above the upper limit of the reference ranges of the laboratory tests for full blood count, INR, renal and biochemical safety parameters. IMUNITI was well tolerated. Furthermore, the nutritional content analysis of IMUNITI showed that it is a high kilojoule, high protein content product which contains a mixture of sugars, vitamins, traces of calcium, phosphorus and minerals. PMID:23983351

  8. Rebuilding immunity with Remune.

    PubMed

    Whitfield, L

    1998-01-01

    Remune, an immune response therapy composed of inactivated HIV, is designed to enhance the immune system's ability to recognize and kill HIV proteins. Developed by Dr. Jonas Salk, researchers hope Remune's actions can alter the course of HIV infection and slow disease progression. Remune has gained Food and Drug Administration (FDA) approval to enter the critical Phase III trial stage. Two clinical trials are tracking Remune's immunogenicity (ability to provoke an immune response), its immunogenicity relative to dose level, and its effect on viral load. An ongoing trial, approved in February of 1996, enrolled 2,500 patients at 74 sites. The manufacturer, Immune Response Corporation (IRC), announced earlier this year that treatment with Remune induces an immune response to HIV that cross-reacts with different strains of the virus. This immune response is crucial for developing an effective worldwide treatment. Remune decreases levels of tumor necrosis factor alpha (TNF-a). IRC recently began a Phase I clinical trial in Great Britain that combines Remune with a protease inhibitor, two antiviral nucleoside analogues, and Interleukin-2. The trial is designed to determine the role that the drug may play in restoring immune response. PMID:11365486

  9. Surficial Geologic Mapping Using Digital Techniques Reveals Late-Phase Basin Evolution and Role of Paleoclimate, Death Valley Junction 30' × 60' Quadrangle, California and Nevada

    NASA Astrophysics Data System (ADS)

    Slate, J.; Berry, M.; Menges, C. M.

    2010-12-01

    levels, abandoning and incising older alluvial units, thus preserving them on the footwall block of the fault. In tectonically inactive areas, streams continue to grade to the same level or aggrade, thus progressively burying older alluvial units. Therefore, map pattern of alluvial units is an important tool to evaluate late-phase basin evolution in the Basin and Range province. Determining the age of these alluvial units enables us to examine the role of paleoclimate during deposition. Six terrestrial cosmogenic-nuclide (TCN) 36Cl depth-profile dates of unit Qai fans along the west side of Death Valley range from about 40 ka to 100 ka (with a mean age of about 65 ka) and thus post-date the marine oxygen-isotope stage (MIS) 6 cycle of Pleistocene Lake Manly, but predate the lesser, MIS 2 successor. TCN 36Cl depth-profile dating establishes the age of a lacustrine bar complex at 30 m above sea level on the north side of Hanaupah Canyon to be 130 (+75/-39) ka and correlates with a deep lake at MIS 6. This bar predates units mapped as Qai and thus provides an important stratigraphic datum.

  10. [Immune mechanisms in uremia].

    PubMed

    Dobbelstein, H

    1975-05-15

    There is both clinical and experimental evidence that cellular and humoral immunity are suppressed in patients with renal insufficiency: observations in organ transplantation and in vitro stimulation of lymphocytes from uraemic patients, investigations of acute and late hypersensitivity reactions, the immune response after active immunization as well as changes of immunoglobulins and lymphatic organs in uraemia are discussed in the paper. The underlying mechanisms are complex and not yet fully understood. Lymphopenia, atrophy of the thymus gland, toxic serum factors, induction of enhancing mechanisms by certain serum fractions and metabolic defects of lymphocytes--all were shown to be involved or at least considered to be. At present, however, it is impossible to define their rank of importance and the exact place they may occupy in the genesis of this type of "natural immunosuppression". PMID:540

  11. Expansion and activation kinetics of immune cells during early phase of GVHD in mouse model based on chemotherapy conditioning.

    PubMed

    Sadeghi, Behnam; Al-Hashmi, Suleiman; Hassan, Zuzana; Rozell, Bjorn; Concha, Hernan; Lundmark, Carin; Grönvik, Kjell-Olov; Abedi-Valugerdi, Manuchehr; Hassan, Moustapha

    2010-01-01

    In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD. PMID:21197273

  12. Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning

    PubMed Central

    Sadeghi, Behnam; Al-Hashmi, Suleiman; Hassan, Zuzana; Rozell, Bjorn; Concha, Hernan; Lundmark, Carin; Grönvik, Kjell-Olov; Abedi-Valugerdi, Manuchehr; Hassan, Moustapha

    2010-01-01

    In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD. PMID:21197273

  13. Immunizations - diabetes

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000331.htm Immunizations - diabetes To use the sharing features on this page, please enable JavaScript. Immunizations (vaccines or vaccinations) help protect you from some ...

  14. Childhood Immunization

    MedlinePlus

    ... lowest levels in history, thanks to years of immunization. Children must get at least some vaccines before ... child provide protection for many years, adults need immunizations too. Centers for Disease Control and Prevention

  15. Limited Density of an Antigen Presented by RMA-S Cells Requires B7-1/CD28 Signaling to Enhance T-Cell Immunity at the Effector Phase

    PubMed Central

    Li, Xiao-Lin; Sluijter, Marjolein; Doorduijn, Elien M.; Kale, Shubha P.; McFerrin, Harris; Liu, Yong-Yu; Li, Yan; Mottamal, Madhusoodanan; Yao, Xin; Du, Fengkun; Gu, Baihan; Hoang, Kim; Nguyen, Yen H.; Taylor, Nichelle; Stephens, Chelsea R.; van Hall, Thorbald; Zhang, Qian-Jin

    2014-01-01

    The association of B7-1/CD28 between antigen presenting cells (APCs) and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide. PMID:25383875

  16. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D; Mansour, Iyad; Hariri, Dana; Motamed, Sara

    2015-01-01

    Metastatic cutaneous melanoma has poor prognosis with 2-year survival rate of 10-20%. Melanoma cells express various antigens including gp100, melanoma antigen recognized by T cells 1 (MART-1), and tyrosinase, which can induce immune-mediated anticancer response via T cell activation. Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immune check point molecule that negatively regulates T cell activation and proliferation. Accordingly, recent phase III clinical trials demonstrated significant survival benefit with ipilimumab, a human monoclonal antibody (IgG1) that blocks the interaction of CTLA-4 with its ligands. Since the efficacy of ipilimumab depends on T cell activation, it is associated with substantial risk of immune mediated adverse reactions such as colitis, hepatitis, thyroiditis, and hypophysitis. We report the first case of late onset pericarditis and cardiac tamponade associated with ipilimumab treatment in patient with metastatic cutaneous melanoma. PMID:25918658

  17. Molecular characterization of two immunity-related acute-phase proteins: Haptoglobin and serum amyloid A from black rockfish (Sebastes schlegeli).

    PubMed

    Jayasinghe, J D H E; Elvitigala, Don Anushka Sandaruwan; Whang, Ilson; Nam, Bo-Hye; Lee, Jehee

    2015-08-01

    Haptoglobin (Hp) and serum amyloid A (SAA) are two vital proteins involved in inflammatory reactions and are classified as acute-phase proteins. They are released from hepatocytes under inflammatory conditions to protect healthy cells from being damaged by pathogens or from self-destructive mechanisms. In this study, a previously constructed black rockfish (Sebastes schlegeli) cDNA library was used to identify the full-length cDNA sequences of Hp and SAA homologs (RfHp and RfSAA, respectively) and characterize them at the molecular level. As expected, in silico analysis of these homologs showed the typical domain architectures of their known counterparts. Open reading frames of RfHp and RfSAA consisted of 942-bp and 313-bp DNA sequences, respectively. The derived polypeptide sequence of RfHp was composed of 313 amino acids (aa) with a predicted molecular weight of 34 kD, whereas RfSAA had a 121-amino acid sequence with a molecular weight of 13 kD. Phylogenetic analysis as well as pairwise sequence alignment results showed that RfHp was more closely related to Oreochromis mossambicus from an evolutionary perspective while RfSAA was closely related to the Epinephelus coioides ortholog. Although both genes were expressed ubiquitously in the tissues analyzed, they were particularly expressed in liver tissue, suggesting their origin in hepatocytes. Quantitative real-time PCR analysis indicated that both RfHp and RfSAA were significantly up-regulated by both bacterial and viral stimulation in liver tissue, affirming their putative importance in the acute phase of first-line host immune defenses. PMID:25989623

  18. A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

    PubMed Central

    Gómez, Carmen Elena; Perdiguero, Beatriz; García-Arriaza, Juan; Cepeda, Victoria; Sánchez-Sorzano, Carlos Óscar; Mothe, Beatriz; Jiménez, José Luis; Muñoz-Fernández, María Ángeles; Gatell, Jose M.; López Bernaldo de Quirós, Juan Carlos; Brander, Christian; García, Felipe; Esteban, Mariano

    2015-01-01

    Trial Design Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART. Methods The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination. Results MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses. Conclusion MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity. Trial Registration ClinicalTrials.gov NCT01571466 PMID:26544853

  19. Echinoderm immunity.

    PubMed

    Smith, L Courtney; Ghosh, Julie; Buckley, Katherine M; Clow, Lori A; Dheilly, Nolwenn M; Haug, Tor; Henson, John H; Li, Chun; Lun, Cheng Man; Majeske, Audrey J; Matranga, Valeria; Nair, Sham V; Rast, Jonathan P; Raftos, David A; Roth, Mattias; Sacchi, Sandro; Schrankel, Catherine S; Stensvåg, Klara

    2010-01-01

    A survey for immune genes in the genome for the purple sea urchin has shown that the immune system is complex and sophisticated. By inference, immune responses of all echinoderms maybe similar. The immune system is mediated by several types of coelomocytes that are also useful as sensors of environmental stresses. There are a number of large gene families in the purple sea urchin genome that function in immunity and of which at least one appears to employ novel approaches for sequence diversification. Echinoderms have a simpler complement system, a large set of lectin genes and a number of antimicrobial peptides. Profiling the immune genes expressed by coelomocytes and the proteins in the coelomic fluid provide detailed information about immune functions in the sea urchin. The importance of echinoderms in maintaining marine ecosystem stability and the disastrous effects of their removal due to disease will require future collaborations between ecologists and immunologists working towards understanding and preserving marine habitats. PMID:21528703

  20. Neuroimmunoregulation and natural immunity.

    PubMed

    Berczi, I; Chow, D A; Sabbadini, E R

    1998-09-01

    The development and function of the immune system is regulated by neuroendocrine factors. Immune function may be divided into adaptive and natural immunity. Adaptive immune responses are driven by specific determinants of the antigen (epitopes), require 5-10 d to fully develop, and show an accelerated or memory response after repeated exposure to the same antigen. Natural immunity may be divided into host defense mediated by non-immune factors (e.g., antimicrobial proteins, enzymes, mucus etc.) and polyspecific responses of the immune system. This polyspecific response relies on natural antibodies and on some other serum proteins (e.g., lipopolysaccharide-binding protein-LBP, C-reactive protein-CRP), and on surface receptors of macrophages, natural killer cells and B and T lymphocytes for activation. Highly conserved homologous (crossreactive) epitopes, or homotopes for short, are recognized by the natural immune system. Natural antibodies, LBP, and CRP are capable of activating the entire immune system after combination with the appropriate homotope. During febrile illness natural immune host defense is promptly elevated because of the rapid rise of natural antibodies, LBP, and CRP in the serum. This is known as the acute phase response (APR), which is initiated by a sudden rise of cytokines in the circulation, such as IL-1, IL-6, and TNF-alpha. The cytokines act on the brain, the neuroendocrine system, and on other tissues and organs, which leads to fever and profound hormonal and metabolic changes. The hypothalamus-pituitary adrenal axis is activated and serves as the primary regulator of immune and inflammatory reactions. Insulin, glucagon, and catecholeamine levels are also raised. Bone marrow activity and leukocyte function are high and the liver is converted to the rapid production of acute-phase proteins (APP). APP include LBP, CRP, fibrinogen, some complement components, enzyme inhibitors, and anti-inflammatory proteins, which may rise in the serum from

  1. The effects of a rhythm and music-based therapy program and therapeutic riding in late recovery phase following stroke: a study protocol for a three-armed randomized controlled trial

    PubMed Central

    2012-01-01

    Background Stroke represents one of the most costly and long-term disabling conditions in adulthood worldwide and there is a need to determine the effectiveness of rehabilitation programs in the late phase after stroke. Limited scientific support exists for training incorporating rhythm and music as well as therapeutic riding and well-designed trials to determine the effectiveness of these treatment modalities are warranted. Methods/Design A single blinded three-armed randomized controlled trial is described with the aim to evaluate whether it is possible to improve the overall health status and functioning of individuals in the late phase of stroke (1-5 years after stroke) through a rhythm and music-based therapy program or therapeutic riding. About 120 individuals will be consecutively and randomly allocated to one of three groups: (T1) rhythm and music-based therapy program; (T2) therapeutic riding; or (T3) control group receiving the T1 training program a year later. Evaluation is conducted prior to and after the 12-week long intervention as well as three and six months later. The evaluation comprises a comprehensive functional and cognitive assessment (both qualitative and quantitative), and questionnaires. Based on the International classification of functioning, disability, and health (ICF), the outcome measures are classified into six comprehensive domains, with participation as the primary outcome measure assessed by the Stroke Impact Scale (SIS, version 2.0.). The secondary outcome measures are grouped within the following domains: body function, activity, environmental factors and personal factors. Life satisfaction and health related quality of life constitute an additional domain. Current status A total of 84 participants were randomised and have completed the intervention. Recruitment proceeds and follow-up is on-going, trial results are expected in early 2014. Discussion This study will ascertain whether any of the two intervention programs can

  2. Organising for immunization.

    PubMed

    Michie, S

    1993-06-01

    In the late 1960s, health workers from a mission hospital in rural Zambia began registering children under 14 years old within 30 miles of the hospital (about 3000 children) by incorporating the cooperation of community leaders. They wanted to give every 0-4 year old child a Road to Health card and every 5-14 year old a vaccine record card and to promote the significance of immunization to parents and community leaders. The mission hospital established mobile health units to conduct regular visits in the center of villages. Staff hugh scales from a tree and borrowed a table to conduct the clinic. They kept a good relationship and communication with the community, leading successful education and communication activities. By 1988, many younger mothers were unfamiliar with a measles or whooping cough epidemic so they tended to not have their infants immunized. Epidemics began killing children nationwide, frightening these mothers so they brought their children for immunizations. The medical mission achieved an 85-90% vaccination coverage rate with immunization clinic attendance climbing quickly. 1 mother even walked 30 miles to have her infant injected with the DPT vaccine, but 10 years earlier, she did not bring her children. Further, measles had not reached her area because the immunization level was so high that it stopped the epidemic. PMID:12318293

  3. Phase I trial with recombinant interleukin-2 (rIL-2): immune activation by rIL-2 alone or following pretreatment with recombinant interferon-gamma.

    PubMed Central

    Farace, F; Mathiot, C; Brandely, M; Tursz, T; Dorval, T; Pouillart, P; Triebel, F; Hercend, T; Fridman, W H

    1990-01-01

    Alterations of immunological parameters were analysed in patients with advanced malignancies during a phase I trial with rIL-2. Five-day infusions of rIL-2 at doses from 1 x 10(6) to 24 x 10(6) biological response modifiers program (BRMP) U/m2 per day were given to 29 patients, with a minimum of three patients per dose. The dose of 24 x 10(6) U/m2 per day was the maximal tolerated dose (MTD). Immunological parameters were analyzed at days 0, 8 and 11 of the rIL-2 courses. Following a leucopenia during rIL-2 infusion, a lymphocytosis was found in all patients except one. The lymphocytosis peaked at day 8 and was detected at doses of rIL-2 as low as 1 x 10(6) U/m2 per day, reaching a plateau at a dose of 16 x 10(6) U/m2 per day. Although all lymphocyte subsets were increased in patients receiving rIL-2, some patients had predominant T cells (CD3+, NKH1(CD56)-), others had predominant natural killer (NK) cells (CD3-, NKH1 (CD56)+), and yet others showed a mixed profile. A strong induction of cells cytotoxic for K562 targets was found in all patients at days 8 and 11. Eighteen patients received, 1 month later, a second treatment in which infusion of rIL-2 was preceded by a course of 5 days infusion of 2 x 10(6) U/m2 per day recombinant interferon-gamma (rIFN-gamma). The infusion of rIFN-gamma prior to rIL-2 had no effect on the rIL-2-induced alterations of immunological parameters. Taken together, our results suggest that immune stimulation by rIL-2 occurs even at low doses and is maximal at a dose below the MTD; and that pretreatment with low-dose rIFN-gamma does not modify the immune stimulation by rIL-2. PMID:2122928

  4. Late Patient-Reported Toxicity After Preoperative Radiotherapy or Chemoradiotherapy in Nonresectable Rectal Cancer: Results From a Randomized Phase III Study

    SciTech Connect

    Braendengen, Morten; Tveit, Kjell Magne; Bruheim, Kjersti; Cvancarova, Milada; Berglund, Ake; Glimelius, Bengt

    2011-11-15

    Purpose: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. Methods and Materials: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy Multiplication-Sign 25 {+-} 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function -vaginal changes questionnaire (SVQ). Results: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. Conclusions: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

  5. Multi-Institutional Phase II Study of Proton Beam Therapy for Organ-Confined Prostate Cancer Focusing on the Incidence of Late Rectal Toxicities

    SciTech Connect

    Nihei, Keiji; Ogino, Takashi; Onozawa, Masakatsu; Murayama, Shigeyuki; Fuji, Hiroshi; Murakami, Masao; Hishikawa, Yoshio

    2011-10-01

    Purpose: Proton beam therapy (PBT) is theoretically an excellent modality for external beam radiotherapy, providing an ideal dose distribution. However, it is not clear whether PBT for prostate cancer can clinically control toxicities. The purpose of the present study was to estimate prospectively the incidence of late rectal toxicities after PBT for organ-confined prostate cancer. Methods and Materials: The major eligibility criteria included clinical Stage T1-T2N0M0; initial prostate-specific antigen level of {<=}20 ng/mL and Gleason score {<=}7; no hormonal therapy or hormonal therapy within 12 months before registration; and written informed consent. The primary endpoint was the incidence of late Grade 2 or greater rectal toxicity at 2 years. Three institutions in Japan participated in the present study after institutional review board approval from each. PBT was delivered to a total dose of 74 GyE in 37 fractions. The patients were prospectively followed up to collect the data on toxicities using the National Cancer Institute-Common Toxicity Criteria, version 2.0. Results: Between 2004 and 2007, 151 patients were enrolled in the present study. Of the 151 patients, 75, 49, 9, 17, and 1 had Stage T1c, T2a, T2b, T2c, and T3a, respectively. The Gleason score was 4, 5, 6, and 7 in 5, 15, 80 and 51 patients, respectively. The initial prostate-specific antigen level was <10 or 10-20 ng/mL in 102 and 49 patients, respectively, and 42 patients had received hormonal therapy and 109 had not. The median follow-up period was 43.4 months. Acute Grade 2 rectal and bladder toxicity temporarily developed in 0.7% and 12%, respectively. Of the 147 patients who had been followed up for >2 years, the incidence of late Grade 2 or greater rectal and bladder toxicity was 2.0% (95% confidence interval, 0-4.3%) and 4.1% (95% confidence interval, 0.9-7.3%) at 2 years, respectively. Conclusion: The results of the present prospective study have revealed a valuable piece of evidence that

  6. The Changing World of Childhood Immunizations

    ERIC Educational Resources Information Center

    Graville, Iris

    2010-01-01

    Theories and practices in early childhood education continually evolve, and the same is true in the health field. Such change is especially apparent in the area of childhood immunizations. Since vaccination to prevent smallpox was first started in the late 1700s, recommendations for which immunizations to give and when to give them have been…

  7. DNA Immunization

    PubMed Central

    Wang, Shixia; Lu, Shan

    2013-01-01

    DNA immunization was discovered in early 1990s and its use has been expanded from vaccine studies to a broader range of biomedical research, such as the generation of high quality polyclonal and monoclonal antibodies as research reagents. In this unit, three common DNA immunization methods are described: needle injection, electroporation and gene gun. In addition, several common considerations related to DNA immunization are discussed. PMID:24510291

  8. Acute-phase protein α1-anti-trypsin: diverting injurious innate and adaptive immune responses from non-authentic threats

    PubMed Central

    Guttman, O; Baranovski, B M; Schuster, R; Kaner, Z; Freixo-Lima, G S; Bahar, N; Kalay, N; Mizrahi, M I; Brami, I; Ochayon, D E; Lewis, E C

    2015-01-01

    One would assume that the anti-inflammatory activity of α1-anti-trypsin (AAT) is the result of inhibiting neutrophil enzymes. However, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition or by reduced inflammatory parameters. Targets outside the serine-protease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is over-emphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumour susceptibilities, stunt B lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acute-phase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds interleukin (IL)-8, ADAM metallopeptidase domain 17 (ADAM17) and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity – ‘relative AAT deficiency’. Unlike immunosuppression, AAT appears to help the immune system to distinguish between desired responses against authentic threats, and unwanted responses fuelled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force: cell injury. PMID:25351931

  9. Immune System

    EPA Science Inventory

    A properly functioning immune system is essential to good health. It defends the body against infectious agents and in some cases tumor cells. Individuals with immune deficiencies resulting from genetic defects, diseases (e.g., AIDS, leukemia), or drug therapies are more suscepti...

  10. Maternal immunization

    PubMed Central

    Moniz, Michelle H; Beigi, Richard H

    2014-01-01

    Maternal immunization holds tremendous promise to improve maternal and neonatal health for a number of infectious conditions. The unique susceptibilities of pregnant women to infectious conditions, as well as the ability of maternally-derived antibody to offer vital neonatal protection (via placental transfer), together have produced the recent increased attention on maternal immunization. The Advisory Committee on Immunization Practices (ACIP) currently recommends 2 immunizations for all pregnant women lacking contraindication, inactivated Influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap). Given ongoing research the number of vaccines recommended during pregnancy is likely to increase. Thus, achieving high vaccination coverage of pregnant women for all recommended immunizations is a key public health enterprise. This review will focus on the present state of vaccine acceptance in pregnancy, with attention to currently identified barriers and determinants of vaccine acceptance. Additionally, opportunities for improvement will be considered. PMID:25483490

  11. A phase I/II trial of irinotecan-cisplatin combined with an anti-late-diarrhoeal programme to evaluate the safety and antitumour response of this combination therapy in patients with advanced non-small-cell lung cancer.

    PubMed

    Takeda, Y; Tsuduki, E; Izumi, S; Hojo, M; Kamimura, M; Naka, G; Kobayashi, K; Kudo, K

    2005-12-12

    We conducted a phase I/II study in patients with advanced non-small-cell lung cancer (NSCLC) to increase the therapeutic index of the cisplatin-irinotecan combination by institution of an anti-late-diarrhoeal program (ADP). A total of 77 chemotherapy-naive patients with advanced NSCLC were enrolled. The cisplatin dose was fixed at 60 mg m(-2) (Day 1). Irinotecan was escalated in 5 mg m(-2) increments, starting from 60 mg m(-2) (Days 1 and 8). ADP consisted of oral sodium bicarbonate, magnesium oxide, basic water, and ursodeoxycholic acid, and was administered orally for 4 days with each dose of irinotecan. In the phase I portion, irinotecan pharmacokinetics was also examined. After the recommended dose of irinotecan with ADP was determined, a phase II study was conducted to evaluate the response. Maximum tolerated dose was reached at an irinotecan dose of 80 mg m(-2) (Grade 4 diarrhoea and neutropenia). Pharmacokinetic studies show that the maximum concentration and the area under the curve of both irinotecan and SN38 (active metabolite of irinotecan) tend to increase in the dose-dependent manner of irinotecan. The phase II portion of the study included 48 patients, who were treated with 75 mg m(-2) of irinotecan. Grade 3/4 toxicities included neutropenia in 65%, leucopenia in 33%, and late diarrhoea in 6% of the patients. During this treatment, PS did not change in 65% of patients. At the end of the chemotherapy, PS did not decline in 90% of patients. In the phase II portion, a response occurred in 63% (95% confidential interval (CI), 47-76%) of patients. Median time to progression was 19 weeks (95% CI, 15-22 weeks), and median survival was 52 weeks (95% CI, 39-64 weeks). This regimen of irinotecan and cisplatin with ADP resulted in promising efficacy with acceptable toxicity for patients with advanced NSCLC. This regimen is a candidate for the experimental arm towards future phase III studies. PMID:16288302

  12. Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection

    PubMed Central

    Gurczynski, Stephen J.; Das, Subhendu

    2014-01-01

    Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the ΔUS17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the ΔUS17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced >3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), ΔUS17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response. PMID:24335296

  13. Chronic constant light-induced hippocampal late-phase long-term potentiation impairment in vitro is attenuated by antagonist of D1/D5 receptors.

    PubMed

    Chai, An-Ping; Ma, Wen-Pei; Wang, Li-Ping; Cao, Jun; Xu, Lin; Yang, Yue-Xiong; Mao, Rong-Rong

    2015-10-01

    Previous study reported that chronic constant light exposure caused hippocampus-dependent long-term memory deficit. However, the underlying cellular mechanism of this impairment is still unclear. Multiple lines of evidence indicated that long-term potentiation (LTP) is a cellular model for memory formation. Here we found that, by recording of field excitatory postsynaptic potential (fEPSP) in vitro, chronic constant light (CCL, 3 weeks) exposure impaired the late long-term potentiation (L-LTP), but not early long-term potentiation (E-LTP) and basal transmission in Schaffer collateral (SC)-CA1 synapses of hippocampal slices from rats. Because L-LTP depends on D1/D5 receptors, we examined whether interference of D1/D5 receptors can modulate L-LTP of CCL rats. Bath application of D1/D5 receptors antagonist SCH23390 (1μM) blocked L-LTP in control rats and attenuated the impaired L-LTP in CCL rats. In contrast, pre-incubation of D1/D5 receptors agonist SKF38393 (25μM) occluded further L-LTP in control rats while exacerbated the L-LTP impairment in CCL rats. These results suggested that CCL-induced L-LTP impairment can be modulated by D1/D5 receptors. Our findings may contribute to the further understanding of synaptic plasticity mechanism underlying hippocampal long-term memory impairment induced by circadian rhythm disruption. PMID:26115584

  14. THERMAL EMISSION IN THE EARLY X-RAY AFTERGLOWS OF GAMMA-RAY BURSTS: FOLLOWING THE PROMPT PHASE TO LATE TIMES

    SciTech Connect

    Friis, Mette; Watson, Darach E-mail: darach@dark-cosmology.dk

    2013-07-01

    Thermal radiation, peaking in soft X-rays, has now been detected in a handful of gamma-ray burst (GRB) afterglows and has to date been interpreted as shock break-out of the GRB's progenitor star. We present a search for thermal emission in the early X-ray afterglows of a sample of Swift bursts selected by their brightness in X-rays at early times. We identify a clear thermal component in eight GRBs and track the evolution. We show that at least some of the emission must come from highly relativistic material since two show an apparent super-luminal expansion of the thermal component. Furthermore, we determine very large luminosities and high temperatures for many of the components-too high to originate in a supernova shock break-out. Instead, we suggest that the component may be modeled as late photospheric emission from the jet, linking it to the apparently thermal component observed in the prompt emission of some GRBs at gamma-ray and hard X-ray energies. By comparing the parameters from the prompt emission and the early afterglow emission, we find that the results are compatible with the interpretation that we are observing the prompt quasi-thermal emission component in soft X-rays at a later point in its evolution.

  15. Inhaled lysine-aspirin as a bronchoprovocation procedure in aspirin-sensitive asthma: its repeatability, absence of a late-phase reaction, and the role of histamine.

    PubMed

    Phillips, G D; Foord, R; Holgate, S T

    1989-08-01

    Inhalation of an aerosolized solution of lysine-aspirin has previously been described as a safer technique than oral challenge with aspirin for the diagnosis of aspirin-sensitive asthma. We describe a modification of this method that involves inhalation of serially doubling incremental concentrations of lysine-aspirin by a standardized technique and allows construction of concentration-response curves. In 11 subjects with asthma, mean (SEM) age 48.2 (2.9) years, the geometric mean (range) provocation concentrations of histamine and lysine-aspirin required to produce a 20% decrease in FEV1 from baseline were 0.6 (0.04 to 3.2) and 48.3 (15.5 to 219) mg/ml, respectively. No relationship was found between these values. In seven of nine subjects investigated on two consecutive occasions, bronchoconstriction with lysine-aspirin was repeatable to within a single doubling concentration difference. Bronchoconstriction provoked by lysine-aspirin was more rapid than with oral aspirin and was not followed by any late asthmatic reaction or increase in nonspecific airway hyperresponsiveness. In six subjects, premedication with the selective H1 histamine-receptor antagonist, terfenadine, had no significant effect on bronchoconstriction provoked by inhaled lysine-aspirin, indicating little role for release of histamine in the response. We conclude that inhalation of lysine-aspirin may be used as a bronchoprovocation procedure for the diagnosis and investigation of aspirin-sensitive asthma. PMID:2503553

  16. Phase III study of cisplatin with pemtrexed or vinorelbine plus concurrent late course accelerated hyperfractionated radiotherapy in patients with unresectable stage III non-small cell lung cancer

    PubMed Central

    Zhao, Qian; Wang, Zhongtang; Huang, Wei; Wang, Qiang; Yu, Shuzeng; Zhou, Tao; Han, Dan; Wu, Zhenying; Gong, Heyi; Sun, Hongfu; Zhang, Jian; Wei, Yumei; Li, Hongsheng; Zhang, Zicheng; Lin, Haiqun; Li, Baosheng

    2016-01-01

    Our aim was to evaluate the efficacy and safety of cisplatin with pemtrexed or vinorelbine and concurrent late course accelerated hyperfractionated radiotherapy (LCAHRT). Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to two regimens. The experimental (PP) arm included cisplatin, pemtrexed and concurrent LCAHRT based on bilateral lung V20 = 33%. The control (NP) arm used cisplatin, vinorelbine with the same radiotherapy protocol. The primary endpoint was overall survival. Median survival times were 26.0 months (95% CI 23.2 to 28.7 months) and 28.5 months (95% CI 17.1 to 39.9 months) for the NP and PP arms, respectively (P = 0.26). Median progression-free survival was 12.5 months and 17.5 months in the NP and PP arms (P = 0.07). In both arms of the study, there were no differences in overall survival between patients with squamous and nonsquamous NSCLC. The incidences of grade 3 or 4 toxicity were higher in NP than PP arm. With concurrent LCAHRT, pemetrexed/cisplatin was equally as efficacious as vinorelbine/cisplatin, but showed a more favorable toxicity profile. PMID:26761213

  17. Immunity challenge.

    PubMed

    Davenport, R John

    2003-06-11

    As people get older, their immune systems falter. The elderly are more susceptible to infections than youngsters are, and hyperactive inflammatory responses appear to contribute to some age-associated illnesses, including Alzheimer's disease and atherosclerosis. Investigating the effect of aging on the immune system was once a scientific stepchild, but card-carrying immunologists are now tackling the problem head-on. Despite the immune system's complexity, researchers have started to make sense of how its components change with age. As the research progresses, scientists hope to bolster elderly people's response to infectious diseases and quiet the inflammation that can make aging a painful experience. PMID:12844525

  18. Maternal Immunization

    PubMed Central

    Chu, Helen Y.; Englund, Janet A.

    2014-01-01

    Maternal immunization has the potential to protect the pregnant woman, fetus, and infant from vaccine-preventable diseases. Maternal immunoglobulin G is actively transported across the placenta, providing passive immunity to the neonate and infant prior to the infant's ability to respond to vaccines. Currently inactivated influenza, tetanus toxoid, and acellular pertussis vaccines are recommended during pregnancy. Several other vaccines have been studied in pregnancy and found to be safe and immunogenic and to provide antibody to infants. These include pneumococcus, group B Streptococcus, Haemophilus influenzae type b, and meningococcus vaccines. Other vaccines in development for potential maternal immunization include respiratory syncytial virus, herpes simplex virus, and cytomegalovirus vaccines. PMID:24799324

  19. Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial

    PubMed Central

    Armand, Philippe; Nagler, Arnon; Weller, Edie A.; Devine, Steven M.; Avigan, David E.; Chen, Yi-Bin; Kaminski, Mark S.; Holland, H. Kent; Winter, Jane N.; Mason, James R.; Fay, Joseph W.; Rizzieri, David A.; Hosing, Chitra M.; Ball, Edward D.; Uberti, Joseph P.; Lazarus, Hillard M.; Mapara, Markus Y.; Gregory, Stephanie A.; Timmerman, John M.; Andorsky, David; Or, Reuven; Waller, Edmund K.; Rotem-Yehudar, Rinat; Gordon, Leo I.

    2013-01-01

    Purpose The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade. Patients and Methods We conducted an international phase II study of pidilizumab, an anti–PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT. Results Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E–bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab. Conclusion This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease. PMID:24127452

  20. Late Silurian plutons in Yucatan

    NASA Astrophysics Data System (ADS)

    Steiner, M. B.; Walker, J. Douglas

    1996-08-01

    U-Pb measurements of zircons from two composite plutons in the Maya Mountains of the Yucatan Block (Belize) give Late Silurian ages. Zircons from one of the five compositional phases of the Mountain Pine Ridge pluton yield an age of 418±3.6 Ma. A second compositional phase gives a minimum age of 404 Ma, and zircons from a third phase, although plagued with high common Pb, yield ages consistent with the other two. Zircons from one compositional phase of the Hummingbird-Mullins River pluton indicate an age of about 410-420 Ma. These data demonstrate that two of the three Maya Mountains plutons residing among the strata of the Late Pennsylvanian through Permian Santa Rosa Group are older than that sedimentation. Although the third pluton was not dated, both the similarity of sedimentary facies patterns adjacent to it to those adjacent to one of the plutons dated as Late Silurian and a published single Rb-Sr age of 428 ± 41 Ma suggest this third pluton also was emergent during Santa Rosa deposition. Thus the new U/Pb dates and other data suggest that all three Maya Mountains plutons pre-date Late Carboniferous sedimentation and that none intrude the Santa Rosa Group. Although very uniform ages of about 230 Ma amongst all plutons, derived from abundant earlier dating by the K-Ar system, led to the conclusion that intrusion mostly had occurred in the Late Triassic, the U-Pb ages (obtained from the same sites as the K-Ar dates) demonstrate that the K-Ar ages do not derive from a Late Triassic intrusive episode. The K-Ar dates probably are a signature of the rifting associated with Pangean breakup and formation of the Gulf of Mexico. In a reconstructed Pangea, the position of the Maya Mountains Late Silurian plutons suggests that the Late Silurian Acadian-Caledonian orogen of eastern North America extended through the region of the future Gulf of Mexico. Finally, the U-Pb ages of the Maya Mountains plutons are the same as those of a group of shocked zircons found in the

  1. Waterlogging in late dormancy and the early growth phase affected root and leaf morphology in Betula pendula and Betula pubescens seedlings.

    PubMed

    Wang, Ai-Fang; Roitto, Marja; Sutinen, Sirkka; Lehto, Tarja; Heinonen, Jaakko; Zhang, Gang; Repo, Tapani

    2016-01-01

    The warmer winters of the future will increase snow-melt frequency and rainfall, thereby increasing the risk of soil waterlogging and its effects on trees in winter and spring at northern latitudes. We studied the morphology of roots and leaves of 1-year-old silver birch (Betula pendula Roth) and pubescent birch (Betula pubescens Ehrh.) seedlings exposed to waterlogging during dormancy or at the beginning of the growing season in a growth-chamber experiment. The experiment included 4-week dormancy (Weeks 1-4), a 4-week early growing season (Weeks 5-8) and a 4-week late growing season (Weeks 9-12). The treatments were: (i) no waterlogging, throughout the experiment ('NW'); (ii) 4-week waterlogging during dormancy (dormancy waterlogging 'DW'); (iii) 4-week waterlogging during the early growing season (growth waterlogging 'GW'); and (iv) 4-week DW followed by 4-week GW during the early growing season ('DWGW'). Dormancy waterlogging affected the roots of silver birch and GW the roots and leaf characteristics of both species. Leaf area was reduced in both species by GW and DWGW. In pubescent birch, temporarily increased formation of thin roots was seen in root systems of GW seedlings, which suggests an adaptive mechanism with respect to excess soil water. Additionally, the high density of non-glandular trichomes and their increase in DWGW leaves were considered possible morphological adaptations to excess water in the soil, as was the constant density of stem lenticels during stem-diameter growth. The higher density in glandular trichomes of DWGW silver birch suggests morphological acclimation in that species. The naturally low density of non-glandular trichomes, low density of stem lenticels in waterlogged seedlings and decrease in root growth seen in DWGW and DW silver birch seedlings explain, at least partly, why silver birch grows more poorly relative to pubescent birch in wet soils. PMID:26420790

  2. Immunization Coverage

    MedlinePlus

    ... underused vaccines is increasing. Immunization currently averts an estimated 2 to 3 million deaths every year. An ... avoided, however, if global vaccination coverage improves. An estimated 19.4 million infants worldwide are still missing ...

  3. Immune response

    MedlinePlus

    ... inflammation and tissue repair. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 24th ed. Philadelphia, PA: ... and adaptive immune systems. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 24th ed. Philadelphia, PA: ...

  4. Childhood Immunization

    MedlinePlus

    Today, children in the United States routinely get vaccines that protect them from more than a dozen ... lowest levels in history, thanks to years of immunization. Children must get at least some vaccines before ...

  5. Immune response

    MedlinePlus Videos and Cool Tools

    The immune system includes specialized white blood cells, called lymphocytes that adapt themselves to fight specific foreign invaders. These cells develop into two groups in the bone marrow. From the bone ...

  6. [Prognosis of dynamics and risk of exceeding permissible levels of 137Cs and 90Sr contents in fish in the Kiev Reservoir at the late phase of the Chernobyl accident].

    PubMed

    Homutinin, Iu V; Kashparov, V A; Kuz'menko, A V; Pavliuchenko, V V

    2013-01-01

    On the basis of the radionuclide specific activity measurements made on 832 samples of fish in 2009-2011 and taking into account literature data, the parameters of the stochastic model have been derived to describe the 137Cs and 90Sr contents in typical commercial fish species in the Kiev Reservoir at the late phase of the Chernobyl accident, including: statistical variability, seasonal changes and monotonous long-term trends. At any fixed moment of the year the standard deviations of logarithms of the 137Cs and 90Sr specific activities in carnivorous and benthophage fish species do not reliably differ, making up at average 0.4. The maximum vari- ation of the 137Cs specific activity (a four-fold decrease from April to November) was observed in pike. The obtained values of the ecological half-life periods for 137Cs and 90Sr (1.3-14 years) in fish of the Kiev reservoir in 2002-2012 were significantly lower than both the radioactive decay periods and the estimates of the IAEA Chernobyl Forum. Based on the obtained model parameters, the dynamics of the 137Cs and 90Sr specific ac- tivities in main commercial fish of the Kiev reservoir has been described and the risk of exceeding the permis- sible levels of these radionuclides in fish at the late phase of the Chernobyl accident has been estimated. Now the risk of catching fish with the specific activities of 137Cs and 90Sr above the permissible levels (150 Bq/kg and 35 Bq/kg, respectively) does not exceed 10% (except perch in the spring spawning period that is banned for fishing in Ukraine). Corresponding risks for roach, white bream and rudd are less than 0.1%. PMID:25427374

  7. [Prognosis of dynamics and risk of exceeding permissible levels of 137Cs and 90Sr contents in fish in the Kiev Reservoir at the late phase of the Chernobyl accident].

    PubMed

    2013-01-01

    On the basis of the radionuclide specific activity measurements made on 832 samples of fish in 2009-2011 and taking into account literature data, the parameters of the stochastic model have been derived to describe the 137Cs and 90Sr contents in typical commercial fish species in the Kiev Reservoir at the late phase of the Chernobyl accident, including: statistical variability, seasonal changes and monotonous long-term trends. At any fixed moment of the year the standard deviations of logarithms of the 137Cs and 90Sr specific activities in carnivorous and benthophage fish species do not reliably differ, making up at average 0.4. The maximum vari- ation of the 137Cs specific activity (a four-fold decrease from April to November) was observed in pike. The obtained values of the ecological half-life periods for 137Cs and 90Sr (1.3-14 years) in fish of the Kiev reservoir in 2002-2012 were significantly lower than both the radioactive decay periods and the estimates of the IAEA Chernobyl Forum. Based on the obtained model parameters, the dynamics of the 137Cs and 90Sr specific ac- tivities in main commercial fish of the Kiev reservoir has been described and the risk of exceeding the permis- sible levels of these radionuclides in fish at the late phase of the Chernobyl accident has been estimated. Now the risk of catching fish with the specific activities of 137Cs and 90Sr above the permissible levels (150 Bq/kg and 35 Bq/kg, respectively) does not exceed 10% (except perch in the spring spawning period that is banned for fishing in Ukraine). Corresponding risks for roach, white bream and rudd are less than 0.1%. PMID:25507624

  8. From Space to the Septic Patient: Assessment of Cellular Immunity in Severely Immune Compromised Conditions

    NASA Technical Reports Server (NTRS)

    Sudhoff, Lars; Kaufmann, Ines; Feuerecker, Matthias; Crucian, Brian; Sams, Clarence; Mehta, Satish; Pierson, Duane; Schelling, Gustav; Chouker, Alexander

    2016-01-01

    PWM, LPS and CD3/28. Moreover, inter-patient comparisons revealed that patients receiving stress doses of hydrocortisone and patients in hypoxemia (pO2 less than 80mmHg) showed a significantly impaired TNF-alpha release in PWM-stimulated whole blood compared to the respective control group. Conclusion: Shortly after the onset of severe sepsis and septic shock, patients attain a general immunosuppressive state affecting both the innate as well as the acquired part of the immune system. This is partly mediated by T-cell apoptosis and a shift of the equilibrium to anti-inflammatory mediators. Its degree of severity correlates with conditions that are commonly present in aeronautics and spaceflight, such as increased hydrocortisone levels and hypoxemia (a condition resulting also from future space habitats). It entails an increase in secondary infection and subsequent late-phase morbidity and mortality. New therapeutic approaches such as reverse isolation and immune-stimulatory interventions should be discussed to improve patient outcome. Those can be of another translational benefit for immune-dysfunctional states in Space.

  9. Cryptococcal heat shock protein 70 homolog Ssa1 contributes to pulmonary expansion of Cryptococcus neoformans during the afferent phase of the immune response by promoting macrophage M2 polarization.

    PubMed

    Eastman, Alison J; He, Xiumiao; Qiu, Yafeng; Davis, Michael J; Vedula, Priya; Lyons, Daniel M; Park, Yoon-Dong; Hardison, Sarah E; Malachowski, Antoni N; Osterholzer, John J; Wormley, Floyd L; Williamson, Peter R; Olszewski, Michal A

    2015-06-15

    Numerous virulence factors expressed by Cryptococcus neoformans modulate host defenses by promoting nonprotective Th2-biased adaptive immune responses. Prior studies demonstrate that the heat shock protein 70 homolog, Ssa1, significantly contributes to serotype D C. neoformans virulence through the induction of laccase, a Th2-skewing and CNS tropic factor. In the present study, we sought to determine whether Ssa1 modulates host defenses in mice infected with a highly virulent serotype A strain of C. neoformans (H99). To investigate this, we assessed pulmonary fungal growth, CNS dissemination, and survival in mice infected with either H99, an SSA1-deleted H99 strain (Δssa1), and a complement strain with restored SSA1 expression (Δssa1::SSA1). Mice infected with the Δssa1 strain displayed substantial reductions in lung fungal burden during the innate phase (days 3 and 7) of the host response, whereas less pronounced reductions were observed during the adaptive phase (day 14) and mouse survival increased only by 5 d. Surprisingly, laccase activity assays revealed that Δssa1 was not laccase deficient, demonstrating that H99 does not require Ssa1 for laccase expression, which explains the CNS tropism we still observed in the Ssa1-deficient strain. Lastly, our immunophenotyping studies showed that Ssa1 directly promotes early M2 skewing of lung mononuclear phagocytes during the innate phase, but not the adaptive phase, of the immune response. We conclude that Ssa1's virulence mechanism in H99 is distinct and laccase-independent. Ssa1 directly interferes with early macrophage polarization, limiting innate control of C. neoformans, but ultimately has no effect on cryptococcal control by adaptive immunity. PMID:25972480

  10. Immune Responses to Intramuscular Administration of Alipogene Tiparvovec (AAV1-LPLS447X) in a Phase II Clinical Trial of Lipoprotein Lipase Deficiency Gene Therapy

    PubMed Central

    Twisk, Jaap; Kwikkers, Karin; Aronica, Eleonora; Brisson, Diane; Methot, Julie; Petry, Harald; Gaudet, Daniel

    2014-01-01

    Abstract Cellular immune responses to adeno-associated viral (AAV) vectors used for gene therapy have been linked to attenuated transgene expression and loss of efficacy. The impact of such cellular immune responses on the clinical efficacy of alipogene tiparvovec (Glybera; AAV1-LPLS447X; uniQure), a gene therapy consisting of intramuscular administration of a recombinant AAV1 mediating muscle-directed expression of lipoprotein lipase (LPL), was investigated. Five subjects with LPL deficiency (LPLD) were administered intramuscularly with a dose of 1×1012 gc/kg alipogene tiparvovec. All subjects were treated with immune suppression starting shortly before administration of alipogene tiparvovec and maintained until 12 weeks after administration. Systemic antibody and T cell responses against AAV1 and LPLS447X, as well as local cellular immune responses in the injected muscle, were investigated in five LPLD subjects. Long-term transgene expression was demonstrated despite a transient systemic cellular response and a stable humoral immune response against the AAV1 capsid protein. Cellular infiltrates were found in four of the five subjects but were not associated with adverse clinical events or elevation of inflammation markers. Consistent herewith, CD8+ T cells in the infiltrates lacked cytotoxic potential. Furthermore, FoxP3+/CD4+ T cells were found in the infiltrates, suggesting that multiple mechanisms contribute to local tolerance. Systemic and local immune responses induced by intramuscular injection of alipogene tiparvovec did not appear to have an impact on safety and did not prevent LPL transgene expression. These findings support the use of alipogene tiparvovec in individuals with LPLD and indicate that muscle-directed AAV-based gene therapy remains a promising approach for the treatment of human diseases. PMID:24299335