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Sample records for late phase immunity

  1. Inhibitory effect of heat-killed Lactobacillus strain on immunoglobulin E-mediated degranulation and late-phase immune reactions of mouse bone marrow-derived mast cells.

    PubMed

    Kawahara, Takeshi

    2010-12-01

    This study investigated the in vitro effect of Lactobacillus strains, a major group of probiotic lactic acid bacteria, on immunoglobulin E (IgE)- and antigen-induced mast cell degranulation and subsequent gene expression. Bone marrow-derived mast cells (BMMCs) from DBA/2 mice were cultured with heat-killed Lactobacillus strains for 24 h. Some strains significantly inhibited IgE- and antigen-induced β-hexosaminidase release from BMMCs. Furthermore, Lactobacillus reuteri NBRC 15892, which exhibited the strongest inhibitory activity, significantly reduced the elevated interleukin (IL)-4, IL-13, tumor necrosis factor-α, and cyclooxygenase-2 expression levels that was induced by 1-2 h of stimulation with IgE and antigens. The suppressive effect of NBRC 15892 strain on BMMC degranulation was significantly reduced in the presence of a toll-like receptor (TLR)2-neutralizing antibody. In addition, downregulation of cell surface FcεRIα expression was observed after 6 h of NBRC 15892 treatment. These results suggest that some Lactobacillus strains inhibited IgE-mediated mast cell degranulation and subsequent late-phase reactions involving mast cells via a TLR2-dependent mechanism with FcεRIα downregulation.

  2. 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.

  3. 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.

  4. Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1.

    PubMed

    Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T; Maier, Steven F; Patterson, Susan L

    2010-06-02

    Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability to physiological and psychological challenges. Exploring the basis of this vulnerability may provide important insights into the mechanisms underlying aging-associated cognitive decline. As we have previously reported, the cognitive abilities of aging (24-month-old) F344 x BN rats are generally good, but are more vulnerable to the consequences of a peripheral immune challenge (an intraperitoneal injection of live Escherichia coli) than those of their younger (3-month-old) counterparts. Four days after the injection, the aging, but not the young rats show profound memory deficits, specific to the consolidation of hippocampus-dependent memory processes. Here, we have extended these observations, using hippocampal slices to examine for the first time the combined effects of aging and a recent infection on several forms of synaptic plasticity. We have found that the specific deficit in long-lasting memory observed in the aged animals after infection is mirrored by a specific deficit in a form of long-lasting synaptic plasticity. The late-phase long-term potentiation induced in area CA1 using theta-burst stimulation is particularly compromised by the combined effects of aging and infection-a deficit that can be ameliorated by intra-cisterna magna administration of the naturally occurring antiinflammatory cytokine IL-1Ra (interleukin-1 receptor antagonist). These data support the idea that the combination of aging and a negative life event such as an infection might produce selective, early-stage failures of synaptic plasticity in the hippocampus, with corresponding selective deficits in memory.

  5. A nonequilibrium phase transition in immune response

    NASA Astrophysics Data System (ADS)

    Zhang, Wei; Qi, An-Shen

    2004-07-01

    The dynamics of immune response correlated to signal transduction in immune thymic cells (T cells) is studied. In particular, the problem of the phosphorylation of the immune-receptor tyrosine-based activation motifs (ITAM) is explored. A nonlinear model is established on the basis of experimental observations. The behaviours of the model can be well analysed using the concepts of nonequilibrium phase transitions. In addition, the Riemann-Hugoniot cusp catastrophe is demonstrated by the model. Due to the application of the theory of nonequilibrium phase transitions, the biological phenomena can be clarified more precisely. The results can also be used to further explain the signal transduction and signal discrimination of an important type of immune T cell.

  6. EXTREMELY LARGE EUV LATE PHASE OF SOLAR FLARES

    SciTech Connect

    Liu, Kai; Wang, Yuming; Liu, Rui; Shen, Chenglong; Zhang, Jie; Cheng, Xin

    2015-03-20

    The second peak in the Fe xvi 33.5 nm line irradiance observed during solar flares by the Extreme-Ultraviolet Variability Experiment (EVE) is known as the EUV late phase. Our previous paper in 2013 by Liu et al. found that the main emissions in the late phase are originated from large-scale loop arcades that are closely connected to but different from the post-flare loops (PFLs), and we also proposed that a long cooling process without additional heating could explain the late phase. In this paper, we define the extremely large late phase because it not only has a bigger peak in the warm 33.5 irradiance profile, but also releases more EUV radiative energy than the main phase. Through detailed inspection of the EUV images from three points of view, it was discovered that aside from the later-phase loop arcades, the main contributor of the extremely large late phase is a hot structure that fails to erupt. This hot structure is identified as a flux rope, which is quickly energized by the flare reconnection and later on continuously produces the thermal energy during the gradual phase. Together with the late-phase loop arcades, the flux rope failing to erupt with the additional heating create the extremely large EUV late phase.

  7. Extremely Large EUV Late Phase of Solar Flares

    NASA Astrophysics Data System (ADS)

    Liu, Kai; Wang, Yuming; Zhang, Jie; Cheng, Xin; Liu, Rui; Shen, Chenglong

    2015-04-01

    The second peak in the Fe XVI 33.5 nm line irradiance observed during solar flares by Extreme ultraviolet Variability Experiment (EVE) is known as Extreme UltraViolet (EUV) late phase. Our previous paper found that the main emissions in the late phase are originated from large-scale loop arcades that are closely connected to but different from the post flare loops (PFLs), and we also proposed that a long cooling process without additional heating could explain the late phase. In this paper, we define the extremely large late phase because it not only has a bigger peak in the warm 33.5 irradiance profile, but also releases more EUV radiative energy than the main phase. Through detailedly inspecting the EUV images from three point-of-view, it is found that, besides the later phase loop arcades, the more contribution of the extremely large late phase is from a hot structure that fails to erupt. This hot structure is identified as a flux rope, which is quickly energized by the flare reconnection and later on continuously produces the thermal energy during the gradual phase. Together with the late-phase loop arcades, the fail to erupt flux rope with the additional heating creates the extremely large EUV late phase.

  8. Extremely Large EUV Late Phase of Solar Flares

    NASA Astrophysics Data System (ADS)

    Liu, Kai; Wang, Yuming; Zhang, Jie; Cheng, Xin; Liu, Rui; Shen, Chenglong

    2015-03-01

    The second peak in the Fe xvi 33.5 nm line irradiance observed during solar flares by the Extreme-Ultraviolet Variability Experiment (EVE) is known as the EUV late phase. Our previous paper in 2013 by Liu et al. found that the main emissions in the late phase are originated from large-scale loop arcades that are closely connected to but different from the post-flare loops (PFLs), and we also proposed that a long cooling process without additional heating could explain the late phase. In this paper, we define the extremely large late phase because it not only has a bigger peak in the warm 33.5 irradiance profile, but also releases more EUV radiative energy than the main phase. Through detailed inspection of the EUV images from three points of view, it was discovered that aside from the later-phase loop arcades, the main contributor of the extremely large late phase is a hot structure that fails to erupt. This hot structure is identified as a flux rope, which is quickly energized by the flare reconnection and later on continuously produces the thermal energy during the gradual phase. Together with the late-phase loop arcades, the flux rope failing to erupt with the additional heating create the extremely large EUV late phase.

  9. 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.

  10. 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.

  11. Effect of short-term water restriction in hot season on some blood parameters and immune response to Newcastle disease vaccine of local and commercial layers in the late phase of production.

    PubMed

    Alamer, M A; Ahmed, A S

    2012-08-01

    Forty-five Hisex commercial layers and forty-five local Saudi breed layers were used to compare and assess the effect of water restriction under hot conditions on blood constituents and immune response to Newcastle disease (ND) vaccine. The trial was divided into three periods: control (7 day), water restriction (14 day) and rehydration (7 day). During water restriction, layers from each breed were divided into three groups that received 0%, 20% and 40% restriction of drinking water relative to the control period. The immune response against ND was affected by breed; it also declined significantly with 40% water restriction 10 days post-restriction. Water restriction did not affect haematocrit value, plasma total protein, albumin, glucose or osmolality, which may not suggest a reduction in plasma volume. However, plasma creatinine increased in both breeds because of water restriction that remained elevated during rehydration. Water restriction increased plasma urea in the local group, while it decreased in the commercial group. Irrespective of rate of water restriction, it can be concluded that the two breeds can withstand up to 40% water restriction during high environmental temperature. However, the local breed may be superior in water conservation in relation to the commercial layers. © 2011 Blackwell Verlag GmbH.

  12. LIMP-2 Links Late Phagosomal Trafficking with the Onset of the Innate Immune Response to Listeria monocytogenes

    PubMed Central

    Carrasco-Marín, Eugenio; Fernández-Prieto, Lorena; Rodriguez-Del Rio, Estela; Madrazo-Toca, Fidel; Reinheckel, Thomas; Saftig, Paul; Alvarez-Dominguez, Carmen

    2011-01-01

    The innate immune response to Listeria monocytogenes depends on phagosomal bacterial degradation by macrophages. Here, we describe the role of LIMP-2, a lysosomal type III transmembrane glycoprotein and scavenger-like protein, in Listeria phagocytosis. LIMP-2-deficient mice display a macrophage-related defect in Listeria innate immunity. They produce less acute phase pro-inflammatory cytokines/chemokines, MCP-1, TNF-α, and IL-6 but normal levels of IL-12, IL-10, and IFN-γ and a 25-fold increase in susceptibility to Listeria infection. This macrophage defect results in a low listericidal potential, poor response to TNF-α activation signals, impaired phago-lysosome transformation into antigen-processing compartments, and uncontrolled LM cytosolic growth that fails to induce normal levels of acute phase pro-inflammatory cytokines. LIMP-2 transfection of CHO cells confirmed that LIMP-2 participates in the degradation of Listeria within phagosomes, controls the late endosomal/lysosomal fusion machinery, and is linked to the activation of Rab5a. Therefore, the role of LIMP-2 appears to be connected to the TNF-α-dependent and early activation of Listeria macrophages through internal signals linking the regulation of late trafficking events with the onset of the innate Listeria immune response. PMID:21123180

  13. MIF is necessary for late-stage melanoma patient MDSC immune suppression and differentiation

    PubMed Central

    Yaddanapudi, Kavitha; Rendon, Beatriz E.; Lamont, Gwyneth; Kim, Eun Jung; Al Rayyan, Numan; Richie, Jamaal; Albeituni, Sabrin; Waigel, Sabine; Wise, Ashley; Mitchell, Robert A.

    2015-01-01

    Highly aggressive cancers “entrain” innate and adaptive immune cells to suppress anti-tumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSCs) constitute the bulk of monocytic immunosuppressive activity in late stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of tumor-associated macrophages (TAMs) and MDSCs in mouse models of melanoma. In the current study we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo co-culture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species (ROS) generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immune suppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor DC responses in late stage melanoma patients. PMID:26603621

  14. Light sterile neutrinos from a late phase transition

    NASA Astrophysics Data System (ADS)

    Vecchi, Luca

    2016-12-01

    Light sterile neutrinos represent a well-motivated extension of the 3-neutrino paradigm. However, the impressive agreement between standard cosmology and data casts doubts on their existence. Here, we present a class of scenarios that robustly avoids this tension. In these models the sterile neutrinos are light, chiral states of a new sector interacting with the Standard Model via the right-handed neutrino portal, and crucially active-sterile neutrino oscillations require a phase transition in the hidden sector. We explore the hidden-couplings/critical-temperature plane and identify regions where several sterile neutrinos can be accommodated. A late phase transition is usually preferred and may also ward off a potential threat posed by the formation of topologically stable defects.

  15. Regulation of the acute phase and immune responses

    SciTech Connect

    Sehgal, P.B.; Grieninger, G.; Tosato, G.

    1989-01-01

    This book contains the conference entitled Regulation of the acute phase and immune responses: Interleukin-L. Topics covered include: Interferon-B{sub 2}/26kDa Protein, Regulation of acute phase liver gene expression, and Genetics and regulation of expression of IL-6.

  16. On the relationship of late phase loop arcades with confined solar flares

    NASA Astrophysics Data System (ADS)

    Liu, Kai; Wang, Yuming; Liu, Rui; Shen, Chenglong

    2017-04-01

    The second enhancement of irradiances of warm line (Fe XVI 33.5 nm) after the solar flare is defined as EUV late phase. According to previous studies (e.g., Liu et al. 2013), the late phase is originated from a set of big loop arcades (late phase loop arcades) besides the flare loops in the same active region. While a failed eruption is involved, the late phase peak tend to be much larger than the main peak, named as extremely large EUV late phase (Liu et al. 2015). In this study, we track a series of flare events with EUV late phase in the same active region (NOAA 11598), which include 4 strong flare events and several C class event, and most of them are confined. From these events, we try to understand the formation, evolution and influence of the late phase loop arcades, and their role in the confined solar flare events.

  17. Identification and analysis of immune-related transcriptome in Asian seabass Lates calcarifer

    PubMed Central

    2010-01-01

    Background Fish diseases caused by pathogens are limiting their production and trade, affecting the economy generated by aquaculture. Innate immunity system is the first line of host defense in opposing pathogenic organisms or any other foreign material. For identification of immune-related genes in Asian seabass Lates calcarifer, an important marine foodfish species, we injected bacterial lipopolysaccharide (LPS), a commonly used elicitor of innate immune responses to eight individuals at the age of 35 days post-hatch and applied the suppression subtractive hybridization (SSH) technique to selectively amplify spleen cDNA of differentially expressed genes. Results Sequencing and bioinformatic analysis of 3351 ESTs from two SSH libraries yielded 1692 unique transcripts. Of which, 618 transcripts were unknown/novel genes and the remaining 1074 were similar to 743 known genes and 105 unannotated mRNA sequences available in public databases. A total of 161 transcripts were classified to the category "response to stimulus" and 115 to "immune system process". We identified 25 significantly up-regulated genes (including 2 unknown transcripts) and 4 down-regulated genes associated with immune-related processes upon challenge with LPS. Quantitative real-time PCR confirmed the differential expression of these genes after LPS challenge. Conclusions The present study identified 1692 unique transcripts upon LPS challenge for the first time in Asian seabass by using SSH, sequencing and bioinformatic analysis. Some of the identified transcripts are vertebrate homologues and others are hitherto unreported putative defence proteins. The obtained immune-related genes may allow for a better understanding of immunity in Asian seabass, carrying out detailed functional analysis of these genes and developing strategies for efficient immune protection against infections in Asian seabass. PMID:20525308

  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.

  19. 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

  20. 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.

  1. On the Nature of the EUV Late Phase of Solar Flares

    NASA Astrophysics Data System (ADS)

    Li, Ying; Ding, Mingde; Guo, Yang; Dai, Yu

    2014-06-01

    The EUV late phase of solar flares is a second peak of the warm coronal emissions (e.g., Fe XVI) many minutes to a few hours after the GOES soft X-ray peak, which was first observed by the EUV Variability Experiment (EVE) 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 explained as being 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'" (EBTEL) experiments. We find that the long cooling process in late phase loops, which definitely exists, can sufficiently explain the emission property of the EUV late phase; meanwhile, we cannot exclude the role of an additional heating of these loops that possibly occurs. Moreover, we provide two preliminary methods based on the UV and EUV emissions from the Atmospheric Imaging Assembly (AIA) on board SDO to determine whether an additional heating plays some role or not in the late phase emission. Through the nonlinear force-free field modeling, we study the magnetic configuration related to 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 large-scale magnetic loops in multipolar magnetic fields. In this paper, we also explain why the EUV late phase appears most obviously in the warm coronal emissions and why the majority of flares do not exhibit an EUV late phase.

  2. Sirtinol abrogates late phase of cardiac ischemia preconditioning in rats.

    PubMed

    Safari, Fereshteh; Shekarforoosh, Shahnaz; Hashemi, Tahmineh; Namvar Aghdash, Simin; Fekri, Asefeh; Safari, Fatemeh

    2016-09-27

    The aim of this study was to investigate the effect of sirtinol, as an inhibitor of sirtuin NAD-dependent histone deacetylases, on myocardial ischemia reperfusion injury following early and late ischemia preconditioning (IPC). Rats underwent sustained ischemia and reperfusion (IR) alone or proceeded by early or late IPC. Sirtinol (S) was administered before IPC. Arrhythmias were evaluated based on the Lambeth model. Infarct size (IS) was measured using triphenyltetrazolium chloride staining. The transcription level of antioxidant-coding genes was assessed by real-time PCR. In early and late IPC groups, IS and the number of arrhythmia were significantly decreased (P < 0.05 and P < 0.01 vs IR, respectively). In S + early IPC, incidences of arrhythmia and IS were not different compared with the early IPC group. However, in S + late IPC the IS was different from the late IPC group (P < 0.05). In late IPC but not early IPC, transcription levels of catalase (P < 0.01) and Mn-SOD (P < 0.05) increased, although this upregulation was not significant in the S + late IPC group. Our results are consistent with the notion that different mechanisms are responsible for early and late IPC. In addition, sirtuin NAD-dependent histone deacetylases may be implicated in late IPC-induced cardioprotection.

  3. Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune Fab antivenom.

    PubMed

    Ruha, Anne-Michelle; Curry, Steven C; Albrecht, Clay; Riley, Brad; Pizon, Anthony

    2011-01-01

    North American rattlesnake envenomations commonly produce defibrination, coagulopathy and/or thrombocytopenia, which may be reversed following treatment with Crotalidae Polyvalent Immune Fab Ovine (FabAV). Despite initial resolution with FabAV, late onset or recurrence of venom-induced hematologic effects may occur. Time at which onset of late hematotoxicity may first be detected is unknown. The purpose of this study was to identify the incidence and time of onset of recurrent or new late hypofibrinogenemia, coagulopathy, or thrombocytopenia in a cohort of rattlesnake envenomation patients seen in outpatient follow-up after treatment with FabAV, and to report hematologic outcomes in these patients. Review of 66 charts of patients with rattlesnake envenomation who were treated with FabAV, and subsequently had outpatient follow-up evaluation at least 48 h after last FabAV, was performed. Demographic information, rattlesnake and bite characteristics, dose and timing of antivenom administration, adverse events, in-patient laboratory values, length of hospital stay, and follow-up laboratory values were collected. The primary outcome parameters were recurrent or delayed onset coagulopathy, hypofibrinogenemia, or thrombocytopenia identified no sooner than 48 h after last dose of FabAV. Prior to control of the envenomation with FabAV, 42 patients (63.6%) experienced hematologic toxicity. At follow-up, 21 patients (32%) were found to have late coagulopathy, hypofibrinogenemia, or thrombocytopenia. Of twenty-three patients (35%) with more than one follow-up visit, fifteen had normal laboratory findings at the first follow-up visit. Five of these 15 patients (8% of total study group; 33% of this subgroup) with normal hematologic studies at first follow-up exhibited late hematologic toxicity at second follow-up. Severe late hematologic toxicity developed in five of 66 (8%) patients. One patient was retreated with FabAV for late severe thrombocytopenia. Recurrent and delayed

  4. MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.

    PubMed

    Yaddanapudi, Kavitha; Rendon, Beatriz E; Lamont, Gwyneth; Kim, Eun Jung; Al Rayyan, Numan; Richie, Jamaal; Albeituni, Sabrin; Waigel, Sabine; Wise, Ashley; Mitchell, Robert A

    2016-02-01

    Highly aggressive cancers "entrain" innate and adaptive immune cells to suppress antitumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSC) constitute the bulk of monocytic immunosuppressive activity in late-stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immunosuppressive function of tumor-associated macrophages and MDSCs in mouse models of melanoma. In the current study, we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo coculture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late-stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immunosuppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E(2) (PGE(2)). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients.

  5. Measles Virus-Specific Immunoglobulin G Isotype Immune Response in Early and Late Infections

    PubMed Central

    Isa, María Beatríz; Martínez, Laura; Giordano, Miguel; Zapata, Marta; Passeggi, Carlos; De Wolff, María Cristina; Nates, Silvia

    2001-01-01

    A total of 154 human serum samples (32 acute-phase and 22 convalescent-phase serum samples obtained within a week and between days 8 and 26 after the onset of rash, respectively, and 100 samples drawn from healthy immune adults) were processed by an immunofluorescence assay for the detection of immunoglobulin M (IgM), total immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 measles virus-specific antibodies. In the acute phase, IgG1 was seen first, followed by IgG2, IgG3, and IgG4 responses, the mean seropositivity of which gradually increased during convalescence, reaching 100% (standard deviation [SD], 84 to 100%), 57% (SD, 34 to 80%), 86% (SD, 66 to 100%), and 86% (SD, 66 to 100%), respectively. IgG2 rose and fell in connection with IgG3 subclass antibodies, showing a rate of detection of IgG2 and/or IgG3 subclass antibodies of 95.5% (range, 100 to 86.5%) in the convalescent phase of infection. The mean percentage of measles IgG2 and IgG3 seropositivity dropped significantly during the memory phase, to 2% (range, 2 to 6%) and 3% (range, 3 to 7%), respectively (P < 0.05); meanwhile IgG1 and IgG4 subclass responses remained relatively unmodified in samples obtained years after infection (mean 100% [SD, 96 to 100%] and 86% [SD, 79 to 93%], respectively). Results obtained defined two highly different immune isotypic response patterns. One pattern is restrictive to IgG2 and/or IgG3 in the convalescent phase and is kinetically similar to the IgM antibody response, so its detection could be referred to as a recent viral activity. On the other hand, IgG1 and IgG4 were detected in both the convalescent and memory phases of the immune response, but their isolated occurrence without IgG2 and IgG3 could be related to the long-lasting immunity. PMID:11136766

  6. 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; hide

    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.

  7. 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

  8. 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.

  9. Effect of late-gestation maternal heat stress on growth and immune function of dairy calves.

    PubMed

    Tao, S; Monteiro, A P A; Thompson, I M; Hayen, M J; Dahl, G E

    2012-12-01

    Heat stress during the dry period affects the cow's mammary gland development, metabolism, and immunity during the transition period. However, the effect of late-gestation heat stress on calf performance and immune status is unknown. Our objective was to evaluate the effect of heat stress during the final ~45 d of gestation on growth and immune function of calves. Calves (17/treatment) were born to cows that were exposed to cooling (CL) or heat stress (HT) during the dry period. Only heifer calves (CL, n=12; HT, n=9) were used in measurements of growth and immune status after birth. Heifer calves were managed under identical conditions. All were fed 3.78 L of colostrum from their respective dams within 4 h of birth and were weaned at 2 mo of age (MOA). Body weight (BW) was obtained at weaning and then monthly until 7 MOA. Withers height (WH) was measured monthly from 3 to 7 MOA. Hematocrit and plasma total protein were assessed at birth, 1, 4, 7, 11, 14, 18, 21, 25, and 28 d of age. Total serum IgG was evaluated at 1, 4, 7, 11, 14, 18, 21, 25, and 28 d of age, and apparent efficiency of absorption was calculated. Peripheral blood mononuclear cells were isolated at 7, 28, 42, and 56 d of age, and proliferation rate was measured by (3)H-thymidine incorporation in vitro. Blood cortisol concentration was measured in the dams during the dry period and in calves in the preweaning period. Gestation length was 4d shorter for HT cows compared with CL cows. Calves from CL cows had greater BW than calves from HT cows at birth (42.5 vs. 36.5 kg). Compared with CL heifers, HT heifers had decreased weaning BW (78.5 vs. 65.9 kg) but similar BW (154.6 vs. 146.4 kg) and WH (104.8 vs. 103.4 cm) from 3 to 7 MOA. Compared with CL, heifers from HT cows had less total plasma protein (6.3 vs. 5.9 g/dL), total serum IgG (1,577.3 vs. 1,057.8 mg/dL), and apparent efficiency of absorption (33.6 vs. 19.2%), and tended to have decreased hematocrit (33 vs. 30%). Additionally, CL heifers had

  10. Cells and secretagogues involved in the human late-phase response.

    PubMed

    Charlesworth, E N; Iliopoulos, O; MacDonald, S M; Kagey-Sobotka, A; Lichtenstein, L M

    1989-01-01

    Those scientists interested in allergic inflammatory processes have recently been focusing on the late-phase response, since it appears most similar to the chronic disease states observed in allergic patients. In this review we will focus on the pattern of mediator release and cellular traffic observed in two in vivo human models of the late-phase reaction, one involving the upper airways and the other the skin. We have observed in these models, as had been observed earlier in blood, that the late-phase reaction is associated with a second increase in the level of mediators. We also describe our studies of the secretagogues responsible for this late-phase mediator release and, in so doing, introduce the subjects of histamine-releasing factors and IgE heterogeneity.

  11. Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

    PubMed

    Meyer, Urs; Nyffeler, Myriel; Yee, Benjamin K; Knuesel, Irene; Feldon, Joram

    2008-05-01

    Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

  12. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice.

    PubMed

    Paun, Alexandra; Kunwar, Amit; Haston, Christina K

    2015-02-20

    The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10-23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R=-0.80, p=0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R=0.81, p=0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains.

  13. American cutaneous leishmaniasis: In situ immune response of patients with recent and late lesions.

    PubMed

    Gomes, Aparecida Helena Souza; Martines, Roosecelis Brasil; Kanamura, Cristina Takami; Barbo, Maria Lourdes Peris; Iglezias, Silvia D'Andretta; Lauletta Lindoso, José Angelo; Pereira-Chioccola, Vera Lucia

    2017-02-26

    TNF-α, IFN-γ, IL-10, IL-17, CD68, and CD57 were evaluated in biopsies of patients with American cutaneous leishmaniasis living in Sorocaba, Brazil. The analyses were performed considering the time of lesions from 23 patients with recent lesions (Group I) and 19 patients with late lesions (Group II). All patients were infected with Leishmania (Viannia) braziliensis. Immunostaining cells for CD68, CD57, TNF- α, IFN-γ, IL-10, and IL-17 were performed by immunohistochemistry. Except for CD68 and IL-17, the distribution of in situ for CD57, IL-10, TNF-α and IFN-γ showed that patients with recent lesions expressed higher levels than those with late lesions. The comparison of cytokine expression/group showed that IL-10 was significantly higher than IL-17 and IFN-γ (similar data was shown in IL-17 compared with TNF-α), suggesting an immunological balance between inflammatory-anti-inflammatory agents. This balance was similar for two Groups of patients. In conclusion, these data suggested that: i. patients from Group I had recent lesions (in the beginning of chronic phase) compared to those from Group II; ii. the modulation of inflammatory response in patients with recent ACL was correlated with IL-10 expression in skin lesions preventing the development of mucosal forms. The parasite treatment also prevented the evolution of severe forms. This article is protected by copyright. All rights reserved.

  14. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report.

    PubMed

    Gea-Banacloche, Juan; Komanduri, Krishna V; Carpenter, Paul; Paczesny, Sophie; Sarantopoulos, Stefanie; Young, Jo-Anne; El Kassar, Nahed; Le, Robert Q; Schultz, Kirk R; Griffith, Linda M; Savani, Bipin N; Wingard, John R

    2016-10-14

    Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long

  15. 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.

  16. Influenza antivirals currently in late-phase clinical trial.

    PubMed

    Koszalka, Paulina; Tilmanis, Danielle; Hurt, Aeron C

    2017-05-01

    Influenza antiviral drugs are important for the control of influenza, most specifically for the treatment of influenza patients with severe disease following infection with a seasonal influenza virus, a newly emerging influenza strain, or in the event of a pandemic. Many influenza antivirals that are currently under investigation in late-stage clinical trials differ in their mechanism of action compared to drugs currently licensed for the treatment of influenza. Nitazoxanide and DAS181 target components of the host cell and alter the ability of the virus to replicate efficiently, while small molecule drugs such as T705, JNJ63623872 and S-033188 bind to the viral polymerase complex and restrict viral replication. Monoclonal antibodies that are currently in clinical trial for the treatment of influenza most commonly are targeted to the stem region of the haemagglutinin molecule. Early findings from animal models and in vitro studies suggest that many of the new antiviral drugs when tested in combination with oseltamivir have improved effectiveness over monotherapy. Clinical trials assessing both monotherapy and combination therapy are currently under investigation. It is hoped that as new antivirals are licensed, they will improve the standard of care and outcomes for influenza patients with severe disease. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

  17. Glutamine Prevents Late-Phase Anaphylaxis via MAPK Phosphatase 1-Dependent Cytosolic Phospholipase A2 Deactivation.

    PubMed

    Kim, Hae-Kyoung; Song, Chang-Ho; Bae, Yun-Soo; Im, Suhn-Young; Lee, Hern-Ku

    2016-01-01

    Cytosolic phospholipase A2 (cPLA2) plays a key role in the development of late-phase anaphylaxis. L-Glutamine (Gln), a nonessential amino acid, has anti-inflammatory activity via inhibiting cPLA2. We used a penicillin-induced murine model of anaphylaxis, and late-phase anaphylaxis was quantified by measuring the increase in the hematocrit (Ht) value. Various inhibitors, small interfering RNA, and knockout mice were used in inhibition experiments. Phosphorylation and protein expression of cPLA2, ERK, and MAPK phosphatase 1 (MKP-1) were detected by Western blotting. Leukotriene (LT) B4 was found to be another potent inducer of late-phase anaphylaxis besides the known mediator platelet-activating-factor (PAF). Gln efficiently prevented late-phase anaphylaxis when it was administered up to 3 h after challenge injection via inhibiting cPLA2. Inhibition studies indicated that p38 MAPK was the major upstream regulator of cPLA2. Gln dephosphorylated p38 and cPLA2 via up-regulating the negative regulator of p38 MAPK, i.e., MKP-1 protein. MKP-1 blockade abrogated all the effects of Gln. Of the cPLA2 metabolites, PAF and LTB4 play a key role in the development of late-phase anaphylaxis, and Gln prevents the reaction via MKP-1-dependent deactivation of cPLA2. © 2016 S. Karger AG, Basel.

  18. The Rate of Conversion from Immune-tolerant Phase to Early Immune-clearance Phase in Children with Chronic Hepatitis B Virus Infection.

    PubMed

    Hong, Suk Jin; Park, Hyo Jung; Chu, Mi Ae; Choi, Bong Seok; Choe, Byung-Ho

    2014-03-01

    The spontaneous seroconversion rate of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) virus infection in children is lower than that in adults. However, few studies have investigated the rate of transition from the immune-tolerant to the early immune-clearance phase in children. From February 2000 to August 2011, we enrolled 133 children aged <18 years who had visited the Department of Pediatrics, Kyungpook National University Hospital. All subjects were in the immune-tolerant phase of HBeAg-positive CHB virus infection. The estimated transition rate into the early immune-clearance phase was calculated using the Kaplan-Meier method. Among the 133 enrolled pediatric CHB virus infection patients in the HBeAg-positive immune-tolerant phase, only 21 children (15.8%) had converted to the early immune-clearance phase. The average age at entry into active hepatitis was 10.6±4.8 years. The incidence of transition from the immune-tolerant to the early immune-clearance phase in these children was 1.7 episodes/100 patient-years. When analyzed by age, the estimated transition rate was 4.6%, 7.1%, and 28.0% for patients aged <6, 6-12, >12 years, respectively. In children with CHB virus infection, the estimated rate of entry into the early immune-clearance phase was 28.0% for patients aged 12-18 years, which was significantly higher than that observed for children aged <12 years (11.7%; p=0.001).

  19. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain

    PubMed Central

    Kawasaki, Yasuhiko; Xu, Zhen-Zhong; Wang, Xiaoying; Park, Jong-Yeon; Zhuang, Zhi-Ye; Tan, Ping-Heng; Gao, Yong-Jing; Roy, Kristine; Corfas, Gabriel; Lo, Eng H.; Ji, Ru-Rong

    2008-01-01

    Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood 1-4. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early and late phase neuropathic pain development after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured DRG primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 via an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. Following nerve injury, MMP-9 induces neuropathic pain through interleukin-1β cleavage and microglia activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1β cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases. PMID:18264108

  20. Hemodynamic response during standing test after blood donation can predict the late phase vasovagal reaction.

    PubMed

    Yoshida, Masayoshi; Ando, Shin-Ichi; Eura, Emi; Hayashi, Atsumi; Kawamura, Natsumi; Narita, Sumito; Matsumoto, Mari; Momii, Hidetoshi; Kadokami, Toshiaki; Kiyokawa, Hiroyuki

    2016-12-01

    A major complication of blood donation is vasovagal reaction (VVR) with or without syncope. VVR occurs not only in the early phase, but also in the late phase after blood donation. We previously reported the hemodynamic characteristics of blood donors susceptible to early phase VVR. In the present study, we investigated the hemodynamic characteristics of those who developed late VVR. Ninety-six healthy volunteers donating 400 ml of whole blood were studied. After asking about their physical condition or routine questions for blood donation, blood pressure (BP) and heart rate (HR) were recorded while the donors were kept standing up for 3 min before and after blood collection. Questionnaires were distributed to all donors for reporting late VVR symptoms within 24 h. Those with younger age and lower diastolic blood pressure were more susceptible to late VVR (both p < 0.05). Furthermore, we identified the increase in HR during the standing test after blood collection as a good predictor of late VVR (odds ratio 1.063, 95 % CI 1.005-1.124; p = 0.031). Also, analysis of questions asked before donation revealed that significantly more donors considered themselves as sensitive to pain in the late VVR group (Odds ratio 0.070, 95 % CI 0.008-0.586; p = 0.014). Excessive HR response to standing after blood collection and subjective sensitivity to pain as well as younger age and lower diastolic BP may be useful to detect donors at high risk for late VVR.

  1. 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.

  2. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

    PubMed Central

    St. John, Lisa S.; de Lima, Marcos; McMannis, John; Rosinski, Steven; McNiece, Ian; Bryan, Susan G.; Kaur, Indreshpal; Martin, Sean; Wieder, Eric D.; Worth, Laura; Cooper, Laurence J. N.; Petropoulos, Demetrios; Molldrem, Jeffrey J.; Champlin, Richard E.; Shpall, Elizabeth J.

    2007-01-01

    Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT. PMID:17671230

  3. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing.

    PubMed

    Komanduri, Krishna V; St John, Lisa S; de Lima, Marcos; McMannis, John; Rosinski, Steven; McNiece, Ian; Bryan, Susan G; Kaur, Indreshpal; Martin, Sean; Wieder, Eric D; Worth, Laura; Cooper, Laurence J N; Petropoulos, Demetrios; Molldrem, Jeffrey J; Champlin, Richard E; Shpall, Elizabeth J

    2007-12-15

    Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT.

  4. Maternal health literacy and late initiation of immunizations among an inner-city birth cohort.

    PubMed

    Pati, Susmita; Feemster, Kristen A; Mohamad, Zeinab; Fiks, Alex; Grundmeier, Robert; Cnaan, Avital

    2011-04-01

    To determine if maternal health literacy influences early infant immunization status. Longitudinal prospective cohort study of 506 Medicaid-eligible mother-infant dyads. Immunization status at age 3 and 7 months was assessed in relation to maternal health literacy measured at birth using the Test of Functional Health Literacy in Adults (short version). Multivariable logistic regression quantified the effect of maternal health literacy on immunization status adjusting for the relevant covariates. The cohort consists of primarily African-American (87%), single (87%) mothers (mean age 23.4 years). Health literacy was inadequate or marginal among 24% of mothers. Immunizations were up-to-date among 73% of infants at age 3 months and 43% at 7 months. Maternal health literacy was not significantly associated with immunization status at either 3 or 7 months. In multivariable analysis, compared to infants who had delayed immunizations at 3 months, infants with up-to-date immunizations at 3 months were 11.3 times (95%CI 6.0-21.3) more likely to be up-to-date at 7 months. The only strong predictors of up-to-date immunization status at 3 months were maternal education (high school graduate or beyond) and attending a hospital-affiliated clinic. Though maternal health literacy is not associated with immunization status in this cohort, later immunization status is most strongly predicted by immunization status at 3 months. These results further support the importance of intervening from an early age to ensure that infants are fully protected against vaccine preventable diseases.

  5. [Active and prodromal phase symptomatology of young-onset and late-onset paranoid schizophrenia].

    PubMed

    Skokou, Maria; Katrivanou, Aggeliki; Andriopoulos, Ioannis; Gourzis, Philippos

    2012-01-01

    Young and late onset patients with paranoid schizophrenia were compared, regarding the initial prodromal and active phases of the disorder, in order to examine the influence of age of onset on the prodromal and active phase symptomatology of the disease. We examined 88 consecutively hospitalized patients with paranoid schizophrenia. Age cutoff points were set at <30 years of age for the young, and ≥35 years of age for the late onset group. Diagnoses were made prospectively, using the Structured Clinical Interview for DSM-IV-Patient Edition for Axis I disorders (SCID-P). Type and severity of psychopathology in the active phase were assessed by applying the Structured Clinical Interview for Positive and Negative Syndrome Scale (PANSS). Patients were retrospectively examined regarding their initial prodromal symptoms by applying the Structured Clinical Interview for DSM-III-R Patient Edition and clinical interviewing for additional symptoms. Comparisons were performed by applying the two-tailed Wilcoxon rank-sum and the chi-square statistical tests. The young onset group was characterized by significantly more negative prodromal symptoms, and heavier negative symptomatology in the active phase, than the late onset group. Differences were more prominently shown in male patients. Older age of onset of paranoid schizophrenia appears to be related to a less severe form of the disease, characterized by less severity of negative symptomatology, already demonstrated in the prodromal phase of the disorder. Copyright © 2011 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

  6. Intramammary immunization with ultraviolet-killed Escherichia coli shows partial protection against late gestation intramammary challenge with a homologous strain.

    PubMed

    Pomeroy, B; Gurjar, A; Sipka, A; Klaessig, S; Salmon, S; Quesnell, R; Schukken, Y H

    2016-11-01

    The objective of this study was to evaluate the efficacy of intramammary immunization with UV-killed Escherichia coli ECC-Z on prevention of intramammary colonization after a challenge with a dose of the homologous E. coli ECC-Z live bacteria. A total of 10 cows were included in a study to evaluate the efficacy of intramammary immunization. All 10 cows received an intramammary immunization of 100 cfu of UV-killed E. coli ECC-Z bacteria into one hind quarter at the time of dry off. Approximately 2wk before the anticipated calving date, both hind quarters of all cows were challenged with 100 cfu of live E. coli ECC-Z bacteria. Five of the cows were vaccinated parenterally with a commercial J5 bacterin, and 5 cows served as controls with no parenteral vaccination. The cows were then followed over time and infection risk, clinical scores, somatic cell count, and milk production were observed over time. The results of these 10 cows showed partial protection of intramammary immunization on the outcome of a subsequent homologous intramammary challenge. Immunization resulted in a lower probability of infection, a lower bacteria count, lower somatic cell counts and milk conductivity, a lower clinical mastitis score, and increased milk production compared with unimmunized control quarters. Once the analysis was corrected for immunization, parenteral J5 vaccination had no significant effect on any of the measured parameters. These results provide the first evidence that intramammary immunization may improve the outcome of an intramammary E. coli infection in late gestation and onset of mastitis immediately following parturition. Unlike systemic vaccination, which generally does not reduce the intramammary infection risk, the intramammary immunization did show a 5-times reduced odds of an established intramammary infection after challenge. Cytokine profiles indicated a local return of proinflammatory response after challenge as the data showed a more pronounced increase in in

  7. Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation

    PubMed Central

    Shah, Nishel Mohan; Herasimtschuk, Anna A.; Boasso, Adriano; Benlahrech, Adel; Fuchs, Dietmar; Imami, Nesrina; Johnson, Mark R.

    2017-01-01

    During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches. PMID:28966619

  8. Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

    PubMed

    Shah, Nishel Mohan; Herasimtschuk, Anna A; Boasso, Adriano; Benlahrech, Adel; Fuchs, Dietmar; Imami, Nesrina; Johnson, Mark R

    2017-01-01

    During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.

  9. Inducible Defenses Stay Up Late: Temporal Patterns of Immune Gene Expression in Tenebrio molitor

    PubMed Central

    Johnston, Paul R; Makarova, Olga; Rolff, Jens

    2014-01-01

    The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo. PMID:24318927

  10. Inducible defenses stay up late: temporal patterns of immune gene expression in Tenebrio molitor.

    PubMed

    Johnston, Paul R; Makarova, Olga; Rolff, Jens

    2013-12-06

    The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo. Copyright © 2014 Johnston et al.

  11. 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.

  12. 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

  13. A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis.

    PubMed

    Ross, Colin J; Towfic, Fadi; Shankar, Jyoti; Laifenfeld, Daphna; Thoma, Mathis; Davis, Matthew; Weiner, Brian; Kusko, Rebecca; Zeskind, Ben; Knappertz, Volker; Grossman, Iris; Hayden, Michael R

    2017-05-31

    Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials. Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials. A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters

  14. Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy

    PubMed Central

    Baiula, Monica; Bedini, Andrea; Baldi, Jacopo; Cavet, Megan E; Govoni, Paolo; Spampinato, Santi

    2014-01-01

    Background Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6–10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines. Methods In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Results Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more

  15. Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy.

    PubMed

    Baiula, Monica; Bedini, Andrea; Baldi, Jacopo; Cavet, Megan E; Govoni, Paolo; Spampinato, Santi

    2014-01-01

    Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6-10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines. In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more effective than dexamethasone in

  16. 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.

  17. 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.

  18. 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.

  19. 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

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

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

    USDA-ARS?s Scientific Manuscript database

    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...

  2. 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.

  3. 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

  4. Improvement in non-specific immunity and disease resistance of barramundi, Lates calcarifer (Bloch), by diets containing Daphnia similis meal.

    PubMed

    Chiu, Shieh-Tsung; Shiu, Ya-Li; Wu, Tsung-Meng; Lin, Yu-Syuan; Liu, Chun-Hung

    2015-05-01

    A 42-day study was conducted with barramundi, Lates calcarifer, to evaluate the effects of Daphnia meal derived from Daphnia similis on fish growth, immune response, and disease resistance to Aeromonas hydrophila. Three isonitrogenous (45%) and isolipid (10%) experimental diets were formulated to contain 0% (control), 5% (D5), and 10% (D10) Daphnia meal. Growth was depressed when fish were fed with the D10 diet for 42 days compared to control. However, the growth in fish fed with control and D5 diets for 42 days was not significantly different. By day 42, the leukocyte phagocytic activity and respiratory burst activity were significantly increased in D5 and D10 groups compared to control. Mx gene expression in the spleen and head kidney of fish after being injected with nerve necrosis virus was also significantly up-regulated in both groups compared to control. In an increased immune response, D5 and D10 fish had significantly higher survival rates than control after being challenged by A. hydrophila. Therefore, we suggest that a 5% Daphnia-meal diet could improve the barramundi immune response and disease resistance without a negative impact on growth. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Improved noise-immune phase-unwrapping algorithm

    NASA Astrophysics Data System (ADS)

    Cusack, R.; Huntley, J. M.; Goldrein, H. T.

    1995-02-01

    An algorithm for unwrapping noisy phase maps has recently been proposed, based on the identification of discontinuity sources that mark the start or end of a 2 pi phase discontinuity. Branch cuts between sources act as barriers to unwrapping, resulting in a unique phase map that is independent of the unwrapping route. We investigate four methods for optimizing the placement of the cuts. A modified nearest neighbor approach is found to be the most successful and can reliably unwrap unfiltered speckle-interferometry phase maps with discontinuity source densities of 0.05 sources pixel-1.

  6. 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.

  7. 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.

  8. 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

  9. Baseline Naive CD4+ T-cell Level Predicting Immune Reconstitution in Treated HIV-infected Late Presenters

    PubMed Central

    Guo, Fu-Ping; Li, Yi-Jia; Qiu, Zhi-Feng; Lv, Wei; Han, Yang; Xie, Jing; Li, Yan-Ling; Song, Xiao-Jing; Du, Shan-Shan; Mehraj, Vikram; Li, Tai-Sheng; Routy, Jean-Pierre

    2016-01-01

    Background: Among HIV-infected patients initiating antiretroviral therapy (ART), early changes in CD4+ T-cell subsets are well described. However, HIV-infected late presenters initiating treatment present with a suboptimal CD4+ T-cell reconstitution and remain at a higher risk for AIDS and non-AIDS events. Therefore, factors associated with CD4+ T-cell reconstitution need to be determined in this population, which will allow designing effective immunotherapeutic strategies. Methods: Thirty-one adult patients with baseline CD4+ T-cell count <350 cells/mm3 exhibiting viral suppression after ART initiation were followed in the HIV/AIDS research center of Peking Union Medical College Hospital in Beijing, China, from October 2002 to September 2013. Changes in T-cell subsets and associated determinants were measured. Results: Median baseline CD4+ T-cell count was 70 cells/mm3. We found a biphasic reconstitution of T-cell subsets and immune activation: a rapid change during the first 6 months followed by a more gradual change over the subsequent 8 years. Baseline CD4+ T-cell count >200 cells/mm3 in comparison to CD4+ T-cell count ≤200 cells/mm3 was associated with more complete immune Reconstitution (77.8% vs. 27.3% respectively; P = 0.017) and normalized CD4/CD8 ratio. We showed that the baseline percentage of naive CD4+ T-cell was a predictive marker for complete immune reconstitution (area under receiver operating characteristic curve 0.907), and 12.4% as cutoff value had a sensitivity of 84.6% and a specificity of 88.2%. Conclusions: Baseline naive CD4+ T-cell percentage may serve as a predictive marker for optimal immune reconstitution during long-term therapy. Such study findings suggest that increasing thymic output should represent an avenue to improve patients who are diagnosed late in the course of infection. PMID:27824000

  10. Late presentation of Nipah virus encephalitis and kinetics of the humoral immune response.

    PubMed

    Wong, S C; Ooi, M H; Wong, M N; Tio, P H; Solomon, T; Cardosa, M J

    2001-10-01

    Nipah virus is a newly discovered paramyxovirus transmitted directly from pigs to humans. During a large encephalitis outbreak in Malaysia and Singapore in 1998-9, most patients presented acutely. A 12 year old child is described who developed encephalitis 4 months after exposure to the virus. She was diagnosed by a new indirect IgG enzyme linked immunosorbent assay (ELISA), which is also described. The late presentation and IgG subclass responses had similarities to subacute sclerosing panencephalitis. Nipah virus should be considered in patients with encephalitis even months after their possible exposure.

  11. Late presentation of Nipah virus encephalitis and kinetics of the humoral immune response

    PubMed Central

    Wong, S; Ooi, M; Wong, M; Tio, P; Solomon, T; Cardosa, M

    2001-01-01

    Nipah virus is a newly discovered paramyxovirus transmitted directly from pigs to humans. During a large encephalitis outbreak in Malaysia and Singapore in 1998-9, most patients presented acutely. A 12 year old child is described who developed encephalitis 4months after exposure to the virus. She was diagnosed by a new indirect IgG enzyme linked immunosorbent assay (ELISA), which is also described. The late presentation and IgG subclass responses had similarities to subacute sclerosing panencephalitis. Nipah virus should be considered in patients with encephalitis even months after their possible exposure.

 PMID:11561048

  12. Examination of uncertainty in late reflood phase behavior of APR1400 LBLOCA

    SciTech Connect

    Sang Won Lee; Han Gon Kim; Seung Jong Oh; Sang Yong Lee

    2004-07-01

    APR1400 is an evolutionary PWR developed in Korea. The ECCS of APR1400 has been improved by adopting 4 safety injection pumps and fluidic devices in safety injection tanks. Also, APR1400 adopted direct vessel injection (DVI) for its ECCS injection: safety injection water is injected into the reactor vessel downcomer directly. The ECCS performance of APR1400 during the double-ended cold leg break LOCA, specially during the late reflood phase, is examined with the KEPRI Realistic Evaluation Methodologies (KREM). The applicability of KREM to the prediction of APR1400 specific thermal hydraulic phenomena in downcomer during the LBLOCA is examined first and the preliminary best estimate analysis is performed for the double-ended cold leg break LOCA. The analysis results show that there is no degradation of core coolability and reheating phenomena during the late reflood phase. All fuel rods are quenched in the early reflood phase during the fluidic devices are active, which shows the effectiveness of the fluidic devices in mitigating the LBLOCA. (authors)

  13. Long-Term Improvements After Multimodal Rehabilitation in Late Phase After Stroke: A Randomized Controlled Trial.

    PubMed

    Bunketorp-Käll, Lina; Lundgren-Nilsson, Åsa; Samuelsson, Hans; Pekny, Tulen; Blomvé, Karin; Pekna, Marcela; Pekny, Milos; Blomstrand, Christian; Nilsson, Michael

    2017-07-01

    Treatments that improve function in late phase after stroke are urgently needed. We assessed whether multimodal interventions based on rhythm-and-music therapy or horse-riding therapy could lead to increased perceived recovery and functional improvement in a mixed population of individuals in late phase after stroke. Participants were assigned to rhythm-and-music therapy, horse-riding therapy, or control using concealed randomization, stratified with respect to sex and stroke laterality. Therapy was given twice a week for 12 weeks. The primary outcome was change in participants' perception of stroke recovery as assessed by the Stroke Impact Scale with an intention-to-treat analysis. Secondary objective outcome measures were changes in balance, gait, grip strength, and cognition. Blinded assessments were performed at baseline, postintervention, and at 3- and 6-month follow-up. One hundred twenty-three participants were assigned to rhythm-and-music therapy (n=41), horse-riding therapy (n=41), or control (n=41). Post-intervention, the perception of stroke recovery (mean change from baseline on a scale ranging from 1 to 100) was higher among rhythm-and-music therapy (5.2 [95% confidence interval, 0.79-9.61]) and horse-riding therapy participants (9.8 [95% confidence interval, 6.00-13.66]), compared with controls (-0.5 [-3.20 to 2.28]); P=0.001 (1-way ANOVA). The improvements were sustained in both intervention groups 6 months later, and corresponding gains were observed for the secondary outcomes. Multimodal interventions can improve long-term perception of recovery, as well as balance, gait, grip strength, and working memory in a mixed population of individuals in late phase after stroke. URL: http//www.ClinicalTrials.gov. Unique identifier: NCT01372059. © 2017 American Heart Association, Inc.

  14. Delay of late-venous phase cortical vein filling in acute ischemic stroke patients: Associations with collateral status.

    PubMed

    Bhaskar, Sonu; Bivard, Andrew; Parsons, Mark; Nilsson, Michael; Attia, John R; Stanwell, Peter; Levi, Christopher

    2017-02-01

    Evaluation of the venous system may be useful in stroke prognostication and patient selection for acute intervention strategies. We report a novel phenomenon, delayed-late venous phase cortical vein filling, observed on dynamic computed tomography angiography obtained using multidetector computed tomography scanner, in acute ischemic stroke patients. The aim of this study was to examine the frequency of delayed-late venous phase cortical vein filling and assess its association to baseline collateral status. Dynamic computed tomography angiography images of acute ischemic stroke patients, being assessed for reperfusion therapy, were prospectively studied. Delayed-late venous phase cortical vein filling was defined by late venous phase opacification of cortical veins despite contrast clearance from contralateral cortical veins on dynamic computed tomography angiography. Time to peak of maximum arterial enhancement was recorded. A total of 117 patients (mean age = 70.6 ± 13.3 years; males = 48%) with hemispheric ischemic stroke who underwent acute dynamic computed tomography angiography were included in the study. Overall, 56 (48%) demonstrated delayed-late venous phase cortical vein filling. Poor collateralization (OR = 13.50; 95% CI = (4.2, 43); p ≤ 0.0001) and longer time to peak of maximum arterial enhancement (OR = 3.2; 95% CI = (1.96, 5.3); p  ≤ 0.0001) were positively associated with delayed-late venous phase cortical vein filling. Delayed-late venous phase cortical vein filling was independently associated with poor baseline collateral status (75% vs. 15%, p ≤ 0.0001; OR = 14.38; 95% CI = (4.33, 47.8); p ≤ 0.0001). Delayed-late venous phase cortical vein filling is frequently seen in patients with acute ischemic stroke and is associated with poor baseline collateralization.

  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. Cutaneous late-phase reaction to environmental antigen in patients with atopic dermatitis.

    PubMed

    Oyama, K

    1993-01-01

    Intradermal testing with 7 environmental allergens was performed on 71 patients with atopic dermatitis (AD) with respiratory atopy (RAT) and 30 pure AD patients, and the cutaneous late-phase reaction (CLPR) was observed several to 48 h after challenge. CLPR was not seen in pure AD. In AD patients with RAT, CLPR was positive in 29 of 71 patients. No macroscopic eczematous lesions appeared. All CLPR-positive patients showed RAST scores of 2 or more. We assume that CLPR can be an exacerbating factor in AD with RAT, while it is not directly involved in pure AD.

  17. Extreme Ultraviolet Late-Phase Flares: Before and During the Solar Dynamics Observatory Mission

    NASA Astrophysics Data System (ADS)

    Woods, Thomas N.

    2014-09-01

    The solar extreme-ultraviolet (EUV) observations from the Solar Dynamics Observatory (SDO) have revealed interesting characteristics of warm coronal emissions, such as Fe xvi 335 Å emission, which peak soon after the hot coronal X-ray emissions peak during a flare and then sometimes peak for a second time hours after the X-ray flare peak. This flare type, with two warm coronal emission peaks but only one X-ray peak, has been named the EUV late phase (Woods et al., Astrophys. J. 739, 59, 2011). These flares have the distinct properties of i) having a complex magnetic-field structure with two initial sets of coronal loops, with one upper set overlaying a lower set, ii) having an eruptive flare initiated in the lower set and disturbing both loop sets, iii) having the hot coronal emissions emitted only from the lower set in conjunction with the X-ray peak, and iv) having the first peak of the warm coronal emissions associated with the lower set and its second peak emitted from the upper set many minutes to hours after the first peak and without a second X-ray enhancement. The disturbance of the coronal loops by the eruption is at about the same time, but the relaxation and cooling down of the heated coronal loops during the post-flare reconnections have different time scales with the longer, upper loops being significantly delayed from the lower loops. The difference in these cooling time scales is related to the difference between the two peak times of the warm coronal emission and is also apparent in the decay profile of the X-ray emissions having two distinct decays, with the first decay slope being steeper (faster) and the delayed decay slope being smaller (slower) during the time of the warm-coronal-emission second peak. The frequency and relationship of the EUV late-phase decay times between the Fe xvi 335 Å two flare peaks and X-ray decay slopes are examined using three years of SDO/ EUV Variability Experiment (EVE) data, and the X-ray dual-decay character is

  18. Immunizations

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness 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 ...

  19. 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. ...

  20. Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337).

    PubMed

    Dietsch, Gregory N; Randall, Tressa D; Gottardo, Raphael; Northfelt, Donald W; Ramanathan, Ramesh K; Cohen, Peter A; Manjarrez, Kristi L; Newkirk, Mona; Bryan, James Kyle; Hershberg, Robert M

    2015-12-15

    Immunotherapy as a treatment for cancer holds the promise of complete and durable tumor remission, yet the immunosuppressive environment created by many tumors, advanced patient age, and previous treatments with cytotoxic agents may limit the approach. The activity of motolimod (VTX-2337), a potent and selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the context of advanced, late-stage cancer patients. The repertoire of mediators induced from human peripheral blood mononuclear cells in response to motolimod was characterized. Translational studies in cynomolgus monkeys elucidated the activity of motolimod on an intact immune system, identified biomarkers of TLR8 activation, and defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) response. The PK/PD relationship for motolimod in cancer patients was assessed, compared with preclinical findings, and contrasted with activity in healthy volunteers. In late-stage cancer patients, plasma levels of multiple biomarkers, including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod dose. The magnitude and breadth of the biomarker response closely aligned with the response seen in preclinical studies, demonstrating that advanced cancer patients remained responsive to TLR8 activation. In addition, the PK/PD response in cancer patients closely aligned with the activity of motolimod seen in healthy volunteers. Late-stage cancer patients are highly sensitive to TLR8 activation by motolimod. Tumor burden, advanced age, and prior treatment history with cytotoxic agents did not moderate or modify the response predicted by nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 21(24); 5445-52. ©2015 AACR. ©2015 American Association for Cancer Research.

  1. Maternal stress during late gestation has moderate but long-lasting effects on the immune system of the piglets.

    PubMed

    Couret, David; Jamin, Agnès; Kuntz-Simon, Gaëlle; Prunier, Armelle; Merlot, Elodie

    2009-09-15

    Events acting prenatally on developing foetuses are important determinants for disorders later in life. Prenatal stress (PNS) is one of these events. The purpose of this study was to determine the consequences of a repeated social stress applied during late gestation of the pregnant gilt on the immune system and hypothalamo-pituitary-adrenal (HPA) axis activity of the piglets from birth to two months of age. Pregnant gilts were submitted to repeated social stress which was induced by housing unfamiliar gilts in pairs modified twice a week during 4 weeks between days 77 and 105 of gestation (S group, n=18). Control gilts were housed in stable pairs during the same period (C group, n=18). Blood cortisol, haptoglobin and IgG levels, immune cell counts, mitogen-induced whole-blood proliferation and TNF-alpha production were evaluated in piglets at 4 days of age (D4), before and after weaning (D26 and 28) and before and after relocation to a new building (D60 and 62). We found that PNS did not affect growth rate of the progeny. It decreased the relative weight of adrenal glands on D4 (P<0.05) but plasma cortisol levels were similar in both groups at all ages. IgG levels in colostrum and in the serum of piglets were not affected. PNS decreased the total numbers of white blood cells, lymphocytes and granulocytes from D26 to D60 (P<0.05), the CD4(+)/CD8(+) T cell ratio on D4 (P<0.05), and LPS induced-TNF-alpha production on D60 (P<0.05). PNS increased the ConA-induced lymphocyte proliferation on D4 and D60 and the PWM-induced proliferation on D60 (P<0.05). Our results demonstrate that a repeated social stress applied to pregnant sows during late gestation can induce long-lasting effects on several parameters of the immune function of the offspring. These effects are not due to modifications of the HPA axis activity and may impair the abilities of the piglets to efficiently react against infections during the suckling period and around weaning.

  2. Identification and initial assessment of candidate BWR late-phase in-vessel accident management strategies

    SciTech Connect

    Hodge, S.A.

    1991-04-15

    Work sponsored by the United States Nuclear Regulatory Commission (USNRC) to identify and perform preliminary assessments of candidate BWR (boiling water reactor) in-vessel accident management strategies was completed at Oak Ridge National Laboratory (ORNL) during fiscal year 1990. Mitigative strategies for containment events have been the subject of a companion study at Brookhaven National Laboratory. The focus of this Oak Ridge effort was the development of new strategies for mitigation of the late phase events, that is, the events that would occur in-vessel after the onset of significant core damage. The work began with an investigation of the current status of BWR in-vessel accident management procedures and proceeded through a preliminary evaluation of several candidate new strategies. The steps leading to the identification of the candidate strategies are described. The four new candidate late-phase (in-vessel) accident mitigation strategies identified by this study and discussed in the report are: (1) keep the reactor vessel depressurized; (2) restore injection in a controlled manner; (3) inject boron if control blade damage has occurred; and (4) containment flooding to maintain core and structural debris in-vessel. Additional assessments of these strategies are proposed.

  3. A late phase of germ plasm accumulation during Drosophila oogenesis requires lost and rumpelstiltskin.

    PubMed

    Sinsimer, Kristina S; Jain, Roshan A; Chatterjee, Seema; Gavis, Elizabeth R

    2011-08-01

    Asymmetric mRNA localization is an effective mechanism for establishing cellular and developmental polarity. Posterior localization of oskar in the Drosophila oocyte targets the synthesis of Oskar to the posterior, where Oskar initiates the assembly of the germ plasm. In addition to harboring germline determinants, the germ plasm is required for localization and translation of the abdominal determinant nanos. Consequently, failure of oskar localization during oogenesis results in embryos lacking germ cells and abdominal segments. oskar accumulates at the oocyte posterior during mid-oogenesis through a well-studied process involving kinesin-mediated transport. Through live imaging of oskar mRNA, we have uncovered a second, mechanistically distinct phase of oskar localization that occurs during late oogenesis and results in amplification of the germ plasm. Analysis of two newly identified oskar localization factors, Rumpelstiltskin and Lost, that are required specifically for this late phase of oskar localization shows that germ plasm amplification ensures robust abdomen and germ cell formation during embryogenesis. In addition, our results indicate the importance of mechanisms for adapting mRNAs to utilize multiple localization pathways as necessitated by the dramatic changes in ovarian physiology that occur during oogenesis.

  4. Hymenolepis diminuta and H. nana: cross immunity against the lumen phase in BALB/c mice.

    PubMed

    Ito, A; Onitake, K

    1987-08-01

    When BALB/c mice initially given cysticercoids of Hymenolepis diminuta orally (Day 0) were challenged with eggs or cysticercoids of H. nana, almost all the mice became completely resistant to H. nana challenges from Day 30 onward, and no luminal adults of H. nana were established. There was a tendency for the number of tissue cysticercoids recovered 4 days after egg challenge in immunized mice to be much less than that in control mice (P less than 0.001, Student's t test). However, when these cysticercoids recovered from immune group mice were inoculated into uninfected mice, they matured in the lumen. Thus, the cross immunity to H. nana challenge evoked by an initial prepatent infection with H. diminuta appeared to be directed not against the tissue phase but against the lumen phase of H. nana. When BALB/c mice initially given eggs of H. nana were challenged with H. diminuta, they became resistant to H. diminuta from Day 15 onward. When the mice given eggs of H. nana were treated with a cestocide, praziquantel, at the beginning of the expected luminal development of H. nana and experienced a tissue phase only before challenge with H. diminuta, they showed no resistance to H. diminuta. Thus, the cross immunity to H. diminuta challenge evoked by an initial patent infection with H. nana appeared to be due to the immunogens of the lumen phase of H. nana but not those of the tissue phase. The cross immunity may be, therefore, essentially evoked by the lumen phase of these two phylogenetically closely related species and not by or against the tissue phase of H. nana.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. A controlled study of light therapy in women with late luteal phase dysphoric disorder.

    PubMed

    Lam, R W; Carter, D; Misri, S; Kuan, A J; Yatham, L N; Zis, A P

    1999-06-30

    Previous studies suggest that light therapy, as used to treat seasonal affective disorder, may be beneficial for pre-menstrual depressive disorders. We conducted a six-menstrual cycle randomized, double-blind, counter-balanced, crossover study of dim vs. bright light therapy in women with late luteal phase dysphoric disorder (LLPDD). Fourteen women who met DSM-III-R criteria for LLPDD completed two menstrual cycles of prospective baseline monitoring of pre-menstrual symptoms, followed by two cycles of each treatment. During the 2-week luteal phase of each treatment cycle, patients were randomized to receive 30 min of evening light therapy using: (1) 10000 lx cool-white fluorescent light (active condition); or (2) 500 lx red fluorescent light (placebo condition), administered by a light box at their homes. After two menstrual cycles of treatment, patients were immediately crossed over to the other condition for another two cycles. Outcome measures were assessed at the mid-follicular and luteal phases of each cycle. Results showed that the active bright white light condition significantly reduced depression and pre-menstrual tension scores during the symptomatic luteal phase, compared to baseline, while the placebo dim red light condition did not. These results suggest that bright light therapy is an effective treatment for LLPDD.

  6. 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

  7. Molecular targeted therapy for pancreatic adenocarcinoma: A review of completed and ongoing late phase clinical trials.

    PubMed

    Mosquera, Catalina; Maglic, Dino; Zervos, Emmanuel E

    2016-12-01

    Molecular targeted therapy is widely utilized and effective in a number of solid tumors. In pancreatic adenocarcinoma, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. The purpose of this study is to review therapeutic molecular targets in completed and ongoing later phase (II and III) clinical trials to have a better understanding of the rationale and progress towards targeted molecular therapies for pancreatic cancer. The PubMed database and the NCDI clinical trial website (www.clinicaltrials.gov) were queried to identify phase II and III completed and published (PubMed) and ongoing (clinicaltrials.gov) trials using the keywords: pancreatic cancer and molecular targeted therapy. The search engines were further limited by adding Phase II or III, active enrollment and North American. A total of 14 completed and published phase II/III clinical trials and 17 ongoing trials were identified. Evaluated strategies included inhibition of growth factor receptors (EGFR, PDGFR, VGFR, IGF-1R), tyrosine kinase inhibitors, MEK1/2, mTOR blockade and PI3K and HER2-neu pathway inhibitors. Only one trial conducted by the National Cancer Institute of Canada and the PANTAR trial have demonstrated a survival improvement from EGFR inhibition using erlotinib. These trials ultimately led to FDA approval of erlotinib/Tarceva in advanced stage disease. It remains unclear whether new combinations of cytotoxic chemotherapy or immunotherapy plus molecular targeted therapy will be beneficial in management of pancreatic adenocarcinoma. Despite a number of phase II and III trials, to date, only erlotinib has emerged as an approved targeted therapy in pancreatic adenocarcinoma. There are several ongoing late phase trials evaluating a number of targets, the results of which will become available over the next 1 to 2 years. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Developmental profile of select immune cells in mice infected with Trichinella spiralis during the intestinal phase

    USDA-ARS?s Scientific Manuscript database

    Trichinella spiralis can cause immunosuppression during the intestinal phase of early infection. However, changes in the peripheral blood during T. spiralis early infection remain unclear. Here, select immune cells in mice infected with 500 muscle larvae (ML) of T. spiralis during the intestinal pha...

  9. Peripheral and placental immune responses in goats after primoinfection with Neospora caninum at early, mid and late gestation.

    PubMed

    Porto, Wagnner José Nascimento; Horcajo, Pilar; Kim, Pomy de Cássia Peixoto; Regidor-Cerrillo, Javier; Romão, Elton Amorim; Álvarez-García, Gema; Mesquita, Emanuela Polimeni de; Mota, Rinaldo Aparecido; Ortega-Mora, Luis Miguel

    2017-08-15

    Neospora caninum can cause reproductive failure in goats. However, the pathogenesis of neosporosis in this domestic species remains largely unknown. We recently demonstrated that the outcome of experimental infection by N. caninum in pregnant goats is highly dependent on the time of gestation, during which infection occurs. In the present study, we examined the peripheral and placental immune responses in these groups of goats infected with 10(6) tachyzoites of the Nc-Spain7 isolate at early (G1, at day 40 of gestation, dg), mid (G2, 90 dg) and late (G3, 120 dg) gestation, together with a group of non-infected goats as a control group (G4). Seroconversion was observed as early as day 10 post-infection (pi) in all goats from G1 that aborted earlier (10-11 pi). The remaining infected goats had seroconverted by day 14 pi. Similar IFN-γ kinetic profiles were found in sera from goats in G1 and G2 with a significant increase in the IFN-γ levels on days 7 and 10 pi. This increase was not observed in G3. A similar pattern of placental cytokine expression was found in all infected groups. IFN-γ and IL-4 showed the highest increase, followed by a weaker up-regulation in TNF-α and IL-10. The lowest up-regulation was observed for IL-12 expression. In summary, this study provides information regarding the dynamics of immune responses and their relationship with the outcome of N. caninum infection in goats during gestation. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    PubMed

    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

    2015-11-23

    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.

  11. 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

  12. The SIT4 protein phosphatase functions in late G1 for progression into S phase.

    PubMed Central

    Sutton, A; Immanuel, D; Arndt, K T

    1991-01-01

    Saccharomyces cerevisiae strains containing temperature-sensitive mutations in the SIT4 protein phosphatase arrest in late G1 at the nonpermissive temperature. Order-of-function analysis shows that SIT4 is required in late G1 for progression into S phase. While the levels of SIT4 do not change in the cell cycle, SIT4 associates with two high-molecular-weight phosphoproteins in a cell-cycle-dependent fashion. In addition, we have identified a polymorphic gene, SSD1, that in some versions can suppress the lethality due to a deletion of SIT4 and can also partially suppress the phenotypic defects due to a null mutation in BCY1. The SSD1 protein is implicated in G1 control and has a region of similarity to the dis3 protein of Schizosaccharomyces pombe. We have also identified a gene, PPH2alpha, that in high copy number can partially suppress the growth defect of sit4 strains. The PPH2 alpha gene encodes a predicted protein that is 80% identical to the catalytic domain of mammalian type 2A protein phosphatases but also has an acidic amino-terminal extension not present in other phosphatases. Images PMID:1848673

  13. Traumatic Brain Injury Pathophysiology and Treatments: Early, Intermediate, and Late Phases Post-Injury

    PubMed Central

    Algattas, Hanna; Huang, Jason H.

    2014-01-01

    Traumatic Brain Injury (TBI) affects a large proportion and extensive array of individuals in the population. While precise pathological mechanisms are lacking, the growing base of knowledge concerning TBI has put increased emphasis on its understanding and treatment. Most treatments of TBI are aimed at ameliorating secondary insults arising from the injury; these insults can be characterized with respect to time post-injury, including early, intermediate, and late pathological changes. Early pathological responses are due to energy depletion and cell death secondary to excitotoxicity, the intermediate phase is characterized by neuroinflammation and the late stage by increased susceptibility to seizures and epilepsy. Current treatments of TBI have been tailored to these distinct pathological stages with some overlap. Many prophylactic, pharmacologic, and surgical treatments are used post-TBI to halt the progression of these pathologic reactions. In the present review, we discuss the mechanisms of the pathological hallmarks of TBI and both current and novel treatments which target the respective pathways. PMID:24381049

  14. Cutaneous immediate and late phase reactions to schistosomin in schistosomiasis patients.

    PubMed

    Marotto, P C; Michalany, N S; Vilela, M P; Mendes, N F; Mendes, E

    1995-01-01

    Cutaneous immediate and late phase reactions (LPR) to schistosomin were studied in 29 patients with schistosomiasis mansoni. In 12 of these patients, the determination of total and specific serum IgE by immunoenzymatic method against schistosome antigen was carried out using serum samples obtained on the same day as the cutaneous tests. Skin biopsies were taken from 4 typical LPRs. Immediate reactions occurred in all except one and LPRs in 12 (41.3%). Patients with positive cutaneous reactions had highe levels of specific serum IgE against schistosome antigen. Histopathological studies showed a moderate exudate consisting mainly of neutrophils (60%) and eosinophils (40%). LPRs in schistosomiasis have the same characteristics reported in the medical literature in relation to time of appearance, morphology and histopathology. The immunopathogenic role played by LPRs in the patients remains to be clarified.

  15. The phenomenological status of late time phase transition models after cosmic background radiation anisotropy measurements

    NASA Technical Reports Server (NTRS)

    Luo, Xiaochun; Schramm, David N.

    1994-01-01

    Some relatively model-independent results for structure formation via late time phase transitions (LTPT) are discussed. In particular, generic LTPT power spectra are presented. The implication of the recent Cosmic Background Explorer (COBE) detection of the cosmic background radiation (CBR) anisotropy at large angular scales (greater than or approximately equal to 7 deg) and the tight upper limits from small angular scales (approximately 1 deg) to LTPT models are discussed. Special attention is focused on the observational constraints and possible non-Gaussian signatures of CBR temperature anisotropies from LTPT and other non-Gaussian models. It is shown that while LTPT have been seriously constrained by the recent data, viable models do remain which provide more power on the 100-200 Mpc scales than do more traditional primordial Gaussian density fluctuation models. Tests for such models are presented, including possible anisotropies on angular scales less than 8 min.

  16. 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.

  17. Late Quaternary intensified monsoon phases control landscape evolution in the northwest Himalaya

    NASA Astrophysics Data System (ADS)

    Bookhagen, Bodo; Thiede, Rasmus C.; Strecker, Manfred R.

    2005-02-01

    The intensity of the Asian summer-monsoon circulation varies over decadal to millennial time scales and is reflected in changes in surface processes, terrestrial environments, and marine sediment records. However, the mechanisms of long-lived (2 5 k.y.) intensified monsoon phases, the related changes in precipitation distribution, and their effect on landscape evolution and sedimentation rates are not yet well understood. The arid high-elevation sectors of the orogen correspond to a climatically sensitive zone that currently receives rain only during abnormal (i.e., strengthened) monsoon seasons. Analogous to present-day rainfall anomalies, enhanced precipitation during an intensified monsoon phase is expected to have penetrated far into these geomorphic threshold regions where hillslopes are close to the angle of failure. We associate landslide triggering during intensified monsoon phases with enhanced precipitation, discharge, and sediment flux leading to an increase in pore-water pressure, lateral scouring of rivers, and oversteepening of hillslopes, eventually resulting in failure of slopes and exceptionally large mass movements. Here we use lacustrine deposits related to spatially and temporally clustered large landslides (>0.5 km3) in the Sutlej Valley region of the northwest Himalaya to calculate sedimentation rates and to infer rainfall patterns during late Pleistocene (29 24 ka) and Holocene (10 4 ka) intensified monsoon phases. Compared to present-day sediment-flux measurements, a fivefold increase in sediment-transport rates recorded by sediments in landslide-dammed lakes characterized these episodes of high climatic variability. These changes thus emphasize the pronounced imprint of millennial-scale climate change on surface processes and landscape evolution.

  18. Cell cycle reentry from the late S phase: implications from stem cell formation in the moss Physcomitrella patens.

    PubMed

    Ishikawa, Masaki; Hasebe, Mitsuyasu

    2015-05-01

    Differentiated cells are in a non-dividing, quiescent state, but some differentiated cells can reenter the cell cycle in response to appropriate stimuli. Quiescent cells are generally arrested at the G0/G1 phase, reenter the cell cycle, and progress to the S phase to replicate their genomic DNA. On the other hand, some types of cells are arrested at the different phase and reenter the cell cycle from there. In the moss Physcomitrella patens, the differentiated leaf cells of gametophores formed in the haploid generation contain approximately 2C DNA content, and DNA synthesis is necessary for reentry into the cell cycle, which is suggested to be arrested at late S phase. Here we review various cell-division reactivation processes in which cells reenter the cell cycle from the late S phase, and discuss possible mechanisms of such unusual cell cycle reentries with special emphasis on Physcomitrella.

  19. 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.

  20. 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

  1. 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.

  2. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Repeated ethanol exposure during late gestation alters the maturation and innate immune status of the ovine fetal lung.

    PubMed

    Sozo, Foula; O'Day, Luke; Maritz, Gert; Kenna, Kelly; Stacy, Victoria; Brew, Nadine; Walker, David; Bocking, Alan; Brien, James; Harding, Richard

    2009-03-01

    Little is known about the effects of fetal ethanol exposure on lung development. Our aim was to determine the effects of repeated ethanol exposure during late gestation on fetal lung growth, maturation, and inflammatory status. Pregnant ewes were chronically catheterized at 91 days of gestational age (DGA; term approximately 147 days). From 95-133 DGA, ewes were given a 1-h daily infusion of either 0.75 g ethanol/kg (n = 9) or saline (n = 8), with tissue collection at 134 DGA. Fetal lungs were examined for changes in tissue growth, structure, maturation, inflammation, and oxidative stress. Between treatment groups, there were no differences in lung weight, DNA and protein contents, percent proliferating and apoptotic cells, tissue and air-space fractions, alveolar number and mean linear intercept, septal thickness, type-II cell number and elastin content. Ethanol exposure caused a 75% increase in pulmonary collagen I alpha1 mRNA levels (P < 0.05) and a significant increase in collagen deposition. Surfactant protein (SP)-A and SP-B mRNA levels were approximately one third of control levels following ethanol exposure (P < 0.05). The mRNA levels of the proinflammatory cytokines interleukin (IL)-1beta and IL-8 were also lower (P < 0.05) in ethanol-exposed fetuses compared with controls. Pulmonary malondialdehyde levels tended to be increased (P = 0.07) in ethanol-exposed fetuses. Daily exposure of the fetus to ethanol during the last third of gestation alters extracellular matrix deposition and surfactant protein gene expression, which could increase the risk of respiratory distress syndrome after birth. Changes to the innate immune status of the fetus could increase the susceptibility of the neonatal lungs to infection.

  4. High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques.

    PubMed

    Vishwanathan, Sundaram A; Guenthner, Patricia C; Lin, Carol Y; Dobard, Charles; Sharma, Sunita; Adams, Debra R; Otten, Ron A; Heneine, Walid; Hendry, R Michael; McNicholl, Janet M; Kersh, Ellen N

    2011-08-01

    Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, the time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIV(SF162P3) exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared with 1 macaque (5%) in the luteal phase (P < 0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24 and 31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support the findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use.

  5. 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.…

  6. 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…

  7. 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…

  8. 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.…

  9. 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…

  10. 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…

  11. Deconstructing the Late Phase of Vimentin Assembly by Total Internal Reflection Fluorescence Microscopy (TIRFM)

    PubMed Central

    Winheim, Stefan; Hieb, Aaron R.; Silbermann, Marleen; Surmann, Eva-Maria; Wedig, Tatjana; Herrmann, Harald; Langowski, Jörg; Mücke, Norbert

    2011-01-01

    Quantitative imaging of intermediate filaments (IF) during the advanced phase of the assembly process is technically difficult, since the structures are several µm long and therefore they exceed the field of view of many electron (EM) or atomic force microscopy (AFM) techniques. Thereby quantitative studies become extremely laborious and time-consuming. To overcome these difficulties, we prepared fluorescently labeled vimentin for visualization by total internal reflection fluorescence microscopy (TIRFM). In order to investigate if the labeling influences the assembly properties of the protein, we first determined the association state of unlabeled vimentin mixed with increasing amounts of labeled vimentin under low ionic conditions by analytical ultracentrifugation. We found that bona fide tetrameric complexes were formed even when half of the vimentin was labeled. Moreover, we demonstrate by quantitative atomic force microscopy and electron microscopy that the morphology and the assembly properties of filaments were not affected when the fraction of labeled vimentin was below 10%. Using fast frame rates we observed the rapid deposition of fluorescently labeled IFs on glass supports by TIRFM in real time. By tracing their contours, we have calculated the persistence length of long immobilized vimentin IFs to 1 µm, a value that is identical to those determined for shorter unlabeled vimentin. These results indicate that the structural properties of the filaments were not affected significantly by the dye. Furthermore, in order to analyze the late elongation phase, we mixed long filaments containing either Alexa 488- or Alexa 647-labeled vimentin. The ‘patchy’ structure of the filaments obtained unambiguously showed the elongation of long IFs through direct end-to-end annealing of individual filaments. PMID:21544245

  12. Distinct phases of eustatic and tectonic forcing for late Quaternary landscape evolution in southwest Crete, Greece

    NASA Astrophysics Data System (ADS)

    Mouslopoulou, Vasiliki; Begg, John; Fülling, Alexander; Moraetis, Daniel; Partsinevelos, Panagiotis; Oncken, Onno

    2017-09-01

    The extent to which climate, eustasy and tectonics interact to shape the late Quaternary landscape is poorly known. Alluvial fans often provide useful indexes that allow the decoding of information recorded on complex coastal landscapes, such as those of the eastern Mediterranean. In this paper we analyse and date (using infrared stimulated luminescence (IRSL) dating) a double alluvial fan system on southwest Crete, an island straddling the forearc of the Hellenic subduction margin, in order to constrain the timing and magnitude of its vertical deformation and discuss the factors contributing to its landscape evolution. The studied alluvial system is exceptional because each of its two juxtaposed fans records individual phases of alluvial and marine incision, thus providing unprecedented resolution in the formation and evolution of its landscape. Specifically, our analysis shows that the fan sequence at Domata developed during Marine Isotope Stage (MIS) 3 due to five distinct stages of marine transgressions and regressions and associated river incision, in response to sea-level fluctuations and tectonic uplift at averaged rates of ˜ 2.2 mm yr-1. Interestingly, comparison of our results with published tectonic uplift rates from western Crete shows that uplift during 20-50 kyr BP was minimal (or even negative). Thus, most of the uplift recorded at Domata must have occurred in the last 20 kyr. This implies that eustasy and tectonism impacted the landscape at Domata over mainly distinct time intervals (e.g. sequentially and not synchronously), with eustasy forming and tectonism preserving the coastal landforms.

  13. SN 2009ip: CONSTRAINING THE LATEST EXPLOSION PROPERTIES BY ITS LATE-PHASE LIGHT CURVE

    SciTech Connect

    Moriya, Takashi J.

    2015-04-20

    We constrain the explosion and circumstellar properties at the 2012b event of SN 2009ip based on its recently reported late-phase bolometric light curve. The explosion energy and ejected mass at the 2012b event are estimated as 0.01 M{sub ⊙} and 2 × 10{sup 49} erg, respectively. The circumstellar medium is assumed to have two components: an inner shell and an outer wind. The inner shell, which is likely created at the 2012a event, has a mass of 0.2 M{sub ⊙}. The outer wind is created by the wind mass loss before the 2012a mass ejection, and the progenitor is estimated to have had a mass-loss rate of about 0.1 M{sub ⊙} yr{sup −1} with a wind velocity of 550 km s{sup −1} before the 2012a event. The estimated explosion energy and ejected mass indicate that the 2012b event is not caused by a regular SN.

  14. The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery.

    PubMed

    Caldwell, G W; Ritchie, D M; Masucci, J A; Hageman, W; Yan, Z

    2001-11-01

    The attrition rates of new chemical entities (NCEs) in preclinical and clinical development are staggeringly high. NCEs are abandoned due to insufficient efficacy, safety issues, and economic reasons. Uncovering drug defects that produce these failures as early as possible in drug discovery would be highly effective in lowing the cost and time of developing therapeutically useful drugs. Unfortunately, there is no single factor that can account for these NCE failures in preclinical and clinical development since factors, such as solubility, pKa, absorption, metabolism, formulation, pharmacokinetics, toxicity and efficacy, to name a few, are all interrelated. In addition, there are many problems in scaling-up drug candidates from the laboratory bench scale to the pilot plant scale. To address the problem of attrition rates of NCEs in preclinical and clinical development and drug scale-up issues, pharmaceutical companies need to reorganize their preclinical departments from a traditional linear approach to a parallel approach. In this review, a strategy is put forth to integrate certain aspects of drug metabolism/pharmacokinetics, toxicology functions and process chemistry into drug discovery. Compound optimization in early and late phase drug discovery occurs by relating factors such as physicochemical properties, in vitro absorption, in vitro metabolism, in vivo pharmacokinetics and drug scale-up issues to efficacy optimization. This pre-preclinical paradigm will improve the success rate of drug candidates entering development.

  15. 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

  16. Mapping Gene Expression in Excitatory Neurons during Hippocampal Late-Phase Long-Term Potentiation

    PubMed Central

    Chen, Patrick B.; Kawaguchi, Riki; Blum, Charles; Achiro, Jennifer M.; Coppola, Giovanni; O'Dell, Thomas J.; Martin, Kelsey C.

    2017-01-01

    The persistence of long-lasting changes in synaptic connectivity that underlie long-term memory require new RNA and protein synthesis. To elucidate the temporal pattern of gene expression that gives rise to long-lasting neuronal plasticity, we analyzed differentially-expressed (DE) RNAs in mouse hippocampal slices following induction of late phase long-term potentiation (L-LTP) specifically within pyramidal excitatory neurons using Translating Ribosome Affinity Purification RNA sequencing (TRAP-seq). We detected time-dependent changes in up- and down-regulated ribosome-associated mRNAs over 2 h following L-LTP induction, with minimal overlap of DE transcripts between time points. TRAP-seq revealed greater numbers of DE transcripts and magnitudes of LTP-induced changes than RNA-seq of all cell types in the hippocampus. Neuron-enriched transcripts had greater changes at the ribosome-loading level than the total RNA level, while RNA-seq identified many non-neuronal DE mRNAs. Our results highlight the importance of considering both time course and cell-type specificity in activity-dependent gene expression during memory formation. PMID:28275336

  17. Mechanical Ventilation Induces an Inflammatory Response in Preinjured Lungs in Late Phase of Sepsis.

    PubMed

    Xuan, Wei; Zhou, Quanjun; Yao, Shanglong; Deng, Qingzhu; Wang, Tingting; Wu, Qingping

    2015-01-01

    Mechanical ventilation (MV) may amplify the lung-specific inflammatory response in preinjured lungs by elevating cytokine release and augmenting damage to the alveolar integrity. In this study, we test the hypothesis that MV exerts different negative impacts on inflammatory response at different time points of postlung injury. Basic lung injury was induced by cecal ligation and puncture (CLP) surgery in rats. Physiological indexes including blood gases were monitored during MV and samples were assessed following each experiment. Low V T (tidal volume) MV caused a slight increase in cytokine release and tissue damage at day 1 and day 4 after sepsis induced lung injury, while cytokine release from the lungs in the two moderately ventilated V T groups was amplified. Interestingly, in the two groups where rats received low V T MV, we found that infiltration of inflammatory cells was only profound at day 4 after CLP. Marked elevation of protein leakage indicated a compromise in alveolar integrity in rats that received moderate V T MV at day 4 following CLP, correlating with architectural damage to the alveoli. Our study indicates that preinjured lungs are more sensitive to mechanical MV at later phases of sepsis, and this situation may be a result of differing immune status.

  18. 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

  19. Intensification of β-poly(L: -malic acid) production by Aureobasidium pullulans ipe-1 in the late exponential growth phase.

    PubMed

    Cao, Weifeng; Luo, Jianquan; Zhao, Juan; Qiao, Changsheng; Ding, Luhui; Qi, Benkun; Su, Yi; Wan, Yinhua

    2012-07-01

    β-Poly(malic acid) (PMLA) has attracted industrial interest because this polyester can be used as a prodrug or for drug delivery systems. In PMLA production by Aureobasidium pullulans ipe-1, it was found that PLMA production was associated with cell growth in the early exponential growth phase and dissociated from cell growth in the late exponential growth phase. To enhance PMLA production in the late phase, different fermentation modes and strategies for controlling culture redox potential (CRP) were studied. The results showed that high concentrations of produced PMLA (above 40 g/l) not only inhibited PMLA production, but also was detrimental to cell growth. Moreover, when CRP increased from 57 to 100 mV in the late exponential growth phase, the lack of reducing power in the broth also decreased PMLA productivity. PMLA productivity could be enhanced by repeated-batch culture to maintain cell growth in the exponential growth phase, or by cell-recycle culture with membrane to remove the produced PMLA, or by maintaining CRP below 70 mV no matter which kind of fermentation mode was adopted. Repeated-batch culture afforded a high PMLA concentration (up to 63.2 g/l) with a productivity of 1.15 g l(-1) h(-1). Cell-recycle culture also confirmed that PMLA production by the strain ipe-1 was associated with cell growth.

  20. 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.

  1. 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.

  2. 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

  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.

  4. Taurine-induced synaptic potentiation and the late phase of long-term potentiation are related mechanistically.

    PubMed

    del Olmo, N; Handler, A; Alvarez, L; Bustamante, J; Martín del Río, R; Solís, J M

    2003-01-01

    The application of taurine (2-aminoethanesulfonic acid) induces a long-lasting increase of synaptic efficacy and axon excitability (LLP-TAU) in rat hippocampal CA1 area. After taurine withdrawal, LLP-TAU lasted at least 3 h. This fact prompted us to assess whether the mechanisms involved in the maintenance of this particular potentiation were similar to those implicated in the late phase of long-term potentiation (L-LTP). In the presence of KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase, taurine perfusion (10 mM, 30 min) did not affect the induction of LLP-TAU. However, LLP-TAU maintenance was completely suppressed by KT5720, an inhibitor of the cAMP-dependent protein kinase (PKA). Moreover, the late phase of LLP-TAU was blocked by inhibiting protein synthesis with anisomycin. In addition, taurine perfusion increased the phosphorylation of cAMP response element-binding protein (CREB), although did not affect cAMP levels. These features of LLP-TAU do not appear to be caused by the activation of D1/D5 dopamine receptors, as taurine also induced synaptic potentiation in the presence of SCH23390, an antagonist of this type of receptors. Finally, the late phase of both L-LTP and LLP-TAU occluded mutually. These results suggest that taurine triggers the sequence of some of the molecular events involved in the induction of L-LTP.

  5. Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis.

    PubMed Central

    Fanelli, C G; De Feo, P; Porcellati, F; Perriello, G; Torlone, E; Santeusanio, F; Brunetti, P; Bolli, G B

    1992-01-01

    Three studies were performed on nine normal volunteers to assess whether catecholamine-mediated lipolysis contributes to counterregulation to hypoglycemia. In these three studies, insulin was intravenously infused for 8 h (0.30 mU.kg-1.min-1 from 0 to 180 min, and 0.40 mU.kg-1.min-1 until 480 min). In study I (control study), only insulin was infused; in study II (direct + indirect effects of catecholamines), propranolol and phentolamine were superimposed to insulin and exogenous glucose was infused to reproduce the same plasma glucose (PG) concentration of study I. Study III (indirect effect of catecholamines) was the same as study II, except heparin (0.2 U.kg-1.min-1 after 80 min), 10% Intralipid (1 ml.min-1 after 160 min) and variable glucose to match PG of study II, were also infused. Glucose production (HGO), glucose utilization (Rd) [3-3H]glucose, and glucose oxidation and lipid oxidation (LO) (indirect calorimetry) were determined. In all three studies, PG decreased from approximately 4.8 to approximately 2.9 mmol/liter (P = NS between studies), and plasma glycerol and FFA decreased to a nadir at 120 min. Afterwards, in study I plasma glycerol and FFA increased by approximately 75% at 480 min, but in study II they remained approximately 40% lower than in study I, whereas in study III they rebounded as in study I (P = NS). In study II, LO was lower than in study I (1.69 +/- 0.13 vs. 3.53 +/- 0.19 mumol.kg-1.min-1, P less than 0.05); HGO was also lower between 60 and 480 min (7.48 +/- 0.57 vs. 11.6 +/- 0.35 mumol.kg-1.min-1, P less than 0.05), whereas Rd was greater between 210 and 480 min (19 +/- 0.38 vs. 11.4 +/- 0.34 mumol.kg-1.min-1, respectively, P less than 0.05). In study III, LO increased to the values of study I; between 4 and 8 h, HGO increased by approximately 2.5 mumol.kg-1.min-1, and Rd decreased by approximately 7 mumol.kg-1.min-1 vs. study II. We conclude that, in a late phase of hypoglycemia, the indirect effects of catecholamines (lipolysis

  6. The genetic immunization with paraflagellar rod protein-2 fused to the HSP70 confers protection against late Trypanosoma cruzi infection.

    PubMed

    Morell, María; Thomas, M Carmen; Caballero, Trinidad; Alonso, Carlos; López, Manuel C

    2006-11-30

    The immunological properties of the Trypanosoma cruzi paraflagellar rod proteins (PFR2 and PFR3) administered alone as well as fused to HSP70 have been analyzed in mice in the context of genetic immunization. The immunization of mice with the DNA vectors containing the PFRs gene or PFRs-HSP70 fused genes induced high level of IgG(2a) anti-PFRs. However, only the immunization with the PFR2-HSP70 fused genes triggers in spleen cells a statistically significant enhancement of expression of IL-12 and IFN-gamma and a decrease in the percentage of cells expressing IL-4. Likewise, the PFR2-HSP70 molecule elicits a statistically significant activation of PFR2 antigen specific CTLs. Immunization with the PFR2-HSP70 chimeric gene provided a protective response against a T. cruzi experimental infection.

  7. 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.

  8. CpG ODN mimicking CpG rich region of myxosporean Myxobolus supamattayai stimulates innate immunity in Asian sea bass (Lates calcarifer) and defense against Streptococcus iniae.

    PubMed

    U-Taynapun, Kittichon; Chirapongsatonkul, Nion; Itami, Toshiaki; Tantikitti, Chutima

    2016-11-01

    Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanine CpG dinucleotides within specific sequence contexts (CpG motifs) have been reported as pathogen-associated molecular patterns (PAMPs). Its immunostimulatory effects have been demonstrated in diverse vertebrate models. CpG ODN is typically found in bacterial or viral genome and recognized by a non-self recognition receptor Toll-like receptor9 (TLR9). Here, a new CpG ODN 1013 which mimics sequence of SSU rDNA of early eukaryotic organism myxosporidia, Myxobolus supamattayai, was employed to stimulate the immune responses of Asian sea bass Lates calcarifer. Its immunostimulant potentiality was comparatively compared with that of CpG ODN 1668, a widely used as functional immunostimulant. Both unmethylated CpG ODNs with some modified phosphorothioated positions were intraperitoneally injection (5 μg/fish). Hematological examination, immunological assays and immune-related genes expression were evaluated 12 h, 1, 3 and 5 d after post CpG ODN challenge. The immunosimulatory effect of these CpG ODNs on fish immunity to protect the bacterial pathogen Streptococcus iniae was also determined. The results demonstrated that these two CpG ODNs could induce immune responses in Asian sea bass including the significant (P < 0.05) increase level of WBC, peroxidase activity and oxidative radicals in head kidney (HK) leukocyte, serum innate immune parameters and up-regulation of four immune responsive genes compared with the control group. Most of immune responses induced by ODN 1668 were strong within 1 d but lesser extended while ODN 1013 prolonged the stimulatory effects during the whole experimental period. After challenge with S. iniae, the survival proportion in ODN 1013-treated fish was apparently higher than that treated with ODN 1668 and PBS, respectively. The results together suggested that CpG ODN 1013 enhanced innate immune responses, including humoral and cellular responses, through

  9. Pediatric Immunization Distress: A Cluster Analyses of Children's, Parents', and Nurses' Behaviors During the Anticipatory Phase.

    PubMed

    Pedro, Helga; Barros, Luísa; Pereira, Ana I

    2016-05-01

    Using cluster analysis, we aimed to identify a typology of nurses', parents', and young children's behaviors during the anticipatory phase of pediatric immunizations to explore the associations between these different typologies and to determine whether these groups differed with respect to the child's procedural distress as rated by the child and the parents and with respect to the adults' self-rated distress. Immunizations given by 23 nurses to 220 children aged 3 years and 10 months to 7 years were recorded with behaviors being scored according to Child-Adult Medical Procedure Interaction Scale-Revised, to which 3 new codes were added, and rated with a 6-point Likert scale. Parents' and nurses' ratings of their own distress and of the child's distress, in addition to children's self-rating of distress were obtained. Nine adult and 12 child behavioral codes were submitted for cluster analysis. A solution with 4 clusters for children, 5 clusters for parents, and 5 clusters for nurses was retained. Our results show high consistency between child and adult clusters. During the anticipatory phase, less distressed children, characterized by either low activity or high coping, interacted with adults who showed low activity or high coping support patterns. More distressed children, characterized by resistance and behavioral distress, interacted with adults who displayed either low activity or less efficient support behaviors, such as reassurance and criticism. The results confirm previous dimensional studies and add relevant knowledge concerning typologies of participant behaviors that may be useful in understanding such behaviors and in helping providers in their management of child immunizations.

  10. Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice

    PubMed Central

    Chen, Gang; Park, Chul-Kyu; Xie, Rou-Gang; Berta, Temugin; Nedergaard, Maiken

    2014-01-01

    Accumulating evidence suggests that spinal cord astrocytes play an important role in neuropathic pain sensitization by releasing astrocytic mediators (e.g. cytokines, chemokines and growth factors). However, it remains unclear how astrocytes control the release of astrocytic mediators and sustain late-phase neuropathic pain. Astrocytic connexin-43 (now known as GJ1) has been implicated in gap junction and hemichannel communication of cytosolic contents through the glial syncytia and to the extracellular space, respectively. Connexin-43 also plays an essential role in facilitating the development of neuropathic pain, yet the mechanism for this contribution remains unknown. In this study, we investigated whether nerve injury could upregulate connexin-43 to sustain late-phase neuropathic pain by releasing chemokine from spinal astrocytes. Chronic constriction injury elicited a persistent upregulation of connexin-43 in spinal astrocytes for >3 weeks. Spinal (intrathecal) injection of carbenoxolone (a non-selective hemichannel blocker) and selective connexin-43 blockers (connexin-43 mimetic peptides 43Gap26 and 37,43Gap27), as well as astroglial toxin but not microglial inhibitors, given 3 weeks after nerve injury, effectively reduced mechanical allodynia, a cardinal feature of late-phase neuropathic pain. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1, and the release was blocked by carbenoxolone, Gap26/Gap27, and connexin-43 small interfering RNA. TNF-α also increased connexin-43 expression and hemichannel activity, but not gap junction communication in astrocyte cultures prepared from cortices and spinal cords. Spinal injection of TNF-α-activated astrocytes was sufficient to induce persistent mechanical allodynia, and this allodynia was suppressed by CXCL1 neutralization, CXCL1 receptor (CXCR2) antagonist, and pretreatment of astrocytes with connexin-43 small interfering RNA. Furthermore, nerve injury persistently increased excitatory

  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. 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

  13. Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension

    PubMed Central

    Foss, Jason D.; Fink, Gregory D.

    2015-01-01

    Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼170 mmHg. RDNX reduced MAP ∼10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves. PMID:26661098

  14. Single-cell gene expression analyses of cellular reprogramming reveal a stochastic early and hierarchic late phase

    PubMed Central

    Buganim, Yosef; Faddah, Dina A.; Cheng, Albert W.; Itskovich, Elena; Markoulaki, Styliani; Ganz, Kibibi; Klemm, Sandy L.; van Oudenaarden, Alexander; Jaenisch, Rudolf

    2012-01-01

    During cellular reprogramming only a small fraction of cells become induced pluripotent stem cells (iPSCs). Previous analyses of gene expression during reprogramming were based on populations of cells, impeding single-cell level identification of reprogramming events. We utilized two gene expression technologies to profile 48 genes in single cells at various stages during the reprogramming process. Analysis of early stages revealed considerable variation in gene expression between cells in contrast to late stages. Expression of Esrrb, Utf1, Lin28, and Dppa2 is a better predictor for cells to progress into iPSCs than expression of Fbxo15, Fgf4, and Oct4 previously suggested to be reprogramming markers. Stochastic gene expression early in reprogramming is followed by a late hierarchical phase with Sox2 being the upstream factor in a gene expression hierarchy. Finally, downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc and Nanog, can activate the pluripotency circuitry. PMID:22980981

  15. The hyper-fluorescent transitional bands in ultra-late phase of indocyanine green angiography in chronic central serous chorioretinopathy.

    PubMed

    Hua, Rui; Yao, Kai; Xia, Fan; Li, Jun; Guo, Lei; Yang, Guoxing; Tao, Jun

    2016-03-01

    Chronic central serous chorioretinopathy (CSCR) is regarded as a type of severe diffuse retinal pigment epitheliopathy. There is an atrophic tract at level of retinal pigment epithelium (RPE) due to hyper-permeability of choroidal vessels, along with photoreceptor (PR) atrophy. Indocyanine green angiography (ICGA) is considered a gold standard for diagnosis. The purpose of this work is to investigate the hyper-fluorescent transitional bands (HFTB) between hypo-fluorescent and normal regions of the retina in the ultra-late phase of ICGA in CSCR. 26 chronic CSCR eyes and 12 relative normal eyes received spectral domain optical coherence tomography (SD-OCT), and ICGA at the 24th hour after indocyanine green (ICG) intravenous injection. In the ultra-late phase, images showed homogenous fluorescence in all normal eyes. On the contrary, geographical hypofluorescent lesions with atrophy of RPE was noted in 26 chronic CSCR eyes. Moreover, HFTB with intact RPE and disrupted PR was detected in 20 out of 26 chronic CSCR eyes (76.9%). The HFTB may indicate the early damage in chronic CSCR. Ultra-late ICGA can monitor not only metabolic status by endogenous melanin, but also membrane function in RPE by exogenous ICG molecule. © 2015 Wiley Periodicals, Inc.

  16. Immunization of mice with live-attenuated late liver stage-arresting Plasmodium yoelii parasites generates protective antibody responses to preerythrocytic stages of malaria.

    PubMed

    Keitany, Gladys J; Sack, Brandon; Smithers, Hannah; Chen, Lin; Jang, Ihn K; Sebastian, Leslie; Gupta, Megha; Sather, D Noah; Vignali, Marissa; Vaughan, Ashley M; Kappe, Stefan H I; Wang, Ruobing

    2014-12-01

    Understanding protective immunity to malaria is essential for the design of an effective vaccine to prevent the large number of infections and deaths caused by this parasitic disease. To date, whole-parasite immunization with attenuated parasites is the most effective method to confer sterile protection against malaria infection in clinical trials. Mouse model studies have highlighted the essential role that CD8(+) T cells play in protection against preerythrocytic stages of malaria; however, there is mounting evidence that antibodies are also important in these stages. Here, we show that experimental immunization of mice with Plasmodium yoelii fabb/f(-) (Pyfabb/f(-)), a genetically attenuated rodent malaria parasite that arrests late in the liver stage, induced functional antibodies that inhibited hepatocyte invasion in vitro and reduced liver-stage burden in vivo. These antibodies were sufficient to induce sterile protection from challenge by P. yoelii sporozoites in the absence of T cells in 50% of mice when sporozoites were administered by mosquito bite but not when they were administered by intravenous injection. Moreover, among mice challenged by mosquito bite, a higher proportion of BALB/c mice than C57BL/6 mice developed sterile protection (62.5% and 37.5%, respectively). Analysis of the antibody isotypes induced by immunization with Pyfabb/f(-) showed that, overall, BALB/c mice developed an IgG1-biased response, whereas C57BL/6 mice developed an IgG2b/c-biased response. Our data demonstrate for the first time that antibodies induced by experimental immunization of mice with a genetically attenuated rodent parasite play a protective role during the preerythrocytic stages of malaria. Furthermore, they highlight the importance of considering both the route of challenge and the genetic background of the mouse strains used when interpreting vaccine efficacy studies in animal models of malaria infection. Copyright © 2014, American Society for Microbiology. All

  17. Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes.

    PubMed

    Rabaglino, Maria B; Keller-Wood, Maureen; Wood, Charles E

    2014-11-19

    Major changes in gene expression occur in the fetal brain to modulate the function of this organ postnatally. Thus, factors can alter the genomics of the fetal brain, predisposing to neurological disorders later in life. We hypothesized that the physiological dynamics of the immune system transcriptome of the fetal brain during the last stage of gestation will reveal patterns of immune function and development in the developing brain. In this study we applied weighted gene co-expression analysis of microarrays performed on ovine fetal brain samples, to model the changes in gene expression throughout the second half of gestation. Clusters of co-expressed genes that strongly increase in expression toward the first day of extra-uterine life are related to the hematopoietic lineage, while activation of immune pathways is induced after birth. Moreover, the pattern of gene expression suggests induction of tolerance mechanisms, probably necessary to protect highly produced proteins--such as myelin basic protein--from an autoimmune attack. This study provides insight into the dramatic changes in gene expression that take place in the brain during the fetal life, especially during the last stage of gestation, and suggests that the immune system may have an important role in maturation of the fetal brain, which if disrupted or altered, could have negative consequences in postnatal life.

  18. Topical tacrolimus and cyclosporin A differentially inhibit early and late effector phases of cutaneous delayed-type and immunoglobulin E hypersensitivity

    PubMed Central

    Geba, Gregory P; Ptak, Wlodzimierz; Askenase, Philip W

    2001-01-01

    Systemic and topical administration routes of tacrolimus and cyclosporin A (CsA) were compared in effects on early and late phases of elicited T-cell-mediated contact sensitivity (CS), and effects on early and late phases of cutaneous immunoglobulin E (IgE) antibody-mediated hypersensitivity responses in mice. Thus, both CS and IgE responses in the skin have an early mast-cell-dependent phase, and also a late inflammatory phase. We measured the effects of both immunosuppressants on both phases of the respective T cell versus IgE responses. Systemic administration of both agents completely suppressed CS and IgE late-phase responses, but failed to affect either early phase. In contrast, when topical CsA was used, low doses abolished the early phase of IgE responses, but even high doses did not inhibit the early phase of CS. Conversely, topical tacrolimus inhibited the early phase of CS more potently than the early phase of cutaneous IgE hypersensitivity responses. Thus, topical treatment was needed to inhibit the early phases and the two agents acted differentially, suggesting differing susceptibility of the early phases, that are probably due to different signalling mechanisms. These studies underscore the potential value of topical administration of these powerful immunosuppressive agents in the treatment of allergic diseases that exhibit features of early-phase mast-cell-dependent inflammation, and late inflammation due to mast cells or to T cells, such as atopic dermatitis or asthma, since the early phase is predominantly susceptible to topical application, while the last phase of both IgE and T-cell inflammation responds to systemic treatment with both agents. PMID:11683964

  19. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Microcystic meningioma with late-phase accumulation on thallium-201 single-photon emission computed tomography: case report.

    PubMed

    Matano, Fumihiro; Adachi, Koji; Murai, Yasuo; Kitamura, Takayuki; Ohashi, Ryuji; Teramoto, Akira; Morita, Akio

    2014-01-01

    Microcystic meningiomas are rare but benign brain tumors. Previous reports have shown that Thallium-201 single-photon emission computed tomography ((201)Tl SPECT) demonstrated a higher late-phase accumulation of (201)Tl in malignant or recurrent meningiomas than in nonaggressive meningiomas. No study has reported (201)Tl SPECT findings in microcystic meningiomas. We here describe a case of a microcystic meningioma with a high (201)Tl SPECT retention rate in a 62-year-old woman who complained of headache. Computed tomography revealed an intracranial tumor in the right frontal lobe. Moreover, (201)Tl SPECT revealed a high uptake of (201)Tl in the tumor, which was particularly prominent in the delayed phase. The uptake index on an early image was 1.46 and that on a delayed image was 1.35. Therefore, the retention index was 0.92. After 2 years of tumor growth, we performed successful radical resection, and histological examination revealed the presence of a microcystic meningioma. Therefore, we concluded that (201)Tl SPECT may be useful for the preoperative diagnosis of microcystic meningiomas and that late-phase accumulation of (201)Tl is not a specific finding of malignant brain tumors. Therefore, we need to be careful in the evaluation and judgment of high retention in a delayed image of (201)Tl SPECT.

  1. Trypanosoma cruzi: dehydroepiandrosterone (DHEA) and immune response during the chronic phase of the experimental Chagas' disease.

    PubMed

    Caetano, Leony Cristina; Santello, Fabricia Helena; Del Vecchio Filipin, Marina; Brazão, Vânia; Caetano, Luana Naiara; Toldo, Miriam Paula Alonso; Caldeira, Jerri C; do Prado Júnior, José Clóvis

    2009-07-07

    Dehydroepiandrosterone (DHEA) has long been considered as a precursor for many steroid hormones. It also enhances the immune responses against a wide range of viral, bacterial, and parasitic pathogens. The aims of this work were to evaluate the influences of exogenous DHEA treatment on Wistar rats infected with the Y strain of Trypanosoma cruzi during the acute and its influence on the chronic phase of infection. Animals were subcutaneous treated with 40 mg/kg body weight/day of DHEA. DHEA treatment promoted increased lymphoproliferative responses as well as enhanced concentrations of NO and IL-12. So, we point in the direction that our results validate the utility of the use of DHEA as an alternative therapy candidate against T. cruzi.

  2. Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles.

    PubMed

    Maruyama, Mitsunori; Ai, Tomohiko; Chua, Su-Kiat; Park, Hyung-Wook; Lee, Young-Soo; Shen, Mark J; Chang, Po-Cheng; Lin, Shien-Fong; Chen, Peng-Sheng

    2014-04-01

    Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear. The purpose of this study was to test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia. Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts. Repeated episodes of electrically induced ventricular fibrillation (VF) at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K(+)]o, 4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K(+)]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K(+)]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K(+)]o (P <.001). Optical mapping showed that isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 μmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small-conductance calcium-activated potassium channel blocker (apamin) failed to prevent recurrent SVF. Beta-adrenergic stimulation and concomitant hypokalemia could cause nonischemic activation of IKATP, heterogeneous APD shortening, and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity, and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  3. 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…

  4. 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…

  5. A Bayesian three-parameter logistic model for early- and late-onset DLTs in oncology Phase I studies.

    PubMed

    Zheng, Wei; Zhao, Yang; Lu, Yuefeng; Miao, Harry; Liu, Hengchang

    2016-01-01

    We introduce a three-parameter logistic model to analyze the dose limiting toxicity (DLT) as a time-to-event endpoint in oncology Phase I trials. In the proposed model, patients are allowed to stay on trial without the constraint of a maximum follow-up time. Our model accommodates late-onset DLT as well as early-onset DLT, by both of which the dose recommendation is informed. A Bayesian approach is used to incorporate prior knowledge of the test treatment into dose recommendation. Simulation examples show that our proposed model has good operating characteristics in assessing the maximum tolerated dose (MTD).

  6. 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.

  7. 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.

  8. Chronic transplantation immunity in newts: temperature susceptibility of an effector phase in allo-skin graft rejection.

    PubMed

    Kinefuchi, Kenjiroh; Kushida, Yoshihiro; Johnouchi, Masato; Shimizu, Yuiko; Ohneda, Hikaru; Fujii, Masato; Hosono, Masamichi

    2011-07-01

    Urodele amphibians are unique due to their greatly reduced immune responsiveness compared to bony fishes, which show acute immune responsiveness. In newts, the mean survival time of allogenic skin grafts in the transplantation immunity was 48.8 ± 8.3 days at 25°C, suggesting that it occurs in a chronic manner. The graft rejection process was categorized into three stages: a latent stage with frequent blood circulation, or the immune induction phase; a vascular stoppage stage with dominant infiltrating cells of T cells; and a rejection stage showing the change of the dominant cells to monocytes/macrophages, probably as effector cells, tetntatively referred to as the immune effector phase. The immune induction phase is susceptible to the cyclophosphamide (CY) mitosis inhibitor, but not to a temperature shift from 18 to 27°C, while the immune effector phase is susceptible to temperature shifts, but not CY-treatment, although the temperature shift failed to shorten the graft survival time to less than 25 days, which nearly equals that of the secondary set of grafts where the lack of complete blood circulation is remarkable and graft rejection is resistant to CY-treatment. In contrast, a very low temperature (5-10°C) completely prevented effector generation in newts; in frogs, however, it is reported that such low temperatures did not prevent the generation of effectors. Taken together, these data suggest that chronic responses in newts are due to effector cells other than cytotoxic T cells; possible effector cells are discussed.

  9. 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.

  10. 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.

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

    PubMed Central

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

    2015-01-01

    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

  12. Effects of maternal protein or energy restriction during late gestation on immune status and responses to lipopolysaccharide challenge in postnatal young goats.

    PubMed

    He, Z X; Sun, Z H; Yang, W Z; Beauchemin, K A; Tang, S X; Zhou, C S; Han, X F; Wang, M; Kang, J H; Tan, Z L

    2014-11-01

    Knowledge of maternal malnutrition of ruminants and effects on development of the immune system of their offspring is lacking. A study was conducted to investigate the effects of maternal protein or energy restriction during late gestation on immune status of their offspring at different ages. Sixty-three pregnant goats (local breed, Liuyang black goat, 22.2 ± 1.5 kg at d 90 of gestation) were fed control (CON, ME = 9.34 MJ/kg and CP = 12.5%, DM basis), 40% protein restricted (PR), or 40% energy restricted (ER) diets from d 91 of gestation to parturition, after which all animals received an adequate diet for nutritional recovery. Plasma concentrations of complement components (C3, C4), C-reactive protein (CRP) and immunoglobulins (IgG and IgM), jejunum cytokines (IL-2, IL-6, and IL-10) expression levels and morphology in the offspring were measured. Additionally, plasma concentration of complement and IL-6, and cytokines expression levels in gastrointestinal tract obtained at 6 wk from young goats were assessed under saline or lipopolysaccharide (LPS) challenging conditions. Maternal PR or ER decreased (P < 0.05) plasma C3, C4, IgG, and IgM concentrations, and IL-2 and IL-6 mRNA expression in the jejunum from neonatal kids, but did not alter (P > 0.05) plasma CRP concentration. The IL-10 mRNA expression of jejunum from PR kids was also less (P < 0.01) than that from CON kids. Moreover, jejunum villous height (P < 0.10 in PR, P < 0.05 in ER) and crypt depth (P < 0.05 both in PR and ER) were reduced in neonatal kids from malnourished mothers. At 6 wk of age, there were no differences (P > 0.05) in any plasma or tissue immune parameters among the 3 treatments. However, when given a LPS challenge, ER and PR kids had greater (P = 0.02) IL-6 concentration compared with CON kids. Our results suggest that both PR and ER during late gestation induced short-term as well as long-lasting alterations on immune responses in their offspring, which may make the animals more

  13. The acute phase response of cod (Gadus morhua L.): expression of immune response genes.

    PubMed

    Audunsdottir, Sigridur S; Magnadottir, Bergljot; Gisladottir, Berglind; Jonsson, Zophonias O; Bragason, Birkir Th

    2012-02-01

    An acute phase response (APR) was experimentally induced in Atlantic cod (Gadus morhua L.) by intramuscular injection of turpentine oil. The change in the expression of immune related genes was monitored in the anterior kidney and the spleen over a period of 7 days. The genes examined were two types of pentraxins, apolipoprotein A1 (ApoA-I), the complement component C3, interleukin-1β (IL-1β), transferrin, cathelicidin, and hepcidin. All genes were constitutively expressed in both organs and their expression amplified by the turpentine injection. A pattern of response was observed both with respect to the organ preference and to the timing of a maximum response. The increased gene expression of the pentraxins, ApoA-I and C3 was restricted to the anterior kidney, the gene expression of IL-1β, cathelicidin, and transferrin increased in both organs, while hepcidin gene expression was only significantly increased in the spleen. The pentraxins and ApoA-I appear to be early mediators of APR in cod, possibly stimulating C3 and IL-1β response, while the antimicrobial peptides may play a minor role. The increase in transferrin gene expression in both organs, and apparent indifference to cortisol release associated with the turpentine injection, suggests that this could be a typical acute phase protein in cod.

  14. Effect of anabolic implants on adrenal cortisol synthesis in feedlot beef cattle implanted early or late in the finishing phase.

    PubMed

    Gifford, C A; Branham, K A; Ellison, J O; Gómez, B I; Lemley, C O; Hart, C G; Krehbiel, C R; Bernhard, B C; Maxwell, C L; Goad, C L; Hallford, D M; Hernandez Gifford, J A

    2015-01-01

    Implantation of anabolic steroids to increase growth rate in beef cattle impacts adrenal glucocorticoid production. The mechanism by which combination androgen and estrogen implants reduce cortisol biosynthesis in heifers is not clear. The objective of this study was to identify whether pituitary or adrenal gene expression and liver enzyme activity may contribute to altered serum cortisol concentrations in heifers receiving a combination implant. On d 0 of a 122-d finishing phase, 187 predominantly Angus heifers (361 kg) approximately 14 months old were randomly assigned to one of three implant groups: (1) non-implanted control, (2) implanted at the beginning of the finishing phase (d 0; early implant) with a combination implant (200mg TBA+20mg E2; Revalor 200®), and (3) implanted during the late stage of the finishing phase (d 56; late implant) with Revalor 200®. At d 56, body weight (BW) was greater (P<0.0001) for the early implanted heifers (456 ± 1.9 kg) compared to 437 and 435 (± 1.8) kg for control and late implanted heifers, respectively. Final BW (d 122) was similar between both implanted groups and heavier than non-implanted controls (P<0.0001). Serum cortisol was similar among groups at d 0 (P=0.86) however, by d 28 heifers receiving the combination implant had reduced (P<0.05) serum cortisol concentrations (31.2 ng/mL) compared to controls (49.4 ng/mL) and late (48.2 ng/mL) groups. On d 84 cortisol was similar (P=0.75) among implanted heifers and was less (P<0.01) than non-implanted heifers. Expression of pituitary and adrenal genes involved in glucocorticoid synthesis was evaluated at d 28/29 or 84/85; however, despite decreased serum cortisol in implanted heifers, no change in mRNA expression was demonstrated. Liver CYP3A enzyme activity at d 28/29 was decreased 59% in early implanted heifers compared to control heifers (P=0.01). Additionally, at d 84/85 AKR1C activity was greatest (P=0.01) in control heifers compared to both implanted groups. Data

  15. The role of Cajal bodies in the expression of late phase adenovirus proteins.

    PubMed

    James, Nicola J; Howell, Gareth J; Walker, John H; Blair, G Eric

    2010-04-10

    Cajal bodies (CBs) are subnuclear structures involved in RNA metabolism. Here we show that, following infection of HeLa cells by adenovirus type 5 (Ad5), CBs fragment and form ordered structures, which we have termed "rosettes". Formation of CB rosettes was prevented by inhibition of viral DNA synthesis and preceded expression of the L4-33K protein. CB rosettes localised to the periphery of E2A-72K-containing replication centers and to the edges of ASF/SF2 and hnRNP A1 ring structures that demarcate sites of viral transcription and splicing. At later times of infection, CB rosettes were undetectable. Furthermore, knock-down of p80-coilin (the major structural protein of CBs) by RNA interference reduced the yield of infectious Ad5 and expression of the late proteins IIIa (from L1), hexon (from L3) and fiber (from L5), whereas the E2A-72K protein was unaffected. We conclude that CBs have an important role in the expression of adenovirus major late gene products.

  16. Decrease in early right alpha band phase synchronization and late gamma band oscillations in processing syntax in music.

    PubMed

    Ruiz, María Herrojo; Koelsch, Stefan; Bhattacharya, Joydeep

    2009-04-01

    The present study investigated the neural correlates associated with the processing of music-syntactical irregularities as compared with regular syntactic structures in music. Previous studies reported an early ( approximately 200 ms) right anterior negative component (ERAN) by traditional event-related-potential analysis during music-syntactical irregularities, yet little is known about the underlying oscillatory and synchronization properties of brain responses which are supposed to play a crucial role in general cognition including music perception. First we showed that the ERAN was primarily represented by low frequency (<8 Hz) brain oscillations. Further, we found that music-syntactical irregularities as compared with music-syntactical regularities, were associated with (i) an early decrease in the alpha band (9-10 Hz) phase synchronization between right fronto-central and left temporal brain regions, and (ii) a late ( approximately 500 ms) decrease in gamma band (38-50 Hz) oscillations over fronto-central brain regions. These results indicate a weaker degree of long-range integration when the musical expectancy is violated. In summary, our results reveal neural mechanisms of music-syntactic processing that operate at different levels of cortical integration, ranging from early decrease in long-range alpha phase synchronization to late local gamma oscillations. 2008 Wiley-Liss, Inc.

  17. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

    PubMed

    Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

    2016-10-03

    Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INa inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

  18. Late-phase miRNA-controlled oncolytic adenovirus for selective killing of cancer cells

    PubMed Central

    Fillat, Cristina

    2015-01-01

    Tissue-specific detargeting by miRNAs has been demonstrated to be a potent strategy to restrict adenoviral replication to cancer cells. These studies have generated adenoviruses with miRNA target sites placed in the 3′UTR of early gene products. In this work, we have studied the feasibility of providing tissue-specific selectivity to replication-competent adenoviruses through the regulation of the late structural protein fiber (L5 gene). We have engineered a 3′UTR containing eight miR-148a binding sites downstream the L5 coding sequence (Ad-L5-8miR148aT). We present in vitro and in vivo evidences of Ad-L5-8miR148aT miRNA-dependent regulation. In vitro data show that at 72 hours post-infection miR-148a-regulation impaired fiber expression leading to a 70% reduction of viral release. The application of seven consecutive rounds of infection in miR-148a cells resulted in 10.000-fold reduction of viral genomes released. In vivo, liver production of infective viral particles was highly impaired, similarly to that triggered by an adenovirus with miRNA target sites regulating the early E1A gene. Noticeably, mice treated with Ad-L5-8miR148aT showed an attenuation of adenoviral-induced hepatotoxicity but retained full lytic activity in cancer cells and exhibited robust antitumoral responses in patient-derived xenografts. Thus, miRNA-control of late proteins constitutes a novel strategy to provide selectivity to adenoviruses. PMID:25714032

  19. Late stages of phase separation/gelation of isotropic solutions of rod-like polymers by video microscopy

    NASA Astrophysics Data System (ADS)

    Chowdhury, Aslam H.; Russo, Paul S.

    1990-05-01

    The late stages of phase separation/gelation in concentrated solutions of poly(γ-benzyl-α, L-glutamate) in N,N-dimethylformamide containing 2% added water have been observed by video optical microscopy. Microscopic phase separation is directly evident on cooling homogeneous, isotropic solutions. Within the phase separating mixture, diffuse structural features are separated from one another by a characteristic distance. Fourier transforms of the real space images, equivalent to scattering patterns, show a radially symmetric ring, which collapses to lower wave number as gelation proceeds. The wave number associated with the maximum intensity, qm, obeys a scaling relationship consistent with the Lifshitz-Slyozov evaporation/condensation model, also consistent with the Binder-Stauffer cluster dynamics model: qm=t-1/3, where t is time. A more general scaling relationship proposed by Furukawa is obeyed very well if the dimensionality of the growth of the new phases is 3. The advantages of video microscopy for such studies and possible implications for the role of spinodal decomposition in rod-like polymer solutions are discussed.

  20. A Custom Made Skeletal Class II Corrector Appliance in Late Adolescent Phase

    PubMed Central

    Tripathi, Tulika; Rai, Priyank; Kalra, Shilpa; Neha

    2017-01-01

    Skeletal Class II correction in deceleration phase of growth is both a challenge and dilemma with choice between extraction and myofunctional therapy. With marginal growth remaining the convenient choice is extraction for camouflage of the skeletal discrepancy. On the other hand, the treatment with Fixed Functional Appliances (FFAs) helps in resolution of the problem without sacrificing the dentition. However, the conventional FFAs requires a phase of alignment which results in further loss of time to utilize any remaining growth. The present report proposes the use of a novel custom made functional appliance for Class II skeletal correction which is simple to fabricate and convenient to use. PMID:28571289

  1. Apoptotic markers and DNA damage are related to late phase of stroke: Involvement of dyslipidemia and inflammation.

    PubMed

    Pascotini, Eduardo Tanuri; Flores, Ariane Ethur; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Algarve, Thais Doeler; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2015-11-01

    Oxidative stress and brain inflammation are thought to contribute to the pathophysiology of cerebral injury in acute stroke, leading to apoptosis and cell death. Lipid accumulation may lead to progression of carotid plaques and inflammation, contributing to increased acute stroke risk. However, little is known about these events and markers in the late stroke (>6 months) and if dyslipidemia could contribute to disease's pathophysiology in a later phase. In this case-control study, we recruited patients in the late stroke phase (n=40) and health subjects (control group; n = 40). Dichlorodihydrofluorescein (DCFH), nitrite/nitrate (NOx), Tumor necrosis factor-alpha (TNF-α), Acetylcholinesterase (AChE), Caspase 8 (CASP 8), Caspase 3 (CASP 3) and Picogreen (PG) were measured in periphery blood samples. Furthermore, a correlation among all measured markers (DCFH, NOx, TNF-α, AChE, CASP 8, CASP 3 and PG) was realized. The marker levels were also compared to triglycerides (TG), total (CHO), LDL and HDL cholesterol levels and medications used. Statistical analyses showed that stroke patients presented an increase of DCFH, NOx, TNF-α and AChE levels when compared to control subjects. In addition, we observed that stroke patients had significantly higher CASP 8, CASP 3 and PG levels than control group. A significant correlation between TNF-α with CASP 8 (r = 0.4) and CASP 3 (r = 0.4) levels was observed, but not with oxidative/nitrosative markers. Moreover, we observed that stroke patients with dyslipidemia had significantly higher TNF-α, CASP 8 and CASP 3 levels than stroke without dyslipidemia and control groups. Our findings suggest that oxidative and inflammatory markers may be still increased and lead to caspase activation and DNA damage even after 6 months to cerebral injury. Furthermore, it is plausible to propose that dyslipidemia may contribute to worsen proinflammatory state in a later phase of stroke and an increased risk to new neurovascular events.

  2. Radiocarbon dating of the Late Cycladic building and destruction phases at Akrotiri, Thera: New evidence

    NASA Astrophysics Data System (ADS)

    Maniatis, Yannis

    2012-01-01

    Akrotiri was a flourishing prehistoric settlement on the Cycladic island of Santorini (Thera) until its life was ended by a huge volcanic eruption in the LCI period. There is much debate as to when this final destruction occurred. Based on the Egyptian historical dating this happened around 1540-1530 BC, while, based on radiocarbon and other scientific data, around 1640-1600 BC. This work is an attempt to date with radiocarbon the whole settlement's life starting from the earlier phases of occupation but focusing in the sequence of the latest events. The samples, coming from the deep shafts dug in the site for the pillars of the new shelter, are pieces of wood and charcoal from house architectural elements and other constructions, including the final earthquake victims temporary camps. Therefore, the dates obtained represent the beginning of the different cultural phases plus the latest events. The results provide novel absolute dates for the commencement of the LMC and LCI Phases at Akrotiri, giving mean ranges around 1820-1790 BC and 1775-1722 BC, respectively, while the final destruction is dated around 1622-1548 BC. These results show that the LCI phase started about 100 years earlier than estimated with the Egyptian Historical chronology while the final destruction around 60 years or less earlier.

  3. Effects of early or late prenatal immune activation in mice on behavioral and neuroanatomical abnormalities relevant to schizophrenia in the adulthood.

    PubMed

    da Silveira, Vivian T; Medeiros, Daniel de Castro; Ropke, Jivago; Guidine, Patricia A; Rezende, Gustavo H; Moraes, Marcio Flavio D; Mendes, Eduardo Mazoni A M; Macedo, Danielle; Moreira, Fabricio A; de Oliveira, Antonio Carlos P

    2017-05-01

    Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

  4. Immune stress in late pregnant rats decreases length of gestation and fecundity, and alters later cognitive and affective behaviour of surviving pre-adolescent offspring

    PubMed Central

    PARIS, JASON J.; BRUNTON, PAULA J.; RUSSELL, JOHN A.; FRYE, CHERYL A.

    2012-01-01

    Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long–Evans rat dams were administered lipopolysaccharide [LPS; 30 μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1 μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17–21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28–30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring. PMID:21995525

  5. 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

    2016-01-06

    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.

  6. Interaction of menstrual cycle phase and sexual activity predicts mucosal and systemic humoral immunity in healthy women.

    PubMed

    Lorenz, Tierney K; Demas, Gregory E; Heiman, Julia R

    2015-12-01

    Several studies have documented shifts in humoral immune parameters (e.g., immunoglobulins) across the menstrual cycle in healthy women. It is thought that these shifts may reflect dynamic balancing between reproduction and pathogen defense, as certain aspects of humoral immunity may disrupt conception and may be temporarily downregulated at ovulation. If so, one could expect maximal cycle-related shifts of humoral immunity in individuals invested in reproduction - that is, women who are currently sexually active - and less pronounced shifts in women who are not reproductively active (i.e., abstinent). We investigated the interaction of sexual activity, menstrual cycle phase, and humoral immunity in a sample of 32 healthy premenopausal women (15 sexually active, 17 abstinent). Participants provided saliva samples during their menses, follicular phase, ovulation (as indicated by urine test for LH surge), and luteal phase, from which IgA was assayed. Participants also provided blood samples at menses and ovulation, from which IgG was assayed. Sexually active participants provided records of their frequency of sexual activity as well as condom use. At ovulation, sexually active women had higher IgG than abstinent women (d=0.77), with women reporting regular condom use showing larger effects (d=0.63) than women reporting no condom use (d=0.11). Frequency of sexual activity predicted changes in IgA (Cohen's f(2)=0.25), with women reporting high frequency of sexual activity showing a decrease in IgA at ovulation, while women reporting low frequency or no sexual activity showing an increase in IgA at ovulation. Taken together, these findings support the hypothesis that shifts in humoral immunity across the menstrual cycle are associated with reproductive effort, and could contribute to the mechanisms by which women's physiology navigates tradeoffs between reproduction and immunity.

  7. Interaction of menstrual cycle phase and sexual activity predicts mucosal and systemic humoral immunity in healthy women

    PubMed Central

    Lorenz, Tierney K.; Demas, Gregory E.; Heiman, Julia R.

    2015-01-01

    Several studies have documented shifts in humoral immune parameters (e.g., immunoglobulins) across the menstrual cycle in healthy women. It is thought that these shifts may reflect dynamic balancing between reproduction and pathogen defense, as certain aspects of humoral immunity may disrupt conception and may be temporarily downregulated at ovulation. If so, one could expect maximal cycle-related shifts of humoral immunity in individuals invested in reproduction – that is, women who are currently sexually active – and less pronounced shifts in women who are not reproductively active (i.e., abstinent). We investigated the interaction of sexual activity, menstrual cycle phase, and humoral immunity in a sample of 32 healthy premenopausal women (15 sexually active, 17 abstinent). Participants provided saliva samples during their menses, follicular phase, ovulation (as indicated by urine test for LH surge), and luteal phase, from which IgA was assayed. Participants also provided blood samples at menses and ovulation, from which IgG was assayed. Sexually active participants provided records of their frequency of sexual activity as well as condom use. At ovulation, sexually active women had higher IgG than abstinent women (d = 0.77), with women reporting regular condom use showing larger effects (d = 0.63) than women reporting no condom use (d = 0.11). Frequency of sexual activity predicted changes in IgA (Cohen’s f2 = 0.25), with women reporting high frequency of sexual activity showing a decrease in IgA at ovulation, while women reporting low frequency or no sexual activity showing an increase in IgA at ovulation. Taken together, these findings support the hypothesis that shifts in humoral immunity across the menstrual cycle are associated with reproductive effort, and could contribute to the mechanisms by which women’s physiology navigates tradeoffs between reproduction and immunity. PMID:26394125

  8. 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.

  9. Characterization of the Histopathologic Features in Patients in the Early and Late Phases of Cutaneous Leishmaniasis

    PubMed Central

    Saldanha, Maíra G.; Queiroz, Adriano; Machado, Paulo Roberto L.; de Carvalho, Lucas P.; Scott, Phillip; de Carvalho Filho, Edgar M.; Arruda, Sérgio

    2017-01-01

    Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical form of human leishmaniasis. Before the ulcer develops, patients infected with Leishmania (Viannia) braziliensis present a small papule at the site of the sandfly bite, referred to as early cutaneous leishmaniasis (E-CL). Two to four weeks later the typical ulcer develops, which is considered here as late CL (L-CL). Although there is a great deal known about T-cell responses in patients with L-CL, there is little information about the in situ inflammatory response in E-CL. Histological sections of skin biopsies from 15 E-CL and 28 L-CL patients were stained by hematoxilin and eosin to measure the area infiltrated by cells, as well as tissue necrosis. Leishmania braziliensis amastigotes, CD4+, CD8+, CD20+, and CD68+ cells were identified and quantified by immunohistochemistry. The number of amastigotes in E-CL was higher than in L-CL, and the inflammation area was larger in classical ulcers than in E-CL. There was no relationship between the number of parasites and magnitude of the inflammation area, or with the lesion size. However, there was a direct correlation between the number of macrophages and the lesion size in E-CL, and between the number of macrophages and necrotic area throughout the course of the disease. These positive correlations suggest that macrophages are directly involved in the pathology of L. braziliensis–induced lesions. PMID:28115669

  10. cAMP initiates early phase neuron-like morphology changes and late phase neural differentiation in mesenchymal stem cells

    PubMed Central

    Zhang, Linxia; Seitz, Linsey C.; Abramczyk, Amy M.; Liu, Li

    2010-01-01

    The intracellular second messenger cAMP is frequently used in induction media to induce mesenchymal stem cells (MSCs) into neural lineage cells. To date, an understanding of the role cAMP exerts on MSCs and whether cAMP can induce MSCs into functional neurons is still lacking. We found cAMP initiated neuron-like morphology changes early and neural differentiation much later. The early phase changes in morphology were due to cell shrinkage, which subsequently rendered some cells apoptotic. While the morphology changes occurred prior to the expression of neural markers, it is not required for neural marker expression and the two processes are differentially regulated downstream of cAMP-activated protein kinase A. cAMP enabled MSCs to gain neural marker expressions with neuronal function, such as, calcium rise in response to neuronal activators, dopamine, glutamate, and potassium chloride. However, only some of the cells induced by cAMP responded to the three neuronal activators and further lack the neuronal morphology, suggesting that although cAMP is able to direct MSCs towards neural differentiation, they do not achieve terminal differentiation. PMID:20725762

  11. 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

  12. Late-time vacuum phase transitions: Connecting sub-eV scale physics with cosmological structure formation

    NASA Astrophysics Data System (ADS)

    Patwardhan, Amol V.; Fuller, George M.

    2014-09-01

    We show that a particular class of postrecombination phase transitions in the vacuum can lead to localized overdense regions on relatively small scales, roughly 106 to 1010M⊙, potentially interesting for the origin of large black hole seeds and for dwarf galaxy evolution. Our study suggests that this mechanism could operate over a range of conditions which are consistent with current cosmological and laboratory bounds. One byproduct of phase transition bubble-wall decay may be extra radiation energy density. This could provide an avenue for constraint, but it could also help reconcile the discordant values of the present Hubble parameter (H0) and σ8 obtained by cosmic microwave background (CMB) fits and direct observational estimates. We also suggest ways in which future probes, including CMB considerations (e.g., early dark energy limits), 21-cm observations, and gravitational radiation limits, could provide more stringent constraints on this mechanism and the sub-eV scale beyond-standard-model physics, perhaps in the neutrino sector, on which it could be based. Late phase transitions associated with sterile neutrino mass and mixing may provide a way to reconcile cosmological limits and laboratory data, should a future disagreement arise.

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

    PubMed

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

    2016-08-25

    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.

  14. Late stage of the phase-separation process: coalescence-induced coalescence, gravitational sedimentation, and collective evaporation mechanisms.

    PubMed

    Kalwarczyk, Tomasz; Ziebacz, Natalia; Fiałkowski, Marcin; Hołyst, Robert

    2008-06-01

    We study the separation in the binary and ternary mixtures of the water/surfactant C12E5/polymer PEG system. The phase separation in the mixtures at late stages is governed by two distinct mechanisms: the coalescence-induced coalescence and the droplet evaporation mechanism. We show that when the coalescence-induced coalescence process is globally terminated in the sample consisting of a dense system of domains, another mechanism, which we call the collective droplet evaporation, starts to dominate. It manifests itself as a front of "evaporating" domains, which propagates at constant speed in the system. We show that the collective evaporation is induced by the gravitational drift of large droplets.

  15. 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.

  16. 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

  17. Flux rope, hyperbolic flux tube, and late extreme ultraviolet phases in a non-eruptive circular-ribbon flare

    NASA Astrophysics Data System (ADS)

    Masson, Sophie; Pariat, Étienne; Valori, Gherardo; Deng, Na; Liu, Chang; Wang, Haimin; Reid, Hamish

    2017-08-01

    Context. The dynamics of ultraviolet (UV) emissions during solar flares provides constraints on the physical mechanisms involved in the trigger and the evolution of flares. In particular it provides some information on the location of the reconnection sites and the associated magnetic fluxes. In this respect, confined flares are far less understood than eruptive flares generating coronal mass ejections. Aims: We present a detailed study of a confined circular flare dynamics associated with three UV late phases in order to understand more precisely which topological elements are present and how they constrain the dynamics of the flare. Methods: We perform a non-linear force-free field extrapolation of the confined flare observed with the Helioseismic and Magnetic Imager (HMI) and Atmospheric Imaging Assembly (AIA) instruments on board Solar Dynamics Observatory (SDO). From the 3D magnetic field we compute the squashing factor and we analyse its distribution. Conjointly, we analyse the AIA extreme ultraviolet (EUV) light curves and images in order to identify the post-flare loops, and their temporal and thermal evolution. By combining the two analyses we are able to propose a detailed scenario that explains the dynamics of the flare. Results: Our topological analysis shows that in addition to a null-point topology with the fan separatrix, the spine lines and its surrounding quasi-separatix layer (QSL) halo (typical for a circular flare), a flux rope and its hyperbolic flux tube (HFT) are enclosed below the null. By comparing the magnetic field topology and the EUV post-flare loops we obtain an almost perfect match between the footpoints of the separatrices and the EUV 1600 Å ribbons and between the HFT field line footpoints and bright spots observed inside the circular ribbons. We show, for the first time in a confined flare, that magnetic reconnection occurred initially at the HFT below the flux rope. Reconnection at the null point between the flux rope and the

  18. 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

  19. 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

  20. Interferon-related and other immune genes are downregulated in peripheral blood leukocytes in the luteal phase of the menstrual cycle.

    PubMed

    Dosiou, Chrysoula; Lathi, Ruth B; Tulac, Suzana; Huang, S-T Joseph; Giudice, Linda C

    2004-05-01

    Interaction between the endocrine and the immune systems has been suggested by observations of sexual dimorphism of the immune response, differential susceptibility to autoimmunity between the sexes, changes in autoimmune disease activity during the menstrual cycle and in pregnancy and in vitro studies of hormonal influence on cytokine production.We hypothesized that if there is hormonal regulation of the immune response, this would be manifest in peripheral blood leukocytes (PBLs) at different phases of the menstrual cycle. In this study, we describe gene profiling of PBLs from the follicular and luteal phases of the menstrual cycle. We observe important differences in immune gene expression, with significant down-regulation of the Th1 immune response in the luteal phase. A significant number of interferon (IFN)-related genes are amongst the downregulated genes. These results support significant hormonal regulation of the immune system and may have therapeutic implications in diseases of autoimmunity in women.

  1. Light and electron microscopic features of early and late phase radiation-induced proctitis

    SciTech Connect

    Haboubi, N.Y.; Schofield, P.F.; Rowland, P.L.

    1988-10-01

    The light and electron microscopic features of rectal biopsies from 10 symptomatic patients treated with irradiation for pelvic malignancies are detailed. They are divided into two groups. Group I: biopsies taken during or shortly after the course of irradiation (six patients). Group II: biopsies taken 4 months or more after course completion (four patients). The distinguishing light microscopic features in the first group are epithelial meganucleosis, lack of mitotic activity, and patchy fibroblastic proliferation in the lamina propria. The blood vessels appear normal. In the second group, there are severe vascular changes characterized by narrowing of the arterioles by subintimal fibrosis, telangiectasia of capillaries and post-capillary venules, endothelial degeneration, and platelet thrombi formation. These vascular changes are always associated with severe fibrosis of the lamina propria and crypt distortion. The ultrastructural and light microscopic findings indicate that the cellular epithelial reaction and fibroblastic proliferation antedate the vascular injury, and the latter has no role in the acute phase reaction.

  2. Serum IgE and IgG4 against muscle larva excretory-secretory products during the early and late phases of human trichinellosis.

    PubMed

    Calcagno, Marcela A; Forastiero, María A; Saracino, María P; Vila, Cecilia C; Venturiello, Stella M

    2017-09-20

    In human trichinellosis, the relevance of the presence and persistence of specific serum IgE and IgG4 during the early and late phases of infection is still controversial.The aim of this work was to determine the percentage of human sera presenting IgE and IgG4 against Trichinella spiralis muscle larvae excretory-secretory products as well as their levels during the early and late phases of the infection. The antigen recognition pattern by serum total immunoglobulins (IgGAM), IgE, and IgG4 was assessed over time. Serum samples during early and late phases were analyzed by ELISA and immunoelectrotransfer blot (IETB).Results showed that (a)-IgE and IgG4 are present at constant levels in both phases; (b)-IgE recognized the glycoproteins of ~ 45 and ~ 55 kDa and IgG4 only the ~ 45 kDa; (c)-in the late phase, the percentage of specific IgE positive sera was higher than that of specific IgG4 by IETB; while in serum samples taken during the early phase, no differences were found between both isotypes; (d)-both isotypes displayed different glycoprotein recognition patterns: the pattern corresponding to IgE was coincident with that of IgGAM, comprising seven glycoproteins (ranging from ~ 116 to ~ 29 kDa), whereas IgG4 revealed four glycoproteins (ranging from ~ 97 to ~ 45 kDa), showing a different sera recognition percentage depending on the phase studied.In conclusion, IgE and IgG4 cannot be considered exclusive isotypes of neither the early nor the late phase of infection and they are as useful as the detection of total antibodies in the early diagnosis.

  3. Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization

    PubMed Central

    Iseda, Sumire; Takahashi, Naofumi; Poplimont, Hugo; Nomura, Takushi; Seki, Sayuri; Nakane, Taku; Nakamura, Midori; Shi, Shoi; Ishii, Hiroshi; Furukawa, Shota; Harada, Shigeyoshi; Naruse, Taeko K.; Kimura, Akinori; Matano, Tetsuro

    2016-01-01

    ABSTRACT Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent in vivo studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8+ cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8+ cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)hi/phosphorylated AMP-activated protein kinase (AMPK)lo subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control. IMPORTANCE In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally

  4. 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)

  5. Contralateral limb deficit after ACL-reconstruction: an analysis of early and late phase of rate of force development.

    PubMed

    Mirkov, Dragan M; Knezevic, Olivera M; Maffiuletti, Nicola A; Kadija, Marko; Nedeljkovic, Aleksandar; Jaric, Slobodan

    2017-03-01

    The aim of this study was to assess the effect of a unilateral anterior cruciate ligament reconstruction (ACLR) on maximum voluntary contraction (MVC) and explosive strength of both the involved limb and the uninvolved limb. Nineteen male athletes completed a standard isometric testing protocol 4 months post-ACLR, while 16 healthy participants served as a control group (CG). The explosive strength of the knee extensors and flexors was assessed as RFD obtained from the slope of the force-time curves over various time intervals. Both muscle groups of the involved limb had significantly lower MVC compared to the uninvolved. The involved limb also had significantly lower RFD in the late phase of contraction (140-250 ms) for both knee extensors and flexors (P < 0.05). There was no difference in MVC between the uninvolved limb and the CG. However, RFD of the uninvolved limb was lower compared to CG for both knee extensors (0-180 ms; P < 0.01) and flexors (0-150 ms; P < 0.05). ACLR leads to lower MVC and explosive strength of the involved limb. As a consequence of potential crossover (presumably neural-mediated) effects, explosive strength deficits could be bilateral, particularly in the early phase of the contraction (<100 ms).

  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. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry

    PubMed Central

    Salmon, J H; Cacoub, P; Combe, B; Sibilia, J; Pallot-Prades, B; Fain, O; Cantagrel, A; Dougados, M; Andres, E; Meyer, O; Carli, P; Pertuiset, E; Pane, I; Maurier, F; Ravaud, P; Mariette, X; Gottenberg, J E

    2015-01-01

    Objectives To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. Methods The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. Results Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm3, 8 (20%) had neutrophils between 500 and 1000/mm3, and 26 (65%) had neutrophils between 1000 and 1500/mm3. Neutropenia occurred after a median period of 4.5 (3–6.5) months after the last RTX infusion in patients with RA, and 5 (3–6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm3, developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. Conclusions Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs. PMID:26509060

  8. Receptors for gonadotrophin and prostaglandin F2 alpha in bovine corpora lutea of early, mid and late luteal phase.

    PubMed

    Rao, C V; Estergreen, V L; Carman, F R; Moss, G E

    1979-07-01

    A total of 15 corpora lutea representing early (day 3), mid (day 13) and late luteal phase (day 20 and 21-24) were obtained by ovariectomy on cycling cows. The luteal weights and peripheral plasma progesterone levels just prior to ovariectomy, were consistent with the above luteal phases. The specific binding of [125I]human chorionic gonadotrophin to membranes prepared from corpora lutea was significantly higher (P less than 0.01) for days 13 and 20 than for days 3 and 21-24. The binding in day 21-24 corpora lutea was higher (P less than 0.01) than day 3. Although there was no different either in number or affinity (apparent dissociation constant (Kd) = 0.04 nM) of gonadotrophin receptors in days 13 and 20 corpora lutea, only in the former did the binding correlate well with plasma progesterone levels. The specific binding of [3H]prostaglanding (PG)F2 alpha to the membranes of the same corpora lutea showed a progressive increase (P less than 0.01) from day 3, reached the highest value at a time when corpora lutea were actively regressing (day 20) and the decline (P less than 0.01) by day 21-24. Although a considerable number of PGF2 alpha receptors existed at day 13, the affinity of these same receptors was 203 times lower (Kd = 3458 nM) than the affinity of receptors in day 20 corpora lutea (Kd = 17 nM). In summary, the above results show that gonadotrophin receptors correlate with luteotrophic, whereas PGF2 alpha receptors correlate with luteolytic phases in bovine corpora lutea.

  9. Timing of first-line cancer treatments - early versus late - a systematic review of phase III randomized trials.

    PubMed

    Mhaskar, A R; Quinn, G; Vadaparampil, S; Djulbegovic, B; Gwede, C K; Kumar, A

    2010-12-01

    To conduct a systematic review and meta-analysis of all phase III randomized controlled trials comparing efficacy of early versus late first-line or initial treatments for cancer. A comprehensive literature search of MEDLINE and Cochrane library databases was performed (1966-2008). Data was extracted and pooled as per the methods recommended by the Cochrane Collaboration. Of the 570 identified studies, 10 (3811 patients) met inclusion criteria: three each in prostate cancer and multiple myeloma (MM), two in chronic lymphocytic leukemia (CLL), and one each in lung cancer, and follicular lymphoma. The analyses showed no survival benefit with early treatment except in prostate cancer (hazard ratio [HR]=1.23, 95% CI 1.11-1.37 p<0.001). There was no survival difference in MM (HR=0.92, 95% CI 0.56-1.52 p=0.74), CLL (HR=0.76, 95% CI 0.56-1.04 p=0.09), lung cancer (HR=0.95, 95% CI 0.72-1.24 p=0.71), or follicular lymphoma (HR=1, 95% CI 0.55-1.83 p=0.99). No statistically significant difference in response rate between early and late treatment was detected in any cancer type. Data shows that delaying cancer treatments does not necessarily compromise therapeutic outcomes except possibly in locally advanced prostate cancer. These findings provide a unique window to oncologists and patients to address time-sensitive issues if desired by patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle.

    PubMed

    Oakes, Vanessa; Wang, Weili; Harrington, Brittney; Lee, Won Jae; Beamish, Heather; Chia, Kee Ming; Pinder, Alex; Goto, Hidemasa; Inagaki, Masaki; Pavey, Sandra; Gabrielli, Brian

    2014-01-01

    Whereas many components regulating the progression from S phase through G2 phase into mitosis have been identified, the mechanism by which these components control this critical cell cycle progression is still not fully elucidated. Cyclin A/Cdk2 has been shown to regulate the timing of Cyclin B/Cdk1 activation and progression into mitosis although the mechanism by which this occurs is only poorly understood. Here we show that depletion of Cyclin A or inhibition of Cdk2 during late S/early G2 phase maintains the G2 phase arrest by reducing Cdh1 transcript and protein levels, thereby stabilizing Claspin and maintaining elevated levels of activated Chk1 which contributes to the G2 phase observed. Interestingly, the Cyclin A/Cdk2 regulated APC/C(Cdh1) activity is selective for only a subset of Cdh1 targets including Claspin. Thus, a normal role for Cyclin A/Cdk2 during early G2 phase is to increase the level of Cdh1 which destabilises Claspin which in turn down regulates Chk1 activation to allow progression into mitosis. This mechanism links S phase exit with G2 phase transit into mitosis, provides a novel insight into the roles of Cyclin A/Cdk2 in G2 phase progression, and identifies a novel role for APC/C(Cdh1) in late S/G2 phase cell cycle progression.

  11. Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection

    PubMed Central

    Li, Fang; Sang, Jiao; Han, Qunying; Lv, Yi; Zhao, Wenxuan; Li, Chunyan; Liu, Zhengwen

    2017-01-01

    Programmed death-1 (PD-1) is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating soluble PD-1 (sPD-1) levels with the phases and clinical diseases in chronic HBV infection. Serum sPD-1 levels were determined by enzyme linked immunosorbent assay in patients with different phases and liver diseases of chronic HBV infection. The sPD-1 levels in patients with chronic HBV infection were significantly elevated compared with HBV infection resolvers or healthy controls. According to phases, sPD-1 level in immune-tolerant phase (IT) was significantly lower than in other phases. Multivariate analysis showed that sPD-1 was an independent factor associated with IT. Area under the receiver operating characteristic (ROC) curves (AUC) showed that sPD-1 was significantly discriminative of IT from other phases with a cut-off of 1.535 ng/mL (AUC, 0.984; P<0.001). According to clinical diseases, sPD-1 level in HBV-related HCC was significantly higher than in other clinical diseases. Multivariate analysis showed that sPD-1 was an independent factor associated with HCC. The sPD-1 was significantly discriminative of HCC from other clinical diseases with a cut-off of 6.058 ng/mL (AUC, 0.962; P<0.001). The sPD-1 levels were significantly associated with HCC patients’ overall survival. HCC resection resulted in remarkable reduction in sPD-1 levels. These results demonstrate the involvement of sPD-1 in the disease course of chronic HBV infection and indicate the potential to apply sPD-1 as a biomarker for differentiating IT from other phases and HCC from other disease conditions in chronic HBV infection. PMID:28545019

  12. Effect of pulsed electromagnetic fields (PEMF) on late-phase osteotomy gap healing in a canine tibial model.

    PubMed

    Inoue, Nozomu; Ohnishi, Isao; Chen, Dongan; Deitz, Luke W; Schwardt, Jeffrey D; Chao, Edmund Y S

    2002-09-01

    The effects of a pulsed electromagnetic field (PEMF) on late bone healing phases using an osteotomy gap model in the canine mid-tibia were investigated. A transverse mid-diaphyseal tibial osteotomy with a 2-mm gap was performed unilaterally in 12 adult mixed-breed dogs and stabilized with external fixation. Animals in the variable group (n = 6) were treated with PEMF for 1 h daily starting 4 weeks after surgery for a total of 8 weeks, whereas no stimulation signal was generated in the control group (n = 6). Functional load-bearing and radiographic assessments were conducted time-sequentially until euthanasia 12 weeks after surgery. Torsional tests and an analysis of undecalcified histology were performed on the retrieved mid-tibial diaphysis containing the osteotomy site. In the PEMF group, load-bearing of the operated limb recovered earlier when compared to the control group (p < 0.05). Load-bearing in the PEMF group at 8 weeks was greater than in the control group (p < 0.02). The periosteal callus area increased following surgery at 6 weeks (p < 0.05) and thereafter (p < 0.01) in the PEMF group, while a significant increase was observed at 8 and 10 weeks after surgery (p < 0.05) in the control group. Both the normalized maximum torque and torsional stiffness of the PEMF group were significantly greater than those of the control group (p < 0.04 and p < 0.007, respectively). Histomorphometric analyses revealed greater new-bone formation (p < 0.05) in the osteotomy gap tissue and increased mineral apposition rate (p < 0.04) and decreased porosity in the cortex adjacent to the osteotomy line (p < 0.02) in the PEMF group. PEMF stimulation of 1 h per day for 8 weeks provided faster recovery of load-bearing, a significant increase in new bone formation, and a higher mechanical strength of the healing mid-tibial osteotomy. This study revealed enhancing effects of PEMF on callus formation and maturation in the late-phase of bone healing.

  13. 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

  14. 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...

  15. 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...

  16. Reduced early and late phase insulin response to glucose in isolated spiny mouse (Acomys cahirinus) islets: a defective link between glycolysis and adenylate cyclase.

    PubMed

    Nesher, R; Abramovitch, E; Cerasi, E

    1989-09-01

    The spiny mouse (Acomys cahirinus) exhibits low insulin responsiveness to glucose with a nearly absent early phase release. The alternative fuel-secretagogue glyceraldehyde (10 mmol/l) produced a maximal early insulin response in rat islets but failed to affect early response in Acomys; however, it potentiated the late insulin response in both species alike. Glucagon (1.5 mumol/l) potentiated the early insulin response to intermediate (8.3 mmol/l) glucose in rat and Acomys islets by two- and four-fold, respectively. Glucose doubled cyclic AMP levels in rat islets but no significant response was noted in Acomys islets. Isobutylmethylxanthine (0.1 mmol/l) and forskolin (25 mumol/l) caused a significant rise in islet cyclic AMP levels in both types of islets; however, neither agent restored the glucose stimulation of cyclic AMP in spiny mouse islets. Forskolin and isobutylmethylxanthine potentiated early and late phase insulin release in both species; however, neither augmented the early response in the Acomys to the degree observed in rat islets. Thus: (1) A deficient link exists in Acomys between glycolysis and subsequent signals. (2) These islets contain a glucose-insensitive adenylate cyclase. (3) The early insulin response may be potentiated by direct activation of adenylate cyclase. (4) The glucose effects on early and late phase insulin release are probably mediated by distinct pathways. (5) In the spiny mouse the signals mediating the early response are deranged to a greater extent than those activating the late phase insulin release.

  17. 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...

  18. 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...

  19. FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice

    PubMed Central

    Ogawa, Yasuhiro; Sano, Takafumi; Irisa, Masahiro; Kodama, Takashi; Saito, Takahiro; Furusawa, Eiri; Kaizu, Katsutoshi; Yanagi, Yusuke; Tsukimura, Takahiro; Togawa, Tadayasu; Yamanaka, Shoji; Itoh, Kohji; Sakuraba, Hitoshi; Oishi, Kazuhiko

    2017-01-01

    Sandhoff disease (SD) is caused by the loss of β-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb−/− mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb−/− mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16–18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb−/−) were crossed to mice lacking an activating immune receptor (FcRγ−/−) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb−/− mice during the asymptomatic phase, and were inhibited in Hexb−/− FcRγ−/− mice. Moreover, early astrogliosis and impaired motor coordination in Hexb−/− mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD. PMID:28084424

  20. 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

  1. Social Isolation During Adolescence Strengthens Retention of Fear Memories and Facilitates Induction of Late-Phase Long-Term Potentiation.

    PubMed

    Liu, Ji-Hong; You, Qiang-Long; Wei, Mei-Dan; Wang, Qian; Luo, Zheng-Yi; Lin, Song; Huang, Lang; Li, Shu-Ji; Li, Xiao-Wen; Gao, Tian-Ming

    2015-12-01

    Social isolation during the vulnerable period of adolescence produces emotional dysregulation that often manifests as abnormal behavior in adulthood. The enduring consequence of isolation might be caused by a weakened ability to forget unpleasant memories. However, it remains unclear whether isolation affects unpleasant memories. To address this, we used a model of associative learning to induce the fear memories and evaluated the influence of isolation mice during adolescence on the subsequent retention of fear memories and its underlying cellular mechanisms. Following adolescent social isolation, we found that mice decreased their social interaction time and had an increase in anxiety-related behavior. Interestingly, when we assessed memory retention, we found that isolated mice were unable to forget aversive memories when tested 4 weeks after the original event. Consistent with this, we observed that a single train of high-frequency stimulation (HFS) enabled a late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of isolated mice, whereas only an early-phase LTP was observed with the same stimulation in the control mice. Social isolation during adolescence also increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and application of a tropomyosin-related kinase B (TrkB) receptor inhibitor ameliorated the facilitated L-LTP seen after isolation. Together, our results suggest that adolescent isolation may result in mental disorders during adulthood and that this may stem from an inability to forget the unpleasant memories via BDNF-mediated synaptic plasticity. These findings may give us a new strategy to prevent mental disorders caused by persistent unpleasant memories.

  2. BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn.

    PubMed

    Zhou, Li-Jun; Zhong, Yi; Ren, Wen-Jie; Li, Yong-Yong; Zhang, Tong; Liu, Xian-Guo

    2008-08-01

    Several lines of evidence have shown that in some brain regions brain-derived neurotrophic factor (BDNF) is important for long-term potentiation (LTP), a synaptic model of memory storage. In the present work we evaluate the role of BDNF in LTP of C-fiber evoked field potentials in spinal dorsal horn, a synaptic model of pain memory. We found that spinal application of BDNF-induced LTP of C-fiber evoked field potentials with a long latency, lasting for >8 h, and the effect was blocked by either tyrosine kinase inhibitor (K252a) or BNDF scavenger (TrkB-Fc). The potentiation produced by BDNF was occluded by late-phase LTP (L-LTP) but not by early-phase LTP (E-LTP) induced by electrical stimulation. Pretreatment of K252a or TrkB-Fc selectively blocked spinal L-LTP induced by low-frequency stimulation (LFS) but not E-LTP. BDNF-induced LTP was completely abolished by the protein synthesis inhibitor (anisomycin), by N-methyl-D-aspartate (NMDA) receptor blocker (MK-801), by extracellular signal-regulated protein kinase (ERK) inhibitor (PD98059) or by p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) but not by c-Jun N-terminal kinase (JNK) inhibitor (SP600125). Nuclear factor-kappaB (NF-kappaB) inhibitor (PDTC) also suppressed spinal BDNF-LTP. The results suggest that BDNF play a crucial role in protein synthesis-dependent L-LTP in spinal dorsal horn via activation of ERK, p38 MAPK and NF-kappaB signal pathways.

  3. Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation.

    PubMed

    Kaneko, Megumi; Xie, Yuxiang; An, Juan Ji; Stryker, Michael P; Xu, Baoji

    2012-04-04

    Sensory experience in early postnatal life shapes neuronal connections in the brain. Here we report that the local synthesis of brain-derived neurotrophic factor (BDNF) in dendrites plays an important role in this process. We found that dendritic spines of layer 2/3 pyramidal neurons of the visual cortex in mutant mice lacking dendritic Bdnf mRNA and thus local BDNF synthesis were normal at 3 weeks of age, but thinner, longer, and more closely spaced (morphological features of immaturity) at 4 months of age than in wild-type (WT) littermates. Layer 2/3 of the visual cortex in these mutant animals also had fewer GABAergic presynaptic terminals at both ages. The overall size and shape of dendritic arbors were, however, similar in mutant and WT mice at both ages. By using optical imaging of intrinsic signals and single-unit recordings, we found that mutant animals failed to recover cortical responsiveness following monocular deprivation (MD) during the critical period, although they displayed normally the competitive loss of responsiveness to an eye briefly deprived of vision. Furthermore, MD still induced a loss of responsiveness to the closed eye in adult mutant mice, but not in adult WT mice. These results indicate that dendritic BDNF synthesis is required for spine pruning, late-phase spine maturation, and recovery of cortical responsiveness following sensory deprivation. They also suggest that maturation of dendritic spines is required for the maintenance of cortical responsiveness following sensory deprivation in adulthood.

  4. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer.

    PubMed Central

    Adachi, I.; Watanabe, T.; Takashima, S.; Narabayashi, M.; Horikoshi, N.; Aoyama, H.; Taguchi, T.

    1996-01-01

    A late phase II clinical trial of RP56976 (docetaxel), derived from Taxus baccata was performed to evaluate anti-tumour activity, time to progression and clinical toxicity in patients with advanced or recurrent breast cancer. The patients, between 15 and 80 years old with performance status (PS) of 0-2, received at least two cycles of docetaxel 60 mg m-2 intravenously at 3-4 week intervals. Of the 81 patients enrolled, the 72 eligible for the study were given a total of 327 cycles, with a median of four cycles each. Five patients obtained a complete response (CR) and 27 a partial response (PR); the response rate (RR) was 44.4% (95% confidence interval 32.7-56.6%). A relatively high RR of 9/28 (32.1%) was observed in patients who had received prior chemotherapy involving anthracyclines. The dose-limiting toxicity was grade 3-4 leucocytopenia or neutropenia, found in 78.9% and 85.9% patients respectively. Other severe (grade > 3) toxicities included alopecia (38%), anorexia (18.3%), nausea/vomiting (11.3%), and fatigue (9.9%). Hypersensitivity reactions, oedema and skin toxicity were not severe and were reversible. One therapy-related death occurred 10 days after the initial dose was given. These findings indicate that docetaxel has potent activity against metastatic breast cancer, and that the dose of 60 mg m-2 is safe. PMID:8546908

  5. 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

  6. Extracellular and intracellular cleavages of proBDNF required at two distinct stages of late-phase LTP

    NASA Astrophysics Data System (ADS)

    Pang, Petti T.; Nagappan, Guhan; Guo, Wei; Lu, Bai

    2016-05-01

    Although late-phase long-term potentiation (L-LTP) is implicated in long-term memory, its molecular mechanisms are largely unknown. Here we provide evidence that L-LTP can be divided into two stages: an induction stage (I) and a maintenance stage (II). Both stages require mature brain-derived neurotrophic factor (mBDNF), but involve distinct underlying mechanisms. Stage I requires secretion of existing proBDNF followed by extracellular cleavage by tPA/plasmin. Stage II depends on newly synthesized BDNF. Surprisingly, mBDNF at stage II is derived from intracellular cleavage of proBDNF by furin/PC1. Moreover, stage I involves BDNF-TrkB signaling mainly through MAP kinase, whereas all three signaling pathways (phospholipase C-γ, PI3 kinase, and MAP kinase) are required for the maintenance of L-LTP at stage II. These results reveal the molecular basis for two temporally distinct stages in L-LTP, and provide insights on how BDNF modulates this long-lasting synaptic alternation at two critical time windows.

  7. 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

    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; Kawaoka, Yoshihiro

    2014-08-01

    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. 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 infection. We

  8. 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

  9. Plasmodium Oocysts: Overlooked Targets of Mosquito Immunity.

    PubMed

    Smith, Ryan C; Barillas-Mury, Carolina

    2016-12-01

    Although the ability of mosquitoes to limit Plasmodium infection is well documented, many questions remain as to how malaria parasites are recognized and killed by the mosquito host. Recent evidence suggests that anti-Plasmodium immunity is multimodal, with different immune mechanisms regulating ookinete and oocyst survival. However, most experiments determine the number of mature oocysts, without considering that different immune mechanisms may target different developmental stages of the parasite. Complement-like proteins have emerged as important determinants of early immunity targeting the ookinete stage, yet the mechanisms by which the mosquito late-phase immune response limits oocyst survival are less understood. Here, we describe the known components of the mosquito immune system that limit oocyst development, and provide insight into their possible mechanisms of action. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. 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

  11. Effects of maternal protein or energy restriction during late gestation on antioxidant status of plasma and immune tissues in postnatal goats.

    PubMed

    He, Z X; Sun, Z H; Tan, Z L; Tang, S X; Zhou, C S; Han, X F; Wang, M; Wu, D Q; Kang, J H; Beauchemin, K A

    2012-12-01

    Maternal malnutrition can have temporary or long-lasting effects on development and physiological function of offspring. Our objective was to investigate whether maternal protein or energy restriction in late gestation affects the antioxidant status of plasma, immune organs (thymus and spleen), and natural barrier organs (jejunum) in neonatal goats and whether the effects could be reversed after nutritional recovery. Forty-five pregnant goats (Liuyang Blacks) of similar age (2.0 ± 0.3 yr) and BW (22.2 ± 1.5 kg at d 90 of gestation) were assigned to 3 dietary treatments during late gestation: control (ME = 9.34 MJ/kg and CP = 12.5%, DM basis), 40% protein restricted (PR), and 40% energy restricted (ER) until parturition, after which offspring received the normal diet for nutritional recovery. Plasma and tissues of kids were sampled to determine antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and catalase (CAT)] and gene expression of antioxidant enzymes (Cu/Zn-SOD [SOD1], CAT, and peroxiredoxin 2 [PRDX2]). Maternal protein or energy restriction decreased (P < 0.05) SOD activities in plasma, liver, thymus, and spleen and SOD1 expression in thymus, and maternal energy restriction also decreased (P < 0.05) plasma GSH-Px activity and expressions of SOD1 and CAT in liver at birth. After nutritional recovery of 6 wk, SOD activities in thymus (both in PR and ER) and spleen (only in PR) were greater (P < 0.05), but CAT activity of thymus (both in PR and ER) and CAT expression (only in ER) were less (P < 0.01) than those in control. After nutritional recovery of 22 wk, SOD1 and PRDX2 expression in thymus (both in PR and ER) and SOD1 expression in liver (only in ER) were greater (P < 0.05) whereas CAT expression in thymus (both in PR and ER) was less (P < 0.001) than in control. The current results indicate that maternal protein or energy restriction can decrease the antioxidant capacity of the neonatal

  12. 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.

  13. 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.

  14. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer's disease.

    PubMed

    Lu, Qiongshi; Powles, Ryan L; Abdallah, Sarah; Ou, Derek; Wang, Qian; Hu, Yiming; Lu, Yisi; Liu, Wei; Li, Boyang; Mukherjee, Shubhabrata; Crane, Paul K; Zhao, Hongyu

    2017-07-01

    Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.

  15. Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding1234

    PubMed Central

    Ziemke, Florencia; Magkos, Faidon; Barrios, Fernando A; Brinkoetter, Mary; Boyd, Ingrid; Rifkin-Graboi, Anne; Yannakoulia, Mary; Rojas, Rafael; Pascual-Leone, Alvaro; Mantzoros, Christos S

    2011-01-01

    Background: Food intake fluctuates throughout the menstrual cycle; it is greater during the early follicular and luteal phases than in the late follicular (periovulatory) phase. Ovarian steroids can influence brain areas that process food-related information, but the specific contribution of individual hormones and the importance of the prandial state remain unknown. Objective: The objective was to examine whether brain activation during food visualization is affected by changes in estradiol concentration in the fasted and fed conditions. Design: Nine eumenorrheic, lean young women [mean (±SD) age: 26.2 ± 3.2 y; body mass index (in kg/m2): 22.4 ± 1.2] completed 2 visits, one in the early (low estradiol) and one in the late (high estradiol) follicular phase of their menstrual cycle. At each visit, subjects underwent functional magnetic resonance imaging while they viewed food and nonfood images, before and after a standardized meal. Region-of-interest analysis was used to examine the effect of follicular phase and prandial state on brain activation (food > nonfood contrast) and its association with estradiol concentration. Results: Differences were identified in the inferior frontal and fusiform gyri. In these areas, visualization of food elicited greater activation in the fed state than during fasting but only in the late follicular phase, when estradiol concentration was high. The change in estradiol concentration across the follicular phase (late minus early) was inversely correlated with the change in fusiform gyrus activation in the fasted state but not in the fed state. Conclusion: Our findings suggest that estradiol may reduce food intake by decreasing sensitivity to food cues in the ventral visual pathway under conditions of energy deprivation. This trial was registered at clinicaltrials.gov as NCT00130117. PMID:21593494

  16. Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding.

    PubMed

    Alonso-Alonso, Miguel; Ziemke, Florencia; Magkos, Faidon; Barrios, Fernando A; Brinkoetter, Mary; Boyd, Ingrid; Rifkin-Graboi, Anne; Yannakoulia, Mary; Rojas, Rafael; Pascual-Leone, Alvaro; Mantzoros, Christos S

    2011-08-01

    Food intake fluctuates throughout the menstrual cycle; it is greater during the early follicular and luteal phases than in the late follicular (periovulatory) phase. Ovarian steroids can influence brain areas that process food-related information, but the specific contribution of individual hormones and the importance of the prandial state remain unknown. The objective was to examine whether brain activation during food visualization is affected by changes in estradiol concentration in the fasted and fed conditions. Nine eumenorrheic, lean young women [mean (±SD) age: 26.2 ± 3.2 y; body mass index (in kg/m(2)): 22.4 ± 1.2] completed 2 visits, one in the early (low estradiol) and one in the late (high estradiol) follicular phase of their menstrual cycle. At each visit, subjects underwent functional magnetic resonance imaging while they viewed food and nonfood images, before and after a standardized meal. Region-of-interest analysis was used to examine the effect of follicular phase and prandial state on brain activation (food > nonfood contrast) and its association with estradiol concentration. Differences were identified in the inferior frontal and fusiform gyri. In these areas, visualization of food elicited greater activation in the fed state than during fasting but only in the late follicular phase, when estradiol concentration was high. The change in estradiol concentration across the follicular phase (late minus early) was inversely correlated with the change in fusiform gyrus activation in the fasted state but not in the fed state. Our findings suggest that estradiol may reduce food intake by decreasing sensitivity to food cues in the ventral visual pathway under conditions of energy deprivation. This trial was registered at clinicaltrials.gov as NCT00130117.

  17. Differential expression profiles of Streptococcus mutans ftf, gtf and vicR genes in the presence of dietary carbohydrates at early and late exponential growth phases.

    PubMed

    Shemesh, Moshe; Tam, Avshalom; Feldman, Mark; Steinberg, Doron

    2006-09-04

    Dental caries is one of the most common infectious diseases that affects humans. Streptococcus mutans, the main pathogenic bacterium associated with dental caries, produces a number of extracellular sucrose-metabolizing enzymes, such as glucosyltransferases (GTFB, GTFC and GTFD) and fructosyltransferase (FTF). The cooperative action of these enzymes is essential for sucrose-dependent cellular adhesion and biofilm formation. A global response regulator (vicR) plays important roles in S. mutans ftf and gtf expression in response to a variety of stimuli. A real-time reverse-transcription polymerase chain-reaction was used to quantify the relative levels of ftf, gtfB, gtfC, gtfD and vicR transcription of S. mutans in the presence of various dietary carbohydrates: sucrose, D-glucose, D-fructose, D-glucitol (D-sorbitol), D-mannitol and xylitol. Ftf was highly expressed at late exponential phase in the presence of sorbitol and mannitol. GtfB was highly expressed in the presence of all the above carbohydrates except for xylitol at early exponential growth phase and glucose and fructose at late exponential growth phase. Similar to gtfB, the expression of gtfC was also induced with the presence of all the tested carbohydrates except for xylitol at early growth and glucose and fructose at late exponential phase. In addition, no effect of mannitol on gtfC expression at early exponential phase was observed. GtfD was less influenced compared to the gtfB and gtfC, demonstrating enhanced expression especially in the presence of sorbitol, glucose, mannitol and xylitol at early exponential phase and mannitol at late exponential phase. VicR expression was induced only at the presence of xylitol at late exponential phase, and a decrease in expression was recorded at early exponential phase. Our findings show that dietary carbohydrates have a major influence on the transcription of ftf, gtfB, gtfC and gtfD, but less on vicR. Sorbitol and mannitol, which are considered as noncariogenic

  18. Effect of a synthetic appeasing pheromone on behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs.

    PubMed

    Siracusa, Carlo; Manteca, Xavier; Cuenca, Rafaela; del Mar Alcalá, Maria; Alba, Aurora; Lavín, Santiago; Pastor, Josep

    2010-09-15

    To study the effects of a synthetic, dog-appeasing pheromone (sDAP) on the behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs undergoing elective orchiectomy or ovariohysterectomy. Randomized, controlled clinical trial. 46 dogs housed in animal shelters and undergoing elective orchiectomy or ovariohysterectomy. Intensive care unit cages were sprayed with sDAP solution or sham treated with the carrier used in the solution 20 minutes prior to use. Dogs (n = 24 and 22 in the sDAP and sham treatment exposure groups, respectively) were placed in treated cages for 30 minutes before and after surgery. Indicators of stress (ie, alterations in behavioral, neuroendocrine, immune, and acute-phase responses) were evaluated perioperatively. Behavioral response variables, salivary cortisol concentration, WBC count, and serum concentrations of glucose, prolactin, haptoglobin, and C-reactive protein were analyzed. Behavioral response variables and serum prolactin concentration were influenced by sDAP exposure. Dogs exposed to sDAP were more likely to have alertness and visual exploration behaviors after surgery than were dogs exposed to sham treatment. Decreases in serum prolactin concentrations in response to perioperative stress were significantly smaller in dogs exposed to sDAP, compared with findings in dogs exposed to the sham treatment. Variables examined to evaluate the hypothalamic-pituitary-adrenal axis, immune system, and acute-phase responses were unaffected by treatment. sDAP appeared to affect behavioral and neuroendocrine perioperative stress responses by modification of lactotropic axis activity. Use of sDAP in a clinical setting may improve the recovery and welfare of dogs undergoing surgery.

  19. 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

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

    PubMed

    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

    2016-03-01

    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. 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. 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. 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.

  1. Impaired error processing in late-phase psychosis: Four-year stability and relationships with negative symptoms.

    PubMed

    Foti, Dan; Perlman, Greg; Hajcak, Greg; Mohanty, Aprajita; Jackson, Felicia; Kotov, Roman

    2016-10-01

    Error processing is impaired in psychosis, and numerous event-related potential studies have found reductions in the error-related negativity (ERN) and, more recently, the error positivity (Pe). The stability of reduced ERN/Pe in psychosis, however, is unknown. In a previous cross-sectional report, reduced ERN was associated with negative symptom severity and reduced Pe with a diagnosis of schizophrenia versus other psychosis. Here, we test the stability of impaired error processing over a four-year follow-up and relationships with subdimensions of negative symptoms. The ERN and Pe were recorded from individuals with psychotic disorders twice: 79 individuals were assessed 15years after first hospitalization, and 69 were assessed at 19years; 59 (26 with schizophrenia, 33 with other psychotic disorders) had data at both assessments. At 19years the Pe was blunted in schizophrenia. The ERN and Pe exhibited temporal stability over the four years (r=0.59 and 0.60, respectively). Reduced ERN and Pe correlated with the negative symptom subdimensions of inexpressivity and avolition, respectively, and not with psychotic or disorganized symptoms. Moreover, 15-year ERN predicted an increase in inexpressivity by year 19. No evidence was found for the reverse: negative symptoms did not predict change in ERN/Pe. Similar to non-clinical samples, the ERN and Pe show impressive four-year stability in late-phase psychosis. The ERN and Pe are promising neural measures for capturing individual differences in psychotic disorders, particularly with regard to negative symptomatology. They may prove to be useful clinically for forecasting illness course and as treatment targets.

  2. The fetal sheep lung does not respond to cortisol infusion during the late canalicular phase of development

    PubMed Central

    McGillick, Erin V; Orgeig, Sandra; McMillen, I Caroline; Morrison, Janna L

    2013-01-01

    The prepartum surge in plasma cortisol concentrations in humans and sheep promotes fetal lung and surfactant system maturation in the support of air breathing after birth. This physiological process has been used to enhance lung maturation in the preterm fetus using maternal administration of betamethasone in the clinical setting in fetuses as young as 24 weeks gestation (term = 40 weeks). Here, we have investigated the impact of fetal intravenous cortisol infusion during the canalicular phase of lung development (from 109- to 116-days gestation, term = 150 ± 3 days) on the expression of genes regulating glucocorticoid (GC) activity, lung liquid reabsorption, and surfactant maturation in the very preterm sheep fetus and compared this to their expression near term. Cortisol infusion had no impact on mRNA expression of the corticosteroid receptors (GC receptor and mineralocorticoid receptor) or HSD11B-2, however, there was increased expression of HSD11B-1 in the fetal lung. Despite this, cortisol infusion had no effect on the expression of genes involved in lung sodium (epithelial sodium channel -α, -β, or -γ subunits and sodium–potassium ATPase-β1 subunit) or water (aquaporin 1, 3, and 5) reabsorption when compared to the level of expression during exposure to the normal prepartum cortisol surge. Furthermore, in comparison to late gestation, cortisol infusion does not increase mRNA expression of surfactant proteins (SFTP-A, -B, and -C) or the number of SFTP-B-positive cells present in the alveolar epithelium, the cells that produce pulmonary surfactant. These data suggest that there may be an age before which the lung is unable to respond biochemically to an increase in fetal plasma cortisol concentrations. PMID:24400136

  3. Left Atrial Late Gadolinium Enhancement with Water-Fat Separation: the Importance of Phase-encoding Order

    PubMed Central

    Shaw, Jaime L.; Knowles, Benjamin R.; Goldfarb, James W.; Manning, Warren J.; Peters, Dana C.

    2014-01-01

    Purpose To compare two late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) methods: a Dixon LGE sequence with sequential phase-encoding order, reconstructed using water-fat separation, and standard fat-saturated LGE. Materials and Methods We have implemented a dual-echo Dixon LGE method for reconstructing water-only images, and compared it to fat-saturated LGE in twelve patients prior to their first pulmonary vein isolation (PVI) procedure. Images were analyzed for quality and fat-suppression. Regions of the left atrium were evaluated by a blinded observer (1=prominent enhancement, 0=mild or absent enhancement) on two sets of images (fat-saturated and water-only LGE), and agreement was assessed. Results Water-only LGE showed a trend toward better fat-suppression (p=0.06), with a significantly more homogeneous blood pool signal and reduced inflow artifacts (both p<0.01). Agreement between fat-saturated LGE and water-only methods was found in 84% of regions, significantly correlated by chi-squared test (p<0.001). The kappa value was 0.52 (moderate). The average number of enhancing segments was higher for fat-saturated LGE than water-only LGE (4.2 ±2.7 vs. 3.2±2.9, p=0.03). Conclusion The two-point Dixon LGE technique reduces artifacts due to a centric k-space order. A similar enhancement pattern was observed irrespective of the LGE technique, with more enhancement detected by fat-saturated LGE. PMID:24105717

  4. Left atrial late gadolinium enhancement with water-fat separation: the importance of phase-encoding order.

    PubMed

    Shaw, Jaime L; Knowles, Benjamin R; Goldfarb, James W; Manning, Warren J; Peters, Dana C

    2014-07-01

    To compare two late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) methods: a Dixon LGE sequence with sequential phase-encoding order, reconstructed using water-fat separation, and standard fat-saturated LGE. We implemented a dual-echo Dixon LGE method for reconstructing water-only images and compared it to fat-saturated LGE in 12 patients prior to their first pulmonary vein isolation (PVI) procedure. Images were analyzed for quality and fat-suppression. Regions of the left atrium were evaluated by a blinded observer (1 = prominent enhancement, 0 = mild or absent enhancement) on two sets of images (fat-saturated and water-only LGE) and agreement was assessed. Water-only LGE showed a trend toward better fat-suppression (P = 0.06), with a significantly more homogeneous blood pool signal and reduced inflow artifacts (both P < 0.01). Agreement between fat-saturated LGE and water-only methods was found in 84% of regions, significantly correlated by chi-squared test (P < 0.001). The kappa value was 0.52 (moderate). The average number of enhancing segments was higher for fat-saturated LGE than water-only LGE (4.2 ± 2.7 vs. 3.2 ± 2.9, P = 0.03). The two-point Dixon LGE technique reduces artifacts due to a centric k-space order. A similar enhancement pattern was observed irrespective of the LGE technique, with more enhancement detected by fat-saturated LGE. © 2013 Wiley Periodicals, Inc.

  5. Changes in cervical range of motion and sagittal alignment in early and late phases after total disc replacement: radiographic follow-up exceeding 2 years.

    PubMed

    Ahn, Poong-Gi; Kim, Keung Nyun; Moon, Sung Whan; Kim, Keun Su

    2009-12-01

    This was a retrospective clinical study in which the follow-up period exceeded 2 years. The authors investigated the time course of radiographic changes in the cervical range of motion (ROM) and sagittal alignment after cervical total disc replacement involving the ProDisc-C artificial disc. Eighteen patients who underwent C5-6 total disc replacement were followed for an average of 27 months. Cervical neutral and flexion-extension lateral radiographs were obtained before and at 1 and 3 months after surgery for early-phase observations and at the last follow-up for late-phase observation. Segmental ROM values in the treated, superior, and inferior adjacent segments were measured. For whole-neck motion, C2-7 ROM was also measured. The percentage contributions of ROM at functional and adjacent segments to whole-neck motion were calculated. For evaluating sagittal alignment, C2-7 and C5-6 Cobb angles were measured. All data from ProDisc-C arthroplasty were compared with the results obtained in 22 patients who underwent C5-6 interbody fusion in which a Solis cage was used and who were followed for an average of 25 months. In the ProDisc-C group, C2-7 and C5-6 ROM significantly decreased in the early phase after surgery and returned to preoperative levels in the late phase. Both superior and inferior adjacent segments showed significantly decreased ROM in the acute phase after surgery and returned to the preoperative values in the late phase. In terms of contributions to whole-neck motion, the ROM of the functional and adjacent segments did not change significantly compared with the preoperative ROM. In the cage group, C2-7 ROM was also significantly decreased in the early phase after surgery and returned to preoperative levels at the late phase. Both superior and inferior adjacent segments exhibited significantly increased ROM and percentage contributions to whole-neck motion in the early and late phases. Sagittal alignment of the whole cervical spine became

  6. Modulation by enteral nutrition of the acute phase response and immune functions.

    PubMed

    Bengmark, Stig

    2003-01-01

    To use nutrition in order to limit the negative consequences of physical and mental stress is not new. Recent advances in immunology and particularly in the understanding of the chemical language used to communicate both by eukarytic and prokarotic cells has made it easier to objectively evaluate effects of various immunomodulating efforts including the use of nutrients, vitamins and antioxidants in preventing or limiting the development of disease and its late consequences.

  7. Maternal immune activation in late gestation enhances locomotor response to acute but not chronic amphetamine treatment in male mice offspring: role of the D1 receptor.

    PubMed

    Zager, Adriano; Mennecier, Gregory; Palermo-Neto, João

    2012-06-15

    Exposure to elevated levels of maternal cytokines can lead to functional abnormalities of the dopaminergic system in the adult offspring, including enhanced amphetamine (AMPH)-induced locomotion. Therefore, it seems reasonable to consider that offspring of challenged mothers would behave differently in models of addictive behavior, such as behavioral sensitization. Thus, we sought to evaluate the effects of prenatal exposure to lipopolysaccharide (LPS) on the locomotor response to acute and chronic AMPH treatment in male mice offspring. For this purpose, LPS (Escherichia coli 0127:B8; 120 μg/kg) was administered intraperitoneally to pregnant Swiss mice on gestational day 17. At adulthood, male offspring were studied under one of the following conditions: (1) locomotor response to acute AMPH treatment (2.5 or 5.0 mg/kg) in an open field test; (2) behavioral sensitization paradigm, which consists of a daily injection of AMPH (1.0 mg/kg) for 10 days and observation of locomotion in the open field on days 1, 5, 10 (development phase), 15 and 17 (expression phase). The LPS stimulated offspring showed enhancement of the locomotor-stimulant effect after an acute AMPH challenge in comparison to baseline and saline pre-treated mice. They also showed development of behavioral sensitization earlier than the saline pre-treated group, although no changes between saline and LPS pre-treated groups were observed on development or expression of locomotor behavioral sensitization to AMPH. Furthermore, there was up-regulation of D1 receptor protein level within striatum in the LPS-stimulated offspring which was strongly correlated with increased grooming behavior. Taken together, our results indicate that motor and dopaminergic alterations caused by maternal immune activation are restricted to the acute AMPH challenge, mostly due to up-regulation of the D1 receptor within the mesolimbic and nigrostriatal pathways, but no locomotor differences were observed for behavioral

  8. Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer.

    PubMed

    Parkes, Eileen E; Walker, Steven M; Taggart, Laura E; McCabe, Nuala; Knight, Laura A; Wilkinson, Richard; McCloskey, Karen D; Buckley, Niamh E; Savage, Kienan I; Salto-Tellez, Manuel; McQuaid, Stephen; Harte, Mary T; Mullan, Paul B; Harkin, D Paul; Kennedy, Richard D

    2017-01-01

    Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher's exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response-proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response-proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle-specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification

  9. Peroxisome Proliferator Activated Receptor Beta (PPARβ) activity increases the immune response and shortens the early phases of skeletal muscle regeneration.

    PubMed

    Mothe-Satney, Isabelle; Piquet, Jessica; Murdaca, Joseph; Sibille, Brigitte; Grimaldi, Paul A; Neels, Jaap G; Rousseau, Anne-Sophie

    2016-12-07

    Peroxisome Proliferator-Activated Receptor Beta (PPARβ) is a transcription factor playing an important role in both muscle myogenesis and remodeling, and in inflammation. However, its role in the coordination of the transient muscle inflammation and reparation process following muscle injury has not yet been fully determined. We postulated that activation of the PPARβ pathway alters the early phase of the muscle regeneration process, i.e. when immune cells infiltrate in injured muscle. Tibialis anteriors of C57BL6/J mice treated or not with the PPARβ agonist GW0742 were injected with cardiotoxin (or with physiological serum for the contralateral muscle). Muscle regeneration was monitored on days 4, 7, and 14 post-injury. We found that treatment of mice with GW0742 increased, at day 4 post-damage, the recruitment of immune cells (M1 and M2 macrophages) and upregulated the expression of the anti-inflammatory cytokine IL-10 and TGF-β mRNA. Those effects were accompanied by a significant increase at day 4 of myogenic regulatory factors (Pax7, MyoD, Myf5, Myogenin) mRNA in GW0742-treated mice. However, we showed an earlier return (7 days vs 14 days) of Myf5 and Myogenin to basal levels in GW0742- compared to DMSO-treated mice. Differential effects of GW0742 observed during the regeneration were associated with variations of PPARβ pathway activity. Collectively, our findings indicate that PPARβ pathway activity shortens the early phases of skeletal muscle regeneration by increasing the immune response.

  10. The Origin of the EUV Late Phase: A Case Study of the C8.8 Flare on 2010 May 5

    NASA Technical Reports Server (NTRS)

    Hock, R. A.; Woods, T. N.; Klimchuk, J. A.; Eparvier, F. G.; Jones, A. R.

    2012-01-01

    Since the launch of NASA's Solar Dynamics Observatory on 2010 February 11, the Extreme ultraviolet Variability Experiment (EVE) has observed numerous flares. One interesting feature observed by EVE is that a subset of flares exhibit an additional enhancement of the 2-3 million K emission several hours after the flares soft X-ray emission. From the Atmospheric Imaging Assembly (AIA) images, we observe that this secondary emission, dubbed the EUV late phase, occurs in the same active region as the flare but not in the same coronal loops. Here, we examine the C8.8 flare that occurred on 2010 May 5 as a case study of EUV late phase flares. In addition to presenting detailed observations from both AIA and EVE, we develop a physical model of this flare and test it using the Enthalpy Based Thermal Evolution of Loops (EBTEL) model.

  11. Comparison of methods for measuring viable E. coli cells during cultivation: great differences in the early and late exponential growth phases.

    PubMed

    Wang, Hengwei; Cheng, Hairong; Wei, Dongzhi; Wang, Fengqing

    2011-01-01

    Four methods, namely enumeration of colony-forming units (CFU), aerobic respiration, MTT reduction capacity and succinate dehydrogenase activity were compared to determine the viability of E. coli cells at the early and late exponential growth phases. Our results revealed that great differences in cell viability existed between these methods and that the choice of method to determine cell viability must be made with caution.

  12. Association of apoptosis of neutrophils and eosinophils and their ingestion by macrophages with resolution of the allergen-induced cutaneous late-phase response in atopic human subjects.

    PubMed

    Ying, S; Meng, Q; Taborda-Barata, L; Kay, A B

    1997-01-01

    The allergen-induced cutaneous late-phase response serves as a model of allergic inflammation and is associated with infiltration of neutrophils, eosinophils, T cells, and macrophages. The mechanisms controlling the resolution of allergic inflammatory processes and the fate of infiltrating cells are uncertain. We observed that both the magnitude of the late-phase response and the numbers of infiltrating neutrophils and eosinophils peaked at 6 hr, persisted for 48 hr, but resolved completely by 7 days. In contrast, T-cell and macrophage numbers peaked between 24 and 72 hr after allergen challenge and persisted for up to 7 days. By using the techniques of terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine 5'-triphosphate (dUTP) nickend-labeling (TUNEL) and by combining TUNEL with immunohistochemistry, we tested the hypothesis that the resolution of the late-phase response is associated with apoptosis of neutrophils and eosinophils, with subsequent engulfment of apoptotic cells and apoptotic bodies by tissue macrophages. As the cutaneous late-phase response resolved, there was a progressive increase (peaking at 72 hr) in the total numbers of TUNEL-positive (TUNEL+) cells and in the numbers of macrophages that had engulfed apoptotic cells and bodies. The majority of TUNEL+ cells were identified as neutrophils and eosinophils. In contrast, very little apoptosis was associated with T cells or macrophages. These experiments represent a novel demonstration of cell type-specific apoptosis in vivo in human allergic inflammatory tissue and suggest that phagocytosis by macrophages of apoptotic neutrophils and eosinophils may be a mechanism that regulates resolution of the atopic allergic inflammatory response.

  13. Association of Immune Response to Endothelial Cell Growth Factor With Early Disseminated and Late Manifestations of Lyme Disease but Not Posttreatment Lyme Disease Syndrome

    PubMed Central

    Tang, Kevin S.; Klempner, Mark S.; Wormser, Gary P.; Marques, Adriana R.; Alaedini, Armin

    2015-01-01

    Endothelial cell growth factor has been recently proposed as a potential autoantigen in manifestations of Lyme disease that are thought to involve immune-mediated mechanisms. Our findings indicate that a humoral immune response to this protein is not associated with posttreatment Lyme disease syndrome. PMID:26219695

  14. 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.

  15. Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

    PubMed

    Akram, Afia Muhammad; Iqbal, Zafar; Akhtar, Tanveer; Khalid, Ahmed Mukhtar; Sabar, Muhammad Farooq; Qazi, Mahmood Hussain; Aziz, Zeba; Sajid, Nadia; Aleem, Aamer; Rasool, Mahmood; Asif, Muhammad; Aloraibi, Saleh; Aljamaan, Khaled; Iqbal, Mudassar

    2017-02-21

    BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was employed for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which eight (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 years respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KD mutation screening in late chronic phase CML patients for improved clinical management of disease.

  16. 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.

  17. Innate immune-stimulatory activity of Porphyromonas gingivalis fimbriae is eliminated by phase separation using Triton X-114.

    PubMed

    Nozoe, Kohji; Sanui, Terukazu; Takeshita, Masaaki; Fukuda, Takao; Haraguchi, Akira; Aida, Yoshitomi; Nishimura, Fusanori

    2017-02-01

    Fimbriae are virulence factors of Porphyromonas gingivalis (P. gingivalis). In this study, the action of fimbriae on neutrophil respiratory burst and cytokine production by mononuclear cells (MNC) were investigated. Native or denatured form of purified P. gingivalis fimbriae contained endotoxin at an equivalence of 1-3μglipopolysaccharides(LPS)/mg protein. The endotoxin could be reduced to the equivalent of 1ng-LPS/mg protein by phase separation using Triton X-114. Unfractionated fimbriae caused serum-dependent priming of neutrophils for enhanced respiratory burst, but both native and denatured forms of Triton X-114-fractionated fimbriae were not active at 100μg/mL. Unfractionated fimbriae induced serum-dependent production of IL-1β by MNC. Triton X-114-fractionated fimbriae (10μg/mL)-induced production of IL-1β, IL-8 or TNF-α was much lower than that induced by unfractionated fimbriae or 10ng/mL P. gingivalis-LPS preparation. Triton X-114-fractionated fimbriae immobilized on polystyrene tubes induced adhesion-stimulated superoxide release by LPS-primed neutrophils in a β2 integrin-dependent manner. P. gingivalis cells caused priming of neutrophils; however, Toll-like receptor (TLR) 4 antagonists did not affect this response. Thus, P. gingivalis fimbriae were ineffective in inducing innate immune response in leukocytes; however, they induced β2 integrin-mediated response by neutrophils. Immune-stimulatory components of P. gingivalis might be recognized by receptors other than TLR4.

  18. CD8 single-cell gene coexpression reveals three different effector types present at distinct phases of the immune response

    PubMed Central

    Peixoto, António; Evaristo, César; Munitic, Ivana; Monteiro, Marta; Charbit, Alain; Rocha, Benedita; Veiga-Fernandes, Henrique

    2007-01-01

    To study in vivo CD8 T cell differentiation, we quantified the coexpression of multiple genes in single cells throughout immune responses. After in vitro activation, CD8 T cells rapidly express effector molecules and cease their expression when the antigen is removed. Gene behavior after in vivo activation, in contrast, was quite heterogeneous. Different mRNAs were induced at very different time points of the response, were transcribed during different time periods, and could decline or persist independently of the antigen load. Consequently, distinct gene coexpression patterns/different cell types were generated at the various phases of the immune responses. During primary stimulation, inflammatory molecules were induced and down-regulated shortly after activation, generating early cells that only mediated inflammation. Cytotoxic T cells were generated at the peak of the primary response, when individual cells simultaneously expressed multiple killer molecules, whereas memory cells lost killer capacity because they no longer coexpressed killer genes. Surprisingly, during secondary responses gene transcription became permanent. Secondary cells recovered after antigen elimination were more efficient killers than cytotoxic T cells present at the peak of the primary response. Thus, primary responses produced two transient effector types. However, after boosting, CD8 T cells differentiate into long-lived killer cells that persist in vivo in the absence of antigen. PMID:17485515

  19. 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

  20. Solid-phase immune electron microscopy with human immunoglobulin M for serotyping of Norwalk-like viruses.

    PubMed Central

    Lewis, D C; Lightfoot, N F; Pether, J V

    1988-01-01

    A solid-phase immune electron microscopy method that uses protein A, goat anti-human immunoglobulin M (IgM), and human serum is described. Evaluation of the method with different immunoglobulin fractions showed that human IgM constituted the major virus capture antibody. The method appeared to distinguish between two Norwalk-like virus serotypes and demonstrated specific IgM responses to these serotypes in infected individuals. Further work is being carried out to define the relationship of these two serotypes to the previously described Norwalk agent (A. Z. Kapikian, R. G. Wyatt, R. Dolin, T. S. Thornhill, A. R. Kalica, and R. M. Chanock, J. Virol. 10:1075-1081, 1972), and four subsequent hospital outbreaks are being studied. PMID:2838506

  1. Tumor Necrosis Factor-α-induced Protein 8-like 2 (TIPE2) is associated with immune phases of patients with chronic hepatitis B.

    PubMed

    Fan, Yu-Chen; Zhang, Yuan-Yuan; Wang, Na; Sun, Yan-Yan; Wang, Kai

    2017-02-24

    Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a newly negative immune regulator but its role in different immune phases of patients with chronic hepatitis B (CHB) is unknown. We determined the mRNA levels of TIPE2, interleukin-6, interleukin-10, tumor necrosis factors-α and interferon-γ in peripheral blood mononuclear cells from 205 naïve treated CHB patients and 15 healthy controls by quantitative real time polymerase chain reaction. Intrahepatic TIPE2 protein was also determined using immunohistochemistry staining. The TIPE2 mRNA level in CHB patients was significantly higher than that in healthy controls. Moreover, the TIPE2 mRNA level in immune clearance (IC) phases was significantly higher than that in immune tolerance (IT) phase; whereas TIPE2 mRNA in HBeAg negative hepatitis (ENH) was obviously higher than low replication (LR) phase. Furthermore, the optional cut off values of 2.02 and 1.59 for TIPE2 mRNA level have strong power in identifying IC and ENH from IT and LR. In addition, intrahepatic TIPE2 protein was predominantly located in hepatocyte plasma and correlated with hepatic inflammatory and fibrosis. Multivariate analysis showed tumor necrosis factors-α, interferon-γ and HBV DNA load were independently correlated with TIPE2 level. In conclusion, TIPE2 might be associated to the immune clearance of patients with chronic hepatitis B.

  2. Tunable phase gate for two atoms with an immunity to decoherence

    SciTech Connect

    Zheng Shibiao; Guo Guangcan

    2006-05-15

    A scheme is presented for realizing a tunable phase gate for two atoms. The scheme is based on atom-cavity interaction and linear optics elements. In comparison with previous schemes, the distinct advantage is that the fidelity of the gate is not affected by the atomic spontaneous emission, cavity decay, and imperfection of the photodetectors, which is important for implementing high-fidelity quantum gates under realistic conditions.

  3. Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers.

    PubMed

    Joachim, Agricola; Munseri, Patricia J; Nilsson, Charlotta; Bakari, Muhammad; Aboud, Said; Lyamuya, Eligius F; Tecleab, Teghesti; Liakina, Valentina; Scarlatti, Gabriella; Robb, Merlin L; Earl, Patricia L; Moss, Bernard; Wahren, Britta; Mhalu, Fred; Ferrari, Guido; Sandstrom, Eric; Biberfeld, Gunnel

    2017-01-27

    We explored the duration of immune responses and the effect of a late third HIV-modified vaccinia virus Ankara (MVA) boost in HIV-DNA primed and HIV-MVA boosted Tanzanian volunteers. Twenty volunteers who had previously received three HIV-DNA and two HIV-MVA immunizations were given a third HIV-MVA immunization 3 years after the second HIV-MVA boost. At the time of the third HIV-MVA, 90% of the vaccinees had antibodies to HIV-1 subtype C gp140 (median titer 200) and 85% to subtype B gp160 (median titer 100). The majority of vaccinees had detectable antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, 70% against CRF01_AE virus-infected cells (median titer 239) and 84% against CRF01_AE gp120-coated cells (median titer 499). A high proportion (74%) of vaccinees had IFN-γ ELISpot responses, 63% to Gag and 42% to Env, 3 years after the second HIV-MVA boost. After the third HIV-MVA, there was an increase in Env-binding antibodies and ADCC-mediating antibodies relative to the response seen at the time of the third HIV-MVA vaccination, p < .0001 and p < .05, respectively. The frequency of IFN-γ ELISpot responses increased to 95% against Gag or Env and 90% to both Gag and Env, p = .064 and p = .002, respectively. In conclusion, the HIV-DNA prime/HIV-MVA boost regimen elicited potent antibody and cellular immune responses with remarkable durability, and a third HIV-MVA immunization significantly boosted both antibody and cellular immune responses relative to the levels detected at the time of the third HIV-MVA, but not to higher levels than after the second HIV-MVA.

  4. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura.

    PubMed

    Bennett, Carolyn M; Rogers, Zora R; Kinnamon, Daniel D; Bussel, James B; Mahoney, Donald H; Abshire, Thomas C; Sawaf, Hadi; Moore, Theodore B; Loh, Mignon L; Glader, Bertil E; McCarthy, Maggie C; Mueller, Brigitta U; Olson, Thomas A; Lorenzana, Adonis N; Mentzer, William C; Buchanan, George R; Feldman, Henry A; Neufeld, Ellis J

    2006-04-01

    We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.

  5. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura

    PubMed Central

    Bennett, Carolyn M.; Rogers, Zora R.; Kinnamon, Daniel D.; Bussel, James B.; Mahoney, Donald H.; Abshire, Thomas C.; Sawaf, Hadi; Moore, Theodore B.; Loh, Mignon L.; Glader, Bertil E.; McCarthy, Maggie C.; Mueller, Brigitta U.; Olson, Thomas A.; Lorenzana, Adonis N.; Mentzer, William C.; Buchanan, George R.; Feldman, Henry A.; Neufeld, Ellis J.

    2006-01-01

    We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 × 109/L (50 000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP. PMID:16352811

  6. Association of immune response to endothelial cell growth factor with early disseminated and late manifestations of Lyme disease but not posttreatment Lyme disease syndrome.

    PubMed

    Tang, Kevin S; Klempner, Mark S; Wormser, Gary P; Marques, Adriana R; Alaedini, Armin

    2015-12-01

    Endothelial cell growth factor has been recently proposed as a potential autoantigen in manifestations of Lyme disease that are thought to involve immune-mediated mechanisms. Our findings indicate that a humoral immune response to this protein is not associated with posttreatment Lyme disease syndrome. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Relationship between ADAMTS13 activity, von Willebrand factor antigen levels and platelet function in the early and late phases after TIA or ischaemic stroke.

    PubMed

    McCabe, Dominick J H; Murphy, Stephen J X; Starke, Richard; Harrison, Paul; Brown, Martin M; Sidhu, Paul S; Mackie, Ian J; Scully, Marie; Machin, Samuel J

    2015-01-15

    Reduced ADAMTS13 activity is seen in thrombotic thrombocytopenic purpura (TTP), and may lead to accumulation of prothrombotic ultra-large von Willebrand factor (ULVWF) multimers in vivo. ADAMTS13 activity and its relationship with VWF antigen (VWF:Ag) levels and platelet function in 'non-TTP related' TIA or ischaemic stroke has not been comprehensively studied. In this prospective pilot observational analytical case-control study, ADAMTS13 activity and VWF:Ag levels were quantified in platelet poor plasma in 53 patients in the early phase (≤ 4 weeks) and 34 of these patients in the late phase (≥ 3 months) after TIA or ischaemic stroke on aspirin. Data were compared with those from 22 controls not on aspirin. The impact of ADAMTS13 on platelet function in whole blood was quantified by measuring Collagen-ADP (C-ADP) and Collagen-Epinephrine closure times on a platelet function analyser (PFA-100(®)). Median ADAMTS13 activity was significantly reduced in the early phase (71.96% vs. 95.5%, P <0.01) but not in the late phase after TIA or stroke compared with controls (86.3% vs. 95.5%, P=0.19). There was a significant inverse relationship between ADAMTS13 activity and VWF:Ag levels in the early phase (r=-0.31; P=0.024), but not in the late phase after TIA or stroke (P=0.74). There was a positive correlation between ADAMTS13 activity and C-ADP closure times in early phase patients only, likely mediated via VWF:Ag levels. ADAMTS13 activity is reduced and VWF:Ag expression is increased within 4 weeks of TIA or ischaemic stroke onset, and can promote enhanced platelet adhesion and aggregation in response to stimulation with collagen and ADP via VWF-mediated pathways. These data improve our understanding of the dynamic haemostatic and thrombotic profiles of ischaemic cerebrovascular disease (CVD) patients, and are important in view of the potential future role that ADAMTS13 may have to play as an anti-thrombotic agent in CVD. Copyright © 2014 Elsevier B.V. All rights

  8. Transient expression of RAD51 in the late G2-phase is required for cell cycle progression in synchronous Physarum cells.

    PubMed

    Le Cigne, Anthony; Menil-Philippot, Vanessa; Fleury, Fabrice; Takahashi, Masayuki; Thiriet, Christophe

    2014-10-01

    The homologous recombination factor RAD51 is highly conserved. This criterion enabled us to identify a RAD51 ortholog in Physarum polycephalum. We found that the Physarum protein presents a high homology to the human protein and cross-reacted with antibodies directed against the human RAD51. Taking advantage of the natural synchrony of millions of nuclei within a single cell of Physarum, we investigated the fluctuation of the amount of the PpRAD51 throughout the cell cycle. Our results showed that in the late G2-phase, RAD51 was transiently expressed in a large quantity. Furthermore, knocking-down RAD51 in the G2-phase abolished this transient expression before mitosis and affected cell cycle progression. These results support the idea that RAD51 plays a role in the progression of the cell cycle in the late G2-phase. © 2014 The Authors Genes to Cells © 2014 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  9. Bridging innate and adaptive immunity.

    PubMed

    Paul, William E

    2011-12-09

    The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.

  10. ACUTE PHASE DEATHS FROM MURINE POLYMICROBIAL SEPSIS ARE CHARACTERIZED BY INNATE IMMUNE SUPPRESSION RATHER THAN EXHAUSTION1

    PubMed Central

    Chiswick, Evan L.; Mella, Juan R.; Bernardo, John; Remick, Daniel

    2015-01-01

    Sepsis, a leading cause of death in the U.S., has poorly understood mechanisms of mortality. To address this, our model of Cecal Ligation and Puncture (CLP) induced sepsis stratifies mice as predicted to Live (Live-P) or Die (Die-P) based on plasma IL-6. Six hours post-CLP, both Live-P and Die-P groups have equivalent peritoneal bacterial colony forming units and recruitment of phagocytes. By 24hr, however, Die-P mice have increased bacterial burden, despite increased neutrophil recruitment, suggesting Die-P phagocytes have impaired bacterial killing. Peritoneal cells were used to study multiple bactericidal processes: bacterial killing, Reactive Oxygen Species (ROS) generation, and phagocytosis. Total phagocytosis and intra-phagosomal processes were determined with triple-labeled E.coli, covalently labeled with ROS and pH sensitive probes, and an ROS/pH insensitive probe for normalization. While similar proportions of Live-P and Die-P phagocytes responded to exogenous stimuli, Die-P phagocytes showed marked deficits in all parameters measured, thus suggesting immunosuppression rather than exhaustion. This contradicts the prevailing sepsis paradigm that acute phase sepsis deaths (<5 days) result from excessive inflammation, whereas chronic phase deaths (>5 days) are characterized by insufficient inflammation and immunosuppression. These data suggest that suppression of cellular innate immunity in sepsis occurs within the first six hours. PMID:26371253

  11. Progesterone change in the late follicular phase affects pregnancy rates both agonist and antagonist protocols in normoresponders: a case-controlled study in ICSI cycles.

    PubMed

    Demir, Berfu; Kahyaoglu, Inci; Guvenir, Altay; Yerebasmaz, Neslihan; Altinbas, Sadiman; Dilbaz, Berna; Dilbaz, Serdar; Mollamahmutoglu, Leyla

    2016-01-01

    The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist protocols in normoresponders. A total of 201 normoresponder patients, who underwent embryo transfer were consecutively selected. 118 patients were stimulated using a long luteal GnRH agonist protocol and 83 using a flexible antagonist protocol. The level of change in late follicular phase progesterone was calculated according to the progesterone levels on the hCG day and pre-hCG day (1 or 2 days prior to hCG day) measurement. Clinical pregnancy rates were comparable between long luteal and antagonist group (35.6 and 41%, respectively). The incidence of progesterone elevation on the hCG day was 11% in long luteal and 18% in antagonist group (p = 0.16). In pregnant cycles, p levels both on the hCG day and pre-hCG day measurement were significantly higher in antagonist than agonist cycles (p = 0.029, p = 0.038, respectively). The change of p level was statistically significant in non-pregnant cycles both for the agonist (-0.17 ± 0.07; 95% CI: -0.29 to -0.37) and antagonist groups (-0.18 ± 0.07; 95%CI: -0.31 to -0.04). Late follicular phase progesterone levels were stable during the cycles of pregnant patients irrespective of the protocols and were shown to be higher in pregnant patients in antagonist cycles when compared to agonist cycles.

  12. Progesterone change in the late follicular phase affects pregnancy rates both agonist and antagonist protocols in normoresponders: a case-controlled study in ICSI cycles

    PubMed Central

    Demir, Berfu; Kahyaoglu, Inci; Guvenir, Altay; Yerebasmaz, Neslihan; Altinbas, Sadiman; Dilbaz, Berna; Dilbaz, Serdar; Mollamahmutoglu, Leyla

    2016-01-01

    Abstract Objective: The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist protocols in normoresponders. Study design: A total of 201 normoresponder patients, who underwent embryo transfer were consecutively selected. 118 patients were stimulated using a long luteal GnRH agonist protocol and 83 using a flexible antagonist protocol. The level of change in late follicular phase progesterone was calculated according to the progesterone levels on the hCG day and pre-hCG day (1 or 2 days prior to hCG day) measurement. Results: Clinical pregnancy rates were comparable between long luteal and antagonist group (35.6 and 41%, respectively). The incidence of progesterone elevation on the hCG day was 11% in long luteal and 18% in antagonist group (p = 0.16). In pregnant cycles, p levels both on the hCG day and pre-hCG day measurement were significantly higher in antagonist than agonist cycles (p = 0.029, p = 0.038, respectively). The change of p level was statistically significant in non-pregnant cycles both for the agonist (-0.17 ± 0.07; 95% CI: −0.29 to −0.37) and antagonist groups (−0.18 ± 0.07; 95%CI: −0.31 to −0.04). Conclusions: Late follicular phase progesterone levels were stable during the cycles of pregnant patients irrespective of the protocols and were shown to be higher in pregnant patients in antagonist cycles when compared to agonist cycles. PMID:26654315

  13. Curcumin Inhibits CD4+ T Cell Activation, but Augments CD69 Expression and TGF-β1-Mediated Generation of Regulatory T Cells at Late Phase

    PubMed Central

    Kim, Girak; Jang, Mi Seon; Son, Young Min; Seo, Min Ji; Ji, Sang Yun; Han, Seung Hyun; Jung, In Duk; Park, Yeong-Min; Jung, Hyun Jung; Yun, Cheol-Heui

    2013-01-01

    Background Curcumin is a promising candidate for a natural medicinal agent to treat chronic inflammatory diseases. Although CD4+ T cells have been implicated in the pathogenesis of chronic inflammation, whether curcumin directly regulates CD4+ T cells has not been definitively established. Here, we showed curcumin-mediated regulation of CD2/CD3/CD28-initiated CD4+ T cell activation in vitro. Methodology/Principal Findings Primary human CD4+ T cells were stimulated with anti-CD2/CD3/CD28 antibody-coated beads as an in vitro surrogate system for antigen presenting cell-T cell interaction and treated with curcumin. We found that curcumin suppresses CD2/CD3/CD28-initiated CD4+ T cell activation by inhibiting cell proliferation, differentiation and cytokine production. On the other hand, curcumin attenuated the spontaneous decline of CD69 expression and indirectly increased expression of CCR7, L-selectin and Transforming growth factor-β1 (TGF-β1) at the late phase of CD2/CD3/CD28-initiated T cell activation. Curcumin-mediated up-regulation of CD69 at late phase was associated with ERK1/2 signaling. Furthermore, TGF-β1 was involved in curcumin-mediated regulation of T cell activation and late-phase generation of regulatory T cells. Conclusions/Significance Curcumin not merely blocks, but regulates CD2/CD3/CD28-initiated CD4+ T cell activation by augmenting CD69, CCR7, L-selectin and TGF-β1 expression followed by regulatory T cell generation. These results suggest that curcumin could directly reduce T cell-dependent inflammatory stress by modulating CD4+ T cell activation at multiple levels. PMID:23658623

  14. Evidence for major basic protein immunoreactivity and interleukin 5 gene activation during the late phase response in explanted airways.

    PubMed

    Eidelman, D H; Minshall, E; Dandurand, R J; Schotman, E; Song, Y L; Yasruel, Z; Moqbel, R; Hamid, Q

    1996-11-01

    Current evidence suggests that the events subsequent to antigen challenge in allergic asthmatics involve eosinophil activation and the synthesis of proinflammatory cytokines, in particular interleukin 5 (IL-5). However, little is known about how local inflammatory cell infiltration and activation are related to the changes in lung function following allergen exposure. We have developed a novel technique to investigate the local inflammatory events during late-onset allergic bronchoconstriction in lung explants from sensitized Brown-Norway (BN) rats. In this study we tested the hypothesis that the in vitro late airway response involves IL-5 gene activation and recruitment and activation of eosinophils. Explants were prepared from excised lungs of BN rats (n = 9) sensitized 2 wk previously to ovalbumin (OVA). Lungs were inflated with liquid agarose solution (2% wt/vol, 48 ml/kg) following perfusion with cold Ca2+/Mg(2+)-free Hanks' solution, and refrigerated briefly to gel the agarose, and 0.5- to 1.0-mm slices were prepared and cultured overnight at 37 degrees C. Airways were identified and challenged by direct application of OVA (20 micrograms). Cryostat sections of explants were immunostained for major basic protein (MBP) and IL-5 mRNA was detected by a 35S-uridine triphosphate-labeled probe and in situ hybridization. Explants harvested immediately prior to challenge showed little evidence of MBP and IL-5 mRNA expression. Explants harvested at 6 h which exhibited evidence of bronchoconstriction showed strong cell-associated immunostaining for MBP and high expression of IL-5 mRNA in the bronchial mucosa. colocalization studies performed in lung explants demonstrating late-onset airway responses suggested that the majority of IL-5 mRNA expression was not found in MBP-positive cells. When compared with explants from sham-sensitized rats (n = 4), there was a significant increase in MBP-positive and IL-5 mRNA-positive cells per millimeter of basement membrane of the

  15. 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.

  16. 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

  17. Differential Effects of Early- and Late-Life Access to Carotenoids on Adult Immune Function and Ornamentation in Mallard Ducks (Anas platyrhynchos)

    PubMed Central

    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

  18. Selenium controls the sex-specific immune response and selenoprotein expression during the acute-phase response in mice.

    PubMed

    Stoedter, Mette; Renko, Kostja; Hög, Antonia; Schomburg, Lutz

    2010-07-01

    Selenium modifies inflammatory reactions in rodents and humans. The liver controls metabolism and transport of selenium via hepatically-derived SEPP (selenoprotein P). Intracellular SEPS (selenoprotein S) modifies endoplasmic-reticulum function and immune-cell activity. Polymorphisms in SEPS have been associated with cytokine levels and inflammatory diseases in a subset of clinical studies. In the present study, we hypothesized that sex and selenium represent decisive parameters controlling the immune response and regulation of SEPS expression in vivo. Male and female mice fed a selenium-poor diet were supplemented or not with selenite for 3 days and injected with saline or LPS (lipopolysaccharide) 24 h before analysis. Selenium supplementation mitigated the LPS-induced rise in circulating cytokines in male mice. Serum SepP and selenium concentrations decreased in response to LPS, whereas hepatic SepS was specifically up-regulated despite declining selenium concentrations in the liver. Hepatic SepS induction was mainly controlled by post-transcriptional mechanisms and attributed to hepatocytes by analysing transgenic mice. Notably, selenium supplementation was essential for an optimal SepS induction. We conclude that selenoprotein biosynthesis becomes redirected in hepatocytes during the acute-phase response at the expense of dispensable selenoproteins (e.g. SepP) and in favour of SepS expression, thereby causing declining serum selenium and improving liver function. The selenium status and sex control SepS expression and modify cytokine response patterns in serum, which might explain contradictory results on associations of SEPS genotype and inflammatory diseases in clinical studies.

  19. Effects of an advanced sleep schedule and morning short wavelength light exposure on circadian phase in young adults with late sleep schedules.

    PubMed

    Sharkey, Katherine M; Carskadon, Mary A; Figueiro, Mariana G; Zhu, Yong; Rea, Mark S

    2011-08-01

    We examined the effects of an advanced sleep/wake schedule and morning short wavelength (blue) light in 25 adults (mean age±SD=21.8±3 years; 13 women) with late sleep schedules and subclinical features of delayed sleep phase disorder (DSPD). After a baseline week, participants kept individualized, fixed, advanced 7.5-h sleep schedules for 6days. Participants were randomly assigned to groups to receive "blue" (470nm, ∼225lux, n=12) or "dim" (<1lux, n=13) light for 1h after waking each day. Head-worn "Daysimeters" measured light exposure; actigraphs and sleep diaries confirmed schedule compliance. Salivary dim light melatonin onset (DLMO), self-reported sleep, and mood were examined with 2×2 ANOVA. After 6days, both groups showed significant circadian phase advances, but morning blue light was not associated with larger phase shifts than dim-light exposure. The average DLMO advances (mean±SD) were 1.5±1.1h in the dim light group and 1.4±0.7h in the blue light group. Adherence to a fixed advanced sleep/wake schedule resulted in significant circadian phase shifts in young adults with subclinical DSPD with or without morning blue light exposure. Light/dark exposures associated with fixed early sleep schedules are sufficient to advance circadian phase in young adults. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Effects of an Advanced Sleep Schedule and Morning Short Wavelength Light Exposure on Circadian Phase in Young Adults with Late Sleep Schedules

    PubMed Central

    Sharkey, Katherine M.; Carskadon, Mary A.; Figueiro, Mariana G.; Zhu, Yong; Rea, Mark S.

    2011-01-01

    Objective We examined the effects of an advanced sleep/wake schedule and morning short wavelength (blue) light in 25 adults (mean age±SD = 21.8±3 years; 13 women) with late sleep schedules and subclinical features of delayed sleep phase syndrome (DSPD). Methods After a baseline week, participants kept individualized, fixed, advanced 7.5-hour sleep schedules for 6 days. Participants were randomly assigned to groups to receive “blue” (470 nm, ~225 lux, n=12) or “dim” (< 1 lux, n=13) light for one hour after waking each day. Head-worn “Daysimeters” measured light exposure; actigraphs and sleep diaries confirmed schedule compliance. Salivary dim light melatonin onset (DLMO), self-reported sleep, and mood were examined with 2×2 ANOVA. Results After 6 days, both groups showed significant circadian phase advances, but morning blue-light was not associated with larger phase shifts than dim-light exposure. The average DLMO advances (mean±SD) were 1.5±1.1 hours in the dim light group and 1.4±0.7 hours in the blue light group. Conclusions Adherence to a fixed advanced sleep/wake schedule resulted in significant circadian phase shifts in young adults with subclinical DSPD with or without morning blue light exposure. Light/dark exposures associated with fixed early sleep schedules are sufficient to advance circadian phase in young adults. PMID:21704557

  1. Cell length growth patterns in fission yeast reveal a novel size control mechanism operating in late G2 phase.

    PubMed

    Horváth, Anna; Rácz-Mónus, Anna; Buchwald, Peter; Sveiczer, Ákos

    2016-09-01

    Because cylindrically shaped fission yeast cells grow exclusively at their tips, cell volume is proportional to length and can be easily monitored by time-lapse microscopy. Here, we analysed the growth pattern of individual cells from several fission yeast strains to determine the growth function that describes them most adequately and to perform size control studies. The growth pattern of most cells during their growth period is best described by a bilinear function (i.e., two linear segments of different growth rates separated by a rate-change point). Linear growth patterns were also observed in several cases, but exponential ones only rarely. Since the bilinear patterns are separated into two segments by a breakpoint, we examined the existence of size control by regression analyses of the appropriate growth parameters in both segments. This confirmed the existence of known size controls in late G1, mid-G2 and late G2 during the fission yeast cycle. The present analyses also revealed that, contrary to the commonly accepted current view, late G2 size control is a general characteristic third event in the cycle. The level of the critical late G2 size that needs to be reached in an individual fission yeast cell is influenced by the growth rate of the cell in a manner similar to budding yeast, suggesting an evolutionary conserved mechanism. The present study of individual cell growth patterns in wild-type and several cell cycle mutant fission yeast strains confirmed that, for most cells, growth is best described by a bilinear function. Three different size control mechanisms were found to operate in the different strains, and, as a novel observation, cell size was always found to be monitored before mitotic onset, irrespective of the existence of any earlier size checkpoints. Studying the pattern of growth and the mechanism of size control helps to clarify the connections between cell growth and division, since their coordination must work properly to maintain size

  2. Is the great attractor really a great wall?. [late-time cosmological phase transition producing coherent velocity caused by relic domain wall repulsive effect

    NASA Technical Reports Server (NTRS)

    Stebbins, Albert; Turner, Michael S.

    1989-01-01

    Some of the cosmological consequences of a late-time phase transition which produces light domain walls are discussed. The observed peculiar velocity field of the universe and the observed isotropy of the microwave backgroud radiation severely constrain the wall surface density in such as scenario: G(omega) less than about 0.0001 H0 (H0 is the present value of the Hubble parameter). The most interesting consequence of such a phase transition is the possibility that the local, coherent streaming motion of about 600 km/s reported by Dressler et al (1987) could be explained by the repulsive effect of a relic domain wall within the Hubble volume provided that G(omega)/H0 = 0.0001.

  3. Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: an analytical challenge involving a multidisciplinary approach.

    PubMed

    Turco, Lucilla; Provera, Stefano; Curcuruto, Ornella; Bernabè, Elena; Nicoletti, Anna; Martini, Luca; Castoldi, Damiano; Cimarosti, Zadeo; Papini, Damiano; Marchioro, Carla; Dams, Riet

    2011-01-05

    During late phase development of the selective NK1 receptor antagonist casopitant mesylate, a de-fluorinated impurity was discovered and quantified by an orthogonal analytical approach, using NMR and LC-MS. A dedicated (19)F NMR method was initially developed for first line identification and semi-quantification of the impurity. Subsequently, a more accurate quantification was achieved by means of a selective normal-phase LC-MS method, which was fully validated. The results obtained on the development batches of the drug substance were used by the project team to set up a suitable control strategy and ultimately to ensure patient safety and the progression of the project. Copyright © 2010 Elsevier B.V. All rights reserved.

  4. 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

  5. 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.

  6. 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.

  7. Effects of chromium propionate on egg production, egg quality, plasma biochemical parameters, and egg chromium deposition in late-phase laying hens.

    PubMed

    Ma, Wenqiang; Gu, Ying; Lu, Jingyu; Yuan, Lvfeng; Zhao, Ruqian

    2014-02-01

    This study was conducted to investigate the effects of chromium propionate on egg production, egg quality, plasma biochemical parameters and egg chromium deposition in late-phase laying hens. Four hundred thirty-two 60-weeks old laying hens were divided into four groups of 108 birds per group according to egg production. The dietary treatments consisted of the basal diet adding with 0, 200, 400, and 600 μg/kg chromium as chromium propionate. All laying hens were given feed and water ad libitum for 8 weeks. The addition of 400 μg/kg Cr as chromium propionate increased egg production (P < 0.01) during the later 4 weeks, but decreased albumen height, yolk color score, and Haugh unit of eggs. Six hundred micrograms per kilogram Cr as chromium propionate supplementation improved shell thickness (P < 0.05). 200 μg/kg Cr as chromium propionate supplementation decreased the uric acid concentration by 31 % (P < 0.05). However, supplemental Cr did not affect the egg chromium deposition of hens (P > 0.05). These data indicated that feeding of late-phase laying hens with chromium propionate could improve egg production, increase eggshell thickness, but do not result in abnormal levels of chromium deposition in eggs.

  8. Record of epicontinental platform evolution and volcanic activity during a major rifting phase: The Late Triassic Zamoranos Formation (Betic Cordillera, S Spain)

    NASA Astrophysics Data System (ADS)

    Pérez-López, Alberto; Pérez-Valera, Fernando; Götz, Annette E.

    2012-03-01

    The study of the Late Triassic Zamoranos Formation and the comparison to coeval carbonate units provides new insights into the evolution and palaeogeography of carbonate platforms during major rifting phases in the Earth's history. The platform carbonates of the Zamoranos Formation record the last major transgression during the Triassic, and document the initial phase of the CAMP volcanism in the external Zone of the Betic Cordillera. New palynological data from the lower part of the Zamoranos Formation indicate a Middle Norian age. The entire succession is built up by limestones, dolomites, and ferruginous red detrital deposits with volcaniclastic breccias. The carbonates are interpreted as tidal and shallow marine sediments, deposited under arid conditions. The red detrital deposits appear in coastal environments in relation to a volcanic event, which triggered hydrothermal processes in these deposits and started the massive magmatic event associated with the Central Atlantic Magmatic Province (CAMP). The Zamoranos Formation was also recognized in the SW part of the Valencia Triassic and is correlated to the Imón Formation (Iberian Ranges), to the Isábena Formation (Pyrenees) and to other carbonate units of the W Tethys realm (Aquitaine, Tunisian Atlas, West Carpathians). These units indicate that an extensive epicontinental platform developed during the Late Triassic.

  9. Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase.

    PubMed

    Yu, Fazhi; Jiang, Ya; Lu, Lucy; Cao, Mimi; Qiao, Yulong; Liu, Xing; Liu, Dan; Van Dyke, Terry; Wang, Fangwei; Yao, Xuebiao; Guo, Jing; Yang, Zhenye

    2017-01-01

    Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.

  10. Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

    PubMed Central

    Yu, Fazhi; Jiang, Ya; Lu, Lucy; Cao, Mimi; Qiao, Yulong; Liu, Xing; Liu, Dan; Van Dyke, Terry; Wang, Fangwei; Yao, Xuebiao; Guo, Jing; Yang, Zhenye

    2017-01-01

    Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly. PMID:28101375

  11. Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

    PubMed Central

    Ham, Claire; Ferguson, Deborah; Tudor, Hannah; Mattiuzzo, Giada; Klaver, Bep; Page, Mark; Stebbings, Richard; Das, Atze T.; Berkhout, Ben; Almond, Neil; Cranage, Martin P.

    2016-01-01

    In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity. PMID:28002473

  12. Effect of heat stress during late gestation on immune function and growth performance of calves: isolation of altered colostral and calf factors.

    PubMed

    Monteiro, A P A; Tao, S; Thompson, I M; Dahl, G E

    2014-10-01

    Calves born to cows exposed to heat stress during the dry period and fed their dams' colostrum have compromised passive and cell-mediated immunity compared with calves born to cows cooled during heat stress. However, it is unknown if this compromised immune response is caused by calf or colostrum intrinsic factors. Two studies were designed to elucidate the effects of colostrum from those innate to the calf. The objective of the first study was to evaluate the effect of maternal heat stress during the dry period on calf-specific factors related to immune response and growth performance. Cows were dried off 46 d before expected calving and randomly assigned to 1 of 2 treatments: heat stress (HT; n=18) or cooling (CL; n=18). Cows of the CL group were housed with sprinklers, fans and shade, whereas cows of HT group had only shade. After calving, the cows were milked and their colostrum was frozen for the subsequent study. Colostrum from cows exposed to a thermoneutral environment during the dry period was pooled and stored frozen (-20 °C). Within 4h of birth, 3.8L of the pooled colostrum from thermoneutral cows was fed to calves born to both HT and CL cows. Day of birth was considered study d 0. All calves were exposed to the same management and weaned at d 49. Blood samples were collected before colostrum feeding, 24h after birth and twice weekly up to d 28. Total serum IgG concentrations were determined. Body weight was recorded at birth and at d 15, 30, 45, and 60. Relative to CL calves, HT calves were lighter at birth (38.3 vs. 43.1 kg), but no difference in weight gain was observed at d 60. Additionally, HT calves had lower apparent efficiency of IgG absorption (26.0 vs. 30.2%), but no differences were observed for total IgG concentration. The objective of the second study was to evaluate the isolated effect of the colostrum from HT cows on calf immune response and growth performance. The experimental design was identical to the first study, but all calves were

  13. Hepatitis B virus depicts a high degree of conservation during the immune-tolerant phase in familiarly transmitted chronic hepatitis B infection: deep-sequencing and phylogenetic analysis.

    PubMed

    Sede, M; Lopez-Ledesma, M; Frider, B; Pozzati, M; Campos, R H; Flichman, D; Quarleri, J

    2014-01-01

    When intrafamilial transmission of hepatitis B virus (HBV) occurs, a virus with the same characteristics interacts with diverse hosts' immune systems and may thus result in different mutations to escape immune pressure. In this study, the HBV genomic characterization was assessed longitudinally after intrafamilial transmission using nucleotide sequence data of phylogenetic and mutational analyses, including those obtained by deep-sequencing for the first time. Furthermore, HBeAg-anti-HBe profile and variability of HBV core-derived epitopes were also evaluated. Strong evidence was obtained from intrafamilial transmission of HBV genotype D1 by phylogenetic inferences. HBV isolates exhibited high degree (~99%) of genomic conservation for almost 20 years, when patients were persistently HBeAg positive with normal amino transferase levels. This identity remained high among immune-tolerant siblings. In contrast, it diminished significantly (P = 0.02) when the mother cleared HBeAg (immune clearance phase). By deep-sequencing, the quantitative analysis of the dynamics of basal core promoter (BCP) (A1762T, G1764A; A1766C; T1773C; 8-bp deletion; and other) and precore (G1896A) variants among HBV isolates from family members exhibited differences during the follow-up. However, only those from the mother showed amino acid variations at core protein that would impair their MHC-II binding. Hence, when intrafamilial transmission occurs, HBV was highly conserved under the immune-tolerant phase, but it exhibited mutations more frequently during the immune clearance phase. The analysis of the HBV BCP and precore mutants after intrafamilial HBV transmission contributes to a better understanding of how they evolve over time. © 2013 John Wiley & Sons Ltd.

  14. Characterization and Palaeoecological Significance of Archaeological Charcoal Assemblages during Late and Post-Glacial Phases in Southern France

    NASA Astrophysics Data System (ADS)

    Heinz, Christine; Thiébault, Stéphanie

    1998-07-01

    Archaeological sites at Abeurador and Font-Juvénal have produced extensive charcoal-rich horizons. The results of the charcoal analysis, based on the identification of woody species from anatomical features, contribute to the elaboration of plain phases within the development of vegetation in southern France. They are presented here in a new diagram and are interpreted as four major vegetation phases from 11,000 14C yr B.P. to the recent past. In order to interpret the palaeoecological significance of the charcoal assemblages we have used multivariate analysis. The data base consists of 42 taxa and 48 archaeological levels. The division into four vegetation phases based on analytical interpretation is complemented by the more synthetic interpretation based on correspondence factor analysis (CFA). The results reveal the patterns of the vegetation history over the last 11 millennia, each being characterized by a key plant species.

  15. Optimization of breathing instructions and timing of late arterial phase acquisition on gadobutrol-enhanced MRI of the liver.

    PubMed

    Pinho, Daniella F; Lev-Cohain, Naama; Awdeh, Haitham; Xi, Yin; Khatri, Gaurav; Yokoo, Takeshi; Pedrosa, Ivan

    To compare a protocol with higher concentration macrocyclic gadolinium-based contrast agent (GBCA) [study group] to the traditional protocol with lower-concentration linear GBCAs [control group] for breath-held arterial phase magnetic resonance imaging. A total of 136 patients were quantitatively evaluated for image quality (IQ), breathing artifacts (BA), and timing of the arterial phase (Tap). Quantitative analysis was also performed. No significant differences in IQ, BA and Tap (P>.05). Study group exhibited less enhancement of the aorta (P=.0091) and smaller standard deviation for the portal vein enhancement (P=.0173). Similar arterial-phase image quality can be achieved with a macrocyclic GBCA compared to traditional linear GBCA. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. 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.

  17. 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.

  18. Reproductive phase dependent daily variation in melatonin receptors (Mel(1a) and Mel(1b)), androgen receptor (AR) and lung associated immunity of Perdicula asiatica.

    PubMed

    Kharwar, R K; Haldar, C

    2011-06-01

    Our knowledge about the involvement of melatonin in the regulation of lung associated immune system (LAIS) is still poor though the melatonin receptor types (Mel(1a) and Mel(1b)) have been localized in lungs of some wild birds. We thought to explore the correlation between daily variation (within a 24h time scale) in peripheral melatonin and testosterone along with expression of melatonin receptors (Mel(1a) and Mel(1b)) and androgen receptor (AR) in lungs during reproductively active and inactive phases. Receptor expression of Mel(1b) was more prominent than Mel(1a) at all the time points during both the reproductive phases. The expression of AR was inversely related to both the melatonin and its receptor expression at the 24h time scale during both the reproductive phases. Results also reflected a parallel relationship of melatonin, melatonin receptors and all the immune parameters (total leukocyte count, lymphocyte count, % stimulation ratio) suggesting that peripheral melatonin might be responsible for daily periodicity of LAIS. The presence of androgen receptors in lung led us to propose that gonadal steroid does influence the LAIS. Therefore melatonin along with testosterone might be acting as a temporal synchronizer for daily rhythms in lung associated immunity in Perdicula asiatica during different reproductive phases. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. 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.

  20. A practical approach to designing operating instructions for medical products in late or post-design phases.

    PubMed

    Gupta, S P; Lyons, M

    2009-01-01

    User instructions, and especially operating instructions, are an essential part of the FDA's "medical device labeling" requirements and are intended to help ensure that the device is used safely and effectively. Their design should go hand-in-hand with the design of the product that they are going to accompany. However, for one reason or another, they are usually treated as something that can be tacked on at the end of the device development process. At this stage, it is often realized that, had the device been designed differently, it would have been easier to instruct the potential users. However, it is generally too late and the instructions have to be formulated around the fixed design of the product. Also, in the clinical engineering environment of healthcare organizations, sometimes there is a requirement to produce tailored operating instructions for certain groups of users (especially patients and carers) in certain circumstances, e.g. when the manufacturer's instructions are inadequate or a device has been configured for a particular type of user group. This paper attempts to demonstrate a practical approach to producing effective operating instructions for a product that is already at the far end of its development process or even marketed.

  1. CaMKII knockdown affects both early and late phases of olfactory long-term memory in the honeybee.

    PubMed

    Scholl, Christina; Kübert, Natalie; Muenz, Thomas S; Rössler, Wolfgang

    2015-12-01

    Honeybees are able to solve complex learning tasks and memorize learned information for long time periods. The molecular mechanisms mediating long-term memory (LTM) in the honeybee Apis mellifera are, to a large part, still unknown. We approached this question by investigating the potential function of the calcium/calmodulin-dependent protein kinase II (CaMKII), an enzyme known as a 'molecular memory switch' in vertebrates. CaMKII is able to switch to a calcium-independent constitutively active state, providing a mechanism for a molecular memory and has further been shown to play an essential role in structural synaptic plasticity. Using a combination of knockdown by RNA interference and pharmacological manipulation, we disrupted the function of CaMKII during olfactory learning and memory formation. We found that learning, memory acquisition and mid-term memory were not affected, but all manipulations consistently resulted in an impaired LTM. Both early LTM (24 h after learning) and late LTM (72 h after learning) were significantly disrupted, indicating the necessity of CaMKII in two successive stages of LTM formation in the honeybee. © 2015. Published by The Company of Biologists Ltd.

  2. Polyethylene glycol-modified avidin: a novel agent for the selective extraction of biotinylated immune-complex in an aqueous two-phase system.

    PubMed

    Nishimura, H; Munakata, N; Hayashi, K; Hayakawa, M; Iwamoto, H; Terayama, S; Takahata, Y; Kodera, Y; Tsurui, H; Shirai, T

    1995-01-01

    Chicken avidin was chemically modified with 2,4-bis[O-methoxypoly(ethylene glycol)]-6-chloro-s-triazine (activated PEG2) to form PEG-avidin. The PEG-avidin, in which 78% of the amino groups were modified, retained 49% of the active biotin-binding sites. The modified avidin was partitioned preferentially into the PEG-phase in an aqueous two-phase system (PEG/dextran). Using PEG-avidin, the immune-complex formed between biotinylated anti-mouse IgG and its antigen IgG (mouse) molecules, was successfully transferred into the PEG-phase in an aqueous two-phase system. This finding leads to the effective isolation of a specific antigen among various kinds of antigens by partitioning with a two-phase system using PEG-avidin.

  3. 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.

  4. Phase II study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed and cisplatin for locally advanced oesophageal squamous cell carcinoma

    PubMed Central

    Fu, C; Guo, L; Li, H; Huang, W; Gong, H; Sun, M; Wang, Z; Zhou, T; Liu, C

    2014-01-01

    Objective: To determine the clinical efficacy and toxicity of pemetrexed combined with low-dose cisplatin (CDDP) concurrent with late-course accelerated hyperfractionated (LCAF) intensity-modulated radiation therapy (IMRT) in patients with inoperable locally advanced oesophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC (less than or equal to 75 years of age, clinical stages IIB–IVA and Karnofsky performance status ≥70) were enrolled into the study. A target group size of 22 was projected based on the estimation that 2-year overall survival (OS) would increase from 20% to 40%. Patients were treated with pemetrexed, low-dose CDDP and LCAF IMRT concurrently. The main objective of the study was for a 2-year OS, and the secondary objectives were progression-free survival (PFS), objective response, locoregional failure rate, and acute and late toxicities. Results: 25 patients were recruited from October 2008 to July 2011. The median OS was 21 months, with 2- and 5-year OS rates of 44% and 44%, respectively. The median PFS was 18.2 months. The objective response rate was 96% (24/25), with 11 complete responses and 13 partial responses. The locoregional failure rate was 16%. Grades 4 and 5 acute toxicity rates were 8% and 4%, respectively, while no Grade 3 or greater late toxicity was observed. Conclusion: The findings of this Phase II study indicated that the therapeutic regimen appears to achieve an excellent response rate and favourable survival for locally advanced ESCC. However, the severe acute side effects should be considered cautiously in further studies. Advances in knowledge: To our knowledge, this is the first study that introduced pemetrexed and low-dose CDDP combined with LCAF IMRT to treat locally advanced ESCC. The 5-year OS rate was as high as 44%, which was more favourable than other studies. PMID:24666012

  5. Involvement of IL‐17A‐producing TCR γδ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection

    PubMed Central

    Okamoto‐Yoshida, Yuko; Yahagi, Ayano; Touyama, Seigo; Nakae, Susumu; Iwakura, Yoichiro; Matsuzaki, Goro

    2016-01-01

    Abstract Introduction Interleukin (IL)‐17A is a cytokine originally reported to induce neutrophil‐mediated inflammation and anti‐microbial activity. The CD4+ T cells, which produce IL‐17A, have been well characterized as Th17 cells. On the other hand, IL‐17A‐producing TCR γδ+ T cells have been reported to participate in the immune response at an early stage of infection with Listeria monocytogenes and Mycobacterium bovis in mice. However, the involvement of IL‐17A in protective immunity was not clearly demonstrated in the chronic stage of M. tuberculosis‐infected mice. Methods We analyzed role of IL‐17A in host defense against chronically infected M. tuberculosis using IL‐17A KO mice. Results We found that TCR γδ+ T cells are a primary source of IL‐17A, but that mycobacterial antigen‐specific Th17 cells were hardly detected even at the chronic stage of M. tuberculosis infection. IL‐17A‐deficient mice showed a decreased survival rate, and increased bacterial burden in the lungs after the infection when compared to the wild‐type mice. Furthermore, a histological analysis showed an impaired granuloma formation in the infected lungs of IL‐17A‐deficient mice, which was considered to be due to a decrease of IFN‐γ and TNF at the chronic stage. Conclusion Our data suggest that the IL‐17A‐producing TCR γδ+ T cells, rather than the Th17 cells, in the infected lungs are an indispensable source of protective immunity against M. tuberculosis infection. PMID:27980775

  6. 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

  7. Practical modifications to the Time-to-Event Continual Reassessment Method for phase I cancer trials with fast patient accrual and late-onset toxicities

    PubMed Central

    Polley, Mei-Yin C.

    2014-01-01

    The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3+3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy. PMID:21590790

  8. Lake sediment-based Late Holocene glacier reconstruction reveals medieval retreat and two-phase Little Ice Age on subantarctic South Georgia

    NASA Astrophysics Data System (ADS)

    van der Bilt, W. G. M.; Bakke, J.; Werner, J.; Paasche, O.; Rosqvist, G. N.; Vatle, S. S.

    2016-12-01

    Southern Ocean climate is rapidly changing. Yet beyond the instrumental period (± 100 years), our comprehension of climate variability in the region is restricted by a lack of high-resolution paleoclimate records. Alpine glaciers, ubiquitous on Southern Ocean islands, may provide such data as they rapidly respond to climate shifts, recording attendant changes in extent by variations in glacial erosion. Rock flour, the fine-grained fraction of this process, is suspended in meltwater streams and transfers this signal to the sediments of downstream lakes, continuously recording glacier history. Here, we use this relationship and present the first reconstruction of the Late Holocene (1250 cal. yr BP - present) glacier history of the Southern Ocean island of South Georgia, using sediments from the glacier-fed Middle Hamberg lake. Variations are resolved on multi-centennial scales due to robust chronological control. To fingerprint a glacial erosion signal, we employed a set of routinely used physical, geochemical and magnetic parameters. Using Titanium counts, validated against changes in sediment density and grain size distribution, we continuously reconstruct glacier variations over the past millennium. Refining local moraine evidence and supporting evidence from other Southern Hemisphere sites, this study shows a progressive diminishing of consecutive Late Holocene advances. These include a two-stage Little Ice Age, in agreement with other Southern Hemisphere glacier evidence. The presented record furthermore captures an unreported retreat phase behind present limits around 500 cal. yr BP.

  9. Low-intensity, short-duration thermal stimulation during the late phase of incubation alters secondary sex ratio in favour of males.

    PubMed

    Elmehdawi, A; Hall, M; Skewes, P; Wicker, D; Maurice, D V; Smith, J; Benton, R

    2015-01-01

    1. In two experiments, two setters and hatchers, with a capacity of 42 240 eggs each, were used to investigate the effect of low-intensity, short-duration thermal stimuli during the late phase of incubation on hatchability, sex ratio and grow-out performance of broilers under field conditions. 2. Eggs in the test group had the same physical environment as eggs in the control group except that incubation temperature was increased by 0.5°C for 2 h/d above the control group from 18 to 20 d of incubation. 3. Thermal stimulation significantly increased the proportion of males hatched in both experiments. In experiment 2, evaluation at 7 d of age showed that the proportion of males in the test group was still significantly higher than in the control group. 4. In experiment 2, hatch residue was examined and the proportion of unhatched male embryos was significantly greater in the control group than in the test group. 5. Thermal stimulation did not have a significant influence on post-hatch performance of broiler chickens to market age. 6. The results demonstrated that thermal stimulation of 0.5°C for 2 h/d above the control during late incubation shifted the sex ratio at hatch and at 7 d in favour of males. The difference in secondary sex ratio was due to increased survival of male embryos in the test group.

  10. 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

  11. Mouse Mast Cell Tryptase mMCP-6 Is a Critical Link between Adaptive and Innate Immunity in the Chronic Phase of Trichinella spiralis Infection1

    PubMed Central

    Shin, Kichul; Watts, Gerald F. M.; Oettgen, Hans C.; Friend, Daniel S.; Pemberton, Alan D.; Gurish, Michael F.; Lee, David M.

    2010-01-01

    Although the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection. PMID:18354212

  12. Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis

    PubMed Central

    Bacsi, Attila; Dharajiya, Nilesh; Choudhury, Barun K.; Sur, Sanjiv; Boldogh, Istvan

    2011-01-01

    Background Allergic eye diseases are complex inflammatory conditions of the conjunctiva that are becoming increasingly prevalent and present an increasing economic burden because of direct and indirect health expenditures. Objective We sought to identify factors that may synergize with antigen-induced allergic inflammation and lead to allergic conjunctivitis. We used a murine model of allergic conjunctivitis to test the effect of oxidative stress generated by pollen oxidases using nicotinamide adenine dinucleotide (reduced) or nicotinamide adenine dinucleotide phosphate (reduced) (NAD[P]H) as an electron donor present in pollen grains. Methods Reactive oxygen species (ROS) generation by hydrated Ambrosia artemisiifolia pollen (short ragweed pollen; RWP) grains was determined by using 2′-7′-dihydro-dichlorofluorescein diacetate, nitroblue tetrazolium reduction, and Amplex Red assay. The RWP-induced changes in intracellular ROS levels were examined in A549 cells, human primary bronchial epithelial cells, and murine conjunctiva. Results Ragweed pollen grains contain NAD(P)H oxidase activity, which is diphenyleneiodonium-sensitive and quinacrine-sensitive and sodium azide-resistant. These NAD(P)H oxidases generate a superoxide anion that can be converted to H2O2 by pollen grain–associated superoxide dismutase. These diffusible oxygen radicals from pollen grains increase intracellular ROS levels in cultured epithelial cells and murine conjunctiva. Similar phenomena were observed in sensitized and naive mice, indicating that the RWP-induced oxidative stress in conjunctival epithelium is independent of adaptive immunity. Inactivation of NAD(P)H oxidase activity in RWP decreases the immediate-type hypersensitivity and inflammatory cell infiltration into the conjunctiva. Conclusion Our data suggest that ROS generated by NAD(P)H oxidases in pollen grains intensify immediate allergic reactions and recruitment of inflammatory cells in murine conjunctiva. PMID:16210058

  13. Oral immunization against porcine pleuropneumonia using the cubic phase of monoolein and purified toxins of Actinobacillus pleuropneumoniae.

    PubMed

    Lopez-Bermudez, Jorge; Quintanar-Guerrero, David; Lara Puente, Horacio; Tórtora Perez, Jorge; Suárez Güemez, Francisco; Ciprián Carrasco, Abel; Mendoza Elvira, Susana

    2014-11-28

    The main goal of this work was to obtain an orally administered immunogen that would protect against infections by Actinobacillus pleuropneumoniae. The Apx I, II and III toxins were obtained from the supernatants of cultures of serotypes 1 and 3 of A. pleuropneumoniae. The capacity of monoolein gel to trap and protect the Apx toxins, and the effect of their incorporation on the stability of the cubic phase were evaluated. The gel was capable of trapping a 400-μg/ml concentration of the antigen with no effects on its structure. Approximately 60% of the protein molecules were released from the gel within 4h. Four experimental groups were formed, each one with four pigs. All challenges were conducted in a nebulization chamber. Group A: Control (-) not vaccinated and not challenged; Group B: Control (+) not vaccinated but challenged; Group C: vaccinated twice intramuscularly with ToxCom (a commercial toxoid) at an interval of 15 days and then challenged; and Group D: vaccinated orally twice a week for 4 weeks with ToxOral (an oral toxoid) and challenged on day 28 of the experiment with a same dose of 2.0 × 10(4) UFC of A. pleuropneumoniae serotypes 1 and 3. The lesions found in group B covered 27.7-43.1% of the lungs; the pigs in group C had lesions over 12.3-28%; and those in group D over 15.4-32.3%. No lesions were found in the Group A pigs. A. pleuropneumoniae induced macroscopic lesions characteristic of infection by and lesions microscopic detected by histopathology. The etiologic agent was recovered from the infected lungs, tonsils and spleen. The serotypes identified were 1 and 3. An indirect ELISA test identified the antibodies against the Apx toxins in the serum of the animals immunized orally. Copyright © 2014. Published by Elsevier Ltd.

  14. Differential expression of structural genes for the late phase of phytic acid biosynthesis in developing seeds of wheat (Triticum aestivum L.).

    PubMed

    Bhati, Kaushal Kumar; Aggarwal, Sipla; Sharma, Shivani; Mantri, Shrikant; Singh, Sudhir P; Bhalla, Sherry; Kaur, Jagdeep; Tiwari, Siddharth; Roy, Joy K; Tuli, Rakesh; Pandey, Ajay K

    2014-07-01

    In cereals, phytic acid (PA) or inositol hexakisphosphate (IP6) is a well-known phosphate storage compound as well as major chelator of important micronutrients (iron, zinc, calcium, etc.). Genes involved in the late phases of PA biosynthesis pathway are known in crops like maize, soybeans and barley but none have been reported from wheat. Our in silico analysis identified six wheat genes that might be involved in the biosynthesis of inositol phosphates. Four of the genes were inositol tetraphosphate kinases (TaITPK1, TaITPK2, TaITPK3, and TaITPK4), and the other two genes encode for inositol triphosphate kinase (TaIPK2) and inositol pentakisphosphate kinase (TaIPK1). Additionally, we identified a homolog of Zmlpa-1, an ABCC subclass multidrug resistance-associated transporter protein (TaMRP3) that is putatively involved in PA transport. Analyses of the mRNA expression levels of these seven genes showed that they are differentially expressed during seed development, and that some are preferentially expressed in aleurone tissue. These results suggest selective roles during PA biosynthesis, and that both lipid-independent and -dependent pathways are active in developing wheat grains. TaIPK1 and TaMRP3 were able to complement the yeast ScΔipk1 and ScΔycf1 mutants, respectively, providing evidence that the wheat genes have the expected biochemical functions. This is the first comprehensive study of the wheat genes involved in the late phase of PA biosynthesis. Knowledge generated from these studies could be utilized to develop strategies for generating low phyate wheat.

  15. The effect of cromolyn sodium and albuterol on early and late phase bronchoconstriction and airway leukocyte infiltration after allergen challenge of nonanesthetized guinea pigs.

    PubMed

    Hutson, P A; Holgate, S T; Church, M K

    1988-11-01

    We describe the effects of the antiallergic drug cromolyn sodium and the beta 2-selective adrenoceptor agonist albuterol against early and late phase changes in specific airways conductance (sGaw) and leukocyte infiltration into the airways after allergen challenge of nonanesthetized guinea pigs. Inhalation of ovalbumin by sensitized guinea pigs induced three phases of airways obstruction: an early asthmatic response (EAR) peaking at 2 h, a late response (LAR) peaking at 17 h, and a further late response (LLAR) being observed at 72 h. The LAR was accompanied by a 13-fold rise in neutrophils and a four-fold rise in eosinophils recovered by bronchoalveolar lavage (BAL) at 17 h. By 72 h, the BAL content of neutrophils had returned to near normal, whereas eosinophil numbers had risen to 6.7-fold above baseline. Inhalation of an aerosolized solution of cromolyn, 10 mg/ml, 15 min before challenge inhibited both the EAR and LAR and the influx of neutrophils into the airways at 17 h but had no effect on eosinophil accumulation. Inhalation of cromolyn at 6 h, i.e., after the completion of the EAR, inhibited the LAR, the LLAR, and the rise in eosinophils at 72 h but did not reduce the influx of neutrophils at 17 h. Administration of cromolyn at both 15 min before and 6 h after challenge inhibited all changes in sGaw and reduced the accumulation of neutrophils at 17 h and the influx of eosinophils at 72 h. In contrast, inhalation of albuterol, 0.1 mg/ml, 15 min before allergen provocation blocked the EAR and the rise in BAL neutrophils at 17 h but did not inhibit the LAR. Inhalation of albuterol at 6 h partially reversed the LAR but had no effect on either the LLAR or cellular changes. Given at both times, albuterol inhibited the EAR and neutrophil accumulation at 17 h and partially reversed the LAR but produced no other effects.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. 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

  17. Comparing the intestinal transcriptome of Meishan and Large White piglets during late fetal development reveals genes involved in glucose and lipid metabolism and immunity as valuable clues of intestinal maturity.

    PubMed

    Yao, Ying; Voillet, Valentin; Jegou, Maeva; SanCristobal, Magali; Dou, Samir; Romé, Véronique; Lippi, Yannick; Billon, Yvon; Père, Marie-Christine; Boudry, Gaëlle; Gress, Laure; Iannucelli, Nathalie; Mormède, Pierre; Quesnel, Hélène; Canario, Laurianne; Liaubet, Laurence; Le Huërou-Luron, Isabelle

    2017-08-22

    Maturity of intestinal functions is critical for neonatal health and survival, but comprehensive description of mechanisms underlying intestinal maturation that occur during late gestation still remain poorly characterized. The aim of this study was to investigate biological processes specifically involved in intestinal maturation by comparing fetal jejunal transcriptomes of two representative porcine breeds (Large White, LW; Meishan, MS) with contrasting neonatal vitality and maturity, at two key time points during late gestation (gestational days 90 and 110). MS and LW sows inseminated with mixed semen (from breed LW and MS) gave birth to both purebred and crossbred fetuses. We hypothesized that part of the differences in neonatal maturity between the two breeds results from distinct developmental profiles of the fetal intestine during late gestation. Reciprocal crossed fetuses were used to analyze the effect of parental genome. Transcriptomic data and 23 phenotypic variables known to be associated with maturity trait were integrated using multivariate analysis with expectation of identifying relevant genes-phenotypic variable relationships involved in intestinal maturation. A moderate maternal genotype effect, but no paternal genotype effect, was observed on offspring intestinal maturation. Four hundred and four differentially expressed probes, corresponding to 274 differentially expressed genes (DEGs), more specifically involved in the maturation process were further studied. In day 110-MS fetuses, Ingenuity® functional enrichment analysis revealed that 46% of DEGs were involved in glucose and lipid metabolism, cell proliferation, vasculogenesis and hormone synthesis compared to day 90-MS fetuses. Expression of genes involved in immune pathways including phagocytosis, inflammation and defense processes was changed in day 110-LW compared to day 90-LW fetuses (corresponding to 13% of DEGs). The transcriptional regulator PPARGC1A was predicted to be an important

  18. Early versus Late-Phase Consolidation of Opiate Reward Memories Requires Distinct Molecular and Temporal Mechanisms in the Amygdala-Prefrontal Cortical Pathway

    PubMed Central

    Gholizadeh, Shervin; Sun, Ninglei; De Jaeger, Xavier; Bechard, Melanie; Coolen, Lique; Laviolette, Steven R.

    2013-01-01

    The consolidation of newly acquired memories involves the temporal transition from a recent, less stable trace to a more permanent consolidated form. Opiates possess potent rewarding effects and produce powerful associative memories. The activation of these memories is associated with opiate abuse relapse phenomena and the persistence of compulsive opiate dependence. However, the neuronal, molecular and temporal mechanisms by which associative opiate reward memories are consolidated are not currently understood. We report that the consolidation of associative opiate reward memories involves a temporal and molecular switch between the basolateral nucleus of the amygdala (BLA) (early consolidation phase) to the medial prefrontal cortex (mPFC) (late consolidation phase). We demonstrate at the molecular, behavioral and neuronal levels that the consolidation of a recently acquired opiate reward memory involves an extracellular signal-related kinase (ERK)-dependent phosphorylation process within the BLA. In contrast, later-stage consolidation of a newly acquired memory is dependent upon a calcium-calmodulin-dependent (CaMKII), ERK-independent, mechanism in the mPFC, over a 12 hr temporal gradient. In addition, using in vivo multi-unit neuronal recordings in the mPFC, we report that protein synthesis within the BLA modulates the consolidation of opiate-reward memory in neuronal mPFC sub-populations, via the same temporal dynamic. PMID:23696837

  19. Yersinia pestis requires the 2-component regulatory system OmpR-EnvZ to resist innate immunity during the early and late stages of plague.

    PubMed

    Reboul, Angéline; Lemaître, Nadine; Titecat, Marie; Merchez, Maud; Deloison, Gaspard; Ricard, Isabelle; Pradel, Elizabeth; Marceau, Michaël; Sebbane, Florent

    2014-11-01

    Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2-component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. 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

    2014-10-10

    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.

  1. Mouse embryos stressed by physiological levels of osmolarity become arrested in the late 2-cell stage before entry into M phase.

    PubMed

    Wang, Fang; Kooistra, Megan; Lee, Martin; Liu, Lin; Baltz, Jay M

    2011-10-01

    Preimplantation mouse embryos of many strains become arrested at the 2-cell stage if the osmolarity of culture medium that normally supports development to blastocysts is raised to approximately that of their normal physiological environment in the oviduct. Arrest can be prevented if molecules that serve as "organic osmolytes" are present in the medium, because organic osmolytes, principally glycine, are accumulated by embryos to provide intracellular osmotic support and regulate cell volume. Medium with an osmolarity of 310 mOsM induced arrest of approximately 80% of CF1 mouse embryos at the 2-cell stage, in contrast to the approximately 100% that progressed beyond the 2-cell stage at 250 or 301 mOsM with glycine. The nature of this arrest induced by physiological levels of osmolarity is unknown. Arrest was reversible by transfer to lower-osmolarity medium at any point during the 2-cell stage, but not after embryos would normally have progressed to the 4-cell stage. Cessation of development likely was not due to apoptosis, as shown by lack of external annexin V binding, detectable cytochrome c release from mitochondria, or nuclear DNA fragmentation. Two-cell embryos cultured at 310 mOsM progressed through the S phase, and zygotic genome activation markers were expressed. However, most embryos failed to initiate the M phase, as evidenced by intact nuclei with decondensed chromosomes, low M-phase promoting factor activity, and an inactive form of CDK1, although a few blastomeres were arrested in metaphase. Thus, embryos become arrested late in the G(2) stage of the second embryonic cell cycle when stressed by physiological osmolarity in the absence of organic osmolytes.

  2. Mouse Embryos Stressed by Physiological Levels of Osmolarity Become Arrested in the Late 2-Cell Stage Before Entry into M Phase1

    PubMed Central

    Wang, Fang; Kooistra, Megan; Lee, Martin; Liu, Lin; Baltz, Jay M.

    2011-01-01

    Preimplantation mouse embryos of many strains become arrested at the 2-cell stage if the osmolarity of culture medium that normally supports development to blastocysts is raised to approximately that of their normal physiological environment in the oviduct. Arrest can be prevented if molecules that serve as “organic osmolytes” are present in the medium, because organic osmolytes, principally glycine, are accumulated by embryos to provide intracellular osmotic support and regulate cell volume. Medium with an osmolarity of 310 mOsM induced arrest of approximately 80% of CF1 mouse embryos at the 2-cell stage, in contrast to the approximately 100% that progressed beyond the 2-cell stage at 250 or 301 mOsM with glycine. The nature of this arrest induced by physiological levels of osmolarity is unknown. Arrest was reversible by transfer to lower-osmolarity medium at any point during the 2-cell stage, but not after embryos would normally have progressed to the 4-cell stage. Cessation of development likely was not due to apoptosis, as shown by lack of external annexin V binding, detectable cytochrome c release from mitochondria, or nuclear DNA fragmentation. Two-cell embryos cultured at 310 mOsM progressed through the S phase, and zygotic genome activation markers were expressed. However, most embryos failed to initiate the M phase, as evidenced by intact nuclei with decondensed chromosomes, low M-phase promoting factor activity, and an inactive form of CDK1, although a few blastomeres were arrested in metaphase. Thus, embryos become arrested late in the G2 stage of the second embryonic cell cycle when stressed by physiological osmolarity in the absence of organic osmolytes. PMID:21697513

  3. Radiation dose reduction in abdominal computed tomography during the late hepatic arterial phase using a model-based iterative reconstruction algorithm: how low can we go?

    PubMed

    Husarik, Daniela B; Marin, Daniele; Samei, Ehsan; Richard, Samuel; Chen, Baiyu; Jaffe, Tracy A; Bashir, Mustafa R; Nelson, Rendon C

    2012-08-01

    The aim of this study was to compare the image quality of abdominal computed tomography scans in an anthropomorphic phantom acquired at different radiation dose levels where each raw data set is reconstructed with both a standard convolution filtered back projection (FBP) and a full model-based iterative reconstruction (MBIR) algorithm. An anthropomorphic phantom in 3 sizes was used with a custom-built liver insert simulating late hepatic arterial enhancement and containing hypervascular liver lesions of various sizes. Imaging was performed on a 64-section multidetector-row computed tomography scanner (Discovery CT750 HD; GE Healthcare, Waukesha, WI) at 3 different tube voltages for each patient size and 5 incrementally decreasing tube current-time products for each tube voltage. Quantitative analysis consisted of contrast-to-noise ratio calculations and image noise assessment. Qualitative image analysis was performed by 3 independent radiologists rating subjective image quality and lesion conspicuity. Contrast-to-noise ratio was significantly higher and mean image noise was significantly lower on MBIR images than on FBP images in all patient sizes, at all tube voltage settings, and all radiation dose levels (P < 0.05). Overall image quality and lesion conspicuity were rated higher for MBIR images compared with FBP images at all radiation dose levels. Image quality and lesion conspicuity on 25% to 50% dose MBIR images were rated equal to full-dose FBP images. This phantom study suggests that depending on patient size, clinically acceptable image quality of the liver in the late hepatic arterial phase can be achieved with MBIR at approximately 50% lower radiation dose compared with FBP.

  4. Kinetics of force recovery following length changes in active skinned single fibres from rabbit psoas muscle: analysis and modelling of the late recovery phase.

    PubMed

    Burton, Kevin; Simmons, Robert M; Sleep, John; Simmons, Robert M; Burton, Kevin; Smith, David A

    2006-06-01

    Redevelopment of isometric force following shortening of skeletal muscle is thought to result from a redistribution of cross-bridge states. We varied the initial force and cross-bridge distribution by applying various length-change protocols to active skinned single fibres from rabbit psoas muscle, and observed the effect on the slowest phase of recovery ('late recovery') that follows transient changes. In response to step releases that reduced force to near zero ( approximately 8 nm (half sarcomere)(-1)) or prolonged shortening at high velocity, late recovery was well described by two exponentials of approximately equal amplitude and rate constants of approximately 2 s(-1) and approximately 9 s(-1) at 5 degrees C. When a large restretch was applied at the end of rapid shortening, recovery was accelerated by (1) the introduction of a slow falling component that truncated the rise in force, and (2) a relative increase in the contribution of the fast exponential component. The rate of the slow fall was similar to that observed after a small isometric step stretch, with a rate of 0.4-0.8 s(-1), and its effects could be reversed by reducing force to near zero immediately after the stretch. Force at the start of late recovery was varied in a series of shortening steps or ramps in order to probe the effect of cross-bridge strain on force redevelopment. The rate constants of the two components fell by 40-50% as initial force was raised to 75-80% of steady isometric force. As initial force increased, the relative contribution of the fast component decreased, and this was associated with a length constant of about 2 nm. The results are consistent with a two-state strain-dependent cross-bridge model. In the model there is a continuous distribution of recovery rate constants, but two-exponential fits show that the fast component results from cross-bridges initially at moderate positive strain and the slow component from cross-bridges at high positive strain.

  5. Trade-off between L-thyroxin and melatonin in immune regulation of the Indian palm squirrel, Funambulus pennanti during the reproductively inactive phase.

    PubMed

    Rai, Seema; Haldar, Chandana; Singh, Shiv Shankar

    2005-01-01

    The thyroid gland and its hormones have been reported to influence reproduction and metabolism in a positive manner. However, research to date provides strong evidence for a reciprocal relationship between the immune system and hormones of the hypothalamus-pituitary-thyroid axis. The present study has been taken to elucidate the effect of L-thyroxin (T(4)) on immune parameters such as total leukocyte count, percent lymphocyte count, blastogenic response and percent stimulation ratio of thymocytes and splenocytes of a seasonally breeding rodent, Funambulus pennanti, during its reproductively inactive phase when peripheral T(4) is low. Treatment with L-thyroxin at a near-physiological dose of 35 microg/100 g body weight during evening hours showed a significant elevation of all immune parameters. However, combined treatment of L-thyroxin and melatonin (25 microg/100 g body weight) had no additive effect. On the other hand, in vitro supplementation of T(4) (10(-6) M) either alone or in combination with melatonin (0.5 microM) did not induce any significant change on thymocyte and splenocyte proliferation. Therefore, a trade-off effect of L-thyroxin and melatonin on the immune system (T- and B-cell differentiation) is suggested for this rodent.

  6. Transfusion of Plasma Collected at Late Phase after Preconditioning Reduces Myocardial Infarct Size Induced by Ischemia-reperfusion in Rats In vivo

    PubMed Central

    Zhao, Yang; Zheng, Zhi-Nan; Cheung, Chi-Wai; Zuo, Zhi-Yi; Jin, San-Qing

    2017-01-01

    Background: Plasma transfusion is a common clinical practice. Remote ischemic preconditioning (RIPC) protects organs against ischemia-reperfusion (IR) injury. Whether preconditioned plasma (PP), collected at late phase after RIPC, could protect organs against IR injury in vivo is unknown. This study explored whether transfusion of PP could reduce myocardial infarct size (IS) after IR in rat in vivo. Methods: Eighty Lewis rats were randomized to eight groups (n = 10 for each group). Two groups of plasma donor rats donated plasma at 48 h after transient limb ischemia (PP) or control protocol (nonpreconditioned plasma [NPP]). Six groups of recipient rats received normal saline (NS; NS-IR 1, and NS-IR 24 groups), NPP (NPP-IR 1 and NPP-IR 24 groups), or PP (PP-IR 1 and PP-IR 24 groups) at one or 24 h before myocardial IR. Myocardial IR consisted of 30-min left anterior descending (LAD) coronary artery occlusion and 180-min reperfusion. The area at risk (AAR) and infarct area were determined by double-staining with Evans blue and triphenyltetrazolium chloride. IS was calculated by infarct area divided by AAR. This was a 3 × 2 factorial design study, and factorial analysis was used to evaluate the data. If an interaction between the fluid and transfusion time existed, one-way analysis of variance with Bonferroni correction for multiple comparisons was used to analyze the single effects of fluid type when the transfusion time was fixed. Results: IS in the NPP-IR 1 and PP-IR 1 groups was smaller than in the NS-IR 1 group (F = 6.838, P = 0.005; NPP-IR 1: 57 ± 8% vs. NS-IR1: 68 ± 6%, t = 2.843, P = 0.020; PP-IR 1: 56 ± 8% vs. NS-IR 1: 68 ± 6%, t = 3.102, P = 0.009), but no significant difference was detected between the NPP-IR 1 and PP-IR 1 groups (57 ± 8% vs. 56 ± 8%, t = 0.069, P = 1.000). IS in the NPP-IR 24 and PP-IR 24 groups was smaller than in the NS-IR 24 group (F = 24.796, P < 0.001; NPP-IR 24: 56% ± 7% vs. NS-IR 24: 68 ± 7%, t = 3.102, P = 0.026; PP-IR 24

  7. Coupling between physiological TSPO expression in brain and myocardium allows stabilization of late-phase cerebral [(18)F]GE180 PET quantification.

    PubMed

    Deussing, Maximilian; Blume, Tanja; Vomacka, Lena; Mahler, Christoph; Focke, Carola; Todica, Andrei; Unterrainer, Marcus; Albert, Nathalie L; Lindner, Simon; von Ungern-Sternberg, Barbara; Baumann, Karlheinz; Zwergal, Andreas; Bartenstein, Peter; Herms, Jochen; Rominger, Axel; Brendel, Matthias

    2017-10-05

    PET imaging of the 18 kDa translocator protein (TSPO), a biomarker of microglial activity, receives growing interest in clinical and preclinical applications of neuroinflammatory and neurodegenerative brain diseases. In globally affected brains, intra-cerebral pseudo reference regions are not feasible. Consequently, many brain-independent approaches have been attempted, including SUV analysis and normalization to muscle- or heart uptake, aiming to stabilize quantitative analysis. In this study, we systematically compared different image normalization methods for static late phase TSPO-PET imaging of rodent brain. We first obtained gamma counter measurements for gold standard quantitation of [(18)F]GE180 uptake in brain of C57Bl/6 mice (N = 10) after PET, aiming to identify factors contributing significantly to the quantitative results. Subsequently, data from a large cohort of C57Bl/6 mice (N = 79) were compiled to precisely determine the weighted influence and variance attributable these factors by regression analysis. Scan-rescan variability and agreement with histology were used to validate the tested normalization methods in an Alzheimer's disease (AD) mouse model with pathologically increased TSPO expression (PS2APP; N = 24). Longitudinal data from AD model mice (N = 10) scanned at four different ages were used to challenge and validate the different normalization methods in a practical application. Gamma counter results revealed that injected dose, body weight and PET-measured radioactivity concentration in the ventral myocardium all significantly accounted for [(18)F]GE180 activity in the brain. Skeletal muscle activity had high test-retest variance in this PET only application and was therefore pursued no further. Regression analysis of the large scale evaluation showed that scaling to injected dose or SUV analysis accounted for little variance in brain activity (R(2) < 0.5), but inclusion of myocardial activity together with injected dose and

  8. Screening probiotic candidates for a mixture of probiotics to enhance the growth performance, immunity, and disease resistance of Asian seabass, Lates calcarifer (Bloch), against Aeromonas hydrophila.

    PubMed

    Lin, Hsueh-Li; Shiu, Ya-Li; Chiu, Chiu-Shia; Huang, Shih-Ling; Liu, Chun-Hung

    2017-01-01

    Six bacteria, including, Lactobacillus casei M15, Lac. plantarum D8, Lac. pentosus BD6, Lac. fermentum LW2, Enterococcus faecium 10-10, and Bacillus subtilis E20, and one yeast, Saccharomyces cerevisiae P13 were selected as probiotics for Asian seabass, Lates calcarifer, by tracking the growth performance and disease resistance of fish against Aeromonas hydrophila in the first trial. The probiotic efficiency screening results showed that B. subtilis E20 and Lac. pentosus BD6, and S. cerevisiae P13 and Lac. fermentum LW2 respectively improved either the growth performance or disease resistance. Therefore, these four probiotics were then selected to prepare a probiotics mixture, and this was incorporated in equal proportions into diets for Asian seabass at levels of 0 (control), and 10(6) (MD6), 10(7) (MD7), 10(8) (MD8), and 10(9) (MD9) colony-forming units (cfu) (kg diet)(-1). A synergistic effect of the combined probiotics was investigated in this study, and the probiotics mixture was able to improve both the growth performance and health status of fish. After 56 days of feeding, fish fed the MD9 diet had a higher final weight and percentage of weight gain. In addition, protein contents in the dorsal muscle of fish fed the MD8 and MD9 diets were significantly higher compared to the control. For the pathogen challenge test, fish fed the MD7, MD8, and MD9 diets had significantly lower cumulative mortalities after A. hydrophila infection compared to those of fish fed the control and MD6 diets, which might have been due to increased respiratory bursts, decreased superoxide dismutase activity in leucocytes, and increased phagocytic activity. Therefore, we considered that the probiotics mixture could adequately provide probiotic efficiency for Asian seabass, and the diet containing 10(9) cfu (kg diet)(-1) probiotic mixture is recommended to improve the growth and health status of Asian seabass.

  9. Effect of delaying prophylaxis against CMV in D+/R- solid organ transplant recipients in the development of CMV-specific cellular immunity and occurrence of late CMV disease.

    PubMed

    San-Juan, R; Navarro, D; García-Reyne, A; Montejo, M; Muñoz, P; Carratala, J; Len, O; Fortun, J; Muñoz-Cobo, B; Gimenez, E; Eworo, A; Sabe, N; Meije, Y; Martin-Davila, P; Andres, A; Delgado, J; Jimenez, C; Amat, P; Fernández-Ruiz, M; López-Medrano, F; Lumbreras, C; Aguado, J M

    2015-11-01

    Evaluate the protective effect against late CMV disease of delaying antiviral prophylaxis initiation in D+/R- patients receiving solid organ transplant (SOT). Prospective multicenter study in D+/R- SOT recipients in Spain (Sept/09-Sept/12). Whole blood specimens were prospectively collected after Tx for CMV-specific cell-mediated immunity (CMI) determination. Two prophylaxis strategies were compared: early prophylaxis (EP; starting within the first 3 days after Tx) and delayed prophylaxis (DP; starting 14 days after Tx). Risk factors for the occurrence of CMV disease were determined by survival analysis and proportional risk Cox regression models. We included 95 patients (50 EP V 45 DP). Twenty six patients (27.4%) developed CMV disease: 32.7% EP vs. 20% DP; (p = 0.2). No cases of CMV disease were reported previously to beginning delayed prophylaxis. The percentage of individuals with detectable CMI response was higher in patients with DP although differences did not reach statistic significance (42% vs 29.6% at day 200 after Tx; p = 0.4). There was a clear trend towards less end-organ CMV disease in patients receiving DP (18.2% EP vs 5% DP; p = 0.09) and DP was the only protective factor in the multivariate analysis (HR: 0.26; CI: 0.05-1.2; p = 0.09). A 14-day delay in CMV prophylaxis in D+/R- SOT recipients is safe and may reduce the incidence of late CMV end-organ disease although correlation of this effect with CMI responses was not complete. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  10. Broad and potent cellular and humoral immune responses after a second late HIV-modified vaccinia virus ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccinees.

    PubMed

    Nilsson, Charlotta; Godoy-Ramirez, Karina; Hejdeman, Bo; Bråve, Andreas; Gudmundsdotter, Lindvi; Hallengärd, David; Currier, Jeffrey R; Wieczorek, Lindsay; Hasselrot, Klara; Earl, Patricia L; Polonis, Victoria R; Marovich, Mary A; Robb, Merlin L; Sandström, Eric; Wahren, Britta; Biberfeld, Gunnel

    2014-03-01

    We have previously shown that an HIV vaccine regimen including three HIV-DNA immunizations and a single HIV-modified vaccinia virus Ankara (MVA) boost was safe and highly immunogenic in Swedish volunteers. A median 38 months after the first HIV-MVA vaccination, 24 volunteers received 10(8) plaque-forming units of HIV-MVA. The vaccine was well tolerated. Two weeks after this HIV-MVA vaccination, 18 (82%) of 22 evaluable vaccinees were interferon (IFN)-γ enzyme-linked immunospot (ELISpot) reactive: 18 to Gag and 10 (45%) to Env. A median minimal epitope count of 4 to Gag or Env was found in a subset of 10 vaccinees. Intracellular cytokine staining revealed CD4(+) and/or CD8(+) T cell responses in 23 (95%) of 24 vaccinees, 19 to Gag and 19 to Env. The frequency of HIV-specific CD4(+) and CD8(+) T cell responses was equally high (75%). A high proportion of CD4(+) and CD8(+) T cell responses to Gag was polyfunctional with production of three or more cytokines (40% and 60%, respectively). Of the Env-specific CD4(+) T cells 40% were polyfunctional. Strong lymphoproliferative responses to Aldrithiol-2 (AT-2)-treated subtype A, B, C, and A_E virus were demonstrable in 21 (95%) of 22 vaccinees. All vaccinees developed binding antibodies to Env and Gag. Neutralizing antibodies were detected in a peripheral blood mononuclear cell (PBMC)-based assay against subtype B and CRF01_AE viruses. The neutralizing antibody response rates were influenced by the vaccine dose and/or mode of delivery used at the previous HIV-MVA vaccination. Thus, a second late HIV-MVA boost induced strong and broad cellular immune responses and improved antibody responses. The data support further exploration of this vaccine concept.

  11. Broad and Potent Cellular and Humoral Immune Responses After a Second Late HIV-Modified Vaccinia Virus Ankara Vaccination in HIV-DNA-Primed and HIV-Modified Vaccinia Virus Ankara-Boosted Swedish Vaccinees

    PubMed Central

    Godoy-Ramirez, Karina; Hejdeman, Bo; Bråve, Andreas; Gudmundsdotter, Lindvi; Hallengärd, David; Currier, Jeffrey R.; Wieczorek, Lindsay; Hasselrot, Klara; Earl, Patricia L.; Polonis, Victoria R.; Marovich, Mary A.; Robb, Merlin L.; Sandström, Eric; Wahren, Britta; Biberfeld, Gunnel

    2014-01-01

    Abstract We have previously shown that an HIV vaccine regimen including three HIV-DNA immunizations and a single HIV-modified vaccinia virus Ankara (MVA) boost was safe and highly immunogenic in Swedish volunteers. A median 38 months after the first HIV-MVA vaccination, 24 volunteers received 108 plaque-forming units of HIV-MVA. The vaccine was well tolerated. Two weeks after this HIV-MVA vaccination, 18 (82%) of 22 evaluable vaccinees were interferon (IFN)-γ enzyme-linked immunospot (ELISpot) reactive: 18 to Gag and 10 (45%) to Env. A median minimal epitope count of 4 to Gag or Env was found in a subset of 10 vaccinees. Intracellular cytokine staining revealed CD4+ and/or CD8+ T cell responses in 23 (95%) of 24 vaccinees, 19 to Gag and 19 to Env. The frequency of HIV-specific CD4+ and CD8+ T cell responses was equally high (75%). A high proportion of CD4+ and CD8+ T cell responses to Gag was polyfunctional with production of three or more cytokines (40% and 60%, respectively). Of the Env-specific CD4+ T cells 40% were polyfunctional. Strong lymphoproliferative responses to Aldrithiol-2 (AT-2)-treated subtype A, B, C, and A_E virus were demonstrable in 21 (95%) of 22 vaccinees. All vaccinees developed binding antibodies to Env and Gag. Neutralizing antibodies were detected in a peripheral blood mononuclear cell (PBMC)-based assay against subtype B and CRF01_AE viruses. The neutralizing antibody response rates were influenced by the vaccine dose and/or mode of delivery used at the previous HIV-MVA vaccination. Thus, a second late HIV-MVA boost induced strong and broad cellular immune responses and improved antibody responses. The data support further exploration of this vaccine concept. PMID:24090081

  12. 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

  13. Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat

    PubMed Central

    Cao, Guan

    2012-01-01

    Long-term potentiation (LTP) is a form of synaptic plasticity thought to underlie memory; thus knowing its developmental profile is fundamental to understanding function. Like memory, LTP has multiple phases with distinct timing and mechanisms. The late phase of LTP (L-LTP), lasting longer than 3 h, is protein synthesis dependent and involves changes in the structure and content of dendritic spines, the major sites of excitatory synapses. In previous work, tetanic stimulation first produced L-LTP at postnatal day 15 (P15) in area CA1 of rat hippocampus. Here we used a more robust induction paradigm involving theta-burst stimulation (TBS) in acute slices and found the developmental onset of L-LTP to be 3 days earlier at P12. In contrast, at P8–11, TBS only reversed the synaptic depression that occurs from test-pulse stimulation in developing (P8–15) hippocampus. A second bout of TBS delivered 30–180 min later produced L-LTP at P10–11 but not at P8–9 and enhanced L-LTP at P12–15. Both the developmental onset and the enhanced L-LTP produced by repeated bouts of TBS were blocked by the N-methyl-d-aspartate receptor antagonist dl-2-amino-5-phosphonovaleric acid. Thus the developmental onset age is P12 for L-LTP induced by the more robust and perhaps more naturalistic TBS induction paradigm. Metaplasticity produced by repeated bouts of TBS is developmentally regulated, advancing the capacity for L-LTP from P12 to P10, but not to younger ages. Together these findings provide a new basis from which to investigate mechanisms that regulate the developmental onset of this important form of synaptic plasticity. PMID:22114158

  14. 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.

  15. Low-frequency stimulation induces a pathway-specific late phase of LTP in the amygdala that is mediated by PKA and dependent on protein synthesis

    PubMed Central

    Huang, Yan-You; Kandel, Eric R.

    2007-01-01

    Activity-dependent changes in synaptic efficacy are thought to be the key cellular mechanism for the formation and storage of both explicit and implicit memory. Different patterns of stimulation can elicit different changes in the efficiency on excitatory synaptic transmission. Here, we examined the synaptic changes in the amygdala of adult mice produced by low-frequency stimulation (1 Hz, 15 min, LFS). We first compared the synaptic changes induced by LFS in three different synaptic pathways of amygdala: cortical–lateral amygdala, thalamic–lateral amygdala, and lateral–basolateral amygdala pathways. We find that the plastic changes induced by LFS are different between synaptic pathways. Low-frequency stimulation selectively elicits a slow onset and protein synthesis-dependent late-phase LTP in the cortical–lateral amygdala pathway, but not in the thalamic–lateral or lateral–basolateral pathways. We next analyzed LTP induced by LFS in the cortical–lateral amygdala pathway and found that three PKA-coupling neurotransmitter receptors are involved: 5-HT4, Dopamine D1, and β-adrenergic receptors. Antagonists of these receptors block the LFS L-LTP, but the effects of agonists of these receptors are clearly different. These results indicate that the threshold for the induction of LFS L-LTP is different among these pathways and that the maintenance of LFS L-LTP requires a cross-talk among multiple neurotransmitters. PMID:17626908

  16. Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase.

    PubMed Central

    Chiariello, M; Gomez, E; Gutkind, J S

    2000-01-01

    Mitogen-activated protein (MAP) kinases, p42(MAPK) and p44(MAPK), are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G(1)/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G(1) phase, once the known mechanisms by which MAP kinase controls G(1) progression, accumulation of G(1) cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control. PMID:10903150

  17. Progesterone supplementation in the late follicular phase of an in-vitro fertilization cycle: a 'natural' way to time oocyte recovery?

    PubMed

    Howles, C M; Macnamee, M C; Edwards, R G

    1988-05-01

    Twenty-eight patients superovulated with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) were given a single injection of 25 mg progesterone (P group) 4 h prior to the ovulation-inducing injection of human chorionic gonadotrophin (HCG). Plasma and urinary LH levels were significantly higher (P less than 0.05) in the P group immediately prior to HCG compared to controls. Plasma progesterone concentrations were also elevated (P less than 0.01) in the P group from the time of injection to oocyte recovery. The number of mature oocytes recovered was also higher (P less than 0.001; 59% versus 40% in controls) and the time interval between oocyte recovery and insemination was also shorter (P less than 0.01) in the P group. The pregnancy rate/replacement 15 days after oocyte recovery was 39% versus 23% in the P and control groups respectively. It was concluded that as more mature oocytes were recovered in the P group, progesterone supplementation in the late follicular phase may be beneficial for patients undergoing GIFT. This was borne out when the first two GIFT patients pretreated in this way became pregnant.

  18. Influence of thermal stimulation during the late phase of incubation on hatching results and post-hatch broiler performance under commercial conditions.

    PubMed

    Elmehdawi, A S; Hall, M A; Skewes, P A; Wicker, D L; Maurice, D V

    2016-12-01

    Two experiments, which differed in breeder age, strain and season, were conducted to study the influence of low-intensity, short-duration thermal stimuli during the late phase of incubation on hatchability and performance. The first experiment conducted in April-June used eggs from Cobb × Ross broiler breeders at 35-41 weeks of age and the second experiment performed in February-April used eggs from Hubbard × Cobb broiler breeders at 49-53 weeks of age. Eggs in the test group had the same physical environment as eggs in the control group except that incubation temperature was increased by 1˚C for 2 h/d above the control group from 18 to 20 d of incubation (DI). The results demonstrated that thermal stimulation of 1˚C for 2 h/d above control incubation temperature during 18-21DI did not have any adverse effects on hatch and post-hatch performance of broilers. In both experiments, treatment did not significantly alter the secondary sex ratio in hatched chickens, but hatch residue showed that the proportion of unhatched male embryos was significantly lower in the test groups than in the control groups. In the first experiment, thermal stimulation improved feed conversion by 1.82% compared with the control.

  19. Use of solid-phase immune electron microscopy for classification of Norwalk-like viruses into six antigenic groups from 10 outbreaks of gastroenteritis in the United States.

    PubMed Central

    Lewis, D; Ando, T; Humphrey, C D; Monroe, S S; Glass, R I

    1995-01-01

    Norwalk-like viruses observed in fecal specimens from 10 outbreaks of gastroenteritis investigated in the United States between 1987 and 1992 were analyzed by solid-phase immune electron microscopy. Outbreak virus strains were classified into six antigenic groups: the four types (UK1 to UK4) previously defined in the United Kingdom, Norwalk virus, and the Oklahoma agent that was newly defined in this study. The diversity of antigenic types demonstrated in these outbreaks was greater than previously recognized and will serve as a basis for characterization of these strains at the molecular level. PMID:7714218

  20. Changes in number of water-filled vesicles of choroid plexus in early and late phase of experimental rabbit subarachnoid hemorrhage model: the role of petrous ganglion of glossopharyngeal nerve.

    PubMed

    Aydin, Mehmet Dumlu; Kanat, Ayhan; Turkmenoglu, Osman Nuri; Yolas, Coskun; Gundogdu, Cemal; Aydın, Nazan

    2014-07-01

    Cerebrospinal fluid (CSF) secretion may be increased in the early phases of subarachnoid hemorrhage (SAH), possibly via ischemic glossopharyngeal nerve discharges, and decreased due to glossopharyngeal nerve degeneration in the late phase of SAH; but this reflex pathway has not been definitively investigated. We studied the relationship between petrous ganglion of the glossopharyngeal nerve (GPN) and water vesicles of the choroid plexus (CP) in the early and late phases of SAH. This study was conducted on 30 rabbits, divided into four groups, with five rabbits in the control group (group I), five rabbits in the sham group (Group II), and 20 rabbits in the SAH group. In the SAH group, five of the animals were decapitated after 4 days of cisternal blood injections (Group III), and the other 15 animals were decapitated after 20 days of injections (Group IV). The Petrous Ganglia and CPs of lateral ventricles were removed and stained for stereological analysis. The mean number of follicles per cubic millimeter was 5.3 ± 1.2 the in control group (Group I), 4.5 ± 0.9 in the sham group (Group II), 16.60 ± 3.77 the in early decapitated group (Group III), and 4.30 ± 0.84 in the late decapitated group (Group IV). The mean number of degenerated neuron density of petrous ganglions was 6 ± 2, 50 ± 6, 742 ± 96, and 2.420 ± 350 in the control (Group I), sham (Group II), early decapitated (Group III), and late decapitated group (Group IV), respectively. The mean number of water vesicles was statistically different after SAH between the early decapitated group (group III) and the late decapitated group (group IV) (P < 0.05). We studied the relationship between petrous ganglion cells of the GPN and water vesicles of CP in the early and late phases of SAH, and found that CP vesicles are increased in the early phase of SAH due to irritation of GPN, and decreased in the late phase due to ischemic insult of the petrous ganglion and

  1. 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

  2. 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

    2016-05-13

    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.

  3. 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

  4. Conditional deletion of Stat3 in mammary epithelium impairs the acute phase response and modulates immune cell numbers during post-lactational regression

    PubMed Central

    Hughes, Katherine; Wickenden, Julie A; Allen, Judith E; Watson, Christine J

    2012-01-01

    Mammary gland regression following weaning (involution) is associated with extensive cell death and the acquisition of an inflammatory signature. Characterizing the interplay between mammary epithelial cells, the re-emerging stroma and immune cells has implications for the understanding of the pathogenesis of pregnancy-associated breast cancer. Stat3 has a role in orchestrating cell death and involution, and we sought to determine whether expression of Stat3 by the mammary epithelium also influences the innate immune environment and inflammatory cell influx in the gland. We examined mice in which Stat3 is conditionally deleted only in the mammary epithelium. Distinct sets of genes associated with the acute phase response and innate immunity are markedly up-regulated during first phase involution in a Stat3-dependent manner. During second phase involution, chitinase 3-like 1, which has been associated with wound healing and chronic inflammatory conditions, is dramatically up-regulated by Stat3. Also at this time, the number of mammary macrophages and mast cells increases per unit area, and this increase is impaired in the absence of epithelial Stat3. Furthermore, expression of arginase-1 and Ym1, markers of alternatively activated macrophages, is significantly decreased in the absence of Stat3, whilst iNOS, a marker associated with classically activated macrophages, shows significantly increased expression in the Stat3-deleted glands. Thus, Stat3 is a key transcriptional regulator of genes associated with innate immunity and wound healing and influences mammary macrophage and mast cell numbers. The presence of epithelial Stat3 appears to polarize the macrophages and epithelial cells towards an alternatively activated phenotype, since in the absence of Stat3, the gland retains a phenotype associated with classically activated macrophages. These findings have relevance to the study of pregnancy-associated breast cancer and the role of Stat3 signalling in recruitment

  5. [Dynamic expression profile of HBsAg according to hepatic parenchyma cells' volume at different liver fibrosis stages in the immune clearance phase].

    PubMed

    Wu, Zhe-bin; Cao, Hong; Liu, Ting; Wu, Ze-qian; Ke, Wei-min; Gao, Zhi-liang

    2012-10-01

    The aim of this study was to determine the dynamic expression profile of hepatitis B surface antigen (HBsAg) according to hepatic parenchyma cells' volume at different stages of liver fibrosis during the immune clearance phase. Eighty-nine patients with HBeAg-positive chronic hepatitis B (CHB) in the immune clearance stage were recruited for study. Each patient's serum HBsAg levels were detected by electrochemiluminescence. The serum HBsAg levels were apportioned according to hepatic parenchyma cells' volume at liver fibrosis stages 1, 2, 3, and 4 and compared by ANOVA. The unapportioned serum HBsAg levels (IU/mL) at liver fibrosis stages 1 (227.2+/-237.7), 2 (211.0+/-131.4), 3(300.1+/-144.6), and 4 (278.7+/-148.8) were not significantly different (all comparisons, P range: 0.061 to 0.759). However, when the serum HBsAg levels were apportioned by the same hepatic parenchyma cells' volume at liver fibrosis stages 1 (343.9+/-359.8), 2 (336.4+/-209.5), 3 (508.7+/-245.1), and 4 (525.2+/-274.8), the levels were significantly different (all comparisons, F = 3.045 and P = 0.033; stage 1 vs. 3, P = 0.041; stage 1 vs. 4, P = 0.046; stage 2 vs. 3, P = 0.028; stage 2 vs. 4, P = 0.034). During the immune clearance phase of chronic hepatitis B, increased HBsAg expression is associated with increased hepatic parenchyma cells' volume and progressive liver fibrosis stage.

  6. Evidence of Significant Energy Input in the Late Phase of a Solar Flare from NuSTAR X-Ray Observations

    NASA Astrophysics Data System (ADS)

    Kuhar, Matej; Krucker, Säm; Hannah, Iain G.; Glesener, Lindsay; Saint-Hilaire, Pascal; Grefenstette, Brian W.; Hudson, Hugh S.; White, Stephen M.; Smith, David M.; Marsh, Andrew J.; Wright, Paul J.; Boggs, Steven E.; Christensen, Finn E.; Craig, William W.; Hailey, Charles J.; Harrison, Fiona A.; Stern, Daniel; Zhang, William W.

    2017-01-01

    We present observations of the occulted active region AR 12222 during the third Nuclear Spectroscopic Telescope ARray (NuSTAR) solar campaign on 2014 December 11, with concurrent Solar Dynamics Observatory (SDO)/AIA and FOXSI-2 sounding rocket observations. The active region produced a medium-size solar flare 1 day before the observations, at ∼18 UT on 2014 December 10, with the post-flare loops still visible at the time of NuSTAR observations. The time evolution of the source emission in the SDO/AIA 335 Å channel reveals the characteristics of an extreme-ultraviolet late-phase event, caused by the continuous formation of new post-flare loops that arch higher and higher in the solar corona. The spectral fitting of NuSTAR observations yields an isothermal source, with temperature 3.8–4.6 MK, emission measure (0.3–1.8) × 1046 cm‑3, and density estimated at (2.5–6.0) × 108 cm‑3. The observed AIA fluxes are consistent with the derived NuSTAR temperature range, favoring temperature values in the range of 4.0–4.3 MK. By examining the post-flare loops’ cooling times and energy content, we estimate that at least 12 sets of post-flare loops were formed and subsequently cooled between the onset of the flare and NuSTAR observations, with their total thermal energy content an order of magnitude larger than the energy content at flare peak time. This indicates that the standard approach of using only the flare peak time to derive the total thermal energy content of a flare can lead to a large underestimation of its value.

  7. A Two-Phase Case-Control Study of Autism Risk Among Children Born From the Late 1990s Through the Early 2000s in the United States.

    PubMed

    Geier, David A; Kern, Janet K; Geier, Mark R

    2016-12-29

    BACKGROUND This study evaluated the hypothesis that the 1999 recommendation by the American Academy of Pediatrics (AAP) and US Public Health Service (PHS) to reduce exposure to mercury (Hg) from Thimerosal in US vaccines would be associated with a reduction in the long-term risk of being diagnosed with autism. MATERIAL AND METHODS A two-phase assessment utilizing a case (n=73) -control (n=11,783) study in the Vaccine Adverse Event Reporting System (VAERS) database (for hypothesis generating) and a more rigorous, independent matched case (n=40) -control (n=40) study (hypothesis testing) was undertaken. RESULTS Analysis of the VAERS database using logistic regression revealed that the odds ratio (OR) for being an autism case in the VAERS database significantly decreased with a more recent year of vaccination in comparison to controls (OR=0.65) from 1998 to 2003. Sex-separated analyses revealed similar significant effects for males (OR=0.62) and females (OR=0.71). Analyses of the matched case-control data revealed, using the t-test statistic, that the mean date of birth among cases diagnosed with an autism spectrum disorder (ASD) (2000.5±1.2) was significantly more in the past than in controls (2001.1±1.3). Logistic regression also revealed that the OR for being diagnosed with ASD significantly decreased with a more recent date of birth in comparison to controls (OR=0.67) from 1998-2003. CONCLUSIONS This study reveals that the risk of autism during from the late1990s to early 2000s in the US significantly decreased with reductions in Hg exposure from Thimerosal-containing childhood vaccines, but future studies should examine this phenomenon in other US populations. Vaccine programs have significantly reduced the morbidity and mortality associated with infectious disease, but Thimerosal should be removed from all vaccines.

  8. 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

  9. A Two-Phase Case-Control Study of Autism Risk Among Children Born From the Late 1990s Through the Early 2000s in the United States

    PubMed Central

    Geier, David A.; Kern, Janet K.; Geier, Mark R.

    2016-01-01

    Background This study evaluated the hypothesis that the 1999 recommendation by the American Academy of Pediatrics (AAP) and US Public Health Service (PHS) to reduce exposure to mercury (Hg) from Thimerosal in US vaccines would be associated with a reduction in the long-term risk of being diagnosed with autism. Material/Methods A two-phase assessment utilizing a case (n=73) -control (n=11,783) study in the Vaccine Adverse Event Reporting System (VAERS) database (for hypothesis generating) and a more rigorous, independent matched case (n=40) -control (n=40) study (hypothesis testing) was undertaken. Results Analysis of the VAERS database using logistic regression revealed that the odds ratio (OR) for being an autism case in the VAERS database significantly decreased with a more recent year of vaccination in comparison to controls (OR=0.65) from 1998 to 2003. Sex-separated analyses revealed similar significant effects for males (OR=0.62) and females (OR=0.71). Analyses of the matched case-control data revealed, using the t-test statistic, that the mean date of birth among cases diagnosed with an autism spectrum disorder (ASD) (2000.5±1.2) was significantly more in the past than in controls (2001.1±1.3). Logistic regression also revealed that the OR for being diagnosed with ASD significantly decreased with a more recent date of birth in comparison to controls (OR=0.67) from 1998–2003. Conclusions This study reveals that the risk of autism during from the late1990s to early 2000s in the US significantly decreased with reductions in Hg exposure from Thimerosal-containing childhood vaccines, but future studies should examine this phenomenon in other US populations. Vaccine programs have significantly reduced the morbidity and mortality associated with infectious disease, but Thimerosal should be removed from all vaccines.

  10. Evidence of Significant Energy Input in the Late Phase of A Solar Flare from NuSTAR X-Ray Observations

    NASA Technical Reports Server (NTRS)

    Kuhar, Matej; Krucker, Sam; Hannah, Iain G.; Glesener, Lindsay; Saint-Hilaire, Pascal; Grefenstette, Brian W.; Hudson, Hugh S.; White, Stephen M.; Smith, David M.; Marsh, Andrew J.; hide

    2017-01-01

    We present observations of the occulted active region AR 12222 during the third Nuclear Spectroscopic Telescope ARray (NuSTAR) solar campaign on 2014 December 11, with concurrent Solar Dynamics Observatory (SDO)/ AIA and FOXSI-2 sounding rocket observations. The active region produced a medium-size solar flare 1 day before the observations, at approximately 18 UT on 2014 December 10, with the post-flare loops still visible at the time of NuSTAR observations. The time evolution of the source emission in the SDO/AIA 335 Å channel reveals the characteristics of an extreme-ultraviolet late-phase event, caused by the continuous formation of new post-flare loops that arch higher and higher in the solar corona. The spectral fitting of NuSTAR observations yields an isothermal source, with temperature 3.8-4.6 MK, emission measure (0.3-1.8) × 1046 cm-3, and density estimated at (2.5-6.0) × 108 cm-3. The observed AIA fluxes are consistent with the derived NuSTAR temperature range, favoring temperature values in the range of 4.0-4.3 MK. By examining the post-flare loops' cooling times and energy content, we estimate that at least 12 sets of post-flare loops were formed and subsequently cooled between the onset of the flare and NuSTAR observations, with their total thermal energy content an order of magnitude larger than the energy content at flare peak time. This indicates that the standard approach of using only the flare peak time to derive the total thermal energy content of a flare can lead to a large underestimation of its value.

  11. Evolution of X-ray activity of 1-3 Msun late-type stars in early post-main-sequence phases

    NASA Astrophysics Data System (ADS)

    Pizzolato, N.; Maggio, A.; Sciortino, S.

    2000-09-01

    We have investigated the variation of coronal X-ray emission during early post-main-sequence phases for a sample of 120 late-type stars within 100 pc, and with estimated masses in the range 1-3 Msun, based on Hipparcos parallaxes and recent evolutionary models. These stars were observed with the ROSAT/PSPC, and the data processed with the Palermo-CfA pipeline, including detection and evaluation of X-ray fluxes (or upper limits) by means of a wavelet transform algorithm. We have studied the evolutionary history of X-ray luminosity and surface flux for stars in selected mass ranges, including stars with inactive A-type progenitors on the main sequence and lower mass solar-type stars. Our stellar sample suggests a trend of increasing X-ray emission level with age for stars with masses M > 1.5 Msun, and a decline for lower-mass stars. A similar behavior holds for the average coronal temperature, which follows a power-law correlation with the X-ray luminosity, independently of their mass and evolutionary state. We have also studied the relationship between X-ray luminosity and surface rotation rate for stars in the same mass ranges, and how this relationships departs from the Lx ~ vrot2 law followed by main-sequence stars. Our results are interpreted in terms of a magnetic dynamo whose efficiency depends on the stellar evolutionary state through the mass-dependent changes of the stellar internal structure, including the properties of envelope convection and the internal rotation profile.

  12. Effect of gestational protein deficiency and excess on hepatic expression of genes related to cell cycle and proliferation in offspring from late gestation to finishing phase in pig.

    PubMed

    Altmann, Simone; Murani, Eduard; Metges, Cornelia C; Schwerin, Manfred; Wimmers, Klaus; Ponsuksili, Siriluck

    2012-06-01

    Maternal diet during gestation is known to affect offspring phenotype induction. In the present study the influence of maternal protein restriction and excess during gestation on offspring candidate gene expression was analysed. German Landrace gilts were fed control, low protein (LP) or high protein (HP) diet throughout gestation (n = 18 per diet group). After birth piglets were cross-fostered and lactated by control diet fed nursing sows. Samples of offspring liver tissue were taken at foetal, newborn, weaning and finishing phase (n = 16, respectively). Transcript amount of selected candidate genes related to cell cycle and cell proliferation was estimated by quantitative real-time PCR. Maternal protein restriction influenced gene expression of candidate genes CCND2, GADD45B, GALK1, GSTP1, MARCKS, MGMT, NEAT1, PSEN1, SNX1 and TRPM7 in liver from foetuses, newborn piglets, weaned and/or finisher pigs. In the offspring of mothers fed a HP diet expression of target genes was affected exclusively in finisher pigs showing increased transcript amount of CCND2, GALK1, MARCKS, SNX1 and TRPM7. The results of the present study clearly show a long-lasting impact of the maternal protein supply during gestation on offspring candidate genes. Remarkably, effects of gestational HP diet became evident in finisher pigs while LP supply already alters genes expression in foetal tissue. Thus it is suggested that LP and HP supply affect the offspring in utero by different physiological mechanisms with the consequence of late effects in case of prenatal protein excess in contrast to early effects in case of protein restriction.

  13. First principles studies of the dependence of magnetism on the crystal phase in 4d and 5d late transition metals

    NASA Astrophysics Data System (ADS)

    Hüger, E.; Osuch, K.

    2005-03-01

    We investigate the possibility of inducing ferromagnetic order in 4d and 5d late transition metals through crystal symmetry change. First principles, self-consistent density functional theory calculations, with spin-orbit coupling included, performed at 0 K show that ferromagnetism occurs in the bulk of Rh and Pd at the optimum lattice constant if Rh is in the bcc and Pd in the hcp/dhcp phase. The ferromagnetic order originates in the d-band occupancy of Rh or Pd which locates the Fermi energy at the top of the highest peak of the respective (paramagnetic) density of states induced by the bcc or hcp/dhcp structure. This peak in the density of states is caused by flat bands which lie at the surface of the respective Brillouin zone. For a bcc crystal these flat bands have the eg character and are positioned at the surface of the bcc Brillouin zone along the N-P line. The origin of the flatness of the bands was found to be the translation symmetry of the cubic lattice which causes the bands with the eg character to be narrow along the k-lines whose k-vector directions are furthest off the directions to which the orbitals of the eg symmetry point. Due to the d-band occupancy of Rh these flat bands lie in the paramagnetic state at the Fermi energy, whereas in the ferromagnetic state they exhibit the largest energetic split. This indicates that a smaller degree of orbital overlap narrows electronic bands enhancing the tendency of the system for ferromagnetic band split. For the hcp/dhcp structure the states contributing to the high density of para-magnetic states at the Fermi level of Pd lie in the vicinity of the M-L line of the hcp Brillouin zone boundary, which possesses a high number of symmetry (M and L) points. Moreover, the M-L line is aligned with the stacking sequence direction ([0001]) which is furthest off the densest-packed atomic chain direction of an hcp-crystal and, consequently, the weakest-bond direction in the crystal. This makes the narrow bands along

  14. Immune System

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Immune System KidsHealth > For Teens > Immune System A A A ... could put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  15. Angiogenin is upregulated during the alloreactive immune response and has no effect on the T-cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T-cell apoptosis

    PubMed Central

    Eleftheriadis, Theodoros; Pissas, Georgios; Sounidaki, Maria; Antoniadis, Nikolaos; Antoniadi, Georgia; Liakopoulos, Vassilios; Stefanidis, Ioannis

    2016-01-01

    Under growth conditions, angiogenin is translocated into the nucleus, where it enhances ribosomal RNA transcription, facilitating increased protein synthesis and cellular proliferation. During stress conditions, angiogenin is sequestered in the cytoplasm, where it cleaves transfer RNA (tRNA) to produce tRNA-derived, stress-induced small RNAs (tiRNAs) that inhibit global protein synthesis, but increase the translation of anti-apoptotic factors. In the present study, the role of angiogenin in the human alloreactive immune response was evaluated using mixed lymphocyte reactions (MLRs) and neamine, an inhibitor of angiogenin nuclear translocation. In MLRs, angiogenin production was significantly (P<0.001) increased compared with resting peripheral blood mononuclear cells. The addition of neamine had no effect on cell proliferation, but did significantly (P<0.001) increase expression of Bcl-2-associated X protein and protein levels of activated caspase-3 in CD4+ T-cells isolated from the MLRs, indicating that angiogenin reduces apoptosis. In conclusion, angiogenin is upregulated during the alloreactive immune response, in which it does not affect the T-cell expansion phase, but inhibits the T-cell contraction phase by protecting against CD4+ T-cell apoptosis. PMID:27882181

  16. 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

  17. Quasispecies tropism and compartmentalization in gut and peripheral blood during early and chronic phases of HIV-1 infection: possible correlation with immune activation markers.

    PubMed

    Rozera, G; Abbate, I; Vlassi, C; Giombini, E; Lionetti, R; Selleri, M; Zaccaro, P; Bartolini, B; Corpolongo, A; D'Offizi, G; Baiocchini, A; Del Nonno, F; Ippolito, G; Capobianchi, M R

    2014-03-01

    HIV quasispecies was analysed in plasma and proviral genomes hosted by duodenal mucosa and peripheral blood cells (PBMC) from patients with early or chronic infection, with respect to viral heterogeneity, tropism compartmentalization and extent of immune activation. Seventeen HIV-1-infected combined antiretroviral therapy naive patients were enrolled (11 early infection and six chronic infection). V3 and nef genomic regions were analysed by ultra-deep pyrosequencing. Sequences were used to infer co-receptor usage and to construct phylogenetic trees. As markers of immune activation, plasma sCD14 and soluble tumour necrosis factor receptor II (sTNFRII) levels were measured. Median diversity of HIV RNA was lower in patients with early infection versus chronic infection patients. Overall, direct correlation was observed between V3 diversity and X4 frequency; V3 diversity of HIV RNA was inversely correlated with CD4 T-cell count; median sCD14 and sTNFRII values were similar in early and chronic patients, but X4 frequency of HIV RNA was directly correlated with plasma sCD14. The proportion of patients harbouring X4 variants and median intra-patient X4 frequency of proviral genomes tended to be higher in chronic infection than early infection patients. More pronounced compartmentalization of proviral quasispecies in gut compared with PBMC samples was observed in patients with early infection compared with chronic patients. The loss of gut/PBMC compartmentalization in more advanced stages of HIV infection was confirmed by longitudinal observation. More studies are needed to understand the pathogenetic significance of early HIV quasispecies compartmentalization and progressive intermixing of viral variants in subsequent phases of the infection, as well as the role of immune activation in tropism switch.

  18. The effects of phytase and root hydroalcoholic extract of Withania somnifera on productive performance and bone mineralisation of laying hens in the late phase of production.

    PubMed

    Tahmasbi, A M; Mirakzehi, M T; Hosseini, S J; Agah, M J; Fard, M Kazemi

    2012-01-01

    1. A 6-week study was conducted to investigate the effects of phytase and hydroalcoholic extract of Withania somnifera root (WS) on productive performance and bone mineralisation of laying hens in the late phase of production. 2. Diets were arranged factorially (3 × 2 × 2) and consisted of a positive control with adequate Ca (4·37%) and nonphytate P (NPP; 0·39%) and a negative control diet with Ca (4·06%) and NPP (0·36 %); three concentrations of Withania somnifera (0, 65 and 130 mg/kg diet); and two concentrations of microbial phytase (0 and 300 U/kg diet). 3. A total of 144 72-week-old Hy-Line W36 laying hens were randomly assigned to the 12 treatment groups. Each treatment was replicated 4 times (4 x 3 hens). Egg production and egg weight were recorded daily, while feed intake and egg quality traits were recorded every two weeks. Bone quality traits were evaluated at the end of experiment. 4. Withania somnifera supplementation increased egg production and lowered egg weight only in the second two weeks of the experiment. Addition of phytase significantly depressed specific gravity of the eggs for the entire experiment period. No dietary treatment effects were observed on egg shell thickness and yolk weight. 5. Withania somnifera at 130 mg/kg did not affect feed intake. The hens fed on the positive control diet had higher albumen weight than the negative control diet in the second two-week period. Supplementation of the positive control diet with 65 mg/kg Withania somnifera in the absence of phytase significantly improved shell weight compared with the negative control (5·779 vs. 5·273 g respectively). 6. Supplementing Withania somnifera significantly improved Ca and P retention in tibia bone. In addition, an increase in tibia bone P was observed with phytase supplementation. There were significant interactions between Withania somnifera content and phytase for tibia bone Ca and P. 7. The results of this experiment indicated that dietary

  19. Participation of Women and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity Drugs and Biologics Approved by the FDA in 2007–2009

    PubMed Central

    Poon, Rita; Khanijow, Keshav; Umarjee, Sphoorti; Yu, Monica; Zhang, Lei; Parekh, Ameeta

    2013-01-01

    Abstract Background Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007–2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. Methods New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. Results Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. Conclusion Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007–2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998–2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics

  20. Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing's disease: 12-month, Phase III pasireotide study.

    PubMed

    Findling, James W; Fleseriu, Maria; Newell-Price, John; Petersenn, Stephan; Pivonello, Rosario; Kandra, Albert; Pedroncelli, Alberto M; Biller, Beverly M K

    2016-11-01

    Measuring salivary cortisol is a simple, convenient and accurate technique with potential value in monitoring patients with hypercortisolism. This analysis reports changes in late-night salivary cortisol (LNSC) during a 12-month, multicentre, Phase III study of patients with Cushing's disease who were randomized to pasireotide 600 or 900 μg sc bid. LNSC assessment was an exploratory objective based on a single, optional measurement at midnight ± 1 h on the same day as one of the 24-h urinary free cortisol (UFC) measurements. Of 162 enrolled patients, baseline LNSC was measured in 93. Sixty-seven patients had levels above the upper limit of normal (ULN); median baseline levels were 19.7 and 20.7 nmol/L in the groups subsequently randomized to 600 μg (n = 40) and 900 μg (n = 27), respectively. Median LNSC levels decreased from baseline to month 12; median changes in patients who had baseline LNSC > ULN in the 600 and 900 μg groups were -13.4 nmol/L (-52.6 %; n = 19) and -11.8 nmol/L (-56.1 %; n = 14), respectively. LNSC normalized at months 6 and 12 in 25/67 (37.3 %) and 13/67 (19.4 %) patients, respectively; 10/25 and 8/13 patients also had normalized UFC, and 7/25 and 4/13 had partial UFC control (UFC > ULN and ≥50 % decrease from baseline). There was a moderate correlation (r = 0.55) on the log scale between individual patient LNSC and UFC values when all time points were pooled. Pasireotide decreased LNSC levels during 12 months of treatment. Salivary cortisol may be a simple, convenient biomarker for assessing treatment response in patients with Cushing's disease.

  1. Productive performance and egg quality of brown egg-laying hens in the late phase of production as influenced by level and source of calcium in the diet.

    PubMed

    Safaa, H M; Serrano, M P; Valencia, D G; Frikha, M; Jiménez-Moreno, E; Mateos, G G

    2008-10-01

    A total of 1,152 Lohmann Brown laying hens were used to study the influence of level (3.5 and 4.0%) and source (coded FIN, COA, and OYS) of Ca in the diet on productive performance and egg quality from 58 to 73 wk of age. The FIN diet contained all the Ca carbonate as fine limestone (LIM). In the COA and OYS diets, 40% of the fine LIM was substituted with either coarse LIM or oyster shell. Each treatment was replicated 8 times (24 hens). Productive performance and egg quality traits were recorded every 4 wk, and tibia characteristics and shell quality traits were determined at 73 wk of age. An increase in Ca intake from 4.08 to 4.64 g/hen per day improved egg production (71.2 vs. 74.9%; P < 0.001), egg mass (49.0 vs. 51.4 g; P < 0.05), and feed conversion ratio (2.43 vs. 2.30 kg of feed/kg of egg; P < 0.001). In addition, an increase in Ca intake improved shell weight (9.98 vs. 10.20%; P < 0.05), shell thickness (0.342 vs. 0.351 mm; P < 0.01), and shell density (82.0 vs. 83.8 mg/cm2; P < 0.001). Calcium source had no effect on productive performance, tibia characteristics, or egg quality except for shell density, which was greater for hens fed COA than for hens fed FIN, with hens fed OYS being intermediate (81.9 vs. 84.0 vs. 82.7 mg/cm2, respectively; P < 0.05). It was concluded that Brown egg-laying hens in the late phase of production require more than 3.5% Ca in the diet (4.08 g of Ca/hen per day) and that the substitution of 40% of fine LIM with COA or OYS does not affect productive performance and has little impact on shell quality and tibia characteristics.

  2. 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

  3. Vaccine generated immunity targets an HPV16 E7 HLA-A2.1-restricted CD8(+) T cell epitope relocated to an early gene or a late gene of the cottontail rabbit papillomavirus (CRPV) genome in HLA-A2.1 transgenic rabbits.

    PubMed

    Bounds, Callie E; Hu, Jiafen; Cladel, Nancy M; Balogh, Karla; Christensen, Neil D

    2011-02-01

    The newly established HLA-A2.1 transgenic rabbit model has proven useful for testing the immunogenicity of well known and computer-predicted A2-restricted epitopes. In the current study we compared the protective immunity induced to a preferred HPV16 E7 A2-restricted epitope that has been relocated to positions within the CRPV E7 gene and the CRPV L2 gene. Epitope expression from both the E7 protein and the L2 protein resulted in increased protection against viral DNA challenge of the HLA-A2.1 transgenic rabbits as compared to control-vaccinated rabbit groups. These data indicate that proteins expressed at both early and late time points during a natural papillomavirus infection can be targeted by epitope-specific immunity and indicate this immunity is increased to early rather than late expressed proteins of papillomaviruses. This study also highlights the broad utility of the HLAA2.1 transgenic rabbit model for testing numerous immunological factors involved in vaccine generated protective immunity.

  4. Acute and Late Toxicity After Dose Escalation to 82 GyE Using Conformal Proton Radiation for Localized Prostate Cancer: Initial Report of American College of Radiology Phase II Study 03-12

    SciTech Connect

    Coen, John J.; Bae, Kyounghwa; Zietman, Anthony L.; Patel, Baldev; Shipley, William U.; Slater, Jerry D.; Rossi, Carl J.

    2011-11-15

    Purpose: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.

  5. 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

  6. 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).

  7. Late results.

    PubMed

    Daly, B D

    1999-08-01

    Pneumonectomy is performed for a number of benign and malignant conditions. It is most commonly performed for lung cancer. Adjuvant and neoadjuvant protocols have increased the number of these operations being performed and the long-term results are improving. Pneumonectomy may also be performed for metastases to lung and for mesothelioma with encouraging results. Some bronchial adenomas require pneumonectomy. Treatment of resistant mycobacteria or the complications of tuberculosis frequently require pneumonectomy. Late bronchopleural fistulae, esophagopleural fistulae, and empyema may occur.

  8. Differential regulation of C5a receptor 1 in innate immune cells during the allergic asthma effector phase

    PubMed Central

    Schmudde, Inken; Sun, Jing; Vollbrandt, Tillman; König, Peter; Köhl, Jörg

    2017-01-01

    C5a drives airway constriction and inflammation during the effector phase of allergic asthma, mainly through the activation of C5a receptor 1 (C5aR1). Yet, C5aR1 expression on myeloid and lymphoid cells during the allergic effector phase is ill-defined. Recently, we generated and characterized a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we used this reporter strain to monitor C5aR1 expression in airway, pulmonary and lymph node cells during the effector phase of OVA-driven allergic asthma. C5aR1 reporter and wildtype mice developed a similar allergic phenotype with comparable airway resistance, mucus production, eosinophilic/neutrophilic airway inflammation and Th2/Th17 cytokine production. During the allergic effector phase, C5aR1 expression increased in lung tissue eosinophils but decreased in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs). Surprisingly, expression in neutrophils was not affected. Of note, moDCs but not CD11b+ cDCs from mediastinal lymph nodes (mLN) expressed less C5aR1 than DCs residing in the lung after OVA challenge. Finally, neither CD103+ cDCs nor cells of the lymphoid lineage such as Th2 or Th17-differentiated CD4+ T cells, B cells or type 2 innate lymphoid cells (ILC2) expressed C5aR1 under allergic conditions. Our findings demonstrate a complex regulation pattern of C5aR1 in the airways, lung tissue and mLN of mice, suggesting that the C5a/C5aR1 axis controls airway constriction and inflammation through activation of myeloid cells in all three compartments in an experimental model of allergic asthma. PMID:28231307

  9. A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma.

    PubMed

    Goydos, J S; Elder, E; Whiteside, T L; Finn, O J; Lotze, M T

    1996-06-01

    We tested a 105 amino acid synthetic mucin MUC-1 peptide that has 5 repeated immunodominant epitopes to evaluate toxicity and detect mucin-specific immune responses in patients with adenocarcinoma. We also studied the enhancement of these responses by vaccinating patients with the synthetic mucin peptide admixed with BCG. Mucins are glycoproteins present on the luminal surface of ductal epithelial cells and on tumors derived from them. The MUC-1 mucin is hypoglycosylated and nonpolarized on tumors and this exposes epitopes that can stimulate cytotoxic T-Cells (CTL). We vaccinated 63 patients with 100 micrograms of the 105aa mucin peptide mixed with BCG. Two additional vaccinations were given at 3-week intervals. All patients were able to tolerate vaccination, with most experiencing local ulceration at the vaccination site. All patients underwent hypersensitivity (DTH) testing with the 105aa and shorter mucin peptides, prior to vaccination. DTH responses were evaluated at 48 hr and the sites of highest peptide concentration were biopsied. Only 3 patients had a strong skin response to the long peptide. Examination of 55 biopsies showed intense T-Cell infiltration in 37 patients and lesser infiltration in 7. Seven of 22 patients tested had a 2- to 4-fold increase in mucin-specific CTLp. Serum levels of IL-6 were measured sequentially using the B9 hybridoma bioassay. Increasing serum levels of IL-6 correlated with constitutional symptoms (significance 0.001) and hypoalbuminemia (significance 0.007) but not with the extent of skin breakdown at vaccination sites. We conclude that mucin vaccination is safe and might serve to enhance specific responses to tumor antigens. IL-6 may be responsible for the constitution symptoms and hypoalbuminemia in these patients.

  10. Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I).

    PubMed

    Sasaki, Tetsuya; Oga, Tomofumi; Nakagaki, Keiko; Sakai, Kazuhisa; Sumida, Kayo; Hoshino, Kohei; Miyawaki, Izuru; Saito, Koichi; Suto, Fumikazu; Ichinohe, Noritaka

    2014-02-14

    The synapse number and the related dendritic spine number in the cerebral cortex of primates shows a rapid increase after birth. Depending on the brain region and species, the number of synapses reaches a peak before adulthood, and pruning takes place after this peak (overshoot-type synaptic formation). Human mental disorders, such as autism and schizophrenia, are hypothesized to be a result of either too weak or excessive pruning after the peak is reached. Thus, it is important to study the molecular mechanisms underlying overshoot-type synaptic formation, particularly the pruning phase. To examine the molecular mechanisms, we used common marmosets (Callithrix jacchus). Microarray analysis of the marmoset cortex was performed in the ventrolateral prefrontal, inferior temporal, and primary visual cortices, where changes in the number of dendritic spines have been observed. The spine number of all the brain regions above showed a peak at 3 months (3 M) after birth and gradually decreased (e.g., at 6 M and in adults). In this study, we focused on genes that showed differential expression between ages of 3 M and 6 M and on the differences whose fold change (FC) was greater than 1.2. The selected genes were subjected to canonical pathway analysis, and in this study, we describe axon guidance signaling, which had high plausibility. The results showed a large number of genes belonging to subsystems within the axon guidance signaling pathway, macrophages/immune system, glutamate system, and others. We divided the data and discussion of these results into 2 papers, and this is the first paper, which deals with the axon guidance signaling and macrophage/immune system. Other systems will be described in the next paper. Many components of subsystems within the axon guidance signaling underwent changes in gene expression from 3 M to 6 M so that the synapse/dendritic spine number would decrease at 6 M. Thus, axon guidance signaling probably contributes to the decrease in

  11. 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.

  12. Immune Thrombocytopenia

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Immune Thrombocytopenia? Immune thrombocytopenia (THROM-bo-si-toe-PE-ne- ... from one person to another. Types of Immune Thrombocytopenia The two types of ITP are acute (temporary ...

  13. Phase analysis of gated myocardial perfusion single-photon emission computed tomography after coronary artery bypass graft surgery: reflection of late reverse remodeling in patients with patent grafts after coronary artery bypass graft surgery.

    PubMed

    Park, Sohyun; Cheon, Gi Jeong; Paeng, Jin Chul; Won, Kyoung Sook; Kang, Keon Wook; Kim, Ki-Bong; Chung, June-Key; Lee, Dong Soo

    2016-11-01

    Phase analysis using gated myocardial perfusion single-photon emission computed tomography (GMPS) is a tool used to assess left ventricular (LV) dyssynchrony. We attempted to investigate the role of LV dyssynchrony assessed by GMPS using phase analysis for the late LV function after coronary artery bypass graft surgery (CABG) in patients with patent grafts. A total of 45 patients who received off-pump CABG with patent graft 1 year after CABG and preserved perfusion reserve were enrolled retrospectively. All patients underwent GMPS before and 3 months and 1 year after CABG. Using the Emory Cardiac Toolbox, both phase histogram bandwidth (PBW) and phase SD derived by phase analysis were used for the analysis, in addition to the conventional perfusion parameters. For the evaluation of LV function, transthoracic echocardiography was also performed. All of the patients showed perfusion improvement (paired t-test, P<0.05) after CABG. Nonetheless, 30 of 45 patients showed LV dyssynchrony 3 months after CABG. One year after CABG, however, 25 out of 45 patients showed reverse remodeling. Among those patients with reverse remodeling, 19 patients had shown LV 3 months after CABG. Using stepwise logistic regression with forward selection, PBW 3 months after CABG could predict reverse remodeling 1 year after CABG (odds ratio 1.03, P<0.05). Using receiver operating characteristic analysis, PBW 3 months after CABG had the largest area under the curve to detect reverse remodeling 1 year after CABG with a cut-off value of 82 (sensitivity 0.95, specificity 0.56, P<0.001). Postoperative LV dyssynchrony assessed by GMPS using phase analysis may reflect late reverse remodeling and potential of further functional improvement in patients with patent grafts and preserved perfusion reserve after CABG.

  14. Simultaneous Immunization against Tuberculosis

    PubMed Central

    Tchilian, Elma Z.; Ronan, Edward O.; de Lara, Catherine; Lee, Lian Ni; Franken, Kees L. M. C.; Vordermeier, Martin H.; Ottenhoff, Tom H. M.; Beverley, Peter C. L.

    2011-01-01

    Background BCG, the only licensed vaccine against tuberculosis, provides some protection against disseminated disease in infants but has little effect on prevention of adult pulmonary disease. Newer parenteral immunization prime boost regimes may provide improved protection in experimental animal models but are unproven in man so that there remains a need for new and improved immunization strategies. Methods and Findings Mice were immunized parenterally, intranasally or simultaneously by both routes with BCG or recombinant mycobacterial antigens plus appropriate adjuvants. They were challenged with Mycobacterium tuberculosis (Mtb) and the kinetics of Mtb growth in the lungs measured. We show that simultaneous immunization (SIM) of mice by the intranasal and parenteral routes is highly effective in increasing protection over parenteral BCG administration alone. Intranasal immunization induces local pulmonary immunity capable of inhibiting the growth of Mtb in the early phase (the first week) of infection, while parenteral immunization has a later effect on Mtb growth. Importantly, these two effects are additive and do not depend on priming and boosting the immune response. The best SIM regimes reduce lung Mtb load by up to 2 logs more than BCG given by either route alone. Conclusions These data establish SIM as a novel and highly effective immunization strategy for Mtb that could be carried out at a single clinic visit. The efficacy of SIM does not depend on priming and boosting an immune response, but SIM is complementary to prime boost strategies and might be combined with them. PMID:22110657

  15. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia.

    PubMed

    Rupp, Mark E; Holley, H Preston; Lutz, Jon; Dicpinigaitis, Peter V; Woods, Christopher W; Levine, Donald P; Veney, Naomi; Fowler, Vance G

    2007-12-01

    New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 mug/ml and 419 mug/ml, respectively, and remained above 100 mug/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

  16. 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

  17. Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukemia treated with nilotinib.

    PubMed

    Gullaksen, Stein-Erik; Skavland, Jørn; Gavasso, Sonia; Tosevski, Vinko; Warzocha, Krzysztof; Dumrese, Claudia; Ferrant, Augustin; Gedde-Dahl, Tobias; Hellmann, Andrzej; Janssen, Jeroen; Labar, Boris; Lang, Alois; Majeed, Waleed; Mihaylov, Georgi; Stentoft, Jesper; Stenke, Leif; Thaler, Josef; Thielen, Noortje; Verhoef, Gregor; Voglova, Jaroslava; Ossenkoppele, Gert; Hochhaus, Andreas; Hjorth-Hansen, Henrik; Mustjoki, Satu; Sopper, Sieghart; Giles, Francis; Porkka, Kimmo; Wolf, Dominik; Gjertsen, Bjørn Tore

    2017-08-01

    Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1(IS) at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177). Copyright© 2017 Ferrata Storti Foundation.

  18. Interaction of Host Nucleolin with Influenza A Virus Nucleoprotein in the Early Phase of Infection Limits the Late Viral Gene Expression

    PubMed Central

    Kumar, Deepshikha; Broor, Shobha; Rajala, Maitreyi S.

    2016-01-01

    Influenza A virus nucleoprotein, is a multifunctional RNA-binding protein, encoded by segment-5 of the negative sense RNA genome. It serves as a key connector between the virus and the host during virus replication. It continuously shuttles between the cytoplasm and the nucleus interacting with various host cellular factors. In the current study, host proteins interacting with nucleoprotein of Influenza A virus of H1N1 2009 pandemic strain were identified by co-immunoprecipitation studies followed by MALDI-TOF/MS analysis. Here we report the host nucleolin, a major RNA-binding protein of the nucleolus as a novel interacting partner to influenza A virus nucleoprotein. We thus, explored the implications of this interaction in virus life cycle and our studies have shown that these two proteins interact early during infection in the cytoplasm of infected cells. Depletion of nucleolin in A549 cells by siRNA targeting endogenous nucleolin followed by influenza A virus infection, disrupted its interaction with viral nucleoprotein, resulting in increased expression of gene transcripts encoding late viral proteins; matrix (M1) and hemagglutinin (HA) in infected cells. On the contrary, over expression of nucleolin in cells transiently transfected with pEGFP-NCL construct followed by virus infection significantly reduced the late viral gene transcripts, and consequently the viral titer. Altered expression of late viral genes and titers following manipulation of host cellular nucleolin, proposes the functional importance of its interaction with nucleoprotein during influenza A virus infection. PMID:27711134

  19. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study.

    PubMed

    Beigel, John H; Tebas, Pablo; Elie-Turenne, Marie-Carmelle; Bajwa, Ednan; Bell, Todd E; Cairns, Charles B; Shoham, Shmuel; Deville, Jaime G; Feucht, Eric; Feinberg, Judith; Luke, Thomas; Raviprakash, Kanakatte; Danko, Janine; O'Neil, Dorothy; Metcalf, Julia A; King, Karen; Burgess, Timothy H; Aga, Evgenia; Lane, H Clifford; Hughes, Michael D; Davey, Richard T

    2017-06-01

    Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza. In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480. Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days

  20. Phase I Trial of Cyclophosphamide as an Immune Modulator for Optimizing Oncolytic Reovirus Delivery to Solid Tumors

    PubMed Central

    Roulstone, Victoria; Khan, Khurum; Pandha, Hardev S.; Rudman, Sarah; Coffey, Matt; Gill, George M.; Melcher, Alan A.; Vile, Richard; Harrington, Kevin J.; de Bono, Johann; Spicer, James

    2016-01-01

    Purpose Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25–1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies. PMID:25424857

  1. Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer

    PubMed Central

    2011-01-01

    Background The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer. Methods/Design This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrolment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrolment. Discussion This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also

  2. 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

  3. 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

    Bunketorp Käll, Lina; Lundgren-Nilsson, Åsa; Blomstrand, Christian; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

    2012-11-21

    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. 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. 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. This study will ascertain whether any of the two intervention programs can improve overall health status and functioning in the late

  4. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP.

    PubMed

    Butler, M P; O'Connor, J J; Moynagh, P N

    2004-01-01

    The pro-inflammatory cytokine tumor-necrosis factor-alpha (TNF-alpha) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-alpha inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-alpha prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 +/- 5%, n = 6 versus control 175 +/- 7%, n = 6, P < 0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-alpha as p38 MAPK has previously been shown to be involved in interleukin-1beta inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-alpha led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 microM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-alpha (SB/TNF-alpha 174 +/- 5%, n = 6 versus TNF-alpha 120 +/- 7%, n = 6, P < 0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 +/- 7%, n = 6). Interestingly however, the depressive effects of TNF-alpha on late LTP (2-3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-alpha 132 +/- 5%, n = 6 versus control LTP 175 +/- 7%, n = 6, P < 0.001, 3 h post-tetanus). This work suggests that TNF-alpha inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.

  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. 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.

  7. IL-12-dependent innate immunity arrests endothelial cells in G0-G1 phase by a p21(Cip1/Waf1)-mediated mechanism.

    PubMed

    Napione, Lucia; Strasly, Marina; Meda, Claudia; Mitola, Stefania; Alvaro, Maria; Doronzo, Gabriella; Marchiò, Serena; Giraudo, Enrico; Primo, Luca; Arese, Marco; Bussolino, Federico

    2012-12-01

    Innate immunity may activate paracrine circuits able to entail vascular system in the onset and progression of several chronic degenerative diseases. In particular, interleukin (IL)-12 triggers a genetic program in lymphomononuclear cells characterized by the production of interferon-γ and specific chemokines resulting in an angiostatic activity. The aim of this study is to identify molecules involved in the regulation of cell cycle in endothelial cells co-cultured with IL-12-stimulated lymphomonuclear cells. By using a transwell mediated co-culture system we demonstrated that IL-12-stimulated lymphomonuclear cells induce an arrest of endothelial cells cycle in G1, which is mainly mediated by the up-regulation of p21(Cip1/Waf1), an inhibitor of cyclin kinases. This effect requires the activation of STAT1, PKCδ and p38 MAPK, while p53 is ineffective. In accordance, siRNA-dependent silencing of these molecules in endothelial cells inhibited the increase of p21(Cip1/Waf1) and the modification in cell cycle promoted by IL-12-stimulated lymphomonuclear cells. These results indicate that the angiostatic action of IL-12-stimulated lymphomononuclear cells may lie in the capability to arrest endothelial cells in G1 phase through a mechanisms mainly based on the specific up-regulation of p21(Cip1/Waf1) induced by the combined activity of STAT1, PKCδ and p38 MAPK.

  8. 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

  9. 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

  10. Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro.

    PubMed

    Neyman, Sergey; Manahan-Vaughan, Denise

    2008-03-01

    The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit differences in their regulation of synaptic plasticity, suggesting that these receptors may subserve separate functional roles in information storage. In addition, although effects in vivo are consistently described, conflicting reports of the involvement of mGluRs in hippocampal synaptic plasticity in vitro exist. We therefore addressed the involvement of mGluR1 and mGluR5 in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region of adult male rats in vitro. The mGluR1 antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzene-acetic acid (LY367385) impaired both induction and late phases of both LTP and LTD, when applied before high-frequency tetanization (HFT; 100 Hz) or low-frequency stimulation (LFS; 1 Hz), respectively. Application after either HFT or LFS had no effect. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), when given before HFT, inhibited both the induction and late phases of LTP. When given after HFT, late LTP was inhibited. MPEP, given prior to LFS, impaired LTD induction, although stable LTD was still expressed. Application after LFS significantly impaired late phases of LTD. Activation of protein synthesis may comprise a key mechanism underlying the group I mGluR contribution to synaptic plasticity. The mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) converted short-term depression into LTD. Effects were prevented by application of the protein synthesis inhibitor anisomycin, suggesting that protein synthesis is triggered by group I mGluR activation to enable persistency of synaptic plasticity. Taken together, these data support the notion that both mGluR1 and mGluR5 are critically involved in bidirectional synaptic plasticity in the CA1 region and may enable functional differences in information encoding through LTP and LTD.

  11. Measurement of plasma human chorionic gonadotropin (hCG) and beta-hCG activities in the late luteal phase: evidence of the occurrence of spontaneous menstrual abortions in infertile women.

    PubMed

    Chartier, M; Roger, M; Barrat, J; Michelon, B

    1979-02-01

    Plasma luteinizing hormone (LH-human chorionic gonadotropin (hCG) and beta-hCG activities were measured during the late luteal phase in 321 cycles of 147 infertile women. In 71 cycles the hCG measurement permitted the diagnosis of pregnancy between the 10th and 14th days after the thermal nadir. The slope of the regression line derived from hCG levels during the first 22 days of pregnancy was significantly lower in pregnancies which aborted before the 60th day than in normal pregnancies (P less than 0.01). Among 72 cycles ended by apparently normal menses which exhibited an LH-hCG activity at least equal to 7 mIU of hCG/ml during the late luteal phase, the beta-hCG activity was measured in 49 cycles during which hCG had not been given. Significant beta-hCG activity (greater than or equal to 4 mIU of hCG/ml) was detected in 19 cases. This finding supports the assumption that secretory trophoblastic tissue had been present and that spontaneous menstrual abortions had occurred in these women.

  12. Cardioprotective Effects of Transfusion of Late-Phase Preconditioned Plasma May Be Induced by Activating the Reperfusion Injury Salvage Kinase Pathway but Not the Survivor Activating Factor Enhancement Pathway in Rats

    PubMed Central

    Zheng, Zhi-nan; Pi, Yan-na; Liang, Xue

    2017-01-01

    A previous study in our laboratory demonstrated that transfusion of plasma collected at the late phase of remote ischemic preconditioning (RIPC) could reduce myocardial infarct size. Here, we tested whether the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways are involved in transferring protection. In a two-part study, donor rats (n = 3) donated plasma 48 hours after RIPC (preconditioned plasma) or control (nonpreconditioned plasma). Normal (part 1) or ischemic (part 2) myocardia were collected from recipients (n = 6) 24 hours after receiving normal saline, nonpreconditioned plasma, and preconditioned plasma or after further suffering ischemia reperfusion. Western blot was performed to analyze STAT3, Akt, and Erk1/2 phosphorylation in normal and ischemic myocardium (central area and border area). In normal myocardia, preconditioned plasma increased Akt and Erk1/2 phosphorylation significantly compared to nonpreconditioned plasma and normal saline; no STAT3 phosphorylation was detected. In ischemic myocardia, preconditioned plasma increased Akt and Erk1/2 phosphorylation significantly in both central and border areas compared to other fluids; no significant difference in STAT3 phosphorylation occurred among groups. Transfusion of preconditioned plasma collected at the late phase of RIPC could activate the RISK but not SAFE pathway, suggesting that RISK pathway may be involved in transferring protection. PMID:28828146

  13. 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.

  14. Expression of the Fis protein is sustained in late-exponential- and stationary-phase cultures of Salmonella enterica serovar Typhimurium grown in the absence of aeration.

    PubMed

    O Cróinín, Tadhg; Dorman, Charles J

    2007-10-01

    The classic expression pattern of the Fis global regulatory protein during batch culture consists of a high peak in the early logarithmic phase of growth, followed by a sharp decrease through mid-exponential growth phase until Fis is almost undetectable at the end of the exponential phase. We discovered that this pattern is contingent on the growth regime. In Salmonella enterica serovar Typhimurium cultures grown in non-aerated SPI1-inducing conditions, Fis can be detected readily in stationary phase. On the other hand, cultures grown with standard aeration showed the classic Fis expression pattern. Sustained Fis expression in non-aerated cultures was also detected in some Escherichia coli strains, but not in others. This novel pattern of Fis expression was independent of sequence differences in the fis promoter regions of Salmonella and E. coli. Instead, a clear negative correlation between the expression of the Fis protein and of the stress-and-stationary-phase sigma factor RpoS was observed in a variety of strains. An rpoS mutant displayed elevated levels of Fis and had a higher frequency of epithelial cell invasion under these growth conditions. We discuss a model whereby Fis and RpoS levels vary in response to environmental signals allowing the expression and repression of SPI1 invasion genes.

  15. Host adaptive immunity deficiency in severe pandemic influenza

    PubMed Central

    2010-01-01

    Introduction Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. Methods We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. Results The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. Conclusions Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza

  16. Immunization Coverage

    MedlinePlus

    ... vaccination strategies and operational plans to address immunization gaps and reach every person with lifesaving vaccines. WHO ... Assembly in 2018, 2020 and 2022 on the achievements against the GVAP goals and targets. World Immunization ...

  17. 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 ...

  18. 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

  19. Different rates of DNA replication at early versus late S-phase sections: multiscale modeling of stochastic events related to DNA content/EdU (5-ethynyl-2'deoxyuridine) incorporation distributions.

    PubMed

    Li, Biao; Zhao, Hong; Rybak, Paulina; Dobrucki, Jurek W; Darzynkiewicz, Zbigniew; Kimmel, Marek

    2014-09-01

    Mathematical modeling allows relating molecular events to single-cell characteristics assessed by multiparameter cytometry. In the present study we labeled newly synthesized DNA in A549 human lung carcinoma cells with 15-120 min pulses of EdU. All DNA was stained with DAPI and cellular fluorescence was measured by laser scanning cytometry. The frequency of cells in the ascending (left) side of the "horseshoe"-shaped EdU/DAPI bivariate distributions reports the rate of DNA replication at the time of entrance to S phase while their frequency in the descending (right) side is a marker of DNA replication rate at the time of transition from S to G2 phase. To understand the connection between molecular-scale events and scatterplot asymmetry, we developed a multiscale stochastic model, which simulates DNA replication and cell cycle progression of individual cells and produces in silico EdU/DAPI scatterplots. For each S-phase cell the time points at which replication origins are fired are modeled by a non-homogeneous Poisson Process (NHPP). Shifted gamma distributions are assumed for durations of cell cycle phases (G1, S and G2 M), Depending on the rate of DNA synthesis being an increasing or decreasing function, simulated EdU/DAPI bivariate graphs show predominance of cells in left (early-S) or right (late-S) side of the horseshoe distribution. Assuming NHPP rate estimated from independent experiments, simulated EdU/DAPI graphs are nearly indistinguishable from those experimentally observed. This finding proves consistency between the S-phase DNA-replication rate based on molecular-scale analyses, and cell population kinetics ascertained from EdU/DAPI scatterplots and demonstrates that DNA replication rate at entrance to S is relatively slow compared with its rather abrupt termination during S to G2 transition. Our approach opens a possibility of similar modeling to study the effect of anticancer drugs on DNA replication/cell cycle progression and also to quantify other

  20. A Phase I Trial of an Immune Checkpoint Inhibitor Plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer

    DTIC Science & Technology

    2016-10-01

    inoperable disease for fear of side effects. As a result, 30% of such patients will die from metastases within 3 years. A new class of drugs called immune...checkpoint inhibitors exploit the body’s immune system to target and kill tumor cells. The drug used in the proposed trial, MPDL3280A (atezolizumab

  1. Lung irradiation increases mortality following influenza A virus challenge occurring late after exposure

    PubMed Central

    Manning, Casey M.; Johnston, Carl J.; Reed, Christina K.; Lawrence, B. Paige; Williams, Jacqueline P.; Finkelstein, Jacob N.

    2012-01-01

    Purpose Whole-body irradiated individuals are at increased risk of infection in the acute phase, whereas pulmonary complications are associated with late events. This study addressed whether irradiation-induced changes in the lung environment alter responses to a viral challenge delivered late after exposure, but prior to the appearance of late lung radiation injury. Methods and Materials C57BL/6 mice received either lung alone or combined lung + whole-body irradiation (0–15 Gy). At 10 weeks post-irradiation, animals were infected with 120 HAU influenza virus strain A/HKx31. Innate and adaptive immune cell recruitment was determined using flow cytometry. Cytokine and chemokine production and protein leakage into the lung following infection were assessed. Results Prior irradiation led to a dose-dependent failure to regain body weight post-infection, exacerbated mortality, but it did not affect virus-specific immune responses or virus clearance. Surviving irradiated animals displayed a persistent increase in total protein in bronchoalveolar lavage fluid and edema. Conclusions Lung irradiation increased susceptibility to death following infection with influenza virus and impaired the ability to complete recovery. This altered response does not appear due to a radiation effect on the immune response, but it may possibly be an effect on epithelial repair. PMID:23195776

  2. ASC plays a role in the priming phase of the immune response to type II collagen in collagen-induced arthritis.

    PubMed

    Yamazaki, Hideshi; Takeoka, Michiko; Kitazawa, Masato; Ehara, Takashi; Itano, Naoki; Kato, Hiroyuki; Taniguchi, Shun'ichiro

    2012-06-01

    Although rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, the role of IL-1β and IL-18 in the pathophysiology of RA has been well established. IL-1β and IL-18 are generated via cleavage of their pro-forms in the presence of the apoptosis-associated speck-like protein containing a caspase recruit domain (ASC), a known adaptor protein that activates procaspase-1. As such, we investigated the involvement of ASC in the progression of murine collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) using ASC-deficient (ASC(-/-)) and wild-type (ASC(+/+)) mice. Analyses were performed by immunohistochemistry for tissues and ELISA for sera. We observed an increase in the expression of ASC, as well as IL-1β and IL-18, in the joints of CIA DBA mice, which indicated that ASC is involved in disease development. Next, we demonstrated that the infiltration of inflammatory cells and cartilage/bone destruction in CIA knee joints were significantly increased in ASC(+/+) mice compared with ASC(-/-) mice. No such differences were noted in ASC(+/+) and ASC(-/-) CAIA mice. In terms of cytokine expression in knee joints, IL-1β and IL-18 were depressed in ASC-deficient CIA mice compared with wild-type mice, but were similarly expressed in CAIA joints in both mice groups. Taken together, we can conclude that ASC is involved in the development of CIA and plays a role in the priming phase of the immune response to type II collagen.

  3. 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

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

    PubMed

    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

    2015-02-01

    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.

  5. Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination

    PubMed Central

    Wang, Lilin; Smith, Dan; Bot, Simona; Dellamary, Luis; Bloom, Amy; Bot, Adrian

    2002-01-01

    The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by “danger” motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity. PMID:12393853

  6. Impacts of climate change on ground level gas-phase pollutants and aerosols in the Iberian Peninsula for the late XXI century

    NASA Astrophysics Data System (ADS)

    Jiménez-Guerrero, Pedro; Montávez, Juan Pedro; Gómez-Navarro, Juan José; Jerez, Sonia; Lorente-Plazas, Raquel

    2012-08-01

    Climate change alone influences future air pollution levels through modifications of gas-phase chemistry, transport, removal, and natural emissions. Hence, the goal of this study is to determine at what extent concentrations of air pollutants respond to changes over the Iberian Peninsula under a climate change scenario. The methodology includes the use of the regional modeling system MM5 (regional climate model version)-CHIMERE for two nested domains covering Europe and the Iberian Peninsula. Two time slices driven by ECHO-G global circulation model covering from 1991 to 2010 and 2071 to 2100 under the SRES A2 scenario have been compared. Climate change influences the concentrations of both gas-phase pollutants and aerosols through changes in temperature, precipitation, mixing height, transport, humidity, and oxidant levels. The trends of variation of ozone (changes up to 5 ppb, +10% increase during summertime) and aerosols over southwestern Europe are influenced by the higher mean temperature modeled for the future climate (up to +5.4 K), since it favors the formation of secondary gas-phase products. It also enhances sulphates (+2 μg m-3) and secondary organic aerosols (SOA) (+2.5 μg m-3 under SRES A2 scenario) and contributes to the decomposition of ammonium nitrate, remaining in the gas phase. Further, the 17% percent decrease of precipitation modeled for 2071-2100 has a strong effect in the frequency of the washout and therefore in the levels of natural aerosols: the concentrations of aerosols decrease with increasing precipitation as wet deposition provides the main aerosol sink.

  7. 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.

  8. Implications for late Grenvillian (Rigolet phase) construction of Rodinia using new U-Pb data from the Mars Hill terrane, Tennessee and North Carolina, United States

    USGS Publications Warehouse

    Aleinikoff, John N.; Southworth, Scott; Merschat, Arthur J.

    2013-01-01

    New data for zircon (external morphology, cathodoluminescence zoning, and sensitive high resolution ion microprobe [SHRIMP] U-Pb ages) from the Carvers Gap granulite gneiss of the Mars Hill terrane (Tennessee and North Carolina, United States) require reevaluation of interpretations of the age and origin of this rock. The new results indicate that the zircon is detrital and that the sedimentary protolith of this gneiss (and related Cloudland gneiss) was deposited no earlier than ca. 1.02 Ga and was metamorphosed at ca. 0.98 Ga. Tectonic models that included the gneiss as a piece of 1.8 Ga Amazonian crust (perhaps as part of the hypothetical Columbia supercontinent) are now untenable. The remarkably fast cycle of exhumation, erosion, deposition, and deep burial also is characteristic of other late Grenvillian (post-Ottawan) Mesoproterozoic paragneisses that occur throughout the Appalachians. These rocks provide new evidence for the duration of the formation of the Rodinia supercontinent lasting until at least 0.98 Ma.

  9. Differential expression of Toll-like receptors in dendritic cells of patients with dengue during early and late acute phases of the disease.

    PubMed

    Torres, Silvia; Hernández, Juan Carlos; Giraldo, Diana; Arboleda, Margarita; Rojas, Mauricio; Smit, Jolanda M; Urcuqui-Inchima, Silvio

    2013-01-01

    Dengue hemorrhagic fever (DHF) is observed in individuals that have pre-existing heterotypic dengue antibodies and is associated with increased viral load and high levels of pro-inflammatory cytokines early in infection. Interestingly, a recent study showed that dengue virus infection in the presence of antibodies resulted in poor stimulation of Toll-like receptors (TLRs), thereby facilitating virus particle production, and also suggesting that TLRs may contribute to disease pathogenesis. We evaluated the expression levels of TLR2, 3, 4 and 9 and the co-stimulatory molecules CD80 and CD86 by flow cytometry. This was evaluated in monocytes, in myeloid and plasmacytoid dendritic cells (mDCs and pDCs) from 30 dengue patients with different clinical outcomes and in 20 healthy controls. Increased expression of TLR3 and TLR9 in DCs of patients with dengue fever (DF) early in infection was detected. In DCs from patients with severe manifestations, poor stimulation of TLR3 and TLR9 was observed. In addition, we found a lower expression of TLR2 in patients with DF compared to DHF. Expression levels of TLR4 were not affected. Furthermore, the expression of CD80 and CD86 was altered in mDCs and CD86 in pDCs of severe dengue cases. We show that interferon alpha production decreased in the presence of dengue virus after stimulation of PBMCs with the TLR9 agonist (CpG A). This suggests that the virus can affect the interferon response through this signaling pathway. These results show that during dengue disease progression, the expression profile of TLRs changes depending on the severity of the disease. Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

  10. Differential Expression of Toll-like Receptors in Dendritic Cells of Patients with Dengue during Early and Late Acute Phases of the Disease

    PubMed Central

    Torres, Silvia; Hernández, Juan Carlos; Giraldo, Diana; Arboleda, Margarita; Rojas, Mauricio; Smit, Jolanda M.; Urcuqui-Inchima, Silvio

    2013-01-01

    Background Dengue hemorrhagic fever (DHF) is observed in individuals that have pre-existing heterotypic dengue antibodies and is associated with increased viral load and high levels of pro-inflammatory cytokines early in infection. Interestingly, a recent study showed that dengue virus infection in the presence of antibodies resulted in poor stimulation of Toll-like receptors (TLRs), thereby facilitating virus particle production, and also suggesting that TLRs may contribute to disease pathogenesis. Methodology/Principal Findings We evaluated the expression levels of TLR2, 3, 4 and 9 and the co-stimulatory molecules CD80 and CD86 by flow cytometry. This was evaluated in monocytes, in myeloid and plasmacytoid dendritic cells (mDCs and pDCs) from 30 dengue patients with different clinical outcomes and in 20 healthy controls. Increased expression of TLR3 and TLR9 in DCs of patients with dengue fever (DF) early in infection was detected. In DCs from patients with severe manifestations, poor stimulation of TLR3 and TLR9 was observed. In addition, we found a lower expression of TLR2 in patients with DF compared to DHF. Expression levels of TLR4 were not affected. Furthermore, the expression of CD80 and CD86 was altered in mDCs and CD86 in pDCs of severe dengue cases. We show that interferon alpha production decreased in the presence of dengue virus after stimulation of PBMCs with the TLR9 agonist (CpG A). This suggests that the virus can affect the interferon response through this signaling pathway. Conclusions/Significance These results show that during dengue disease progression, the expression profile of TLRs changes depending on the severity of the disease. Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response. PMID:23469297

  11. [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%.

  12. 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…

  13. 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…

  14. Inhibition of the sodium-translocating NADH-ubiquinone oxidoreductase [Na+-NQR] decreases cholera toxin production in Vibrio cholerae O1 at the late exponential growth phase

    PubMed Central

    Minato, Yusuke; Fassio, Sara R.; Reddekopp, Rylan L.; Häse, Claudia C.

    2014-01-01

    Two virulence factors produced by Vibrio cholerae, cholera toxin (CT) and toxin-corregulated pilus (TCP), are indispensable for cholera infection. ToxT is the central regulatory protein involved in activation of CT and TCP expression. We previously reported that lack of a respiration-linked sodium-translocating NADH–ubiquinone oxidoreductase (Na+-NQR) significantly increases toxT transcription. In this study, we further characterized this link and found that Na+-NQR affects toxT expression only at the early-log growth phase, whereas lack of Na+-NQR decreases CT production after the mid-log growth phase. Such decreased CT production was independent of toxT and ctxB transcription. Supplementing a respiratory substrate, L-lactate, into the growth media restored CT production in the nqrA-F mutant, suggesting that decreased CT production in the Na+-NQR mutant is dependent on electron transport chain (ETC) activity. This notion was supported by the observations that two chemical inhibitors, a Na+-NQR specific inhibitor 2-n-Heptyl-4-hydroxyquinoline N-oxide (HQNO) and a succinate dehydrogenase (SDH) inhibitor, thenoyltrifluoroacetone (TTFA), strongly inhibited CT production in both classical and El Tor biotype strains of V. cholerae. Accordingly, we propose the main respiratory enzyme of V. cholerae, as a potential drug target to treat cholera because human mitochondria do not contain Na+-NQR orthologs. PMID:24361395

  15. Inhibition of the sodium-translocating NADH-ubiquinone oxidoreductase [Na+-NQR] decreases cholera toxin production in Vibrio cholerae O1 at the late exponential growth phase.

    PubMed

    Minato, Yusuke; Fassio, Sara R; Reddekopp, Rylan L; Häse, Claudia C

    2014-01-01

    Two virulence factors produced by Vibrio cholerae, cholera toxin (CT) and toxin-corregulated pilus (TCP), are indispensable for cholera infection. ToxT is the central regulatory protein involved in activation of CT and TCP expression. We previously reported that lack of a respiration-linked sodium-translocating NADH-ubiquinone oxidoreductase (Na(+)-NQR) significantly increases toxT transcription. In this study, we further characterized this link and found that Na(+)-NQR affects toxT expression only at the early-log growth phase, whereas lack of Na(+)-NQR decreases CT production after the mid-log growth phase. Such decreased CT production was independent of toxT and ctxB transcription. Supplementing a respiratory substrate, l-lactate, into the growth media restored CT production in the nqrA-F mutant, suggesting that decreased CT production in the Na(+)-NQR mutant is dependent on electron transport chain (ETC) activity. This notion was supported by the observations that two chemical inhibitors, a Na(+)-NQR specific inhibitor 2-n-Heptyl-4-hydroxyquinoline N-oxide (HQNO) and a succinate dehydrogenase (SDH) inhibitor, thenoyltrifluoroacetone (TTFA), strongly inhibited CT production in both classical and El Tor biotype strains of V. cholerae. Accordingly, we propose the main respiratory enzyme of V. cholerae, as a potential drug target to treat cholera because human mitochondria do not contain Na(+)-NQR orthologs.

  16. Linking Transcriptional Changes over Time in Stimulated Dendritic Cells to Identify Gene Networks Activated during the Innate Immune Response

    PubMed Central

    Patil, Ashwini; Kumagai, Yutaro; Liang, Kuo-ching; Suzuki, Yutaka; Nakai, Kenta

    2013-01-01

    The innate immune response is primarily mediated by the Toll-like receptors functioning through the MyD88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of genes activated during the innate immune response using a novel approach to analyze time-course gene expression profiles of activated immune cells in combination with a large gene regulatory and protein-protein interaction network. We classified the immune response into three consecutive time-dependent stages and identified the most probable paths between genes showing a significant change in expression at each stage. The resultant network contained several novel and known regulators of the innate immune response, many of which did not show any observable change in expression at the sampled time points. The response network shows the dominance of genes from specific functional classes during different stages of the immune response. It also suggests a role for the protein phosphatase 2a catalytic subunit α in the regulation of the immunoproteasome during the late phase of the response. In order to clarify the differences between the MyD88-dependent and TRIF-dependent pathways in the innate immune response, time-course gene expression profiles from MyD88-knockout and TRIF-knockout dendritic cells were analyzed. Their response networks suggest the dominance of the MyD88-dependent pathway in the innate immune response, and an association of the circadian regulators and immunoproteasomal degradation with the TRIF-dependent pathway. The response network presented here provides the most probable associations between genes expressed in the early and the late phases of the innate immune response, while taking into account the intermediate regulators. We propose that the method described here can also be used in the identification of time-dependent gene sub

  17. Linking transcriptional changes over time in stimulated dendritic cells to identify gene networks activated during the innate immune response.

    PubMed

    Patil, Ashwini; Kumagai, Yutaro; Liang, Kuo-Ching; Suzuki, Yutaka; Nakai, Kenta

    2013-01-01

    The innate immune response is primarily mediated by the Toll-like receptors functioning through the MyD88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of genes activated during the innate immune response using a novel approach to analyze time-course gene expression profiles of activated immune cells in combination with a large gene regulatory and protein-protein interaction network. We classified the immune response into three consecutive time-dependent stages and identified the most probable paths between genes showing a significant change in expression at each stage. The resultant network contained several novel and known regulators of the innate immune response, many of which did not show any observable change in expression at the sampled time points. The response network shows the dominance of genes from specific functional classes during different stages of the immune response. It also suggests a role for the protein phosphatase 2a catalytic subunit α in the regulation of the immunoproteasome during the late phase of the response. In order to clarify the differences between the MyD88-dependent and TRIF-dependent pathways in the innate immune response, time-course gene expression profiles from MyD88-knockout and TRIF-knockout dendritic cells were analyzed. Their response networks suggest the dominance of the MyD88-dependent pathway in the innate immune response, and an association of the circadian regulators and immunoproteasomal degradation with the TRIF-dependent pathway. The response network presented here provides the most probable associations between genes expressed in the early and the late phases of the innate immune response, while taking into account the intermediate regulators. We propose that the method described here can also be used in the identification of time-dependent gene sub

  18. The formation and evolution of youthful gullies on Mars: Gullies as the late-stage phase of Mars’ most recent ice age

    NASA Astrophysics Data System (ADS)

    Dickson, James L.; Head, James W.

    2009-11-01

    Gullies are extremely young erosional/depositional systems on Mars that have been carved by an agent that was likely to have been comprised in part by liquid water [Malin, M.C., Edgett, K.S., 2000. Evidence for recent groundwater seepage and surface runoff on Mars. Science 288, 2330-2335; McEwen, A.S. et al., 2007. A closer look at water-related geologic activity on Mars. Science 317, 1706-1709]. The strong latitude and orientation dependencies that have been documented for gullies require (1) a volatile near the surface, and (2) that insolation is an important factor for forming gullies. These constraints have led to two categories of interpretations for the source of the volatiles: (1) liquid water at depth beneath the melting isotherm that erupts suddenly ("groundwater"), and (2) ice at the surface or within the uppermost layer of soil that melts during optimal insolation conditions ("surface/near-surface melting"). In this contribution we synthesize global, hemispheric, regional and local studies of gullies across Mars and outline the criteria that must be met by any successful explanation for the formation of gullies. We further document trends in both hemispheres that emphasize the importance of top-down melting of recent ice-rich deposits and the cold-trapping of atmospherically-derived H 2O frost/snow as important components in the formation of gullies. This provides context for the incorporation of high-resolution multi-spectral and hyper-spectral data from the Mars Reconnaissance Orbiter that show that (1) cold-trapping of seasonal H 2O frost occurs at the alcove/channel-level on contemporary Mars; (2) gullies are episodically active systems; (3) gullies preferentially form in the presence of deposits plausibly interpreted as remnants of the Late Amazonian emplacement of ice-rich material; and (4) gully channels frequently emanate from the crest of alcoves instead of the base, showing that alcove generation is not necessarily a product of undermining and

  19. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For

  20. Atomic layer deposition coating of carbon nanotubes with zinc oxide causes acute phase immune responses in human monocytes in vitro and in mice after pulmonary exposure.

    PubMed

    Dandley, Erinn C; Taylor, Alexia J; Duke, Katherine S; Ihrie, Mark D; Shipkowski, Kelly A; Parsons, Gregory N; Bonner, James C

    2016-06-08

    Atomic layer deposition (ALD) is a method for applying conformal nanoscale coatings on three-dimensional structures. We hypothesized that surface functionalization of multi-walled carbon nanotubes (MWCNTs) with polycrystalline ZnO by ALD would alter pro-inflammatory cytokine expression by human monocytes in vitro and modulate the lung and systemic immune response following oropharyngeal aspiration in mice. Pristine (U-MWCNTs) were coated with alternating doses of diethyl zinc and water over increasing ALD cycles (10 to 100 ALD cycles) to yield conformal ZnO-coated MWCNTs (Z-MWCNTs). Human THP-1 monocytic cells were exposed to U-MWCNTs or Z-MWCNTs in vitro and cytokine mRNAs measured by Taqman real-time RT-PCR. Male C57BL6 mice were exposed to U- or Z-MWCNTs by oropharyngeal aspiration (OPA) and lung inflammation evaluated at one day post-exposure by histopathology, cytokine expression and differential counting of cells in bronchoalveolar lavage fluid (BALF) cells. Lung fibrosis was evaluated at 28 days. Cytokine mRNAs (IL-6, IL-1β, CXCL10, TNF-α) in lung, heart, spleen, and liver were quantified at one and 28 days. DNA synthesis in lung tissue was measured by bromodeoxyuridine (BrdU) uptake. ALD resulted in a conformal coating of MWCNTs with ZnO that increased proportionally to the number of coating cycles. Z-MWCNTs released Zn(+2) ions in media and increased IL-6, IL-1β, CXCL10, and TNF-α mRNAs in THP-1 cells in vitro. Mice exposed to Z-MWCNTs by OPA had exaggerated lung inflammation and a 3-fold increase in monocytes and neutrophils in BALF compared to U-MWCNTs. Z-MWCNTs, but not U-MWCNTs, induced IL-6 and CXCL10 mRNA and protein in the lungs of mice and increased IL-6 mRNA in heart and liver. U-MWCNTs but not Z-MWCNTs stimulated airway epithelial DNA synthesis in vivo. Lung fibrosis at 28 days was not significantly different between mice treated with U-MWCNT or Z-MWCNT. Pulmonary exposure to ZnO-coated MWCNTs produces a systemic acute phase response that

  1. Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial.

    PubMed

    Chen, Guo; McQuade, Jennifer L; Panka, David J; Hudgens, Courtney W; Amin-Mansour, Ali; Mu, Xinmeng Jasmine; Bahl, Samira; Jané-Valbuena, Judit; Wani, Khalida M; Reuben, Alexandre; Creasy, Caitlyn A; Jiang, Hong; Cooper, Zachary A; Roszik, Jason; Bassett, Roland L; Joon, Aron Y; Simpson, Lauren M; Mouton, Rosalind D; Glitza, Isabella C; Patel, Sapna P; Hwu, Wen-Jen; Amaria, Rodabe N; Diab, Adi; Hwu, Patrick; Lazar, Alexander J; Wargo, Jennifer A; Garraway, Levi A; Tetzlaff, Michael T; Sullivan, Ryan J; Kim, Kevin B; Davies, Michael A

    2016-08-01

    Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75

  2. Clinical, molecular and immune analysis of dabrafenib and trametinib in metastatic melanoma patients that progressed on BRAF inhibitor monotherapy: a phase II clinical trial

    PubMed Central

    Chen, Guo; McQuade, Jennifer L.; Panka, David J.; Hudgens, Courtney W.; Amin-Mansour, Ali; Mu, Xinmeng Jasmine; Bahl, Samira; Jane-Valbuena, Judit; Wani, Khalida M.; Reuben, Alexandre; Creasy, Caitlyn A.; Jiang, Hong; Cooper, Zachary A.; Roszik, Jason; Bassett, Roland L.; Joon, Aron Y.; Simpson, Lauren M.; Mouton, Rosalind D.; Glitza, Isabella C.; Patel, Sapna P.; Hwu, Wen-Jen; Amaria, Rodabe N.; Diab, Adi; Hwu, Patrick; Lazar, Alexander J.; Wargo, Jennifer A.; Garraway, Levi A.; Tetzlaff, Michael T.; Sullivan, Ryan J.; Kim, Kevin B.; Davies, Michael A.

    2016-01-01

    Importance Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only ~15% of BRAF inhibitor (BRAFi)-refractory metastatic melanoma patients, in contrast to the high activity observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. Objective To determine correlates of benefit from CombiDT therapy in BRAFi-refractory metastatic melanoma patients. Design Single-center, single-arm prospective phase II study of CombiDT in patients with BRAFV600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014. Setting University of Texas MD Anderson Cancer Center. Participants 28 patients were screened and 23 enrolled. Key eligibility criteria included: BRAFV600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and accessible tumor for biopsy. Intervention Patients were treated with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsies were performed on-treatment and at progression. Whole-exome sequencing, RT-PCR for BRAF splicing, RNAseq and IHC were performed on tumor samples, and blood was analyzed for levels of circulating BRAFV600. Main outcome measures Primary endpoint was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical endpoints. Results Among evaluable patients, the confirmed ORR was 10%, disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi >6 months (DCR 73% vs. 11% for ≤6 months, p=0.02) and decrease in circulating BRAFV600 at day 8 of cycle 1 (DCR 75% vs. 18% for no decrease, p=0.015), but not by pre-treatment MAPK pathway mutations or activation. On

  3. 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

  4. 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

  5. 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

    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

    2013-11-20

    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. 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. 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. 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.

  6. 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

  7. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat

    PubMed Central

    Tomita, Yusuke; Lee, Min-Jung; Lee, Sunmin; Tomita, Saori; Chumsri, Saranya; Cruickshank, Scott; Ordentlich, Peter; Trepel, Jane B.

    2016-01-01

    ABSTRACT Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301. We found that entinostat significantly decreased granulocytic and monocytic MDSCs at cycle 1 day 15. MDSC CD40 was significantly downregulated by entinostat. A significant increase in HLA-DR expression on CD14+ monocytes by entinostat was observed. Entinostat did not impact T-cell subsets or T-cell immune checkpoint receptor expression. Our findings suggest that a significant interplay between this epigenetic regimen and host immune homeostatic mechanisms may impact therapeutic outcome. PMID:27999738

  8. 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.

  9. Biliopancreatic diversion with duodenal switch modifies plasma chemerin in early and late post-operative periods.

    PubMed

    Parlee, Sebastian D; Wang, Yan; Poirier, Paul; Lapointe, Marc; Martin, Julie; Bastien, Marjorie; Cianflone, Katherine; Goralski, Kerry B

    2015-06-01

    Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgical benefit arises from early-phase resolution of hyperglycemia and late-phase weight loss. The adipokine chemerin is of interest given its roles in immunity, adipogenesis, and metabolism. The study objective was to examine the effects of biliopancreatic diversion with duodenal switch (BPD-DS) on plasma chemerin in the early and late post-operative stages. 83 adults with obesity undergoing BPD-DS, 45 obese non-surgical controls, and 9 lean surgical controls were enrolled. Plasma parameters and anthropometric measures were obtained at baseline and at, early (24 h, 5 D) and late (6 months and 12 months) post-operative stages. Plasma chemerin dropped from 176±49 ng/mL at baseline to 132±52 ng/mL 24 h after BPD-DS, rebounded to 200±66 ng/mL after 5 D, and declined to 124±51 and 110±34 ng/mL after 6 and 12 months. Plasma chemerin correlated negatively with measures of inflammation and hepatic injury and positively with measures of obesity, metabolic syndrome, and inflammation in the early and late post-operative periods, respectively. Chemerin has a novel role in surgical injury but not hyperglycemia resolution early after BPD-DS. Over the long term, plasma chemerin declines to a new set point that is partially determined by body fat reductions. © 2015 The Obesity Society.

  10. Ultrastructural evidence of a vesicle-mediated mode of cell degranulation in chicken chromaffin cells during the late phase of embryonic development

    PubMed Central

    Crivellato, Enrico; Nico, Beatrice; Travan, Luciana; Isola, Miriam; Ribatti, Domenico

    2009-01-01

    In the present investigation, we attempted to determine whether ultrastructural features indicative of a vesicle-mediated mode of cell secretion were detectable in chick chromaffin cells during embryo development. The adrenal anlagen of domestic fowls were examined at embryonic days (E) 12, 15, 19 and 21 by electron microscopy quantitative analysis. Morphometric evaluation revealed a series of granule and cytoplasmic changes highly specific for piecemeal degranulation (PMD), a secretory process based on vesicular transport of cargoes from within granules for extracellular release. At E19 and E21 we found a significant peak in the percentage of granules exhibiting changes indicative of progressive release of secretory materials, i.e. granules with lucent areas in their cores, reduced electron density, disassembled matrices, residual cores and membrane empty containers. A dramatic raise in the density of 30–80-nm-diameter, membrane-bound, electron-dense and electron-lucent vesicles – which were located either next to granules or close to the plasma membrane – was recognizable at E19, that is, during the prehatching phase. The cytoplasmic burst of dense and clear vesicles was paralleled by the appearance of chromaffin granules showing outpouches or protrusions of their profiles (‘budding features’). These ultrastructural data are indicative of an augmented vesicle-mediated transport of chromaffin granule products for extracellular release in chick embryo chromaffin cells during the prehatching stage. In conclusion, this study provides new data on the fine structure of chromaffin cell organelles during organ development and suggests that PMD may be part of an adrenomedullary secretory response that occurs towards the end of chicken embryogenesis. From an evolutionary point of view, this study lends support to the concept that PMD is a secretory mechanism highly conserved throughout vertebrate classes. PMID:19245498

  11. 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...

  12. 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...

  13. Clinical, radiological, and gene expression analyses in smokers and non-smokers, Part 2: RCT on the late healing phase of osseointegration.

    PubMed

    Sayardoust, Shariel; Omar, Omar; Norderyd, Ola; Thomsen, Peter

    2017-07-26

    The mechanisms behind the impact of smoking on osseointegration are not fully understood. To investigate the initial clinical and molecular course of osseointegration of different implants in smokers and non-smokers in a randomized controlled trial (RCT). Smoking (n = 16) and non-smoking (n = 16) patients received 3 implant types: machined, oxidized, and laser-modified surfaces. Baseline bone biopsies were retrieved from the implant sites. After 60 and 90 days, the pain score, implant stability quotient (ISQ), and peri-implant crevicular fluid (PICF) gene expression were analyzed. Furthermore, radiological and clinical assessments were made at 90 days. At 90 days, no pain was reported, irrespective of smoking habit. A higher ISQ was found in smokers compared with non-smokers. Marginal bone loss (MBL) was greater in smokers than in non-smokers. The comparison of implant surfaces revealed greater MBL exclusively at the machined implants in smokers. At 90 days in smokers, the PICF around machined implants revealed a higher expression of the proinflammatory cytokine, interleukin-6 (IL-6), and a lower expression of the osteogenic gene, osteocalcin (OC), compared with the PICF around modified implants. Furthermore, OC expression was lower at machined implants in smokers compared with machined implants in non-smokers. After adjustment for age and implant location (maxilla/mandible), multivariate regression revealed the following predictors of MBL: smoking, bleeding on probing at 90 days, hypoxia-inducible factor 1 alpha (HIF-1α) expression at baseline and IL-6 expression in PICF at 90 days. During the early phase of osseointegration, non-smokers and smokers present a similar, high implant survival. In contrast, smokers present a greater MBL, particularly at machined implants. HIF-1α baseline expression in the recipient bone and IL-6 expression in PICF cells are important molecular determinants for MBL after 90 days. It is concluded that smoking has an early

  14. [Ultraviolet: a regulator of immunity].

    PubMed

    Komura, Kazuhiro

    2008-06-01

    Humans establish acquired immune systems during the growth, which can sufficiently eliminate pathogen avoiding immune responses to self, such as allergy and autoimmunity. An imbalance of the acquired immune system leads up to immune-mediated disorders. Ultraviolet (UV) exposure helps to establish the normal peripheral tolerance to contact allergen avoiding excessive immune responses. By contrast, UV develops kinds of autoimmune diseases on rare occasions, suggesting that abnormality in the process of UV-induced peripheral tolerance may induce these diseases. To elucidate the mechanism of UV-induced tolerance is possible to provide a new approach for the management of immune diseases. In the current review, focus is on the suggested players of UV-induced tolerance, blocking mechanisms on the elicitation phase of contact hypersensitivity, and the association between UV and autoimmunity. The major impact in basic immunology in this area is the discovery of cell surface marker of regulatory T cells. Therefore, we first discuss about the association of regulatory/suppressor T cells with UV-induced tolerance. Since the elicitation phase depends on cellular influx into the inflammatory sites, which is tightly regulated by adhesion molecules, we also focused on the role of adhesion molecules. Finally, this paper also includes statistical findings concerning the association between UV-radiation and the prevalence of a myositis specific autoantibody. Thus, UV is one of the nice regulators of an immune network and the knowledge of UV-mediated immune regulation will be translated into new therapeutic strategies to human immune-mediated disorders.

  15. Innate immunity.

    PubMed

    Revillard, Jean-Pierre

    2002-01-01

    For more than half a century immunological research has been almost exclusively orientated towards the acquired immune response and the mechanisms of immune tolerance. Major discoveries have enabled us to better understand the functioning of the specific immune system: the structure of antibody molecules, the genetic mechanisms leading to the molecular diversity of B (BCR) and T (TCR) lymphocyte antigen receptors, the biological function of major histocompatibility complex (MHC) molecules in the presentation of peptides to alpha/beta receptor bearing T lymphocytes, the processes of positive and negative selection of lymphocytes during the course of their differentiation. The major role of specific or acquired immunity has been shown by the rapidly lethal character of severe combined immune deficiency diseases and various alterations in the mechanisms of tolerance have been proposed to explain the chronic inflammatory illnesses which are considered to be auto-immune. Natural or innate immunity has been known since the first description of an inflammatory reaction attributed to Cornelius Celsus. It entered into the scientific era at the end of the 19th century with the discovery of phagocytes by Metchnikoff and of the properties of the complement system by Bordet [1] but due to the vastness of the field and its lack of clear definition, it failed to excite the interest of researchers. The discovery of cytokines and progress in knowledge of the mechanisms of the inflammatory reaction have certainly helped to banish preconceived ideas about natural immunity, which was wrongly labelled as non-specific. This has led to the proposition of a wider role for immune functions beyond the level of the cell or the organism [2] and to a better understanding of the importance of the immediate defence mechanisms and their role in the later orientation of the acquired response.

  16. Immune reconstitution complicated by CMV retinitis in a pediatric patient who underwent haploidentical CD34+-selected hematopoietic stem cell transplant for acute lymphoblastic leukemia.

    PubMed

    Cesaro, Simone; Boaro, Maria Paola; Pillon, Marta; Calore, Elisabetta; Cermakova, Ivete; Perruccio, Katia; Mengoli, Carlo; Messina, Chiara

    2008-09-01

    We describe two episodes of CMV retinitis in a pediatric patient who underwent a CD34+ selected graft from his haploidentical father. Both recipient and donor were cytomegalovirus (CMV) seropositive. Both episodes occurred late post-grafting during a phase of complete immunological recovery with sufficient numbers of circulating CMV-specific clones. Antiviral treatment with foscarnet and ganciclovir was successful but prolonged treatment was required to prevent relapses. We hypothesize that this complication was more related to an immune reconstitution process than to an immune-deficient state post-grafting. We conclude that CMV retinitis is a late complication of HSCT that can occur despite satisfactory immune reconstitution. Usually, it is responsive to antiviral therapy. Dilated fundoscopic examination is essential both for examining patients with reduced visual acuity and for screening asymptomatic patients.

  17. 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

  18. Broad Blockade Antibody Responses in Human Volunteers after Immunization with a Multivalent Norovirus VLP Candidate Vaccine: Immunological Analyses from a Phase I Clinical Trial

    PubMed Central

    Lindesmith, Lisa C.; Ferris, Martin T.; Mullan, Clancy W.; Ferreira, Jennifer; Debbink, Kari; Swanstrom, Jesica; Richardson, Charles; Goodwin, Robert R.; Baehner, Frank; Mendelman, Paul M.; Bargatze, Robert F.; Baric, Ralph S.

    2015-01-01

    Background Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers. Methods and Findings Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. Conclusions Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and

  19. Long-term effects of 60-Hz electric vs. magnetic fields on IL-1 and other immune parameters in sheep: Phase 5 study. Final report

    SciTech Connect

    Hefeneider, S.H.; McCoy, S.L.; Hausman, F.A.

    1998-10-01

    This study was designed to assess the effect of exposure to long-term low-frequency electric and magnetic fields (EMF) from a 500-kV transmission line on immune function in sheep. The primary hypothesis was that the reduction in IL-1 activity observed in two previous short-term studies (9 months) was due to EMF exposure from this transmission line. The secondary hypothesis was that long-term exposure (27 months) would impact immune function and animal health. To characterize the components of EMF responsible for the previously observed reduction in IL-1 activity, the experiment was designed not only to examine the effect of exposure to electric and magnetic fields, but also to examine the magnetic field component alone.

  20. Long-term effects of 60-Hz electric vs. magnetic fields on IL-1 and other immune parameters in sheep: Phase 4 study. Final report

    SciTech Connect

    Hefeneider, S.H.; McCoy, S.L.; Hausman, F.A.

    1998-10-01

    This study was designed to assess the effect of exposure to long-term low-frequency electric and magnetic fields (EMF) from an environmental 500-kV transmission line on immune function in sheep. The primary hypothesis tested was that the reduction in IL-1 activity observed in two previous short-term studies (9 months) was due to exposure to EMF from this transmission line. The secondary hypothesis was that long-term exposure (27 months) would impact immune function and animal health. To characterize the components of the EMF environment responsible for the previously observed reduction in IL-1 activity, the experiment was designed not only to examine the effect of exposure to electric and magnetic fields, but also to examine the magnetic field component alone. This was done by constructing a third pen (MF) which was shielded with wire to effectively eliminate the electric field while not significantly affecting the magnitude of the magnetic field.

  1. Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non-obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI

    PubMed Central

    Moon, Jei-Won; Kang, Hyuk-Jae; Ahn, Jun-Woo; Kim, Sung-Hoon; Chae, Hee-Dong; Kang, Byung-Moon

    2012-01-01

    Objective To evaluate the effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase (MDP-EL) in comparison with standard GnRH agonist luteal long protocol (LP) in each non-obese and obese polycystic ovary syndrome (PCOS) women undergoing IVF. Methods Two hundred eleven infertile women with PCOS were recruited and randomized to undergo either GnRH antagonist MDP-EL (antagonist group) or standard GnRH agonist luteal LP (agonist group). IVF cycle outcomes were compared between the two groups. Results Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the antagonist group than in the agonist group. Incidence of severe ovarian hyperstimulation syndrome was significantly lower in the antagonist group. However, IVF and pregnancy outcomes were similar in the two groups. When all subjects were divided into non-obese and obese subgroups, in non-obese PCOS subgroup, IVF and pregnancy outcomes were comparable in the antagonist and agonist groups but total dose and days of rhFSH were also significantly fewer in the antagonist group. Similar findings were also observed in obese PCOS subgroup. Conclusion GnRH antagonist MDP-EL is at least as effective as GnRH agonist LP and may be a more patient-friendly alternative in controlled ovarian stimulation for PCOS patients undergoing IVF, independent of body mass index. PMID:22563547

  2. Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes.

    PubMed

    Wu, Jian; Kakoola, Dorothy N; Lenchik, Nataliya I; Desiderio, Dominic M; Marshall, Dana R; Gerling, Ivan C

    2012-01-01

    Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse--a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (~90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes.

  3. Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression.

    PubMed

    Noguchi, Masanori; Arai, Gaku; Matsumoto, Kazumasa; Naito, Seiji; Moriya, Fukuko; Suekane, Shigetaka; Komatsu, Nobukazu; Matsueda, Satoko; Sasada, Tetsuro; Yamada, Akira; Kakuma, Tatsuyuki; Itoh, Kyogo

    2015-04-01

    The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.

  4. Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

    PubMed Central

    Vivas, Yurena; Díez-Hochleitner, Monica; Izquierdo-Lahuerta, Adriana; Corrales, Patricia; Horrillo, Daniel; Velasco, Ismael; Martínez-García, Cristina; Campbell, Mark; Sevillano, Julio; Ricote, Mercedes; Ros, Manuel; Ramos, Maria Pilar; Medina-Gomez, Gema

    2016-01-01

    Pregnancy requires adaptation of maternal energy metabolism, including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARγ2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARγ2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARγ2 knockout (KO) mice, we found that deletion of PPARγ2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in the liver. Lack of PPARγ2 provoked changes in the distribution of fat mass and preferentially prevented expansion of the perigonadal depot while at the same time exacerbating inflammation. Pregnant PPARγ2KO mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARγ2 is essential in promoting healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term. PMID:27782293

  5. Comprehensive Transcriptome Analyses Reveal that Potato Spindle Tuber Viroid Triggers Genome-Wide Changes in Alternative Splicing, Inducible trans-Acting Activity of Phased Secondary Small Interfering RNAs, and Immune Responses.

    PubMed

    Zheng, Yi; Wang, Ying; Ding, Biao; Fei, Zhangjun

    2017-06-01

    Many pathogens express noncoding RNAs (ncRNAs) during infection processes. In the most extreme case, pathogenic ncRNAs alone (such as viroids) can infect eukaryotic organisms, leading to diseases. While a few pathogenic ncRNAs have been implicated in regulating gene expression, the functions of most pathogenic ncRNAs in host-pathogen interactions remain unclear. Here, we employ potato spindle tuber viroid (PSTVd) infecting tomato as a system to dissect host interactions with pathogenic ncRNAs, using comprehensive transcriptome analyses. We uncover various new activities in regulating gene expression during PSTVd infection, such as genome-wide alteration in alternative splicing of host protein-coding genes, enhanced guided-cleavage activities of a host microRNA, and induction of the trans-acting function of phased secondary small interfering RNAs. Furthermore, we reveal that PSTVd infection massively activates genes involved in plant immune responses, mainly those in the calcium-dependent protein kinase and mitogen-activated protein kinase cascades, as well as prominent genes involved in hypersensitive responses, cell wall fortification, and hormone signaling. Intriguingly, our data support a notion that plant immune systems can respond to pathogenic ncRNAs, which has broad implications for providing new opportunities for understanding the complexity of immune systems in differentiating "self" and "nonself," as well as lay the foundation for resolving the long-standing question regarding the pathogenesis mechanisms of viroids and perhaps other infectious RNAs.IMPORTANCE Numerous pathogens, including viruses, express pathogenic noncoding transcripts during infection. In the most extreme case, pathogenic noncoding RNAs alone (i.e., viroids) can cause disease in plants. While some work has demonstrated that pathogenic noncoding RNAs interact with host factors for function, the biological significance of pathogenic noncoding RNAs in host-pathogen interactions remains

  6. Plant Immunity

    USDA-ARS?s Scientific Manuscript database

    Plants are faced with defending themselves against a multitude of pathogens, including bacteria, fungi, viruses, nematodes, etc. Immunity is multi-layered and complex. Plants can induce defenses when they recognize small peptides, proteins or double-stranded RNA associated with pathogens. Recognitio...

  7. Molecular Phenotyping of Immune Cells from Young NOD Mice Reveals Abnormal Metabolic Pathways in the Early Induction Phase of Autoimmune Diabetes

    PubMed Central

    Wu, Jian; Kakoola, Dorothy N.; Lenchik, Nataliya I.; Desiderio, Dominic M.; Marshall, Dana R.; Gerling, Ivan C.

    2012-01-01

    Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse – a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (∼90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes. PMID:23071669

  8. Late recurrence of medulloblastoma.

    PubMed

    Stevens, Brittney; Razzaqi, Faisal; Yu, Lolie; Craver, Randall

    2008-01-01

    We present a child with a cerebellar medulloblastoma, diagnosed at age three, treated with near total surgical resection, radiotherapy, and chemotherapy, that recurred 13 years after the initial diagnosis. This late recurrence exceeds the typical 10-year survival statistics that are in common use, and exceeds the Collins rule. Continued follow-up of these children is justified to increase the likelihood of detecting these late recurrences early and to learn more about these late recurrences.

  9. Phase II trial of albumin-bound paclitaxel and granulocyte macrophage colony-stimulating factor as an immune modulator in recurrent platinum resistant ovarian cancer.

    PubMed

    Liao, John B; Swensen, Ron E; Ovenell, Kelsie J; Hitchcock-Bernhardt, Katie M; Reichow, Jessica L; Apodaca, Minjun C; D'Amico, Leonard; Childs, Jennifer S; Higgins, Doreen M; Buening, Barbara J; Goff, Barbara A; Disis, Mary L

    2017-03-01

    Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates immunity via recruitment of antigen presenting cells and tumor specific T-cell stimulation. Albumin-bound paclitaxel (nab-paclitaxel) followed by GM-CSF may enhance antitumor responses and prolong remissions in ovarian cancer. Immune phenotypes present before treatment may identify responders to chemo-immunotherapy. Recurrent platinum-resistant ovarian, peritoneal, or fallopian tube cancer patients received nab-paclitaxel, 100mg/m(2) days 1, 8, 15 followed by GM-CSF 250μg days 16-26 every 28days for 6 planned cycles. The primary endpoint was remission duration compared to immediate prior remission. Peripheral blood was evaluated by flow cytometry and interferon-γ ELISPOT. Twenty-one patients were enrolled. Six patients (29%) achieved a biochemical complete response and 9 (43%) a partial response for an overall response rate of 72%. Median time to progression was 4months and 10% of patients achieved longer remissions than the immediate prior regimen. Median overall survival (OS) was 16.8months. Fewer myeloid derived suppressor cells (MDSC) at enrollment significantly associated with complete response (p=0.05). T-cell responses to IGF1R-p1332-1346 (r=0.827, p=0.0003) and IGF1R-p1242-1256 (r=0.850, p=0.0001) during treatment correlated with time to progression. Nab-paclitaxel combined with GM-CSF demonstrated biochemical responses in a majority of patients, although responses were not sustained. This combination did not demonstrate an advantage in OS over prior studies of nab-paclitaxel monotherapy. Agents that modulate MDSC should be studied as potential adjuvants to therapy. Strategies to expand T cells recognizing tumor-associated antigens biologically significant in ovarian cancer should also continue to be investigated. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Vaccines (immunizations) - overview

    MedlinePlus

    Vaccinations; Immunizations; Immunize; Vaccine shots; Prevention - vaccine ... component) of the vaccine. VACCINE SCHEDULE The recommended vaccination (immunization) schedule is updated every 12 months by ...

  11. Late preterm: obstetric management.

    PubMed

    Meloni, Alessandra; Antonelli, Antonello; Deiana, Sara; Rocca, Alessio; Atzei, Alessandra; Paoletti, Anna Maria; Melis, Gian Benedetto

    2010-10-01

    Late preterm is the recommended definition for infants born at 34 0/7 to 36 6/7 weeks' gestation after the onset of the mother's last menstrual period. Late-preterm infants are known to have greater mortality and morbidity when compared with term infants during the neonatal period. Obstetric management plays a substantial role in influencing neonatal outcomes. We conducted a retrospective study on late-preterm births based on data collected by regional certificates of birth attendance, comparing overall data with those relative to our Department, the aim of our study was to evaluate if obstetric management, related to different delivery settings, could influence the prevalence and the method of delivery in late preterm gestational age. Preterm births represent about 10% of 25,011 births in Sardinia, and 72.6% of them are late preterm. Elective cesarean section results significantly higher in late preterm than in term deliveries. In our Department, both late-preterm delivery rate and elective cesarean sections rate were lower if compared with country region data. Obstetric management strategies play an important role in delaying deliveries and reducing late-preterm birth rates.

  12. Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placeb