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  1. Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.

    Science.gov (United States)

    Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jeremy; Minault, David; Baker, Paul; Ville, Simon; Le Bas-Bernardet, Stephanie; Dilek, Nahzli; Belarif, Lyssia; Cassagnau, Elisabeth; Scobie, Linda; Blancho, Gilles; Vanhove, Bernard

    2016-01-01

    Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation. PMID:26597009

  2. Regulatory T Cell-Dependent and -Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade.

    Science.gov (United States)

    Vogel, Isabel; Verbinnen, Bert; Van Gool, Stefaan; Ceuppens, Jan L

    2016-07-15

    Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation. PMID:27288533

  3. Anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways act as potent immunoregulatory cells in vitro and vivo

    Institute of Scientific and Technical Information of China (English)

    蔡勇; 周佩军; 唐孝达

    2004-01-01

    Background This study was to evaluate whether anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways can act as potent immunoregulatory cells in vitro and prolong cardiac allograft survival after adoptive transfer.Methods Anergic cells were induced in vitro by the addition of anti-CD154 and anti-CD80 monoclonal antibodies (mAbs) to primary MLR (mixed lymphocyte reaction) consisting of BALB/c as responder and C3H as stimulator. Anergic cells were added to a newly formed MLR in assessing the regulatory capacity and antigen specificity of anergic cells. The ability of anergic cells to respond to antigen and/or exogenous recombinant mouse interleukin-2 (rmIL-2) was tested. For in vivo studies, anergic cells were intravenously injected into 3.0-Gy γ-irradiated BALB/c mice immediately after heterotopic abdominal cardiac transplantation. To prolong allograft survival, recipient mice injected with anergic cells received rapamycin therapy (1 mg·day-1·kg-1).Results Anergic cells strongly suppressed the proliferation of naǐve BALB/c splenocytes against the original (C3H) stimulator in a dose-dependent manner, but they failed to suppress the proliferation of naǐve BALB/c splenocytes against the third-party (C57BL/6J) stimulator. The anergic state was reversed by both original (C3H) stimulator and additional exogenous IL-2. In in vivo studies, untreated irradiated BALB/c mice rejected C3H cardiac allografts with a mean survival time of (8.6±1.1) days, whereas those injected with the anergic cells rejected the allografts with a mean survival time of (11.8±1.9) days, which was slightly longer than that of the untreated mice. The protocol based on anergic cells injection plus rapamycin therapy could prolong allograft survival significantly [(29.6±4.4) days]. Conclusions Anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways can act as potent immunoregulatory cells in vitro, and prolong cardiac allograft

  4. RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter.

    OpenAIRE

    Lai, J. H.; HORVATH, G; Subleski, J; Bruder, J.; P. Ghosh; Tan, T H

    1995-01-01

    T-cell activation requires two different signals. The T-cell receptor's recognition of a specific antigen on antigen-presenting cells provides one, and the second signal comes from costimulatory molecules such as CD28. In contrast, T cells that are stimulated with antigen in the absence of the CD28 costimulatory signal can become anergic (nonresponsive). The CD28 response element (CD28RE) has been identified as the DNA element mediating interleukin 2 (IL-2) gene activation by CD28 costimulati...

  5. Hyperlipidemia Alters Regulatory T Cell Function and Promotes Resistance to Tolerance Induction Through Costimulatory Molecule Blockade.

    Science.gov (United States)

    Bagley, J; Yuan, J; Chandrakar, A; Iacomini, J

    2015-09-01

    Recent work from our laboratory has shown that hyperlipidemia promotes accelerated rejection of vascularized cardiac allografts in mice by inducing anti-donor Th17 reactivity and production of IL-17. Here, we show that hyperlipidemia also affects FoxP3(+) regulatory T cells (Tregs). Hyperlipidemia promotes the development of Tregs that express low levels of CD25. Hyperlipidemia also promotes a decrease in central Tregs and an increase in effector Tregs that appears to account for the increase in the frequency of CD25(low) Tregs. Alterations in Treg subsets also appear to lead to alterations in Treg function. The ability of FoxP3(+) , CD25(high) , CD4(+) Tregs from hyperlipidemic mice to inhibit proliferation of effector T cells stimulated with anti-CD3 and CD28 was reduced when compared with Tregs from control mice. Regulatory T cells isolated from hyperlipidemic recipients exhibit increased activation of Akt, and a reduction in Bim levels that permits the expansion of FoxP3(+) CD25(low) CD4(+) T cells. Hyperlipidemic mice were also resistant to tolerance induction using costimulatory molecule blockade consisting of anti-CD154 and CTLA4Ig, a strategy that requires Tregs. Together, our data suggest that hyperlipidemia profoundly affects Treg subsets and function as well as the ability to induce tolerance.

  6. Evidence implicating the Ras pathway in multiple CD28 costimulatory functions in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Sujit V Janardhan

    Full Text Available CD28 costimulation is a critical event in the full activation of CD4(+ T cells that augments cytokine gene transcription, promotes cytokine mRNA stability, prevents induction of anergy, increases cellular metabolism, and increases cell survival. However, despite extensive biochemical analysis of the signaling events downstream of CD28, molecular pathways sufficient to functionally replace the diverse aspects of CD28-mediated costimulation in normal T cells have not been identified. Ras/MAPK signaling is a critical pathway downstream of T cell receptor stimulation, but its role in CD28-mediated costimulation has been controversial. We observed that physiologic CD28 costimulation caused a relocalization of the RasGEF RasGRP to the T cell-APC interface by confocal microscopy. In whole cell biochemical analysis, CD28 cross-linking with either anti-CD28 antibody or B7.1-Ig augmented TCR-induced Ras activation. To determine whether Ras signaling was sufficient to functionally mimic CD28 costimulation, we utilized an adenoviral vector encoding constitutively active H-Ras (61L to transduce normal, Coxsackie-Adenovirus Receptor (CAR transgenic CD4(+ T cells. Like costimulation via CD28, active Ras induced AKT, JNK and ERK phosphorylation. In addition, constitutive Ras signaling mimicked the ability of CD28 to costimulate IL-2 protein secretion, prevent anergy induction, increase glucose uptake, and promote cell survival. Importantly, we also found that active Ras mimicked the mechanism by which CD28 costimulates IL-2 production: by increasing IL-2 gene transcription, and promoting IL-2 mRNA stability. Finally, active Ras was able to induce IL-2 production when combined with ionomycin stimulation in a MEK-1-dependent fashion. Our results are consistent with a central role for Ras signaling in CD28-mediated costimulation.

  7. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing?

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    Kathrin Maly

    2015-01-01

    Full Text Available CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

  8. The story of CD4+ CD28- T cells revisited: solved or still ongoing?

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    Maly, Kathrin; Schirmer, Michael

    2015-01-01

    CD4(+)CD28(-) T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4(+) T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4(+)CD28(-) T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4(+)CD28(-) T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4(+)CD28(-) T cell level. The clinical relevance of targeting CD4(+)CD28(-) T cells as a therapeutic option has not been examined so far. PMID:25834833

  9. Costimulatory receptors in a teleost fish: Typical CD28, elusive CTLA4

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    Bernard, D.; Riteau, B.; Hansen, J.D.; Phillips, R.B.; Michel, F.; Boudinot, P.; Benmansour, A.

    2006-01-01

    T cell activation requires both specific recognition of the peptide-MHC complex by the TCR and additional signals delivered by costimulatory receptors. We have identified rainbow trout sequences similar to CD28 (rbtCD28) and CTLA4 (rbtCTLA4). rbtCD28 and rbtCTLA4 are composed of an extracellular Ig-superfamily V domain, a transmembrane region, and a cytoplasmic tail. The presence of a conserved ligand binding site within the V domain of both molecules suggests that these receptors likely recognize the fish homologues of the B7 family. The mRNA expression pattern of rbtCD28 and rbtCTLA4 in naive trout is reminiscent to that reported in humans and mice, because rbtCTLA4 expression within trout leukocytes was quickly up-regulated following PHA stimulation and virus infection. The cytoplasmic tail of rbtCD28 possesses a typical motif that is conserved in mammalian costimulatory receptors for signaling purposes. A chimeric receptor made of the extracellular domain of human CD28 fused to the cytoplasmic tail of rbtCD28 promoted TCR-induced IL-2 production in a human T cell line, indicating that rbtCD28 is indeed a positive costimulator. The cytoplasmic tail of rtrtCTLA4 lacked obvious signaling motifs and accordingly failed to signal when fused to the huCD28 extracellular domain. Interestingly, rbtCTLA4 and rbtCD28 are not positioned on the same chromosome and thus do not belong to a unique costimulatory cluster as in mammals. Finally, oar results raise questions about the origin and evolution of positive and negative costimulation in vertebrate immune systems. Copyright ?? 2006 by The American Association of Immunologists, Inc.

  10. Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

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    I. Y. Ledezma-Lozano

    2011-01-01

    Full Text Available Objective: Rheumatoid arthritis (RA is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28 could be related to clinical activity.

  11. Inhibiting the expression of CD28 costimulatory molecule on human lymphocytes by special siRNA

    Institute of Scientific and Technical Information of China (English)

    XU Kai-lin; ZHANG Ying; PAN Xiu-ying; LU Qun-xian

    2005-01-01

    synthesized and transfected into lymphocytes. They could reduce the expression of CD28 and the CD28 mRNA level. siRNA-2 was the most efficient. The cell viability reduced correspondingly. Therefore, the silencing effect on CD28 mRNA induced by siRNA may contribute to costimulatory blockade. This result show that siRNA may be useful for further study on graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT).

  12. Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice.

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    Mahvi, David A; Meyers, Justin V; Tatar, Andrew J; Contreras, Amanda; Suresh, Marulasiddappa; Leverson, Glen E; Sen, Siddhartha; Cho, Clifford S

    2015-01-01

    Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.

  13. CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells.

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    Macal, Monica; Tam, Miguel A; Hesser, Charles; Di Domizio, Jeremy; Leger, Psylvia; Gilliet, Michel; Zuniga, Elina I

    2016-02-15

    Type I IFNs (IFN-I) are key innate mediators that create a profound antiviral state and orchestrate the activation of almost all immune cells. Plasmacytoid dendritic cells (pDCs) are the most powerful IFN-I-producing cells and play important roles during viral infections, cancer, and autoimmune diseases. By comparing gene expression profiles of murine pDCs and conventional DCs, we found that CD28, a prototypic T cell stimulatory receptor, was highly expressed in pDCs. Strikingly, CD28 acted as a negative regulator of pDC IFN-I production upon TLR stimulation but did not affect pDC survival or maturation. Importantly, cell-intrinsic CD28 expression restrained pDC (and systemic) IFN-I production during in vivo RNA and DNA viral infections, limiting antiviral responses and enhancing viral growth early after exposure. Finally, CD28 also downregulated IFN-I response upon skin injury. Our study identified a new pDC regulatory mechanism by which the same CD28 molecule that promotes stimulation in most cells that express it is co-opted to negatively regulate pDC IFN-I production and limit innate responses. PMID:26773151

  14. Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

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    Ledezma-Lozano, I. Y.; Padilla-Martínez, J. J.; Leyva-Torres, S. D.; Parra-Rojas, I.; Ramírez-Dueñas, M. G.; Pereira-Suárez, Ana Laura; Rangel-Villalobos, H.; Ruiz-Quezada, S. L.; Sánchez-Hernández, P. E.; Muñoz-Valle, J. F.

    2011-01-01

    Objective: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity. Methods: We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients. Methods: We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients. Results: RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p = 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p = 0.026). The RA patients showed higher sCD28 serum levels than HS (p = 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p = 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272; p = 0.016), was found. Conclusion: The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients. PMID:21508506

  15. Interrupting CD28 costimulation before antigen rechallenge affects CD8(+) T-cell expansion and effector functions during secondary response in mice.

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    Fröhlich, Monika; Gogishvili, Tea; Langenhorst, Daniela; Lühder, Fred; Hünig, Thomas

    2016-07-01

    The role of CD28-mediated costimulation in secondary CD8(+) T-cell responses remains controversial. Here, we have used two tools - blocking mouse anti-mouse CD28-specific antibodies and inducible CD28-deleting mice - to obtain definitive answers in mice infected with ovalbumin-secreting Listeria monocytogenes. We report that both blockade and global deletion of CD28 reveal its requirement for full clonal expansion and effector functions such as degranulation and IFN-γ production during the secondary immune response. In contrast, cell-intrinsic deletion of CD28 in transferred TCR-transgenic CD8(+) T cells before primary infection leads to impaired clonal expansion but an increase in cells able to express effector functions in both primary and secondary responses. We suggest that the proliferation-impaired CD8(+) T cells respond to CD28-dependent help from their environment by enhanced functional differentiation. Finally, we report that cell-intrinsic deletion of CD28 after the peak of the primary response does not affect the establishment, maintenance, or recall of long-term memory. Thus, if given sufficient time, the progeny of primed CD8(+) T cells adapt to the absence of this costimulator. PMID:27122236

  16. CD28表达与幼年特发性关节炎发病的相关性研究%Association between CD28 expression and juvenile idiopathic arthritis

    Institute of Scientific and Technical Information of China (English)

    梁卉; 李强; 魏平平; 刘华林

    2013-01-01

    .01).During the resting phase,CD4 +/CD8 + T cell counts and CD28 expression in the peripheral blood of children with JIA were significantly different from normal controls (P > 0.05).Conclusions The frequency of CD4 + CD28-T cells can be used as an indicator of the active phase of JIA.CD4 + T cell and CD4+ CD28-T cell apoptosis was inhibited in JIA patients.These immune-active T lymphocytes with continued survival can promote the occurrence and development of JIA.

  17. CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

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    Marcos V. Silva

    2012-01-01

    Full Text Available Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.

  18. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Schaub, M; Issazadeh-Navikas, Shohreh; Stadlbauer, T H;

    1999-01-01

    Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to block...

  19. Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells.

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    Nahzli Dilek

    Full Text Available CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs. What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff but inhibition of suppression by regulatory T cells (Tregs, while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.

  20. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs.

    Science.gov (United States)

    Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-Bo; Shimizu, Yoji; Bache, Robert J; Chen, Yingjie

    2016-09-01

    The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3(+)CD44(high) cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction-induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction-induced CD45(+) leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-α and interleukin-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 μg/mouse every 3 days) attenuated transverse aortic constriction-induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF.

  1. CD28 ligation increases macrophage suppression of T-cell proliferation.

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    Silberman, Daniel; Bucknum, Amanda; Bartlett, Thomas; Composto, Gabriella; Kozlowski, Megan; Walker, Amanda; Werda, Amy; Cua, Jackelyn; Sharpe, Arlene H; Somerville, John E; Riggs, James E

    2012-07-01

    When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T-cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T-cell response. Peritoneal macrophages exhibit an immature phenotype (MHC class II(lo), B7(lo)) that reduces their efficacy as antigen-presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T-cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T-cell costimulation to recover the peritoneal T-cell response. We show that CD28 ligation failed to recover the peritoneal T-cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing monoclonal antibody (mAb) treatment, this 'cosuppression' response was due to CD28 ligation increasing the number of interferon (IFN)-γ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T-cell costimulation biology.Cellular & Molecular Immunology advance online publication, 23 April 2012; doi:10.1038/cmi.2012.13.

  2. Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1

    OpenAIRE

    Jacobs, Sarah R.; Herman, Catherine E.; MacIver, Nancie J.; Wofford, Jessica A.; Wieman, Heather L.; Hammen, Jeremy J.; Rathmell, Jeffrey C.

    2008-01-01

    T cell activation potently stimulates cellular metabolism to support the elevated energetic and biosynthetic demands of growth, proliferation, and effector function. We show that glucose uptake is limiting in T cell activation and that CD28 costimulation is required to allow maximal glucose uptake following TCR stimulation by up-regulating expression and promoting the cell surface trafficking of the glucose transporter Glut1. Regulation of T cell glucose uptake and Glut1 was critical, as low ...

  3. CD3(+)CD8(+)CD28(-) T Lymphocytes in Patients with Lupus Nephritis.

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    Żabińska, Marcelina; Krajewska, Magdalena; Kościelska-Kasprzak, Katarzyna; Klinger, Marian

    2016-01-01

    The results of studies on the CD3(+)CD8(+)CD28(-) cells in SLE are inconsistent since several analyses describe CD3(+)CD8(+)CD28(-) as either immunosuppressive or cytotoxic. The aim of this study is to inquire whether the quantitative changes of CD3(+)CD8(+)CD28(-) T lymphocytes subpopulation are related to the clinical status of patients with lupus nephritis. Evaluation of Foxp3 expression on CD3(+)CD8(+)CD28(-) cells may shed some light on functional properties of these cells. 54 adult SLE patients and 19 sex and age matched healthy volunteers were enrolled in the study. There were 15 patients in inactive (SLEDAI ≤ 5) and 39 in active (SLEDAI > 5) phase of disease. We determined absolute count of CD3(+)CD8(+)CD28(-) and CD3(+)CD8(+)CD28(-)Foxp3(+) subpopulations by flow cytometry. We observed a statistically significant increase in absolute count and percentage of CD3(+)CD8(+)CD28(-) in SLE patients compared to HC (p < 0.001). Moreover there was significant positive correlation between increasing absolute count of CD3(+)CD8(+)CD28(-) cells and disease activity measured by SLEDAI (rs = 0.281, p = 0.038). Active LN patients had increased absolute count of CD3(+)CD8(+)CD28(-) cells compared to HC. Positive correlation of CD3(+)CD8(+)CD28(-) number with disease activity, and lack of Foxp3 expression on these cells, suggests that CD3(+)CD8(+)CD28(-) lymphocytes might be responsible for an increased proinflammatory response in the exacerbation of SLE. PMID:27446964

  4. Costimulation of IL-2 Production through CD28 Is Dependent on the Size of Its Ligand.

    Science.gov (United States)

    Lim, Hong-Sheng; Cordoba, Shaun-Paul; Dushek, Omer; Goyette, Jesse; Taylor, Alison; Rudd, Christopher E; van der Merwe, P Anton

    2015-12-01

    Optimal T cell activation typically requires engagement of both the TCR and costimulatory receptors, such as CD28. Engagement of CD28 leads to tyrosine phosphorylation of its cytoplasmic region and recruitment of cytoplasmic signaling proteins. Although the exact mechanism of CD28 signal transduction is unknown, CD28 triggering has similarities to the TCR, which was proposed to use the kinetic-segregation (KS) mechanism. The KS model postulates that, when small receptors engage their ligands within areas of close (∼15 nm) contact in the T cell/APC interface, this facilitates phosphorylation by segregating the engaged receptor/ligand complex from receptor protein tyrosine phosphatases with large ectodomains, such as CD45. To test this hypothesis, we examined the effect of elongating the extracellular region of the CD28 ligand, CD80, on its ability to costimulate IL-2 production by primary T cells. CD80 elongation reduced its costimulatory effect without abrogating CD28 binding. Confocal microscopy revealed that elongated CD80 molecules were less well segregated from CD45 at the T cell/APC interface. T cells expressing CD28 harboring a key tyrosine-170 mutation were less sensitive to CD80 elongation. In summary, the effectiveness of CD28 costimulation is inversely proportional to the dimensions of the CD28-CD80 complex. Small CD28-CD80 complex dimensions are required for optimal costimulation by segregation from large inhibitory tyrosine phosphatases. These results demonstrate the importance of ligand dimensions for optimal costimulation of IL-2 production by T cells and suggest that the KS mechanism contributes to CD28 signaling.

  5. B7-H5 costimulates human T cells via CD28H

    Science.gov (United States)

    Zhu, Yuwen; Yao, Sheng; Iliopoulou, Bettina P.; Han, Xue; Augustine, Mathew M.; Xu, Haiying; Phennicie, Ryan T.; Flies, Sarah J.; Broadwater, Megan; Ruff, William; Taube, Janis M.; Zheng, Linghua; Luo, Liqun; Zhu, Gefeng; Chen, Jianzhu; Chen, Lieping

    2013-01-01

    The B7/CD28 family has profound modulatory effects in immune responses and constitutes important targets for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homolog (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H-negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homolog 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction co-stimulates human T cell growth and cytokine production, selectively via an AKT-dependent signaling cascade. Our study identifies a novel co-stimulatory pathway regulating human T cell responses. PMID:23784006

  6. The expression and their significance of membrane type CD28 on T cells and the production of soluble CD28 in serum from GD patients%Graves′病患者外周血T细胞表面膜型CD28及血清中可溶性CD28的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    王凤鸣; 沈双; 李琼; 刘彤; 孙静

    2012-01-01

    Objective To analyze the expression of membrane type CD28 on T cells and the serum production of soluble CD28 in peripheral blood from GD patients, to investigate the role of CD28 molecule in the immunological pathogenesis of GD. Methods The peripheral blood mononuclear cells (PBMCs) were collected from 105 cases of GD patients as experiment group and from 67 healthy donors as control group. The expression of membrane type CD28 in peripheral blood of all donors was detected by flow cytometry (FCM). The production of soluble CD28 in serum was detected using the skills of enzyme-linked immunosorbent assay (ELISA). Results The percentage of CD4+CD28+ and CD8+CD28+ T cells in peripheral blood of patients from experiment group were respectively (23.367±8.562)% and (10.156±3.114)%, and were declined markedly compared with that of control group [(30.786±5.143)% and (17.200±3.624)%, respectively] (P < 0.0.5, P < 0.0.1). In addition, compared with control group [(0.53±0.23)μg/L], the level of soluble CD28 was increased significantly in serum of experiment group [(2.35±0.58)μg/L] (P < 0.01). Conclusion The costimulatory molecule CD28 maybe take part in the im- munological pathogenesis mechanism of GD.%目的 分析Graves′病(Graves′ disease,GD)患者外周血T细胞表面膜型CD28及血清中可溶性CD28的表达水平,探讨CD28分子在GD免疫病理机制中的作用.方法 选取105例GD患者为试验组,67例健康者为对照组,通过溶血及流式细胞术检测所有受试对象外周血T细胞表面膜型CD28的表达,酶联免疫吸附法(ELISA)检测血清中可溶性CD28的含量.结果 试验组外周血CD4+CD28+T细胞为(23.367±8.562)%,CD8+CD28+T细胞为(10.156±3.114)%,较对照组[分别为(30.786±5.143)%和(17.200±3.624)%]显著减少(P < 0.0.5、P < 0.0.1),血清中可溶性CD28水平观察组[(2.35±0.58)μg/L]较对照组[(0.53±0.23)μg/L]显著增加(P < 0.01).结论 共刺激分子CD28很有可能参与了GD的免疫病理机制.

  7. Expression of Costimulatory Molecules B7/CD28 in Systemic Lupus Erythematosus

    Institute of Scientific and Technical Information of China (English)

    胡绍先; 陶德定; 何培根

    2004-01-01

    Summary: The expression of the costimulatory molecules B7/CD28 in peripheral blood mononuclear cells (PBMC) of the patients with systemic lupus erythematosus (SLE) and its relation to the pathogenesis of SLE were studied. The expression of the costimulatory molecules in PBMC in 30 patients with active SLE and 20 cases of healthy controls was detected by using the techniques of immunofluorescence and flow cytometer. The result showed that the expression percentage of CD28+ ,CD4+ CD28+ in T cells of PBMC from the patients with SLE decreased significantly as compared with that in healthy control group, while the expression percentage of CD80+ , CD19+ CD80+ in B cells was significantly increased than that in healthy control group (P<0.01). It suggested that the abnormal expression of costimulatory molecules B7/CD28 played a role in the pathogenesis of SLE.

  8. Schistosoma mansoni PIII antigen modulates in vitro granuloma formation by regulating CD28, CTLA-4, and CD86 expression in humans.

    Science.gov (United States)

    Zouain, C S; Falcão, P L; Goes, T S; Leite, M F; Goes, A M

    2004-02-15

    We investigated the in vitro responses of peripheral blood mononuclear cells (PBMC) from intestinal chronic schistosomiasis patients to PIII, a multivalent antigen prepared from Schistosoma mansoni adult worm. PIII decreased cellular proliferation and granulomatous reaction. Moreover, induced the reduction of IFN-gamma levels and increased IL-10 production. To better understand the mechanism through which the observed suppression occurs, the present study focused on the phenotypic pattern displayed by PBMC treated with PIII in an in vitro granuloma assay. Expression of the surface markers CD28, CTLA-4 and CD86 by lymphocytes and monocytes were analyzed by flow cytometry. Our results demonstrated a significant decrease of CD28+CD4+ and CD28+CD8+ T-cell percentage stimulated by PIII compared to its non-infected counterparts. This suppressive effect was related to a significant increase in the percentage of T-cells expressing CTLA-4. PIII also promoted a significant increase in the percentage of cells expressing CD86. Indeed, our results demonstrated that PIII was capable of modulating in vitro granuloma reaction, and this event was related to the balance of IL-10, IFN-gamma and CD28, CTLA-4, CD86 bringing new insight to the immunoregulation of granulomatous hypersensitivity in human schistosomiasis. PMID:15019278

  9. Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling.

    Science.gov (United States)

    Dobbins, Jessica; Gagnon, Etienne; Godec, Jernej; Pyrdol, Jason; Vignali, Dario A A; Sharpe, Arlene H; Wucherpfennig, Kai W

    2016-01-01

    The T cell costimulatory receptor CD28 is required for the full activation of naïve T cells and for the development and maintenance of Foxp3(+) regulatory T (Treg) cells. We showed that the cytoplasmic domain of CD28 was bound to the plasma membrane in resting cells and that ligand binding to CD28 resulted in its release. Membrane binding by the CD28 cytoplasmic domain required two clusters of basic amino acid residues, which interacted with the negatively charged inner leaflet of the plasma membrane. These same clusters of basic residues also served as interaction sites for Lck, a Src family kinase critical for CD28 function. This signaling complex was further stabilized by the Lck-mediated phosphorylation of CD28 Tyr(207) and the subsequent binding of the Src homology 2 (SH2) domain of Lck to this phosphorylated tyrosine. Mutation of the basic clusters in the CD28 cytoplasmic domain reduced the recruitment to the CD28-Lck complex of protein kinase Cθ (PKCθ), which serves as a key effector kinase in the CD28 signaling pathway. Consequently, mutation of either a basic cluster or Tyr(207) impaired CD28 function in mice as shown by the reduced thymic differentiation of FoxP3(+) Treg cells. On the basis of these results, we propose a previously undescribed model for the initiation of CD28 signaling. PMID:27460989

  10. Differential expression of the costimulatory molecules CD86, CD28, CD152 and PD-1 correlates with the host-parasite outcome in leprosy

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes Palermo

    2012-12-01

    Full Text Available Leprosy is a spectral disease exhibiting two polar sides, namely, lepromatous leprosy (LL characterised by impaired T-cell responses and tuberculoid leprosy in which T-cell responses are strong. Proper T-cell activation requires signalling through costimulatory molecules expressed by antigen presenting cells and their ligands on T-cells. We studied the influence of costimulatory molecules on the immune responses of subjects along the leprosy spectrum. The expression of the costimulatory molecules was evaluated in in vitro-stimulated peripheral blood mononuclear cells of lepromatous and tuberculoid patients and healthy exposed individuals (contacts. We show that LL patients have defective monocyte CD86 expression, which likely contributes to the impairment of the antigen presentation process and to patients anergy. Accordingly, CD86 but not CD80 blockade inhibited the lymphoproliferative response to Mycobacterium leprae. Consistent with the LL anergy, there was reduced expression of the positive signalling costimulatory molecules CD28 and CD86 on the T-cells in these patients. In contrast, tuberculoid leprosy patients displayed increased expression of the negative signalling molecules CD152 and programmed death-1 (PD-1, which represents a probable means of modulating an exacerbated immune response and avoiding immunopathology. Notably, the contacts exhibited proper CD86 and CD28 expression but not exacerbated CD152 or PD-1 expression, suggesting that they tend to develop a balanced immunity without requiring immunosuppressive costimulatory signalling.

  11. Polymorphisms in the CD28/CTLA4/ICOS genes: Role in malignant melanoma susceptibility and prognosis?

    NARCIS (Netherlands)

    M.G. Bouwhuis (Marna); A. Gast (Andreas); A. Figl (Adina); A.M.M. Eggermont (Alexander); K. Hemminki (Kari); D. Schadendorf (Dirk); R. Kumar (Rajiv)

    2010-01-01

    textabstractThe appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and

  12. Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model

    DEFF Research Database (Denmark)

    Gallon, L; Chandraker, A; Issazadeh-Navikas, Shohreh;

    1997-01-01

    Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that...

  13. Acute em>P. falciparum malaria induces a loss of CD28- T IFN-¿ producing cells

    DEFF Research Database (Denmark)

    Kemp, Kåre; Akanmori, Bartholomew D; Kurtzhals, Jørgen A L;

    2002-01-01

    P. falciparum malaria is associated with increased activation among peripheral lymphocytes. In the present study, we investigated markers of susceptibility to apoptosis and expression of IFN-gamma and IL-4 by CD28-and CD28+T cells in West African children with acute P. falciparum malaria. The stu...

  14. Control of autoimmune diseases by the B7-CD28 family molecules.

    Science.gov (United States)

    Anand, Sudarshan; Chen, Lieping

    2004-01-01

    The roles of B7-CD28 family molecules in the regulation of immune responses have been intensively studied over the past decade. The findings resulting from these studies not only broaden our understanding in the control of immune responses at the molecular level, but also lead to identification of molecular targets for future manipulation and potential treatment of human diseases. There is convincing evidence that the B7-CD28 family molecules play critical roles in the control of initiation, progression and pathogenesis of autoimmune diseases, which is the focus of this review. Currently, five molecular pathways within this family have been identified and each of them appears to overlap but have distinct functions in the control of priming, activation, maturation and amplification of cellular and humoral immune responses. Rationale-based design of intervention, targeting on multiple pathways should lead to new methods and approaches for management of autoimmune diseases. PMID:14754392

  15. Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.

    Science.gov (United States)

    Melhorn, Susan J; Tyagi, Vidhi; Smeraglio, Anne; Roth, Christian L; Schur, Ellen A

    2014-11-01

    Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.

  16. CD28单抗和IL-15对CIK增殖和杀肿瘤作用的研究%Study of anti-CD28 antibody and IL-15 on proliferation and anti-tumor activity of CIK

    Institute of Scientific and Technical Information of China (English)

    刘军权; 唐莉; 朱云; 陈复兴; 周燏; 杨宛莹; 吕小婷; 张颂; 陶征中; 李昳

    2012-01-01

    fully automatic five categories of blood analyzer. The expressions of granzyme B, perforin, CD107a were detected by flow cy-tometry. Cytokines of IL-10, IL-12, INF-y and TNF-a were quantified by ELISA. Cytotoxicities of CIK on lung cancer cell line (A549), breast adenocarcinoma cell line (MFC-7) and human melanoma cell line (HME1) were measured by lactate dehy-drogenase releasing assay. Adding anti-CD28 antibody and IL-15 into CIK conventional culture system could significantly increase proliferation rate and promote expression of granzyme B, perforin, and CD107a(P0. 05). This study demonstrated that adding anti-CD28 antibody and IL-15 into CIK conventional culture system could enhance CIK proliferation and anti-tumor activity.

  17. Blockade of CTLA-4 promotes the development of effector CD8+ T lymphocytes and the therapeutic effect of vaccination with an attenuated protozoan expressing NY-ESO-1.

    Science.gov (United States)

    Dos Santos, Luara Isabela; Galvão-Filho, Bruno; de Faria, Paula Cristina; Junqueira, Caroline; Dutra, Miriam Santos; Teixeira, Santuza Maria Ribeiro; Rodrigues, Maurício Martins; Ritter, Gerd; Bannard, Oliver; Fearon, Douglas Thomas; Antonelli, Lis Ribeiro; Gazzinelli, Ricardo Tostes

    2015-03-01

    The development of cancer immunotherapy has long been a challenge. Here, we report that prophylactic vaccination with a highly attenuated Trypanosoma cruzi strain expressing NY-ESO-1 (CL-14-NY-ESO-1) induces both effector memory and effector CD8(+) T lymphocytes that efficiently prevent tumor development. However, the therapeutic effect of such a vaccine is limited. We also demonstrate that blockade of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) during vaccination enhances the frequency of NY-ESO-1-specific effector CD8(+) T cells producing IFN-γ and promotes lymphocyte migration to the tumor infiltrate. As a result, therapy with CL-14-NY-ESO-1 together with anti-CTLA-4 is highly effective in controlling the development of an established melanoma.

  18. Outbreak of Pasteurella pneumotropica in a closed colony of STOCK-Cd28(tm1Mak) mice

    DEFF Research Database (Denmark)

    Artwohl, J.E.; Flynn, J.C.; Bunte, R.M.;

    2000-01-01

    Fifteen mice with Pasteurella pneumotropica orbital abscesses were noted in mice that were homozygous for a targeted Cd28 gene mutation. Only one mouse heterozygous for the Cd28 mutation was affected. According to phenotypic reactions and 16S rDNA sequencing, the isolates were most similar to bio...... to biotype Heyl, This article provides evidence for an immunologic basis of susceptibility to P. pneumotropica infection....

  19. 2型糖尿病患者外周血中膜型及可溶性 CD28分子的表达及意义%The significance and expression of serum membrane type CD28 and soluble CD28 of among 2 diabetes pa-tients

    Institute of Scientific and Technical Information of China (English)

    赵江萍; 陈海龙; 王凤鸣

    2014-01-01

    目的:分析2型糖尿病患者外周血中膜型及可溶性 CD28分子的表达及其意义。方法分别收集2012年12月至2013年12月在北京军区联勤部门诊部就诊的30例2型糖尿病患者(糖尿病组)及同期30名健康体检者(对照组)的外周血,通过溶血及流式细胞术检测其外周血 T 细胞表面 CD28分子的表达,酶联免疫吸附(ELISA)法检测血清中可溶性 CD28的水平,并进行对比分析。结果糖尿病组外周血 CD4+CD28+T 细胞和 CD8+CD28+T 细胞显著低于对照组[(28.29±7.71)%比(32.77±4.28)%和(12.18±3.17)%比(18.53±3.27)%,均 P <0.01],血清中可溶性 CD28水平显著高于对照组[(2.86±0.96)比(0.61±0.19)μg/L,P <0.01]。结论协同刺激分子 CD28很可能参与了2型糖尿病的免疫病理机制。%Objective To analyze the expression of membrane type CD28 and soluble CD28 in peripheral blood of type 2 diabetes patients.Methods The peripheral blood mononuclear cells (PBMCs)of 30 subjects with type 2 diabetes (diabetes group)and 30 healthy donors (control group)were collected from December 201 2 to De-cember 201 3 in the out -patient department of Outreach Logistics Department of Beijing Military Region.The expres-sion of CD28 on T cells in peripheral blood of type 2 diabetes patients was detected by flow cytometry (FCM).The secretion of soluble CD28 in serum was detected using the skills of Enzyme -linked immunosorbent assay (ELISA). The data was analyzed by the Graphpad Prism 5.01 program.Results The percentage of CD4 +CD28 +and CD8+CD28 +T cells in peripheral blood of type 2 diabetes patients were (28.29 ±7.71 )% and (1 2.1 8 ±3.1 7)% re-spectively,and were decreased markedly compared with healthy control (32.77 ±4.28% and 1 8.53 ±3.27%,P <0.01 and P <0.001 ).Compared with control,the level of soluble CD28 was increased significantly in serum of type 2 diabetes patients ((2

  20. Graves病患者外周血CD4+CD28-T细胞亚群检测的临床意义%The Role of Circulating CD4+ CD28- T Cell in the Development of Graves' Disease

    Institute of Scientific and Technical Information of China (English)

    陈蕾; 李廷; 於葛华; 蒋联; 吴敏; 张学光

    2010-01-01

    目的 分析Graves病(GD)患者外周血CD4+CD28-T细胞亚群的数量和功能的变化,并初步探讨其在GD发病中的可能作用.方法 采用荧光标记、胞内细胞因子染色和流式细胞术分析61例GD患者外周血CD4+CD28-T细胞的表型特征,并与30名GD组相匹配的健康受试者作对照.结果 与正常对照组相比,CD4+CD28-T细胞在GD患者外周血中显著升高(P<0.01),并且呈现其百分率与该病的临床体征甲状腺肿大和突眼及甲状腺自身抗体TRAb成正相关;CD4+CD28-T细胞表面上调表达共刺激分子ICOS,活化诱导后分泌IFN-γ,呈现出Th1样功能特征.结论 循环CD4+CD28-T细胞可能是参与GD自身免疫病理的自身免疫反应性T细胞.

  1. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.

    Directory of Open Access Journals (Sweden)

    Gila Arad

    2011-09-01

    Full Text Available Bacterial superantigens, a diverse family of toxins, induce an inflammatory cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands, yet we show here that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality. Mice were protected from lethal superantigen challenge by short peptide mimetics of the CD28 dimer interface and by peptides selected to compete with the superantigen for its binding site in CD28. Superantigens use a conserved β-strand/hinge/α-helix domain of hitherto unknown function to engage CD28. Mutation of this superantigen domain abolished inflammatory cytokine gene induction and lethality. Structural analysis showed that when a superantigen binds to the T cell receptor on the T cell and major histocompatibility class II molecule on the antigen-presenting cell, CD28 can be accommodated readily as third superantigen receptor in the quaternary complex, with the CD28 dimer interface oriented towards the β-strand/hinge/α-helix domain in the superantigen. Our findings identify the CD28 homodimer interface as a critical receptor target for superantigens. The novel role of CD28 as receptor for a class of microbial pathogens, the superantigen toxins, broadens the scope of pathogen recognition mechanisms.

  2. T Lymphocyte Co-Signaling Pathways of the B7-CD28 Family

    Institute of Scientific and Technical Information of China (English)

    Shengdian Wang; Lieping Chen

    2004-01-01

    The past years have witnessed significant advance in our understanding of critical roles of T cell co-signals in B7-CD28 family molecules in regulating T cell activation and tolerance. New co-signaling molecules have been identified and their functions have been delineated. These co-signaling pathways play overlapping and distinct regulatory roles at various stages of a T cell response. By expressing in appropriate time and location, these pathways have different regulatory functions through independent receptors or on different subsets of lymphocytes. Precise understanding of these pathways will allow the development of novel approaches to treatment of human diseases such as cancer, viral infection, autoimmune diseases and transplantation rejection.Cellular & Molecular Immunology. 2004;1(1):37-42.

  3. T Lymphocyte Co-Signaling Pathways of the B7-CD28 Family

    Institute of Scientific and Technical Information of China (English)

    ShengdianWang; LiepingChen

    2004-01-01

    The past years have witnessed significant advance in our understanding of critical roles of T cell co-signals in B7-CD28 family molecules in regulating T cell activation and tolerance. New co-signaling molecules have been identified and their functions have been delineated. These co-signaling pathways play overlapping and distinct regulatory roles at various stages of a T cell response. By expressing in appropriate time and location, these pathways have different regulatory functions through independent receptors or on different subsets of lymphocytes. Precise understanding of these pathways will allow the development of novel approaches to treatment of human diseases such as cancer, viral infection, autoimmune diseases and transplantation rejection. Cellular & Molecular Immunology. 2004; 1(1):37-42.

  4. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system

    International Nuclear Information System (INIS)

    CD28 (Tp44) is a human T-cell-specific homodimer surface protein that may participate in T-cell activation. The authors have isolated a cDNA clone encoding CD28 by a simple and highly efficient cloning strategy based on transient expression in COS cells. Central to this strategy is the use of an efficient method to prepare large plasmid cDNA libraries. The libraries are introduced into COS cells, where transient expression of surface antigen allows the isolation of cDNAs by way of monoclonal antibody binding. The CD28 cDNA encodes a highly glycosylated membrane protein with homology to the immunoglobulin superfamily and directs the production of a homodimer in transfected COS cells

  5. B7 interactions with CD28 and CTLA-4 control tolerance or induction of mucosal inflammation in chronic experimental colitis.

    Science.gov (United States)

    Liu, Z; Geboes, K; Hellings, P; Maerten, P; Heremans, H; Vandenberghe, P; Boon, L; van Kooten, P; Rutgeerts, P; Ceuppens, J L

    2001-08-01

    CD28-B7 interaction plays a critical costimulatory role in inducing T cell activation, while CTLA-4-B7 interaction provides a negative signal that is essential in immune homeostasis. Transfer of CD45RB(high)CD4(+) T cells from syngeneic mice induces transmural colon inflammation in SCID recipients. This adoptive transfer model was used to investigate the contribution of B7-CD28/CTLA-4 interactions to the control of intestinal inflammation. CD45RB(high)CD4(+) cells from CD28(-/-) mice failed to induce mucosal inflammation in SCID recipients. Administration of anti-B7.1 (but not anti-B7.2) after transfer of wild-type CD45RB(high)CD4(+) cells also prevented wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of proinflammatory cytokines IL-2 and IFN-gamma by lamina propria CD4(+) cells. In contrast, anti-CTLA-4 treatment led to deterioration of disease, to more severe inflammation, and to enhanced production of proinflammatory cytokines. Of note, CD25(+)CD4(+) cells from CD28(-/-) mice similar to those from the wild-type mice were efficient to prevent intestinal mucosal inflammation induced by the wild-type CD45RB(high) cells. The inhibitory functions of these regulatory T cells were effectively blocked by anti-CTLA-4. These data show that the B7-CD28 costimulatory pathway is required for induction of effector T cells and for intestinal mucosal inflammation, while the regulatory T cells function in a CD28-independent way. CTLA-4 signaling plays a key role in maintaining mucosal lymphocyte tolerance, most likely by activating the regulatory T cells. PMID:11466409

  6. Prevention of renal allograft rejection in primates by blocking the B7/CD28 pathway

    NARCIS (Netherlands)

    Ossevoort, MA; Ringers, J; Kuhn, EM; Boon, L; Lorre, K; van den Hout, Y; Bruijn, JA; de Boer, H; Jonker, M; de Waele, P

    1999-01-01

    Background. There is accumulating evidence that blockade of the costimulatory pathways offers a valid approach for immune suppression after solid organ transplantation. In this study, the efficacy of anti-CD86 and anti-CD86 monoclonal antibodies (mAbs) in combination with cyclosporine (CsA) to preve

  7. Changes of CD8+CD28- T regulatory cells in rat model of colitis induced by 2,4-dinitrofluorobenzene

    Institute of Scientific and Technical Information of China (English)

    Wen-Bin Xiao; Yu-Lan Liu

    2003-01-01

    AIM: To determine the changes of CD8+ T subsets especially CD8+CD28- T regulatory cells in rat model of experimental colitis induced by 2,4-dinitrofiuorobenzene (DNFB).METHODS: The rat model of experimental colitis was induced by enema with DNFB. Ten days later, colonic intraepithelial and splenic lymphocytes were isolated from colitis animals (n=16) and controls (n=8). The proportion of CD8+ T cells, CD8+CD28+ T cells and CD8+CD28- T regulatory cells were determined by flow cytometry.RESULTS: The model of experimental colitis was successfully established by DNFB that was demonstrated by bloody diarrhea, weight loss and colonic histopathology. The proportion of CD8+ T cells in either splenic or colonic intraepithelial lymphocytes was not significantly different between colitis animals and controls (spleen: 34.6±7.24 % vs33.5±9.41%,colon: 14.0±8.93 % vs 18.0±4.06 %, P>0.05). But CD8+CD28-T regulatory cells from colitis animals were significantly more than those from controls (spleen: 11.3±2.26 % vs5.64±1.01%,colon: 6.50±5.37 % vs 1.07±0.65 %, P<0.05). In contrast,CD8+CD28+ T cells from colitis animals were less than those from controls (spleen: 23.3±6.14 % vs27.8±9.70 %, P=0.06;colon: 7.52±4.18 % vs 16.9±4.07 %, P<0.05). The proportion of CD8+CD28- T regulatory cells in splenic and colonintraepithelial CD8+ T cells from colitis animals was higher than that from controls (spleen: 33.3±5.49 % vs 18.4±7.26 %,colon: 46.0±14.3 % vs6.10±3.72 %, P<0.005).CONCLUSION: Experimental colitis of rats can be induced by DNFB with simplicity and good reproducibility. The proportion of CD8+CD28- T regulatory cells in rats with experimental colitis is increased, which may be associated with the pathogenesis of colitis.

  8. Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

    Directory of Open Access Journals (Sweden)

    Burç Dedeoglu

    Full Text Available End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR.222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters.Of the 222 patients analyzed, 30 (14% developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively and the number of related donor kidney transplantation was significantly lower (p = 0.018 in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01 and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08. No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028. In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001.Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.

  9. From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Tyrsin, Dmitry; Chuvpilo, Sergey; Matskevich, Alexey; Nemenov, Daniil; Römer, Paula S; Tabares, Paula; Hünig, Thomas

    2016-01-01

    CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study. PMID:27586803

  10. CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation

    OpenAIRE

    1992-01-01

    Activation of an immune response requires intercellular contact between T lymphocytes and antigen-presenting cells (APC). Interaction of the T cell antigen receptor (TCR) with antigen in the context of major histocompatibility molecules mediates signal transduction, but T cell activation appears to require the induction of a second costimulatory signal transduction pathway. Recent studies suggest that interaction of CD28 with B7 on APC might deliver such a costimulatory signal. To investigate...

  11. The Role of CD28/TLA-4 Costimulatory Molecules in the Pathogenesis of Multiple Sclerosis Immunity%CD28/TLA4共刺激分子在多发性硬化免疫发病机制中的作用

    Institute of Scientific and Technical Information of China (English)

    李光宗; 朱晨; 詹成; 李作孝

    2011-01-01

    目的 探讨CD28、CTLA-4在多发性硬化免疫发病机制中的作用.方法 选择临床确诊的20例多发性硬化患者(10例发病期,10例缓解期)和10例正常人.以流式细胞术分别分析其外周血CD3 +T细胞膜表面CD28和CTLA-4的表达率.比较3组患者的外周血CD3 +T细胞膜表面CD28和CTLA-4的表达率及CD28/CTLA-4比值.结果 3组的外周血CD3 +T细胞膜表面CD28、CTLA-4的表达率、CD28/CTLA-4比值间差异均有统计学意义(P<0.05).发病期CD28,CD28/CTLA-4比值均高于其他两组(P<0.05);CTLA-4低于其他两组(P<0.05).多发性硬化患者CD28 /CTLA-4比值与Th1/Th2比值有关联.结论 ①多发性硬化患者外周血CD3 +T细胞膜表面共刺激分子表达异常,T细胞处于"预激活"状态;②CD28、cTLA4表达失衡可引起Th细胞格局偏移,Th1型细胞增多;③CD28、CTLA4与多发性硬化的发生、发展有关.%Objective To investigate the role of CD28 ,CTLA-4 in the immune pathogenesis of multiple sclerosis immunity. Methods 20 patients with clinically diagnosedh multiple sclerosis( 10 cases onset period , 10 cases in remission )and 10 normal subjects were analyzed by flow cytometry of peripheral blood CD7+ T cell surface CD28 and CTLA-4 expression rate. Peripheral blood CD3+ T cell surface CD28 and CTLA-4 expression rate and CD28/CTLA-4 ratio of the three groups were compared. Results The peripheral blood CD3 +T cell surface CD28 , CTLA-4 expression rate, CD28/CTLA-4 were statistically significantly different ( P <0. 05 ). Onset phase CD28 , CD28/CTLA-4 ratios are higher than the other two groups( P < 0. 05 );CTLA-4 lower than the other two groups( P < 0. 05 ). Patients with multiple sclerosis CD28/CTLA-4 ratio is associated with Th1/Th2 ratio. Conclusion ①multiple sclerosis patients with CD3+ T cell surface expression of costimulatory molecules ahnormal,T cells in a " pre-active" state;②CD28 , cTLA4 expression imbalance can cause Th cells pattern offset , Thl-type cells

  12. Immuno-suppressive effect of blocking the CD28 signaling pathway in T-cells by an active component of Echinacea found by a novel pharmaceutical screening method.

    Science.gov (United States)

    Dong, Guo-Chung; Chuang, Ping-Hsien; Forrest, Michael D; Lin, Yi-Chen; Chen, Hueih Min

    2006-03-23

    AFTIR (after flowing through immobilized receptor) is a novel method for screening herbal extracts for pharmaceutical properties. Using AFTIR, we identified Cynarin in Echinacea purpurea by its selective binding to chip immobilized CD28, a receptor of T-cells, which is instrumental to immune functioning. The results of surface plasma resonance show that binding between immobilized CD28 and Cynarin is stronger than the binding between CD28 and CD80, a co-stimulated receptor of antigen presenting cells. Cynarin's function was verified by its ability to downregulate CD28-dependent interleukin-2 (IL-2) expression in a T-cell culture line. AFTIR offers promise as an efficient screening method for herbal medicines. PMID:16539370

  13. Impact of Cytomegalovirus and Grafts versus Host Disease on the Dynamics of CD57+CD28−CD8+ T Cells After Bone Marrow Transplant

    OpenAIRE

    Ana Verena Almeida Mendes; Esper Georges Kallas; Gil Benard; Cláudio Sérgio Pannuti; Reneé Menezes; Frederico Luiz Dulley; Thomas George Evans; Reinaldo Salomão; Clarisse Martins Machado

    2008-01-01

    OBJECTIVES: The present study aimed to evaluate the dynamics of CD28 and CD57 expression in CD8+ T lymphocytes during cytomegalovirus viremia in bone marrow transplant recipients. METHODS: In a prospective study, blood samples were obtained once weekly once from 33 healthy volunteers and weekly from 33 patients. To evaluate the expression of CD57 and CD28 on CD8+ T lymphocytes, flow cytometry analysis was performed on blood samples for four months after bone marrow transplant, together with c...

  14. A novel mode of human immunodeficiency virus type 1 (HIV-1) activation: ligation of CD28 alone induces HIV-1 replication in naturally infected lymphocytes.

    OpenAIRE

    1993-01-01

    Induction of human immunodeficiency virus (HIV) replication in infected CD4+ T lymphocytes requires cellular activation. The ligation of CD28, a signal-transducing receptor with a natural ligand on activated B cells and antigen-presenting cells, provides a costimulating signal for interleukin 2 production and T-cell proliferation as well as coactivation of the transfected HIV long terminal repeat in Jurkat cells. The aim of the present study was to investigate the ability of CD28 ligation to ...

  15. Increased percentage of CD8 CD28– suppressor lymphocytes in peripheral blood and skin infiltrates correlates with advanced disease in patients with cutaneous T-cell lymphomas

    Directory of Open Access Journals (Sweden)

    Donata Urbaniak-Kujda

    2009-07-01

    Full Text Available Introduction: T cells with the CD8 CD28– phenotype are CD8 lymphocytes with regulatory function. Their increased numbers were observed in infections, autoimmune and neoplastic diseases, and in elderly healthy individuals. CD8 CD28– lymphocyte levels in patients with cutaneous T-cell lymphoma (CTCL has not yet been described. The aim of the study was to determine their levels in these patients’ peripheral blood and cutaneous infiltrates and their relation to the clinical stage of disease.Material/Methods: Forty-one untreated patients, 26 males and 15 females, with CTCL were enrolled in the study. CD8 CD28– lymphocyte levels were determined by flow cytometry in peripheral blood and by immunochemistry in skin infiltrates.Results: The percentage of CD8 CD28– lymphocytes in the peripheral blood of the patients was significantly higher than in the controls. Patients with advanced disease displayed a higher percentage of CD8 CD28– lymphocytes in the peripheral blood and skin than did the individuals with early stages of the disease. Moreover, positive correlations between CD8 CD28– lymphocyte level in peripheral blood and age, clinical stage, and the levels in the skin infiltrates was revealed. Additionally, the percentage of CD8 CD28– T cells in the skin infiltrates correlated positively with age and clinical stage of the disease.Conclusions: These data suggest that CD8 CD28– lymphocytes play an important role in the development of immunotolerance in the progression of cutaneous T-cell lymphoma.

  16. Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion

    OpenAIRE

    1992-01-01

    Regulated adhesion enables T cells to migrate through tissue and transiently interact with an endless succession of cells. Monoclonal antibody (mAb) engagement of the CD3/T cell receptor (TCR) complex results in a rapid and transient augmentation of the adhesion function of LFA-1 and VLA integrin molecules on human T cells. We show in this study that mAb crosslinking of the T cell-specific accessory molecules CD7 and CD28, or treatment with the Ca2+ ionophore A23187, results in the rapid indu...

  17. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

    Science.gov (United States)

    Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Feng, Yang; Dimitrov, Dimiter S; Jones, David R; Sadelain, Michel; Adusumilli, Prasad S

    2016-08-01

    Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.

  18. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

    Science.gov (United States)

    Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Feng, Yang; Dimitrov, Dimiter S; Jones, David R; Sadelain, Michel; Adusumilli, Prasad S

    2016-08-01

    Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. PMID:27454297

  19. Heat Shock Proteins 60 and 70 Specific Proinflammatory and Cytotoxic Response of CD4+CD28null Cells in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Ashok K. Yadav

    2013-01-01

    Full Text Available Background. CD4+CD28null T cells are expanded in peripheral blood of patients with chronic kidney disease and associated with subclinical atherosclerosis. However, triggers for the oligoclonal expansion and activation of these cells are not clear. Methods. We investigated twenty-five stage V-IV chronic kidney disease (CKD patients and eight healthy subjects (HC. Peripheral mononuclear cells were isolated and incubated with heat shock protein- (HSP 60 and 70. CD4+CD28null and CD4+CD28+ cells were sorted by flowcytometry and antigen specific response was assessed by the mRNA and protein expression of interferon (IFN-γ, perforin, and granzyme B using qRT-PCR and Elispot. Results. The basal mRNA expression of IFN-γ, perforin, and granzyme B in CD4+CD28null cells was higher in subjects with CKD compared to that in HC (P<0.0001. Subjects with CKD also showed expression of IFN-γ, perforin, and granzyme B in the CD4+CD28+ subset, but this was much weaker than that seen in the CD4+CD28null population (P<0.0001. We did not note the expression of these molecules at mRNA or protein level in either subset of CD4 cells in HC. After incubation with HSP60 and HSP70, CD4+CD28null cells showed increased expression at mRNA (P<0.001 and protein level (P<0.001. CD4+CD28+ cells also showed a weak increase in expression. No antigen-specific response was noted in HC. Conclusion. These data show that CD4+CD28null cells in subjects with CKD react with HSP60 and HSP70 by upregulating the expression of IFN-γ, perforin and granzyme B. Increased circulating level of HSP60 and HSP70 might play a role in initiation and/or progression of atherosclerosis in CKD subjects through perturbation of CD4+CD28null cells.

  20. Differential requirement of CD28 costimulation for activation of murine CD8+ intestinal intraepithelial lymphocyte subsets and lymph node cells.

    Science.gov (United States)

    Gelfanov, V; Lai, Y G; Gelfanova, V; Dong, J Y; Su, J P; Liao, N S

    1995-07-01

    The CD8+CD4- (CD8+) murine small intestinal intraepithelial lymphocytes (IELs) contain two subpopulations, one expressing alpha alpha-CD8 homodimers and another alpha beta-CD8 heterodimers. In this study, plate-bound anti-TCR beta-chain (TCR-beta) mAb alone or combined with anti-CD28 mAb is used as a model system to study activation requirement of these two CD8+ IEL subsets. In contrast to CD8+ lymph node (LN) cells that require both TCR and CD28 triggering for activation, alpha beta-CD8+ IELs proliferate and produce IL-2 and IFN-gamma when stimulated with anti-TCR-beta mAb alone, and soluble CTLA-4 Ig has no effect on their responses. On the other hand, alpha alpha-CD8+ IELs neither make IL-2 or IFN-gamma nor proliferate even when both stimuli are provided. However, alpha alpha-CD8+ IELs are capable of proliferation in both CD8+ IEL subsets is lower than in CD8+ LN cells, which contributes to the weaker and delayed response of CD8+ IELs. PMID:7602124

  1. Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+CD28-CD8+ T cells after bone marrow transplant

    Directory of Open Access Journals (Sweden)

    Ana Verena Almeida Mendes

    2008-01-01

    Full Text Available OBJECTIVES: The present study aimed to evaluate the dynamics of CD28 and CD57 expression in CD8+ T lymphocytes during cytomegalovirus viremia in bone marrow transplant recipients. METHODS: In a prospective study, blood samples were obtained once weekly once from 33 healthy volunteers and weekly from 33 patients. To evaluate the expression of CD57 and CD28 on CD8+ T lymphocytes, flow cytometry analysis was performed on blood samples for four months after bone marrow transplant, together with cytomegalovirus antigenemia assays. RESULTS: Compared to cytomegalovirus-seronegative healthy subjects, seropositive healthy subjects demonstrated a higher percentage of CD57+ and a lower percentage of CD28+ cells (p<0.05. A linear regression model demonstrated a continuous decrease in CD28+ expression and a continuous increase in CD57+ expression after bone marrow transplant. The occurrence of cytomegalovirus antigenemia was associated with a steep drop in the percentage of CD28+ cells (5.94%, p<0.01 and an increase in CD57+ lymphocytes (5.60%, p<0.01. This cytomegalovirus-dependent effect was for the most part concentrated in the allogeneic bone marrow transplant patients. The development of acute graft versus host disease, which occurred at an earlier time than antigenemia (day 26 vs. day 56 post- bone marrow transplant, also had an impact on the CD57+ subset, triggering an increase of 4.9% in CD57+ lymphocytes (p<0.05. CONCLUSION: We found continuous relative changes in the CD28+ and CD57+ subsets during the first 120 days post- bone marrow transplant, as part of immune system reconstitution and maturation. A clear correlation was observed between the expansion of the CD57+CD28-CD8+ T lymphocyte subpopulation and the occurrence of graft versus host disease and cytomegalovirus viremia.

  2. Graves病合并眼征患者外周血T淋巴细胞CD4及共刺激分子CD28的表达变化%Expression of CD4 and costimulatry molecules CD28 on T leukomonocyte in peripheral Blood from patients with Graves disease having eye symptom

    Institute of Scientific and Technical Information of China (English)

    杨乐; 孙亚东; 关红; 何金婷

    2012-01-01

    Objective To investigate the relationship between CD4 or costimulatory molecules CD28 in Graves disease and eye symptom and understand connection with its lesion degree. Methods Kxprcssion of CD4 and costimulatry molecules CD28 in peripheral blood from patients with Graves disease and eye symptom was measured by flow cytomc-try,Results ①Expression of CD4+ of infiltrativc cxophthalmos patients is increased compared with rctinitis simplex and control groupCPCD28+ in of infiltrativc cxophthalmos patients is decreased compared with rctinitis simplex and control group (PCD28+ in rctinitis simplex eye symptom of Graves disease is decreased compared with control group (PCD28+ pathogencsis longer than 2 years is decreased compared with pathogencsis shorter than 2 years (P<0. 05). (3) Expression of CD4 is connection with CD28. Conclusion ConclusionThc expression of CD4+ increased is companicd with decreased expression of CD28 , and CD28 play an important role in the abnormal activation of CD4+T lcukomono-cytc in patients with Graves disease having eye symptom, the expression of CD4 and CD28 is conccrnd with relapse and relief.%目的 探讨Graves病合并眼征患者外周血T淋巴细胞CD4 共刺激分子CD28表达变化与病情严重程度的关系.方法 应用流式细胞仪技术对Graves病合并眼征患者外周血T淋巴细胞CD4及共刺激分子CD28的表达水平进行检测.结果 ①Graves浸润性突眼患者CD4+表达高于单纯性突眼患者 (P<0.05),而Graves浸润性突眼患者外周血CD28+表达低于单纯性突眼患者(P<0.05)②病程>2年患者CD4+表达高于病程≤2年的Graves眼征患者(P<0

  3. Artificial antigen-presenting cells plus IL-15 and IL-21 efficiently induce melanoma-specific cytotoxic CD8+CD28+ T lymphocyte responses

    Institute of Scientific and Technical Information of China (English)

    Xia Yu; Yuan Fang; Xi Li; Nuo Zhou; Yong-Xiang Zhao; Xiao-Ling Lu; Jian He; Sodaly Mongkhoune; Yi Peng; Yuan Xie; Jing Su; Su-Fang Zhou; Xiao-Xun Xie; Guo-Rong Luo

    2013-01-01

    To develop a novel artificial antigen-presenting system for efficiently inducing melanoma-specific CD8+CD28+ cytotoxic T lymphocyte (CTL) responses. Methods: Cell-sized Dynabeads® M-450 Epoxy beads coated with H-2Kb:Ig-TRP2180-188 and anti-CD28 antibody were used as artificial antigen-presenting cells (aAPCs) to induce melanoma-specific CD8+CD28+CTL responses with the help of IL-21 and IL-15. Dimer staining, proliferation, ELISPOT, and cytotoxicity experiments were conducted to evaluate the frequency and activity of induced CTLs. Results: Dimer staining demonstrated that the new artificial antigen-presenting system efficiently induced melanoma TRP2-specific CD8+CD28+ CTLs. Proliferation and ELISPOT assays indicated that the induced CTLs rapidly proliferate and produce increased IFN-γ under the stimulation of H-2Kb:Ig-TRP2-aAPCs, IL-15, and IL-21. In addition, cytotoxicity experiments showed that induced CTLs have specific killing activity of target cells. Conclusions: The new artificial antigen-presenting system including aAPCs plus IL-21 and IL-15 can induce a large number of antigen-specific CD8+CD28+ CTLs against the melanoma. Our study provides evidence for a novel adoptive immunotherapy against tumors.

  4. CD28⁻ CD8⁺ T cells are significantly reduced and correlate with disease duration in juveniles with type 1 diabetes.

    Science.gov (United States)

    Yarde, Danielle N; Lorenzo-Arteaga, Kristina; Corley, Kevin P; Cabrera, Monina; Sarvetnick, Nora E

    2014-10-01

    Type 1 diabetes (T1D) is a chronic disease caused by autoimmune destruction of insulin-producing pancreatic β-cells. T1D is typically diagnosed in children, but information regarding immune cell subsets in juveniles with T1D is scarce. Therefore, we studied various lymphocytic populations found in the peripheral blood of juveniles with T1D compared to age-matched controls (ages 2-17). One population of interest is the CD28(-) CD8(+) T cell subset, which are late-differentiated cells also described as suppressors. These cells are altered in a number of disease states and have been shown to be reduced in adults with T1D. We found that the proportion of CD28(-) cells within the CD8(+) T cell population is significantly reduced in juvenile type 1 diabetics. Furthermore, this reduction is not correlated with age in T1D juveniles, although a significant negative correlation between proportion CD28(-) CD8(+) T cells and age was observed in the healthy controls. Finally, correlation analysis revealed a significant and negative correlation between the proportion of CD28(-) CD8(+) T cells and T1D disease duration. These findings show that the CD28(-) CD8(+) T cell population is perturbed following onset of disease and may prove to be a valuable marker for monitoring the progression of T1D.

  5. Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti- Reward

    Directory of Open Access Journals (Sweden)

    Kenneth Blum

    2015-02-01

    Full Text Available Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana, Δ9-tetrahydrocannabinol (THC enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1 receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718 have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Longterm blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and nonsubstance (behavioral addictions.

  6. The regulation of protein synthesis and translation factors by CD3 and CD28 in human primary T lymphocytes

    Directory of Open Access Journals (Sweden)

    Proud Christopher G

    2002-05-01

    Full Text Available Abstract Background Activation of human resting T lymphocytes results in an immediate increase in protein synthesis. The increase in protein synthesis after 16–24 h has been linked to the increased protein levels of translation initiation factors. However, the regulation of protein synthesis during the early onset of T cell activation has not been studied in great detail. We studied the regulation of protein synthesis after 1 h of activation using αCD3 antibody to stimulate the T cell receptor and αCD28 antibody to provide the co-stimulus. Results Activation of the T cells with both antibodies led to a sustained increase in the rate of protein synthesis. The activities and/or phosphorylation states of several translation factors were studied during the first hour of stimulation with αCD3 and αCD28 to explore the mechanism underlying the activation of protein synthesis. The initial increase in protein synthesis was accompanied by activation of the guanine nucleotide exchange factor, eukaryotic initiation factor (eIF 2B, and of p70 S6 kinase and by dephosphorylation of eukaryotic elongation factor (eEF 2. Similar signal transduction pathways, as assessed using signal transduction inhibitors, are involved in the regulation of protein synthesis, eIF2B activity and p70 S6 kinase activity. A new finding was that the p38 MAPK α/β pathway was involved in the regulation of overall protein synthesis in primary T cells. Unexpectedly, no changes were detected in the phosphorylation state of the cap-binding protein eIF4E and the eIF4E-binding protein 4E-BP1, or the formation of the cap-binding complex eIF4F. Conclusions Both eIF2B and p70 S6 kinase play important roles in the regulation of protein synthesis during the early onset of T cell activation.

  7. Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

    NARCIS (Netherlands)

    P.S. Römer; S. Berr; E. Avota; S.Y. Na; M. Battaglia; I. ten Berge; H. Einsele; T. Hünig

    2011-01-01

    Human volunteers receiving TGN1412, a humanized CD28-specific monoclonal antibody, experienced a life-threatening cytokine release syndrome during a recent trial. Preclinical tests using human PBMCs had failed to announce the rapid release of TNF, IFN-gamma, and other toxic cytokines in response to

  8. Expression of costimulatry molecules CD+28 in peripheral blood from patients with Graves disease having eye symptom%共刺激分子CD28在Graves病合并眼征患者外周血中的表达变化

    Institute of Scientific and Technical Information of China (English)

    杨乐; 何金婷; 孙亚东

    2012-01-01

    目的:探讨共刺激分子CD28在Graves病合并眼征患者外周血中表达变化与病情严重程度的关系.方法:应用流式细胞仪技术对Graves病合并眼征患者外周血T淋巴细胞共刺激分子CD28的表达水平进行检测,同时检测患者甲状腺功能.结果:① Graves浸润性突眼组患者外周血CD+28表达低于单纯性突眼患者(P<0.05),单纯性突眼组患者外周血CD+28表达亦低于对照组(P<0.05);②浸润组Graves眼病患者外周血TSH表达低于单纯组和对照组(P<0.05),单纯组患者外周血TSH表达亦低于对照组(P<0.05).结论:Graves病合并眼征患者共刺激分子CD+28在CD+4;淋巴细胞异常活化中起重要作用,CD+28表达随眼征病情加重而降低,CD+28与TSH表达呈正相关.

  9. Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk

    Science.gov (United States)

    Raychaudhuri, Soumya; Thomson, Brian P.; Remmers, Elaine F.; Eyre, Stephen; Hinks, Anne; Guiducci, Candace; Catanese, Joseph J.; Xie, Gang; Stahl, Eli A.; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Burtt, Noel P.; Chang, Monica; Coblyn, Jonathan; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; De Jager, Phillip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Kurreeman, Fina A. S.; Lee, Annette T.; Liu, Xiangdong; Li, Yonghong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, Paul; Altshuler, David; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Siminovitch, Katherine A.; Worthington, Jane; Klareskog, Lars; Gregersen, Peter K.; Daly, Mark J.; Plenge, Robert M.

    2010-01-01

    To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases. PMID:19898481

  10. Phenotypic characteristics of the CD4+CD28- T cell subsets in peripheral blood of patients with Graves disease and its clinical significance%GD患者外周血CD4+CD28-T细胞亚群的表型特征及临床意义

    Institute of Scientific and Technical Information of China (English)

    孙治平; 陈蕾; 淤葛华; 朱一蓓; 仲维学; 施毕旻; 陈冰; 周春刚; 张学光

    2007-01-01

    检测Graves病(GD)患者外周血CD4+ CD28-T细胞水平及其表面CD45RO/CD45RA及ICOS的表达,探讨CD4+ CD28-T细胞亚群在GD免疫致病机制中的作用.采用三色荧光抗体染色及流式细胞术检测了42例初发GD患者和30例健康者外周血中CD4+ CD28-T细胞的百分率及其表面CD45RO/CD45RA和ICOS表达水平,同时检测其甲状腺功能并进行相关性分析.结果GD患者外周血中CD4+ CD28-T细胞百分率明显高于健康对照组,并高表达ICOS分子,与FT3水平显著正相关;与健康对照组相比,GD患者CD4+ CD28- CD45RO+ T细胞百分率也显著增高,而CD4+ CD28- CD45RA+ T细胞呈下降趋势,FT3、FT4水平与CD4+ CD28-T细胞表面CD45RO的表达率呈正相关,而FT3水平与CD45RA表达呈负相关.结论GD患者外周血CD4+ CD28-T细胞异常增高,表面高表达ICOS分子,具有记忆性细胞的表型特征,与甲状腺功能异常有一定的相关性,CD4+ CD28-T细胞可能是参与GD免疫病理反应的自身反应性T细胞.

  11. Traceable Coulomb Blockade Thermometry

    CERN Document Server

    Hahtela, Ossi; Kemppinen, Antti; Meschke, Matthias; Prunnila, Mika; Gunnarsson, David; Roschier, Leif; Penttila, Jari; Pekola, Jukka

    2016-01-01

    We present a measurement and analysis scheme for determining traceable thermodynamic temperature at cryogenic temperatures using Coulomb blockade thermometry. The uncertainty of the electrical measurement is improved by utilizing two sampling digital voltmeters instead of the traditional lock-in technique. The remaining uncertainty is dominated by that of the numerical analysis of the measurement data. Two analysis methods, the numerical fitting of the full conductance curve and measuring the height of the conductance dip yield almost identical results. The complete uncertainty analysis shows that the relative expanded uncertainty (k = 2) in determining the thermodynamic temperature in the temperature range from 20 mK to 200 mK is below 1 %. A good agreement within the measurement uncertainty is experimentally demonstrated between the Coulomb blockade thermometer and a superconducting reference point device that has been directly calibrated against the Provisional Low Temperature Scale of 2000.

  12. CD28嵌合抗体及与抗原分子的3D空间结构模建%Construction of 3D model of CD28 chimeric antibody with its antigen docked

    Institute of Scientific and Technical Information of China (English)

    程钢; 秦媛媛; 程迪; 陈曦; 张学光; 邱玉华

    2012-01-01

    AIM: To construct a 3D model of the chimeric antibodies (AntiCD28: ch-2F5) with corresponding antigen molecuie docked to theoretically verify the rationality of the binding of antibody with its antigen and to provide a method of 3D identification between antigen and antibody and spatial structure analysis. METHODS; We analyzed the sequence by submitting it to http://www. ncbi. nlm. nih. gov/ and made a comparison using integratly the 3 databases of Gen-Bank, Protein data bank and GENO-3D. The 3D model was constructed by Swiss-model homology modeling server and molecular docking online was performed by GRAMM-X Protein Docking Web Server. Chimeric heavy chain, light chain, heavy-light chain complex, heavy-light chain and antigen complex were displayed and photographed by the Chimera Software. Meanwhile, the spatial structures of heavy, light chains, variable region, constant region, CDR and frame area were marked by different colours respectively to exhibit the 3D structure on every side. RESULTS: The 3D structure of the heavy-light chain and antigen complex we constructed was consistent well with the theory of antigen binding to antibody molecules. CONCLUSON; The structure of the chimeric antibody we constructed with the bioinformatic method was in accordance with the general structure of antibody, and its antigen binding site was also consistent with the molecular theory. Thus, the model helps to analyze the 3D structure of antibody and antigen-antibody interaction.%目的:对1株嵌合抗体(antiCD28:ch-2F5)进行3D建模,并与其抗原分子进行对接,验证是否与抗原抗体结合理论相符,并提供一种抗原抗体及其识别的空间结构分析方法.方法:在http://www.ncbi.nlm.nih.gov网站提交序列进行分析,综合运用GenBank、Protein data bank、GENO-3D等数据库比对分析,用Swiss-model同源建模服务器模建,运用GRAMM-X Protein Docking Web Server在线进行对接,结果采用Chimera软件对嵌合抗体的重、轻链、

  13. The blockade of T-cell co-stimulation as a therapeutic stratagem for immunosuppression: Focus on belatacept.

    Science.gov (United States)

    Snanoudj, Renaud; Frangié, Carlos; Deroure, Benjamin; François, Hélène; Créput, Caroline; Beaudreuil, Séverine; Dürrbach, Antoine; Charpentier, Bernard

    2007-09-01

    The development of immunosuppressive drugs has in recent years been focused on prevention of acute rejection. This has led to an increase in one-year allograft survival. However, these drugs have non-immune effects which contribute to the high incidence of late graft loss, as a consequence of chronic allograft nephropathy, and the death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools have been developed; they target the costimulation signal of T-cell activation, particularly by the "classical" B7/CD28 and CD40/CD40L pathways. Here, we review the limitations of current immunosuppressive protocols, the benefits of classical B7/CD28 costimulation blockade, and the first large-scale clinical application of this strategy to human transplantation with belatacept. We will also consider novel costimulatory molecules of the B7/CD28 and TNF/TNF-R families, which appear to be important for the functions of memory and effector T-cells. PMID:19707331

  14. Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    German Bernal-Fernandez

    2010-01-01

    Full Text Available Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P<.001 and CD8 (P<.01 lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P<.05; this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P<.001. Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response.

  15. Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28, and their mRNA in inflammatory myopathies.

    Science.gov (United States)

    Murata, K; Dalakas, M C

    1999-08-01

    To examine if the muscle fibers in patients with inflammatory myopathies have the potential to behave as antigen presenting cells (APCs), we investigated the expression of costimulatory molecules BB-1, B7-1 (CD80), and B7-2 (CD86), and their counterreceptors, CD28 or CTLA-4 (CD152), in the muscle biopsies of patients with polymyositis (PM), PM associated with human immunodeficiency virus infection (HIV-PM), sporadic inclusion body myositis (s-IBM), dermatomyositis (DM), and normal or disease controls. The expression of the B7 family of molecules on the muscle fibers was limited to BB-1. In PM, HIV-PM, and s-IBM, but not the disease controls, the nonnecrotic, MHC-class I-expressing muscle fibers, invaded or not by CD8+ T cells, had prominent membrane expression of BB-1. Several of the BB-1-positive fibers bound strongly in a cell-to-cell contact with their CD28 or CTLA-4 ligands on the autoinvasive CD8+ T cells, as confirmed by confocal microscopy. By reverse transcription-polymerase chain reaction, the expression of CD28 and CTLA-4 was up-regulated in PM, HIV-PM, and s-IBM, but not the controls. Because the BB-1-positive fibers expressed MHC-class I antigen and bound to up-regulated counterreceptors CD28 and CTLA-4 on the autoinvasive CD8+ T cells only in PM, HIV-PM, and s-IBM, the BB-1 molecule in these diseases should have a functional role in antigen presentation and T cell differentiation. These findings complement recent studies and suggest that in PM, HIV-PM, and s-IBM the muscle fibers are not only targets of CD8+ cytotoxic T cells but may also behave as "professional" APC.

  16. Differences in allergen-induced T cell activation between allergic asthma and rhinitis: Role of CD28, ICOS and CTLA-4

    Directory of Open Access Journals (Sweden)

    Lacoeuille Yannick

    2011-02-01

    Full Text Available Abstract Background Th2 cell activation and T regulatory cell (Treg deficiency are key features of allergy. This applies for asthma and rhinitis. However with a same atopic background, some patients will develop rhinitis and asthma, whereas others will display rhinitis only. Co-receptors are pivotal in determining the type of T cell activation, but their role in allergic asthma and rhinitis has not been explored. Our objective was to assess whether allergen-induced T cell activation differs from allergic rhinitis to allergic rhinitis with asthma, and explore the role of ICOS, CD28 and CTLA-4. Methods T cell co-receptor and cytokine expressions were assessed by flow cytometry in PBMC from 18 house dust mite (HDM allergic rhinitics (R, 18 HDM allergic rhinitics and asthmatics (AR, 13 non allergic asthmatics (A and 20 controls, with or without anti-co-receptors antibodies. Results In asthmatics (A+AR, a constitutive decrease of CTLA-4+ and of CD4+CD25+Foxp3+ cells was found, with an increase of IFN-γ+ cells. In allergic subjects (R + AR, allergen stimulation induced CD28 together with IL-4 and IL-13, and decreased the proportion of CTLA-4+, IL-10+ and CD4+CD25+Foxp3+ cells. Anti-ICOS and anti-CD28 antibodies blocked allergen-induced IL-4 and IL-13. IL-13 production also involved CTLA-4. Conclusions T cell activation differs between allergic rhinitis and asthma. In asthma, a constitutive, co-receptor independent, Th1 activation and Treg deficiency is found. In allergic rhinitis, an allergen-induced Treg cell deficiency is seen, as well as an ICOS-, CD28- and CTLA-4-dependent Th2 activation. Allergic asthmatics display both characteristics.

  17. Growth hormone (GH)‐induced reconstitution of CD8+ CD28+ T lymphocytes in a rare case of severe lymphopenia associated with Juvenile Haemochromatosis and Turner's syndrome.

    OpenAIRE

    Porto, G; Cruz, E.; Miranda, H. de; Porto, B.; J. Vasconcelos; Lacerda, R.; Roetto, A; Daraio, F.; BACELAR, C.

    2004-01-01

    Clin Endocrinol (Oxf). 2004 Oct;61(4):437-40. Growth hormone (GH)-induced reconstitution of CD8+ CD28+ T lymphocytes in a rare case of severe lymphopenia associated with Juvenile Haemochromatosis and Turner's syndrome. Porto G, Cruz E, Miranda HP, Porto B, Vasconcelos JC, Lacerda R, Roetto A, Daraio F, Bacelar C. Santo António General Hospital, Porto, Portugal. Abstract This paper describes a rare case of Turner's syndrome associated with Juvenile Haemochro...

  18. A low level of CD4+CD28+ T cells is an independent predictor of high mortality in human immunodeficiency virus type 1-infected patients

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Gerstoft, Jan; Pedersen, Bente K;

    2003-01-01

    This study investigated coexpression of CD28, CD45RA, and CD45RO on CD4(+) and CD8(+) cells in 107 human immunodeficiency virus (HIV) type 1-infected patients, who were followed-up prospectively and were not treated with highly active antiretroviral therapy, and 65 control subjects. The most...... important novel finding was that a 50% reduction in CD4(+)CD28(+) cells predicted increased mortality (relative hazards [HR], 1.6; 95% confidence interval [CI], 1.0-2.6; P=.04), even after adjusting for the CD4(+) cell counts, virus load, beta(2)-microglobulin and hemoglobin levels, and HIV disease stage....... Patients with progressed HIV infection had decreased concentrations of all studied cell subsets. Concerning the proportions of cells, only CD4(+)CD28(+), CD4(+)CD45RA(+), and CD8(+)CD45RO(+) cells decreased with HIV progression. Low proportions of CD4(+)CD45RA(+), CD8(+)CD45RA(+), and CD8(+)CD45RO(+) cells...

  19. TNF and CD28 Signaling Play Unique but Complementary Roles in the Systemic Recruitment of Innate Immune Cells after Staphylococcus aureus Enterotoxin A Inhalation.

    Science.gov (United States)

    Svedova, Julia; Tsurutani, Naomi; Liu, Wenhai; Khanna, Kamal M; Vella, Anthony T

    2016-06-01

    Staphylococcus aureus enterotoxins cause debilitating systemic inflammatory responses, but how they spread systemically and trigger inflammatory cascade is unclear. In this study, we showed in mice that after inhalation, Staphylococcus aureus enterotoxin A rapidly entered the bloodstream and induced T cells to orchestrate systemic recruitment of inflammatory monocytes and neutrophils. To study the mechanism used by specific T cells that mediate this process, a systems approach revealed inducible and noninducible pathways as potential targets. It was found that TNF caused neutrophil entry into the peripheral blood, whereas CD28 signaling, but not TNF, was needed for chemotaxis of inflammatory monocytes into blood and lymphoid tissue. However, both pathways triggered local recruitment of neutrophils into lymph nodes. Thus, our findings revealed a dual mechanism of monocyte and neutrophil recruitment by T cells relying on overlapping and nonoverlapping roles for the noninducible costimulatory receptor CD28 and the inflammatory cytokine TNF. During sepsis, there might be clinical value in inhibiting CD28 signaling to decrease T cell-mediated inflammation and recruitment of innate cells while retaining bioactive TNF to foster neutrophil circulation. PMID:27183621

  20. Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.

    Science.gov (United States)

    Linch, Stefanie N; Kasiewicz, Melissa J; McNamara, Michael J; Hilgart-Martiszus, Ian F; Farhad, Mohammad; Redmond, William L

    2016-01-19

    Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that dual aOX40 (anti-CD134)/aCTLA-4 (anti-cytotoxic T-lymphocyte-associated protein 4) immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promoting their maximal expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205 (dendritic and epithelial cells, 205 kDa)-HER2 (human epidermal growth factor receptor 2) had significantly improved survival in a mammary carcinoma model. Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment. Furthermore, this therapy was associated with extensive tumor destruction and T-cell infiltration into the tumor. Notably, in a spontaneous model of prostate adenocarcinoma, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen. Collectively, these data demonstrate that the addition of a vaccine with combined aOX40/aCTLA-4 immunotherapy augmented antitumor CD8 T-cell function while limiting Th2 polarization in CD4 cells and improved overall survival. PMID:26729864

  1. Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect.

    Directory of Open Access Journals (Sweden)

    Abdul Malik Tyagi

    Full Text Available Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4⁺ CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2 and have osteoprotective role. This study explores the effect of daidzein (Daid on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx. After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4⁺ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4⁺CD28null T cells, however, treatment with Daid increased the percentage of CD4⁺CD28⁺ T cells. Co-culture of CD4⁺CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4⁺CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220⁺ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency.

  2. Potential therapeutic strategy for non-Hodgkin lymphoma by anti-CD20scFvFc/CD28/CD3zeta gene tranfected T cells

    Directory of Open Access Journals (Sweden)

    Zheng Yihu

    2010-09-01

    Full Text Available Abstract Background Anti-CD20 monoclonal antibody treatment has not only increased survival and cure rates in many non-Hodgkin lymphomas, but also has prompted an explosion in the development of novel antibodies and biologically active substances with specific cellular targets in the field of malignancies treatment. Since the robust immune responses are elicited by the gene-modified T cells, gene based T cell therapy may also provide a powerful tool for cancer immunotherapy. Methods In this study, we developed a vector construction encoding a chimeric T cell receptor that recognizes the CD20 antigen and delivers co-stimulatory signals to achieve T cell activation. One non-Hodgkin lymphoma cell line Raji cells co-cultured with peripheral blood-derived T cells were stably transfected with anti-CD20scFvFc/CD28/CD3zeta gene or anti-CD20scFvFc gene. T cells expressing anti-CD20scFvFc/CD28/CD3zeta or anti-CD20scFvFc gene co-cultured with CD20 positive Raji cells for different times. Cell lysis assay was carried by [3H]TdR release assay. The expressions of Fas, Bcl-2 and Caspase-3 of Raji cells were detected by flow cytometric. The secretion of IFN-gamma and IL-2 in co-culture medium was tested by ELISA assay. Activity of AP-1 was analyzed by EMSA. Results Following efficient transduction of peripheral blood-derived T cells with anti-CD20scFvFc/CD28/CD3zeta gene, an obvious cell lysis of Raji cells was observed in co-culture. T cells transduced anti-CD20scFvFc/CD28/CD3zeta gene had superior secretion of IFN-gamma and IL-2 compared to T cells transduced anti-CD20scFvFc gene. Also it led to a much stronger Fas-induced apoptosis signaling transduction in target cancer cells. Conclusion So adoptively T cells transduced anti-CD20scFvFc/CD28/CD3zeta gene mediates enhanced anti-tumor activities against CD20 positive tumor cells, suggesting a potential of gene-based immunotherapy for non-Hodgkin lymphoma.

  3. The Expression Characteristics of CD28, CD38 Molecular on CD8+ T Lymphocytes of HIV/HCV Co-Infected Patients%HIV/HCV共感染者T淋巴细胞亚群CD28、CD38分子表达特征的分析

    Institute of Scientific and Technical Information of China (English)

    杨国强

    2016-01-01

    目的:通过观察HIV/HCV共感染者外周血T淋巴细胞亚群CD28、CD38分子的表达规律,探讨其与疾病进展的相关性。方法本研究选择本院2012年8月至2014年10月门诊HIV感染者40例、HIV/HCV共感染患者40例及体检中心2014年9~10月体检健康人群20例,采用流式细胞术检测HIV/HCV共感染患者(40例)、HIV感染者(40例)和健康人(20例)外周血CD8+T淋巴细胞表面CD28、CD38分子的表达,分析HIV/HCV共感染者CD28、CD38分子在T淋巴细胞亚群的表达特征;按照CD4+T数值对HIV/HCV共感染者进行分组,分析不同CD4+T水平CD8+CD28+、CD8+CD38+的表达差异,探讨CD8+T淋巴细胞CD28、CD38分子与疾病进展的相关性。结果与健康人群及HIV感染者比较,HIV/HCV共感染者CD8+CD38+T细胞的绝对计数与百分比明显升高,CD8+CD28+T细胞百分比明显降低;随着CD4+T水平的降低,CD8+CD28+T有逐渐降低趋势,CD8+CD38+T有逐渐升高趋势。结论 HIV/HCV共感染者CD8+T淋巴细胞表面CD28分子表达降低, CD38分子表达升高,且这种变化与患者CD4+T水平密切相关,可作为判断疾病进展的重要指标。%Objective To study the expression of CD28, CD38 molecular on CD8+T cell of peripheral blood of HIV/HCV co-infected patients, and explore its correlation with disease progression.Methods 40 cases of HIV infection and 40 cases of HIV/HCV coinfection come from Outpatient service of our hospital from October 2012 to August 2012, while 20 cases of healthy people were chosen from medical examination center from September 2014 to October check-up 20, the CD28, CD38 molecule expression on CD8+T lymphocytes of 40 HIV/HCV co-infected patients, 40 HIV patients and 20 healthy people were detected by flow cytometry instrument, analyzed the expression characteristics of CD28, CD38 molecular on CD8+T lymphocytes of HIV/HCV co-infected patients; grouped the HIV/HCV co-infected patients according to the CD4+T

  4. Dynamic expression of B7∶CD28/CTLA4 costimulatory molecules on peripheral blood cells in myasthenia gravis%重症肌无力患者外周血B7∶CD28/CTLA4共刺激分子表达的动态变化

    Institute of Scientific and Technical Information of China (English)

    韩钊; 郑荣远; 刘红雨; 沈志坚; 高申孟; 叶好好; 张旭

    2003-01-01

    目的研究重症肌无力(MG)患者B7∶CD28/CTLA4共刺激通路相关分子表达动态变化及其与MG发病的关系. 方法用流式细胞仪检测18例MG患者和16例健康对照者外周血单个核细胞(PBMC)在经PMA(佛波酯)+ionomycin(钙离子导入剂)刺激的0 h、6 h、24 h、48 h时B7-1、B7-2、CD28、CTLA4分子在CD4+ T细胞和CD8+ T细胞表面的表达. 结果 (1) 0 h,MG患者B7-1、B7-2分子总体表达增加,CD4+、CD8+ T细胞表面B7-1、B7-2的表达未见明显增加,PMA+ionomycin刺激后B7-1、B7-2在CD4+、CD8+ T细胞表面也无增加;(2) 0 h,CD28、CTLA4的表达增强,其中CD28+细胞的增多主要表现在CD4+ T细胞亚群,CTLA4的表达增强主要在CD8+ T细胞,在PMA+ionomycin激活后,CD28表达明显增强,持续到48 h都处于较高水平(与对照组相比P<0.01),CTLA4表达出现短暂增强,6 h即达高峰,以后下降,与对照组相比无显著增强(P>0.05). 结论 MG患者外周血中B7∶CD28/CTLA4通路共刺激相关分子表达增高,持续时间延长,检测共刺激分子的表达可反映机体的免疫激活状态,B7∶CD28/CTLA4通路在MG发病中可能起重要作用.

  5. Phenolic-glycolipid-1 and lipoarabinomannan preferentially modulate TCR- and CD28-triggered proximal biochemical events, leading to T-cell unresponsiveness in mycobacterial diseases

    Directory of Open Access Journals (Sweden)

    Dagur Pradeep

    2012-09-01

    Full Text Available Background Advanced stages of leprosy show T cell unresponsiveness and lipids of mycobacterial origin are speculated to modulate immune responses in these patients. Present study elucidates the role of phenolicglycolipid (PGL-1 and Mannose-capped lipoarabinomannan (Man-LAM on TCR- and TCR/CD28- mediated signalling. Results We observed that lipid antigens significantly inhibit proximal early signalling events like Zap-70 phosphorylation and calcium mobilization. Interestingly, these antigens preferentially curtailed TCR-triggered early downstream signalling events like p38 phosphorylation whereas potentiated that of Erk1/2. Further, at later stages inhibition of NFAT binding, IL-2 message, CD25 expression and T-cell blastogenesis by PGL-1 and Man-LAM was noted. Conclusion Altogether, we report that Man-LAM and PGL-1 preferentially interfere with TCR/CD28-triggered upstream cell signalling events, leading to reduced IL-2 secretion and T-cell blastogenesis which potentially could lead to immunosupression and thus, disease exacerbation, as noted in disease spectrum.

  6. Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion

    DEFF Research Database (Denmark)

    Brimnes, Marie Klinge; Gang, Anne Ortved; Donia, Marco;

    2012-01-01

    ® ClinExVivo™CD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide-pulsed dendritic cells (DCs) as well as allogeneic tumor lysate......, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells...... demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate....

  7. Association of single nucleotide polymorphism (SND of CD28 (IVS3+17+K and CTLA-4 (+49 A/G with thyroid autoimmunity AIT Asociación de polimorfismos de simple nucleótido (SNP de CD28 (IVS3+17T/C Y CTLA-4 (+49A/G con autoinmunidad tiroidea (AIT

    Directory of Open Access Journals (Sweden)

    P Galarza

    2010-06-01

    Full Text Available The autoimmune thyroid disease is the most prevalent autoimmune affection and affects until 5% of the general population; its development is given by the interaction between genetic susceptibility and other factors. One particularity is the early production of thyroid autoantibodies against thyroid peroxidase (aTPO which often predicts the clinical development of the disease. The genetic susceptibility for the thyroid autoimmunity (AIT is generated by genes of the HLA and by other genes candidates of the chromosome 2q33. This region contains the genes: CTLA-4 and CD 28. Several polymorphisms of both would be associated according to previous studies. Objective: To analyze and to compare the simple nucleotide polymorphism distribution (SNP of CD28 (IVS3+17 T/C and CTLA-4 (+ 49 A/G in patients with aTPO> 10 IU/ml (AIT compared to a control group aTPO ≤ 10 IU/ml with no AIT. Subjects and Methods: We have studied 69 patients with AIT and 36 control subjects. Serum aTPO were measured by using chemiluminescence immunoassay (IMMULITE1000, Siemens. Genomic DNA was prepared from peripheral white blood cells. The amplification of the genes was carry out by polymerase chain reaction (PCR. Statistical analyses : the differences between groups were made using the chisquare test. P less than 0.05 was considered statistically significant. Results: There was a significant difference of genotype CD 28 C/T in patients with AIT compared with controls (p=0.026. The genotypes of CTLA-4 was analyzed and there was no significant difference between AIT and controls. Analysis of genotypes association CD 28 C/T and CTLA-4 A/A or A/G, revealed significant difference comparing AIT versus controls (p= 0.013. Conclusions: We found a possible association of genotype CD 28 C/T in individuals with AIT, since carriers of genotype C/T would have a risk three times higher to acquire AIT. The combination of genotypes CD 28 C/T and CTLA-4 A/A or A/G would increase the risk of

  8. Circulating CD4~+CD25~+ and CD8~+CD28~- T regulate cells in multiple myeloma%多发性骨髓瘤患者外周血CD4~+CD25~+和CD8~+CD28~-调节性T细胞研究

    Institute of Scientific and Technical Information of China (English)

    贾丽; 谢晓宝; 邱国强; 钱新瑜; 周民; 肖溶

    2009-01-01

    Objective: The study was designed to evaluate the changes and significance of circulating CD4~+CD25~+ and CD8~+CD28~- regulatory T cells (Tregs) in patients with multiple myeloma (MM).Methods:CD4~+CD25~+ and CD8~+CD28~-Tregs in peripheral blood of 38 patients with MM and of 20 healthy doners were measured by flow cytometry.Serum albumin and β_2-MG in patients with MM were measured using bromocresol green method,transmission turbidimetry respectively.Results:Compared to those of the controls,the proportions of CD4~+CD25~(+/high),CD4~+CD25~(high) CD127~(low) and CD8~+CD28~-Treg cells in newly diagnosed MM patients were elevated.Furthermore,the proportions of CD4~+CD25~(high) and CD4~+CD25~(high)CD127~(low) Tregs in each clinical stage were elevated when compared to those of the controls.The number of the Tregs were increasing with clinical stages and were significantly higher in stage Ⅲ MM than in stageⅠ MM;In stageⅡand Ⅲ MM,there were also elevated proportions of CD8~+CD28~- Tregs,increasing with clinical stages.However,there were no differences when compared between stage Ⅰ MM and the controls;Both the proportions of CD4~+CD25~(+/high) and CD4~+CD25~(high)CD127~(low) Tregs in active MM were not different from stable MM,although all of them were higher than those of controls.The proportion of CD8~+CD28~- Tregs was higher in active MM than in stable MM and controls,but there were no differences when compared between active and stable MM.The proportions of both CD4~+CD25~(high) Tregs and CD4~+CD25~(high)CD127~(low)Tregs had negative correlation with the levels of serum albumin.Conclusion:MM patients have elevated levels of circulating CD4~+CD25~+ and CD8~+CD28~-Tregs,which may be an important mechanism of MM immune evasion,and may be associated with clinical stages,disease progression and prognosis of MM to some extent.%目的:探讨CD4~+CD25~+和CD8~+CD28~-调节性T细胞(Tregs)在多发性骨髓瘤(MM)患者外周血中的变化及意义.方

  9. Renin-angiotensin system blockade: Its contribution and controversy.

    Science.gov (United States)

    Miyajima, Akira; Kosaka, Takeo; Kikuchi, Eiji; Oya, Mototsugu

    2015-08-01

    Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin-angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin-angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time.

  10. 大鼠腹主动脉瘤形成过程中T细胞及CD4+CD28-T细胞的动态变化及意义%T cell and CD4+ CD28-T cell changes in the occurrence of rat abdominal aortic aneurysm

    Institute of Scientific and Technical Information of China (English)

    许文平; 谢志泉; 李志樑; 邱健; 吴自强; 傅锐斌

    2013-01-01

    目的 探讨T淋巴细胞及其亚群在腹主动脉瘤发病中的作用.方法 50只Wistar大鼠随机分成A、B、C、D、E5组,每组10只,A组为正常对照组,B、C、D、E组分别为术后3、7、14、28 d组,运用猪胰弹力酶灌注法建立腹主动脉瘤模型.免疫组化方法检测上述各组大鼠腹主动脉局部T、B淋巴细胞及巨噬细胞的表达水平,流式细胞术检测各组大鼠外周血中CD4+ CD28-T淋巴细胞亚群的分布变化.结果 大鼠腹主动脉局部T、B淋巴细胞及巨噬细胞表达的变化:术后7dT细胞显著升高(40±15,P<0.05),B细胞及巨噬细胞有升高,但差异无统计学意义(P>0.05);术后14 d,3种细胞表达升高最为显著(P<0.05);术后28 d,3种细胞的表达较术后14 d明显下降.术后各组大鼠外周血CD4+、CD28-T细胞均有升高(P<0.05),以术后7d比例最高(8.1%±2.1%,P<0.05).结论 T淋巴细胞是腹主动脉瘤形成过程中最重要的炎症细胞之一,T淋巴细胞的浸润及其亚群分布变化所致的免疫及炎症反应在腹主动脉瘤形成早期可能起着重要的触发及调节作用.%Objective To evaluate T cell and CD4+ CD28-T in the development and progression of abdominal aortic aneurysms (AAAs).Methods Fifty Wistar rats were randomly divided into 5 groups (n =10 each).An AAA animal model is established by enhancing perfusing elastase to the infrarenal abdominal aorta of the rats.The levels of T cell,B cell and macrophage cell of abdominal aorta of the rats on days 3,7,14 and 28,were detected by enzyme linked immunosorbent assay(ELISA).CD4+ CD28-T cell of the peripheral blood were measured by flow cytometry.Result There was significant T-lymphocyte infiltration both in middle and outer membrane of the artery of the rats on day 7 after surgery.T-lymphocyte,B-lymphocyte and macrophage cell infiltration were on the peak in middle and outer membrane of the artery on day 14 after surgery.The ratio of CD4+ CD28-T cell in rat

  11. 急性冠脉综合征患者CD4+CD28-T细胞表面OX40和4-1BB表达上调

    Institute of Scientific and Technical Information of China (English)

    崔亚飞

    2016-01-01

    目的 探讨急性冠脉综合征(ACS)患者CD4+ CD28-T细胞表面OX40和4-1BB的表达及其临床意义.方法 采用流式细胞术检测57例ACS患者、46例稳定性心绞痛(SA)患者和60例健康体检者(HC)外周血CD4+ CD28-T细胞表面OX40和4-1BB的表达.结果 HC组、SA组和ACS组,三组相比CD4+ CD28-T细胞表面OX40的表达水平依次升高;HC组、SA组和ACS组,三组相比CD4+ CD28-T细胞表面4-1BB的表达水平依次升高.结论 ACS患者外周血CD4+ CD28-T细胞表面OX40和4-1BB表达上调.

  12. The number of responding CD4 T cells and the dose of antigen conjointly determine the TH1/TH2 phenotype by modulating B7/CD28 interactions.

    Science.gov (United States)

    Rudulier, Christopher D; McKinstry, K Kai; Al-Yassin, Ghassan A; Kroeger, David R; Bretscher, Peter A

    2014-06-01

    Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.

  13. Study on the relationship between regulatory T cell CD 4+ CD25+ and CD8+ CD28- in the peripheral blood between graves disease%外周血中 CD4+CD25+与 CD8+CD28-调节性 T 细胞与Graves 病的关系研究

    Institute of Scientific and Technical Information of China (English)

    韦巍; 林英辉; 黄小琪

    2015-01-01

    目的:分析Graves病(GD)患者外周血中CD4+ CD25+和CD8+ CD28-调节性 T (Tr)细胞的变化。方法选择该院内分泌科门诊或住院部43例GD患者为研究对象,其中内分泌科门诊确诊的19例GD患者为试验初发组。接受治疗且甲状腺功能恢复正常的24例GD患者为治疗缓解组;选择同期健康体检者20例为健康对照组。采用流式细胞术检测3组外周血中CD4+ CD25+和CD8+ CD28- T r细胞水平。结果试验初发组外周血CD4+CD25+ T r细胞水平为(4.56±4.14)%,明显低于健康对照组的(8.84±4.45)%,差异有统计学意义( P<0.05),CD8+CD28- T r细胞水平为(14.95±5.38)%,与健康对照组的(10.65±6.37)%比较,差异无统计学意义(P>0.05)。治疗缓解组外周血中CD4+CD25+ Tr细胞水平为(6.99±6.35)%,与健康对照组比较,差异无统计学意义( P>0.05),但其CD8+ CD28- T r细胞水平为(20.48±6.07)%,高于健康对照组,差异有统计学意义( P<0.05)。结论 CD4+CD25+ T r细胞水平可能与GD发病有关,CD8+CD28-T r细胞可能与GD病程发展有关。%Objective To analyze the changes of the levels of CD4+CD25+ and CD8+CD28- T cells in the pe‐ripheral blood in patients with graves disease(GD) .Methods A total of 43 patients with GD were selected as objects in this study ,19 cases who were diagnosis in outpatient department were selected into incipience group ,24 cases who were treated and the thyroid function return to normal status were selected into alleviation group ,meanwhile 20 healthy persons were recruited into control group .The levels of CD4+ CD25+ and CD8+ CD28- regulator T cells in the peripheral blood were detected by flow cytometry .Results The CD4+CD25+ regulatory T cell levels in incipience group were (4 .56 ± 4 .14)% ,which was significant lower than(8 .84 ± 4 .45)% in the

  14. CD28-, CD45RAnull/dim and natural killer-like CD8+ T cells are increased in peripheral blood of women with low-grade cervical lesions

    OpenAIRE

    Pita-Lopez, Maria Luisa; Ortiz-Lazareno, Pablo Cesar; Navarro-Meza, Monica; Santoyo-Telles, Felipe; Peralta-Zaragoza, Oscar

    2014-01-01

    Background In response to antigen naive CD8+, T cells differentiate into effector cells, which express Natural killer (NK) receptors, lose CD28 expression, and die by apoptosis. However, in smaller quantities, the cells are retained for subsequent exposure to the same antigen. Knowledge is limited regarding whether the percentages of CD28-, Effector memory (EMRAnull/dim), and the CD16+/CD56 + CD8+ T cells of women with low-grade cervical lesions are altered at a systemic level. Methods We enr...

  15. Promotion

    OpenAIRE

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed.

  16. NSOM/QD-based direct visualization of CD3-induced and CD28-enhanced nanospatial coclustering of TCR and coreceptor in nanodomains in T cell activation.

    Directory of Open Access Journals (Sweden)

    Liyun Zhong

    Full Text Available Direct molecular imaging of nano-spatial relationship between T cell receptor (TCR/CD3 and CD4 or CD8 co-receptor before and after activation of a primary T cell has not been reported. We have recently innovated application of near-field scanning optical microscopy (NSOM and immune-labeling quantum dots (QD to image Ag-specific TCR response during in vivo clonal expansion, and now up-graded the NSOM/QD-based nanotechnology through dipole-polarization and dual-color imaging. Using this imaging system scanning cell-membrane molecules at a best-optical lateral resolution, we demonstrated that CD3, CD4 or CD8 molecules were distinctly distributed as single QD-bound molecules or nano-clusters equivalent to 2-4 QD fluorescence-intensity/size on cell-membrane of un-stimulated primary T cells, and approximately 6-10% of CD3 were co-clustering with CD4 or CD8 as 70-110 nm nano-clusters without forming nano-domains. The ligation of TCR/CD3 on CD4 or CD8 T cells led to CD3 nanoscale co-clustering or interaction with CD4 or CD8 co-receptors forming 200-500 nm nano-domains or >500 nm micro-domains. Such nano-spatial co-clustering of CD3 and CD4 or CD3 and CD8 appeared to be an intrinsic event of TCR/CD3 ligation, not purely limited to MHC engagement, and be driven by Lck phosphorylation. Importantly, CD28 co-stimulation remarkably enhanced TCR/CD3 nanoscale co-clustering or interaction with CD4 co-receptor within nano- or micro-domains on the membrane. In contrast, CD28 co-stimulation did not enhance CD8 clustering or CD3-CD8 co-clustering in nano-domains although it increased molecular number and density of CD3 clustering in the enlarged nano-domains. These nanoscale findings provide new insights into TCR/CD3 interaction with CD4 or CD8 co-receptor in T-cell activation.

  17. NSOM/QD-based direct visualization of CD3-induced and CD28-enhanced nanospatial coclustering of TCR and coreceptor in nanodomains in T cell activation.

    Science.gov (United States)

    Zhong, Liyun; Zeng, Gucheng; Lu, Xiaoxu; Wang, Richard C; Gong, Guangming; Yan, Lin; Huang, Dan; Chen, Zheng W

    2009-01-01

    Direct molecular imaging of nano-spatial relationship between T cell receptor (TCR)/CD3 and CD4 or CD8 co-receptor before and after activation of a primary T cell has not been reported. We have recently innovated application of near-field scanning optical microscopy (NSOM) and immune-labeling quantum dots (QD) to image Ag-specific TCR response during in vivo clonal expansion, and now up-graded the NSOM/QD-based nanotechnology through dipole-polarization and dual-color imaging. Using this imaging system scanning cell-membrane molecules at a best-optical lateral resolution, we demonstrated that CD3, CD4 or CD8 molecules were distinctly distributed as single QD-bound molecules or nano-clusters equivalent to 2-4 QD fluorescence-intensity/size on cell-membrane of un-stimulated primary T cells, and approximately 6-10% of CD3 were co-clustering with CD4 or CD8 as 70-110 nm nano-clusters without forming nano-domains. The ligation of TCR/CD3 on CD4 or CD8 T cells led to CD3 nanoscale co-clustering or interaction with CD4 or CD8 co-receptors forming 200-500 nm nano-domains or >500 nm micro-domains. Such nano-spatial co-clustering of CD3 and CD4 or CD3 and CD8 appeared to be an intrinsic event of TCR/CD3 ligation, not purely limited to MHC engagement, and be driven by Lck phosphorylation. Importantly, CD28 co-stimulation remarkably enhanced TCR/CD3 nanoscale co-clustering or interaction with CD4 co-receptor within nano- or micro-domains on the membrane. In contrast, CD28 co-stimulation did not enhance CD8 clustering or CD3-CD8 co-clustering in nano-domains although it increased molecular number and density of CD3 clustering in the enlarged nano-domains. These nanoscale findings provide new insights into TCR/CD3 interaction with CD4 or CD8 co-receptor in T-cell activation. PMID:19536289

  18. A Combination of CD28 (rs1980422 and IRF5 (rs10488631 Polymorphisms Is Associated with Seropositivity in Rheumatoid Arthritis: A Case Control Study.

    Directory of Open Access Journals (Sweden)

    Lucia Vernerova

    Full Text Available The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA and redundancy analysis (RDA.A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601, STAT4 G/T (rs7574865, CTLA4 A/G (rs3087243, TRAF1/C5 A/G (rs3761847, IRF5 T/C (rs10488631, TNFAIP3 C/T (rs5029937, AFF3 A/T (rs11676922, PADI4 C/T (rs2240340, CD28 T/C (rs1980422, CSK G/A (rs34933034 and FCGR3A A/C (rs396991, rheumatoid factor (RF, anti-citrullinated protein antibodies (ACPA and clinical status was analysed using the LDA and RDA.HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002. The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001. The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA.The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.

  19. The immunological characteristics of CD8+ CD28- suppressor T cells induced by siRNA technique%利用RNA干扰诱导产生的CD8+CD28-抑制性T淋巴细胞的免疫学特性

    Institute of Scientific and Technical Information of China (English)

    薛利军; 彭承宏; 李宏为; 尹路; 陈春球; 张贵阳; 孙广涛; 杜海磊; 倪俊声; 陈雪华; 林谋斌

    2009-01-01

    目的 探讨通过RNA干扰技术诱导产生的CD8+ CD28-抑制性T淋巴细胞(Ts细胞)的免疫学特性.方法 取SD大鼠骨髓,培养分离树突状细胞(DC),设计、合成主要组织相容性复合物(MHC)Ⅰ类小片段干扰RNA(siRNA),以MHC Ⅰ siRNA转染DC.先以Wistar大鼠肠系膜淋巴组织液刺激转染MHCI siRNA的DC,然后将DC与从SD大鼠脾脏分离得到的CD8+T淋巴细胞共同培养,通过磁珠法分离出Ts细胞.分别在由SD大鼠脾脏淋巴细胞(反应细胞)和Wistar大鼠肠系膜淋巴组织细胞(刺激细胞)组成的混合淋巴细胞培养体系中加入数量不等的Ts细胞,检测反应细胞增殖情况;分别以Wistar大鼠肠系膜淋巴组织细胞和卵白蛋白(OVA)刺激SD大鼠脾脏淋巴细胞,然后再按不同比例加入Ts细胞,检测各组脾脏淋巴细胞的增殖情况;在由SD大鼠脾脏淋巴细胞、Wistar大鼠肠系膜淋巴组织液和Ts细胞组成的混合淋巴细胞培养体系中加入可溶性重组白细胞介素2(rrIL-2),观察IL-2对Ts细胞功能的影响;采用实时定量聚合酶链反应(PCR)测定Ts细胞中转化生长因子β(TGF-β和γ干扰素(IFN-γ)mRNA的表达,流式细胞仪和实时PCR检测Ts细胞上CD25分子的表达.结果 Ts细胞对SD大鼠脾脏淋巴细胞和Wistar大鼠肠系膜淋巴组织细胞之问的混合淋巴细胞反应(MLR)具有抑制作用,但对于SD大鼠脾脏淋巴细胞和OVA之间的MLR则无抑制作用.在SD大鼠脾脏淋巴细胞、Wistar大鼠肠系膜淋巴组织液和Ts细胞组成的混合淋巴细胞培养体系中加入rrIL-2后,SD大鼠脾脏细胞的增殖并无明显增加(P>0.05).与CD8+CD28+T淋巴细胞和CD8+ T淋巴细胞比较,Ts细胞的TGF-β和IFN-γ mRNA的表达量明显升高(P<0.01,P<0.05),而CD25的表达量明显降低(P<0.05).结论 采用经MHC I siRNA干扰的DC能够诱导CD8+T淋巴细胞产生CD8+ CD28-Ts细胞;Ts细胞在体外具有免疫抑制特性,其免疫抑制作用不被外源性IL-2

  20. In vitro propagation and dynamics of T cells from skin biopsies by methods using interleukins-2 and -4 or anti-CD3/CD28 antibody-coated microbeads

    DEFF Research Database (Denmark)

    Hashizume, Hideo; Hansen, Anker; Poulsen, Lars K;

    2010-01-01

    In order to explore the mechanisms of inflammatory skin disorders, we established two methods of expanding skin-derived lymphocytes, one using high levels of interleukin (IL)-2 and IL-4 (method A) and the other using low levels of cytokines and anti-CD3/CD28 microbeads (method B). Both methods...

  1. Coulomb-Blockade Oscillations in Semiconductor Nanostructures

    OpenAIRE

    Houten, van, H.; Beenakker, C. W. J.; Staring, A.A.M.

    2005-01-01

    I. Introduction (Preface, Basic properties of semiconductor nanostructures). II. Theory of Coulomb-blockade oscillations (Periodicity of the oscillations, Amplitude and lineshape). III. Experiments on Coulomb-blockade oscillations (Quantum dots, Disordered quantum wires, Relation to earlier work on disordered quantum wires). IV. Quantum Hall effect regime (The Aharonov-Bohm effect in a quantum dot, Coulomb blockade of the Aharonov-Bohm effect, Experiments on quantum dots, Experiments on disor...

  2. Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS.

    Science.gov (United States)

    Sanmamed, Miguel F; Pastor, Fernando; Rodriguez, Alfonso; Perez-Gracia, Jose Luis; Rodriguez-Ruiz, Maria E; Jure-Kunkel, Maria; Melero, Ignacio

    2015-08-01

    T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules. However, the functional outcome of T-cell stimulation towards clonal expansion and effector function acquisition is contingent on the contact of additional surface receptor-ligand pairs and on the actions of cytokines in the milieu. While some of those interactions are inhibitory, others are activating and are collectively termed co-stimulatory receptors. The best studied belong to either the immunoglobulin superfamily or the tumor necrosis factor-receptor (TNFR) family. Co-stimulatory receptors include surface moieties that are constitutively expressed on resting lymphocytes such as CD28 or CD27 and others whose expression is induced upon recent previous antigen priming, ie, CD137, GITR, OX40, and ICOS. Ligation of these glycoproteins with agonist antibodies actively conveys activating signals to the lymphocyte. Those signals, acting through a potentiation of the cellular immune response, give rise to anti-tumor effects in mouse models. Anti-CD137 antibodies are undergoing clinical trials with evidence of clinical activity and anti-OX40 monoclonal antibodies (mAbs) induce interesting immunomodulation effects in humans. Antibodies anti-CD27 and GITR have recently entered clinical trials. The inherent dangers of these immunomodulation strategies are the precipitation of excessive systemic inflammation or/and invigorating silent autoimmunity. Agonist antibodies, recombinant forms of the natural ligands, and polynucleotide

  3. Perioperative Nerve Blockade: Clues from the Bench

    Directory of Open Access Journals (Sweden)

    M. R. Suter

    2011-01-01

    Full Text Available Peripheral and neuraxial nerve blockades are widely used in the perioperative period. Their values to diminish acute postoperative pain are established but other important outcomes such as chronic postoperative pain, or newly, cancer recurrence, or infections could also be influenced. The long-term effects of perioperative nerve blockade are still controversial. We will review current knowledge of the effects of blocking peripheral electrical activity in different animal models of pain. We will first go over the mechanisms of pain development and evaluate which types of fibers are activated after an injury. In the light of experimental results, we will propose some hypotheses explaining the mitigated results obtained in clinical studies on chronic postoperative pain. Finally, we will discuss three major disadvantages of the current blockade: the absence of blockade of myelinated fibers, the inappropriate duration of blockade, and the existence of activity-independent mechanisms.

  4. Valley blockade quantum switching in Silicon nanostructures.

    Science.gov (United States)

    Prati, Enrico

    2011-10-01

    In analogy to the Coulomb and the Pauli spin blockade, based on the electrostatic repulsion and the Pauli exclusion principle respectively, the concept of valley blockade in Silicon nanostructures is explored. The valley parity operator is defined. Valley blockade is determined by the parity conservation of valley composition eigenvectors in quantum transport. A Silicon quantum changeover switch based on a triple of donor quantum dots capable to separate electrons having opposite valley parity by virtue of the valley parity conservation is proposed. The quantum changeover switch represents a novel kind of hybrid quantum based classical logic device.

  5. Induction of xenogeneic islet transplantation tolerance by simultaneously blocking CD28-B7 and OX40-OX40L co-stimulatory pathways

    Institute of Scientific and Technical Information of China (English)

    WANG; Guangming; FENG; Yougang; HAO; Jie; LI; Ailing; GAO

    2005-01-01

    It has been demonstrated that prolonged graft survival can be achieved through inhibiting the activation of T cells, and addition of soluble CTLA4Ig and OX40Ig proteins to mixed lymphocyte reactions can effectively inhibit T cell proliferation. To explore the potential of this type of treatment in xenotransplantation, we infected streptozotocin-induced diabetic BalB/c mice (H-2d) (200 mg/kg, IV) with 5×108 pfu AdCTLA4Ig-IRES-OX40Ig on day 1 before islets transplantation through the tail vein. The results showed that this treatment prolonged the islet xenografts survival significantly. The reaction to exogenous glucose stimulation was normal and the cytokine secretion of the type Th1 cells was inhibited. The AdCTLA4Ig-IRES-OX40Ig-mediated treatment effectively induced the T cells into anergy and the Th1/Th2 cells into deviation. These results strongly supported the therapeutic potential of blockade of costimulation by AdCTLA4Ig-IRES-OX40Ig genes transfer in inducing the organ transplantation tolerance.

  6. Sugammadex: A Review of Neuromuscular Blockade Reversal.

    Science.gov (United States)

    Keating, Gillian M

    2016-07-01

    Sugammadex (Bridion(®)) is a modified γ-cyclodextrin that reverses the effect of the steroidal nondepolarizing neuromuscular blocking agents rocuronium and vecuronium. Intravenous sugammadex resulted in rapid, predictable recovery from moderate and deep neuromuscular blockade in patients undergoing surgery who received rocuronium or vecuronium. Recovery from moderate neuromuscular blockade was significantly faster with sugammadex 2 mg/kg than with neostigmine, and recovery from deep neuromuscular blockade was significantly faster with sugammadex 4 mg/kg than with neostigmine or spontaneous recovery. In addition, recovery from neuromuscular blockade was significantly faster when sugammadex 16 mg/kg was administered 3 min after rocuronium than when patients spontaneously recovered from succinylcholine. Sugammadex also demonstrated efficacy in various special patient populations, including patients with pulmonary disease, cardiac disease, hepatic dysfunction or myasthenia gravis and morbidly obese patients. Intravenous sugammadex was generally well tolerated. In conclusion, sugammadex is an important option for the rapid reversal of rocuronium- or vecuronium-induced neuromuscular blockade. PMID:27324403

  7. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

    Directory of Open Access Journals (Sweden)

    Karina Kroll-Palhares

    2008-06-01

    Full Text Available In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-α is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-α levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-α, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-α+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-α treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-α-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-α treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

  8. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-alpha blockade.

    Science.gov (United States)

    Kroll-Palhares, Karina; Silvério, Jaline Coutinho; Silva, Andrea Alice da; Michailowsky, Vladimir; Marino, Ana Paula; Silva, Neide Maria; Carvalho, Cristiano Marcelo Espinola; Pinto, Luzia Maria de Oliveira; Gazzinelli, Ricardo Tostes; Lannes-Vieira, Joseli

    2008-06-01

    In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-alpha levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-alpha, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-alpha+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

  9. Atomic Fock State Preparation Using Rydberg Blockade

    CERN Document Server

    Ebert, Matthew; Gibbons, Michael; Zhang, Xianli; Saffman, Mark; Walker, Thad G

    2013-01-01

    We use coherent excitation of 3-16 atom ensembles to demonstrate collective Rabi flopping mediated by Rydberg blockade. Using calibrated atom number measurements, we quantitatively confirm the expected $\\sqrt{N}$ Rabi frequency enhancement to within 4%. The resulting atom number distributions are consistent with essentially perfect blockade. We then use collective Rabi $\\pi$ pulses to produce ${\\cal N}=1,2$ atom number Fock states with fidelities of 62% and 48% respectively. The ${\\cal N}=2$ Fock state shows the collective Rabi frequency enhancement without corruption from atom number fluctuations.

  10. TOM1L Is Involved in a Novel Signaling Pathway Important for the IL-2 Production in Jurkat T Cells Stimulated by CD3/CD28 CoLigation

    Directory of Open Access Journals (Sweden)

    Ahmed Elmarghani

    2009-01-01

    Full Text Available TOM1L (target of Myb-1 Like was identified as a binding partner for the full length and catalytically-active Lck in a yeast 2-hybrid screening assay. Here we show that in Jurkat T cells stimulated by CD3/CD28 coligation where the expression of TOM1L is reduced by lenti virus mediated-siRNA results in a dramatically lower IL-2 production. The production of IL-2 in siRNA treated cells stimulated with PMA/ionomycin was not affected indicating an involvement of TOM1L in a pathway proximal of TCR and CD28. The coexpression of Fyn with TOM1L increased the level of the phosphorylated form of Fyn indicating that TOM1L has the ability to activate Fyn. The ability of TOM1L to activate Fyn was further shown in a kinase assay using angiotensin II as a substrate. By confocal microscopy, we show that the expression of TOM1L in non-treated HeLa and SK-N-SH cells colocalizes with the mitochondrial membrane but not with lysosomal compartments or the trans-Golgi network. Furthermore, we show that the over-expression of TOM1L in Jurkat cells causes an increase of the STAT3 expression . Based on our results, we here propose that TOM1L is involved in a novel signaling pathway that is important for the IL-2 production in T cells.

  11. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade

    DEFF Research Database (Denmark)

    Brueckmann, B; Sasaki, N; Grobara, P;

    2015-01-01

    BACKGROUND: This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. METHODS: Adult patients undergoing abdominal surgery received rocuronium, follow...

  12. OX40L blockade protects against inflammation-driven fibrosis.

    Science.gov (United States)

    Elhai, Muriel; Avouac, Jérôme; Hoffmann-Vold, Anna Maria; Ruzehaji, Nadira; Amiar, Olivia; Ruiz, Barbara; Brahiti, Hassina; Ponsoye, Matthieu; Fréchet, Maxime; Burgevin, Anne; Pezet, Sonia; Sadoine, Jérémy; Guilbert, Thomas; Nicco, Carole; Akiba, Hisaya; Heissmeyer, Vigo; Subramaniam, Arun; Resnick, Robert; Molberg, Øyvind; Kahan, André; Chiocchia, Gilles; Allanore, Yannick

    2016-07-01

    Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation. PMID:27298374

  13. Efficient Grover search with Rydberg blockade

    DEFF Research Database (Denmark)

    Mølmer, Klaus; Isenhower, Larry; Saffman, Mark

    2011-01-01

    We present efficient methods to implement the quantum computing Grover search algorithm using the Rydberg blockade interaction. We show that simple π-pulse excitation sequences between ground and Rydberg excited states readily produce the key conditional phase shift and inversion...

  14. Priming of CD8 T Cells by Adenoviral Vectors Is Critically Dependent on B7 and Dendritic Cells but Only Partially Dependent on CD28 Ligation on CD8 T Cells

    DEFF Research Database (Denmark)

    Nielsen, Karen N; Steffensen, Maria A; Christensen, Jan P;

    2014-01-01

    expression resulted in a delayed primary response, whereas memory CD8 T cells generated in CD28-deficient mice appeared almost normal in terms of both phenotype and effector cytokine profile, but they exhibited a significantly reduced proliferative capacity upon secondary challenge while retaining immediate...... in vivo effector capabilities: in vivo cytotoxicity and short-term in vivo protective capacity. Overall, our data point to an absolute requirement for professional APCs and the expression of the costimulatory molecules CD80/86 for efficient CD8 T cell priming by adenoviral vectors. Additionally, our......Adenoviral vectors have long been forerunners in the development of effective CD8 T cell-based vaccines; therefore, it is imperative that we understand the factors controlling the induction of robust and long-lasting transgene-specific immune responses by these vectors. In this study, we...

  15. Single administration of p2TA (AB103, a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.

    Directory of Open Access Journals (Sweden)

    Salida Mirzoeva

    Full Text Available The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103 that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C, Peptide (P; 5 mg/kg of p2TA peptide, Radiation (R; total body irradiation with 8 Gy γ-rays, and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later. Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1 and inflammation (COX-2 markers, as well as the presence of macrophages (F4/80. Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.

  16. CSF1 Receptor Targeting In Prostate Cancer Reverses Macrophage-Mediated Resistance To Androgen Blockade Therapy

    Science.gov (United States)

    Escamilla, Jemima; Schokrpur, Shiruyeh; Liu, Connie; Priceman, Saul J.; Moughon, Diana; Jiang, Ziyue; Pouliot, Frederic; Magyar, Clara; Sung, James L.; Xu, Jingying; Deng, Gang; West, Brian L.; Bollag, Gideon; Fradet, Yves; Lacombe, Louis; Jung, Michael E.; Huang, Jiaoti; Wu, Lily

    2015-01-01

    Growing evidence suggests that tumor-associated macrophages (TAMs) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling and immunosuppression. In this study prostate cancer (PCa) under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to PCa disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF-1 or CSF-1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF-1 signaling through its receptor, CSF-1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared to ABT alone. PMID:25736687

  17. [Cancer immunotherapy by immuno-checkpoint blockade].

    Science.gov (United States)

    Kawakami, Yutaka

    2015-10-01

    As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

  18. Rocuronium blockade reversal with sugammadex vs. neostigmine

    DEFF Research Database (Denmark)

    Wu, Xinmin; Oerding, Helle; Liu, Jin;

    2014-01-01

    BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 μg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety-assessor......BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 μg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety...... Chinese subjects (sugammadex, n = 119, neostigmine, n = 111); and 59 Caucasian subjects (sugammadex, n = 29, neostigmine, n = 30) had evaluable data. Geometric mean (95% CI) time to recovery to TOF ratio 0.9 was 1.6 (1.5-1.7) min with sugammadex vs 9.1 (8.0-10.3) min with neostigmine in Chinese subjects...

  19. The photon blockade effect in optomechanical systems

    OpenAIRE

    Rabl, Peter

    2011-01-01

    We analyze the photon statistics of a weakly driven optomechanical system and discuss the effect of photon blockade under single photon strong coupling conditions. We present an intuitive interpretation of this effect in terms of displaced oscillator states and derive analytic expressions for the cavity excitation spectrum and the two photon correlation function $g^{(2)}(0)$. Our results predict the appearance of non-classical photon correlations in the combined strong coupling and sideband r...

  20. Efficient Multiparticle Entanglement via Asymmetric Rydberg Blockade

    DEFF Research Database (Denmark)

    Saffman, Mark; Mølmer, Klaus

    2009-01-01

    We present an efficient method for producing N particle entangled states using Rydberg blockade interactions. Optical excitation of Rydberg states that interact weakly, yet have a strong coupling to a second control state is used to achieve state dependent qubit rotations in small ensembles....... On the basis of quantitative calculations, we predict that an entangled quantum superposition state of eight atoms can be produced with a fidelity of 84% in cold Rb atoms....

  1. Rydberg-interaction-based quantum gates free from blockade error

    CERN Document Server

    Shi, Xiao-Feng

    2016-01-01

    Accurate quantum gates are basic elements for building quantum computers. There has been great interest in designing quantum gates by using blockade effect of Rydberg atoms recently. The fidelity and operation speed of these gates, however, are fundamentally limited by the blockade error. Here we propose another type of quantum gates, which are based on Rydberg blockade effect, yet free from any blockade error. In contrast to the `blocking' method in previous schemes, we use Rydberg energy shift to realise a rational generalised Rabi frequency so that a novel $\\pi$ phase for one input state of the gate emerges. This leads to an accurate Rydberg-blockade based two-qubit quantum gate that can operate in a $0.1\\mu s$ timescale or faster thanks to that it operates by a Rabi frequency which is comparable to the blockade shift.

  2. Antilocalization of Coulomb Blockade in a Ge-Si Nanowire

    DEFF Research Database (Denmark)

    Higginbotham, Andrew P.; Kuemmeth, Ferdinand; Larsen, Thorvald Wadum;

    2014-01-01

    The distribution of Coulomb blockade peak heights as a function of magnetic field is investigated experimentally in a Ge-Si nanowire quantum dot. Strong spin-orbit coupling in this hole-gas system leads to antilocalization of Coulomb blockade peaks, consistent with theory. In particular, the peak...

  3. Coulomb blockade of spin-dependent shuttling

    Science.gov (United States)

    Park, Hee Chul; Kadigrobov, Anatoli M.; Shekhter, Robert I.; Jonson, M.

    2013-12-01

    We show that nanomechanical shuttling of single electrons may enable qualitatively new functionality if spin-polarized electrons are injected into a nanoelectromechanical single-electron tunneling (NEM-SET) device. This is due to the combined effects of spin-dependent electron tunneling and Coulomb blockade of tunneling, which are phenomena that occur in certain magnetic NEM-SET devices. Two effects are predicted to occur in such structures. The first is a reentrant shuttle instability, by which we mean the sequential appearance, disappearance and again the appearance of a shuttle instability as the driving voltage is increased (or the mechanical dissipation is diminished). The second effect is an enhanced spin polarization of the nanomechanically assisted current flow.

  4. All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.

    Directory of Open Access Journals (Sweden)

    Ling Lu

    Full Text Available BACKGROUND: It has been documented all-trans retinoic acid (atRA promotes the development of TGF-β-induced CD4(+Foxp3(+ regulatory T cells (iTreg that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs. METHODOLOGY/PRINCIPAL FINDINGS: Addition of atRA to naïve CD4(+CD25(- cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered. CONCLUSIONS/SIGNIFICANCE: We have identified the cellular and molecular mechanism(s by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.

  5. Ionic Coulomb Blockade and Resonant Conduction in Biological Ion Channels

    CERN Document Server

    Kaufman, I Kh; Eisenberg, R S

    2014-01-01

    The conduction and selectivity of calcium/sodium ion channels are described in terms of ionic Coulomb blockade, a phenomenon based on charge discreteness and an electrostatic model of an ion channel. This novel approach provides a unified explanation of numerous observed and modelled conductance and selectivity phenomena, including the anomalous mole fraction effect and discrete conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The model is equally applicable to other nanopores.

  6. Pauli Spin Blockade and the Ultrasmall Magnetic Field Effect

    KAUST Repository

    Danon, Jeroen

    2013-08-06

    Based on the spin-blockade model for organic magnetoresistance, we present an analytic expression for the polaron-bipolaron transition rate, taking into account the effective nuclear fields on the two sites. We reveal the physics behind the qualitatively different magnetoconductance line shapes observed in experiment, as well as the ultrasmall magnetic field effect (USFE). Since our findings agree in detail with recent experiments, they also indirectly provide support for the spin-blockade interpretation of organic magnetoresistance. In addition, we predict the existence of a similar USFE in semiconductor double quantum dots tuned to the spin-blockade regime.

  7. Interferon-γ Production by Peripheral Lymphocytes Predicts Survival of Tumor-Bearing Mice Receiving Dual PD-1/CTLA-4 Blockade.

    Science.gov (United States)

    McNamara, Michael J; Hilgart-Martiszus, Ian; Barragan Echenique, Diego M; Linch, Stefanie N; Kasiewicz, Melissa J; Redmond, William L

    2016-08-01

    Immune checkpoint inhibitors are transforming the way cancer is treated. However, these therapies do not benefit all patients and frequently cause significant immune-related adverse events. Biomarkers that identify patients with a favorable early response to therapy are essential for guiding treatment decisions and improving patient outcomes. In this report of our study, we present evidence that shortly after administration of dual PD-1/CTLA-4 blockade, the proinflammatory capacity of peripheral lymphocytes is predictive of tumor progression and survival outcomes in multiple murine models. Specifically, we observed that the quantity of interferon-γ (IFNγ) produced by peripheral lymphocytes in response to CD3/CD28 stimulation was robustly correlated with subsequent survival outcomes. In the tumor models and early time points assessed in this study, this relationship was considerably more predictive than a host of other potential biomarkers, several of which have been previously reported. Overall, these findings suggest that measuring the capacity of peripheral lymphocytes to produce IFNγ may help identify which patients are benefitting from combination anti-PD-1/anti-CTLA-4 immunotherapy. Cancer Immunol Res; 4(8); 650-7. ©2016 AACR. PMID:27262113

  8. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    OpenAIRE

    Christine eDugovic; Shelton, Jonathan E.; Sujin eYun; Pascal eBonaventure; Shireman, Brock T.; Lovenberg, Timothy W.

    2014-01-01

    In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagon...

  9. Aldosterone blockade in post-acute myocardial infarction heart failure

    NARCIS (Netherlands)

    Pitt, Bertram; Ferrari, Roberto; Gheorghiade, Mihai; van Veldhuisen, Dirk J.; Krum, Henry; McMurray, John; Lopez-Sendon, Jose

    2006-01-01

    Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setti

  10. Checkpoint Blockade in Cancer Immunotherapy: Squaring the Circle

    Directory of Open Access Journals (Sweden)

    Maria A.V. Marzolini

    2015-03-01

    Full Text Available Manipulating the complex interaction between the immune system and tumour cells has been the focus of cancer research for many years, but it is only in the past decade that significant progress has been made in the field of cancer immunotherapy resulting in clinically effective treatments. The blockade of co-inhibitory immune checkpoints, essential for maintaining lymphocyte homeostasis and self-tolerance, by immunomodulatory monoclonal antibodies has resulted in the augmentation of anti-tumour responses. The greatest successes so far have been seen with the blockade of cytotoxic T lymphocyte associated antigen-4, which has resulted in the first Phase III clinical trial showing an overall survival benefit in metastatic melanoma, and in the blockade of the programmed cell death protein-1 axis. This concise review will focus on the clinical advances made by the blockade of these two pathways and their role in current cancer treatment strategies.

  11. Dipole blockade in a cold Rydberg atomic sample

    CERN Document Server

    Comparat, Daniel; 10.1364/JOSAB.27.00A208

    2010-01-01

    We review here the studies performed about interactions in an assembly of cold Rydberg atoms. We focus more specially the review on the dipole-dipole interactions and on the effect of the dipole blockade in the laser Rydberg excitation, which offers attractive possibilities for quantum engineering. We present first the various interactions between Rydberg atoms. The laser Rydberg excitation of such an assembly is then described with the introduction of the dipole blockade phenomenon. We report recent experiments performed in this subject by starting with the case of a pair of atoms allowing the entanglement of the wave-functions of the atoms and opening a fascinating way for the realization of quantum bits and quantum gates. We consider then several works on the blockade effect in a large assembly of atoms for three different configurations: blockade through electric-field induced dipole, through F\\"orster resonance and in van der Waals interaction. The properties of coherence and cooperativity are analyzed. ...

  12. COULOMB BLOCKADE OSCILLATIONS OF Si SINGLE-ELECTRON TRANSISTORS

    Institute of Scientific and Technical Information of China (English)

    王太宏; 李宏伟; 周均铭

    2001-01-01

    Coulomb blockade oscillations of Si single-electron transistors, which are fabricated completely by the conventional photolithography technique, have been investigated. Most of the single-electron transistors clearly show Coulomb blockade oscillations and these oscillations can be periodic by applying negative voltages to the in-plane gates. A shift of the peak positions is observed at high temperatures. It is also found that the fluctuation of the peak spacing cannot be neglected.

  13. Transport Through a Coulomb Blockaded Majorana Nanowire

    Science.gov (United States)

    Zazunov, Alex; Egger, Reinhold; Yeyati, Alfredo Levy; Hützen, Roland; Braunecker, Bernd

    In one-dimensional (1D) quantum wires with strong spin-orbit coupling and a Zeeman field, a superconducting substrate can induce zero-energy Majorana bound states located near the ends of the wire. We study electronic properties when such a wire is contacted by normal metallic or superconducting electrodes. A special attention is devoted to Coulomb blockade effects. We analyze the "Majorana single-charge transistor" (MSCT), i.e., a floating Majorana wire contacted by normal metallic source and drain contacts, where charging effects are important. We describe Coulomb oscillations in this system and predict that Majorana fermions could be unambiguously detected by the emergence of sideband peaks in the nonlinear differential conductance. We also study a superconducting variant of the MSCT setup with s-wave superconducting (instead of normal-conducting) leads. In the noninteracting case, we derive the exact current-phase relation (CPR) and find π-periodic behavior with negative critical current for weak tunnel couplings. Charging effects then cause the anomalous CPR I(\\varphi ) = Ic\\cos \\varphi, where the parity-sensitive critical current I c provides a signature for Majorana states.

  14. Blockade of mast cell activation reduces cutaneous scar formation.

    Science.gov (United States)

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound. PMID:24465509

  15. Blockade of mast cell activation reduces cutaneous scar formation.

    Science.gov (United States)

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

  16. Blockade of mast cell activation reduces cutaneous scar formation.

    Directory of Open Access Journals (Sweden)

    Lin Chen

    Full Text Available Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG, on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

  17. Insulin-like growth factor-I receptor signaling blockade combined with radiation.

    Science.gov (United States)

    Allen, Gregory W; Saba, Corey; Armstrong, Eric A; Huang, Shyh-Min; Benavente, Sergio; Ludwig, Dale L; Hicklin, Daniel J; Harari, Paul M

    2007-02-01

    Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials. PMID:17283150

  18. Observation of ionic Coulomb blockade in nanopores.

    Science.gov (United States)

    Feng, Jiandong; Liu, Ke; Graf, Michael; Dumcenco, Dumitru; Kis, Andras; Di Ventra, Massimiliano; Radenovic, Aleksandra

    2016-08-01

    Emergent behaviour from electron-transport properties is routinely observed in systems with dimensions approaching the nanoscale. However, analogous mesoscopic behaviour resulting from ionic transport has so far not been observed, most probably because of bottlenecks in the controlled fabrication of subnanometre nanopores for use in nanofluidics. Here, we report measurements of ionic transport through a single subnanometre pore junction, and the observation of ionic Coulomb blockade: the ionic counterpart of the electronic Coulomb blockade observed for quantum dots. Our findings demonstrate that nanoscopic, atomically thin pores allow for the exploration of phenomena in ionic transport, and suggest that nanopores may also further our understanding of transport through biological ion channels. PMID:27019385

  19. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse;

    2016-01-01

    Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multi......Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed...

  20. Stellate ganglion blockade for analgesia following upper limb surgery.

    LENUS (Irish Health Repository)

    McDonnell, J G

    2012-01-31

    We report the successful use of a stellate ganglion block as part of a multi-modal postoperative analgesic regimen. Four patients scheduled for orthopaedic surgery following upper limb trauma underwent blockade of the stellate ganglion pre-operatively under ultrasound guidance. Patients reported excellent postoperative analgesia, with postoperative VAS pain scores between 0 and 2, and consumption of morphine in the first 24 h ranging from 0 to 14 mg. While these are preliminary findings, and must be confirmed in a clinical trial, they highlight the potential for stellate ganglion blockade to provide analgesia following major upper limb surgery.

  1. Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease

    Science.gov (United States)

    Zhou, Guangxi; Yu, Lin; Yang, Wenjing; Wu, Wei; Fang, Leilei

    2016-01-01

    Background. Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronically remittent and progressive inflammatory disorders. Phospholipase D2 (PLD2) is reported to be involved in the pathogenesis of several inflammatory diseases. However, the exact role of PLD2 in IBD is obscure. Methods. PLD2 expression was determined in peripheral blood cells and inflamed mucosa from patients with IBD by qRT-PCR. Colonic biopsies were also obtained from CD patients before and after infliximab (IFX) treatment to examine PLD2 expression. PLD2 selective inhibitor (CAY10594) was administrated daily by oral gavage in DSS-induced colitis mice. Bone marrow neutrophils from colitis mice were harvested to examine the migration using Transwell plate. Results. PLD2 was found to be significantly increased in peripheral blood cells and inflamed mucosa in patients with active IBD. Treatment with IFX could significantly decrease PLD2 expression in intestinal mucosa in patients with CD. Moreover, blockade of PLD2 with CAY10594 could markedly ameliorate DSS-induced colitis in mice and promote neutrophil migration. Conclusions. PLD2 plays a critical role in the pathogenesis of IBD. Blockade of PLD2 may serve as a new therapeutic approach for treatment of IBD. PMID:27721573

  2. Effect of spinal sympathetic blockade upon postural changes of blood flow in human peripheral tissues

    DEFF Research Database (Denmark)

    Skagen, K; Haxholdt, O; Henriksen, O;

    1982-01-01

    local nervous blockade was induced by Lidocaine in 133Xe labelled subcutaneous tissue on one side. During epidural blockade and tilt blood flow increased by 12% whereas blood flow decreased by 30% on the control side. Thus epidural blockade had no influence on the vasoconstrictor response...

  3. Benefits and harms of perioperative beta-blockade

    DEFF Research Database (Denmark)

    Wetterslev, Jørn; Juul, Anne Benedicte

    2006-01-01

    randomized trials. However, confidence intervals of the intervention effects in the meta-analyses are wide, leaving room for both benefits and harms. The largest observational study performed suggests that perioperative beta-blockade is associated with higher mortality in patients with low cardiac risk...

  4. Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

    Science.gov (United States)

    Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

    1997-01-01

    Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

  5. Non-linear HRV indices under autonomic nervous system blockade.

    Science.gov (United States)

    Bolea, Juan; Pueyo, Esther; Laguna, Pablo; Bailón, Raquel

    2014-01-01

    Heart rate variability (HRV) has been studied as a non-invasive technique to characterize the autonomic nervous system (ANS) regulation of the heart. Non-linear methods based on chaos theory have been used during the last decades as markers for risk stratification. However, interpretation of these nonlinear methods in terms of sympathetic and parasympathetic activity is not fully established. In this work we study linear and non-linear HRV indices during ANS blockades in order to assess their relation with sympathetic and parasympathetic activities. Power spectral content in low frequency (0.04-0.15 Hz) and high frequency (0.15-0.4 Hz) bands of HRV, as well as correlation dimension, sample and approximate entropies were computed in a database of subjects during single and dual ANS blockade with atropine and/or propranolol. Parasympathetic blockade caused a significant decrease in the low and high frequency power of HRV, as well as in correlation dimension and sample and approximate entropies. Sympathetic blockade caused a significant increase in approximate entropy. Sympathetic activation due to postural change from supine to standing caused a significant decrease in all the investigated non-linear indices and a significant increase in the normalized power in the low frequency band. The other investigated linear indices did not show significant changes. Results suggest that parasympathetic activity has a direct relation with sample and approximate entropies.

  6. Why not treat human cancer with interleukin-1 blockade?

    NARCIS (Netherlands)

    Dinarello, C.A.

    2010-01-01

    The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1beta as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the en

  7. Entanglement of two ground state neutral atoms using Rydberg blockade

    DEFF Research Database (Denmark)

    Miroshnychenko, Yevhen; Browaeys, Antoine; Evellin, Charles;

    2011-01-01

    We report on our recent progress in trapping and manipulation of internal states of single neutral rubidium atoms in optical tweezers. We demonstrate the creation of an entangled state between two ground state atoms trapped in separate tweezers using the effect of Rydberg blockade. The quality...... of the entanglement is measured using global rotations of the internal states of both atoms....

  8. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    Full Text Available BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an

  9. Deep neuromuscular blockade leads to a larger intraabdominal volume during laparoscopy

    DEFF Research Database (Denmark)

    Lindekaer, Astrid Listov; Halvor Springborg, Henrik; Istre, Olav

    2013-01-01

    for measuring the intra-abdominal space available to the surgeon during laproscopy, in order to examine whether the relaxation produced by deep neuromuscular blockade can increase the working surgical space sufficiently to permit a reduction in the CO2 insufflation pressure. Using the laproscopic grasper...... patients shows that the intra-abdominal space at 8 mm Hg with blockade is comparable to the intra-abdominal space measured at 12 mm Hg without blockade. The impact of neuromuscular blockade was not correlated with patient height, weight, BMI, and age. Thus, using neuromuscular blockade to maintain a steady...

  10. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    Directory of Open Access Journals (Sweden)

    Christine eDugovic

    2014-02-01

    Full Text Available In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R and orexin-2 (OX2R receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM and REM sleep following oral dosing (10 and 30 mg/kg at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion. When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

  11. Effect of beta blockade and beta stimulation on stage fright.

    Science.gov (United States)

    Brantigan, C O; Brantigan, T A; Joseph, N

    1982-01-01

    Stage fright, physiologically the "fight or flight" reaction, is a disabling condition to the professional musician. Because it is mediated by the sympathetic nervous system, we have investigated the effects of beta blockade on musical performance with propranolol in a double blind fashion and the effects of beta stimulation using terbutaline. Stage fright symptoms were evaluated in two trials, which included a total of 29 subjects, by questionnaire and by the State Trai Anxiety Inventory. Quality of musical performance was evaluated by experienced music critics. Beta blockade eliminates the physical impediments to performance caused by stage fright and even eliminates the dry mouth so frequently encountered. The quality of musical performance as judged by experienced music critics is significantly improved. This effect is achieved without tranquilization. Beta stimulating drugs increase stage fright problems, and should be used in performing musicians only after consideration of the detrimental effects which they may have on musical performance. PMID:6120650

  12. Immunotherapeutic implications of IL-6 blockade for cytokine storm.

    Science.gov (United States)

    Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

    2016-07-01

    IL-6 contributes to host defense against infections and tissue injuries. However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as 'cytokine storm', since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function. Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with cytokine release syndrome complicated by T-cell engaged therapy. In this review we propose the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. PMID:27381687

  13. Dynamical Coulomb blockade and spin-entangled electrons

    OpenAIRE

    Recher, Patrik; Loss, Daniel

    2003-01-01

    We consider the production of mobile and nonlocal pairwise spin-entangled electrons from tunneling of a BCS-superconductor (SC) to two normal Fermi liquid leads. The necessary mechanism to separate the two electrons coming from the same Cooper pair (spin-singlet) is achieved by coupling the SC to leads with a finite resistance. The resulting dynamical Coulomb blockade effect, which we describe phenomenologically in terms of an electromagnetic environment, is shown to be enhanced for tunneling...

  14. Neuromuscular blockade in cardiac surgery: An update for clinicians

    OpenAIRE

    Hemmerling Thomas; Russo Gianluca; Bracco David

    2008-01-01

    There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and i...

  15. Indirect androgen doping by oestrogen blockade in sports

    OpenAIRE

    Handelsman, D J

    2008-01-01

    Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drug...

  16. H2-receptor blockade and exercise-induced asthma.

    OpenAIRE

    Nogrady, S G; Hahn, A G

    1984-01-01

    While in vitro studies suggest that H2-receptor blockade enhances mediator release from bronchial mast cells and leads to bronchoconstriction, in vivo studies have given conflicting results. Eight asthmatic subjects were given cimetidine 800 mg and placebo double-blind on different days. Baseline values of forced expiratory volume in one second (FEV1) were obtained before an 8 min standardized exercise test using a bicycle ergometer. Subjects inhaled cold, dry air and exercise on cimetidine a...

  17. Input-output theory of the unconventional photon blockade

    OpenAIRE

    Flayac, H.; Savona, V.

    2013-01-01

    We study the unconventional photon blockade, recently proposed for a coupled-cavity system, in the presence of input and output quantum fields. Mixing of the input or output channels still allows strong photon antibunching of the output field, but for optimal values of the system parameters that differ substantially from those that maximize antibunching of the intracavity field. This result shows that the specific input-output geometry in a photonic system determines the optimal design in vie...

  18. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    Science.gov (United States)

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi-anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52μmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine.

  19. Neuromuscular blockade in cardiac surgery: An update for clinicians

    Directory of Open Access Journals (Sweden)

    Hemmerling Thomas

    2008-01-01

    Full Text Available There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

  20. Dynamical Coulomb blockade of tunnel junctions driven by alternating voltages

    Science.gov (United States)

    Grabert, Hermann

    2015-12-01

    The theory of the dynamical Coulomb blockade is extended to tunneling elements driven by a time-dependent voltage. It is shown that, for standard setups where an external voltage is applied to a tunnel junction via an impedance, time-dependent driving entails an excitation of the modes of the electromagnetic environment by the applied voltage. Previous approaches for ac driven circuits need to be extended to account for the driven bath modes. A unitary transformation involving also the variables of the electromagnetic environment is introduced which allows us to split off the time dependence from the Hamiltonian in the absence of tunneling. This greatly simplifies perturbation-theoretical calculations based on treating the tunneling Hamiltonian as a perturbation. In particular, the average current flowing in the leads of the tunnel junction is studied. Explicit results are given for the case of an applied voltage with a constant dc part and a sinusoidal ac part. The connection with standard dynamical Coulomb blockade theory for constant applied voltage is established. It is shown that an alternating voltage source reveals significant additional effects caused by the electromagnetic environment. The hallmark of the dynamical Coulomb blockade in ac driven devices is a suppression of higher harmonics of the current by the electromagnetic environment. The theory presented basically applies to all tunneling devices driven by alternating voltages.

  1. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  2. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria

    OpenAIRE

    Barnes, M. J.; Griseri, T; Johnson, A M F; Young, W; Powrie, F; Izcue, A

    2012-01-01

    Thymic induction of CD4+Foxp3+ regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4+ T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4+ T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Fo...

  3. Putative role of monoamines in the antidepressant-like mechanism induced by striatal MT2 blockade.

    Science.gov (United States)

    Noseda, Ana Carolina D; Rodrigues, Lais S; Targa, Adriano D S; Aurich, Mariana F; Vital, Maria A B F; Da Cunha, Cláudio; Lima, Marcelo M S

    2014-12-15

    It has been observed that the secretion pattern of melatonin is modified in Parkinson's disease (PD). Hence, it is hypothesized that dysregulations of melatonin MT2 receptors may be involved in the installation of depression in PD patients. Together with recent evidence based on the use of the intranigral rotenone model of PD, have led to the hypothesis that modulating the striatal MT2 receptor could provide a more comprehensive understanding of the antidepressant properties triggered. To further investigate this issue, male Wistar rats were infused with intranigral rotenone (12μg/μL) and seven days later subjected to a rapid eye movement sleep deprivation (REMSD) for 24h. After, we injected within the striatum the MT2 selective agonist, 8-M-PDOT (10μg/μL), the MT2 selective antagonist, 4-P-PDOT (5μg/μL) or vehicle. Subsequently, they were tested in the forced swimming test and were allowed to perform the sleep rebound (REB). Then, the rats were re-tested, and the striatum, hippocampus and substantia nigra pars compacta (SNpc) were collected for neurochemical purposes. Results indicated substantial antidepressant effects promoted by the blockade of striatal MT2 receptors that were potentiated by REMSD. MT2 activation increased DA levels in the striatum and hippocampus, while MT2 blockade increase DA in the SNpc. 4-P-PDOT treatment of the rotenone REMSD group generated a decrement in 5-HT levels within the striatum, hippocampus and SNpc. However, increased 5-HT turnover was observed among these structures. Therefore, we demonstrated the neurochemical antidepressant effect induced by striatal MT2 blockage associated with REMSD in the rotenone model of PD. PMID:25218873

  4. Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty

    DEFF Research Database (Denmark)

    Jenstrup, M T; Jæger, P; Lund, J;

    2012-01-01

    Total knee arthroplasty (TKA) is associated with intense post-operative pain. Besides providing optimal analgesia, reduction in side effects and enhanced mobilization are important in this elderly population. The adductor-canal-blockade is theoretically an almost pure sensory blockade. We...... hypothesized that the adductor-canal-blockade may reduce morphine consumption (primary endpoint), improve pain relief, enhance early ambulation ability, and reduce side effects (secondary endpoints) after TKA compared with placebo....

  5. Consequences of Zeeman Degeneracy for van der Waals Blockade between Rydberg Atoms

    OpenAIRE

    Walker, Thad G.; Saffman, M.

    2007-01-01

    We analyze the effects of Zeeman degeneracies on the long-range interactions between like Rydberg atoms, with particular emphasis on applications to quantum information processing using van der Waals blockade. We present a general analysis of how degeneracies affect the primary error sources in blockade experiments, emphasizing that blockade errors are sensitive primarily to the weakest possible atom-atom interactions between the degenerate states, not the mean interaction strength. We presen...

  6. Effect of epidural blockade and oxygen therapy on changes in subcutaneous oxygen tension after abdominal surgery

    DEFF Research Database (Denmark)

    Rosenberg, J; Pedersen, U; Erichsen, C J;

    1994-01-01

    The effect of oxygen therapy (37% by face mask) and epidural local anesthetic blockade (9 ml 0.5% bupivacaine at Th9-11 level) on wound oxygenation was evaluated in eight otherwise healthy patients undergoing elective colorectal resection. The patients were monitored continuously for subcutaneous...... any of the measured values. Oxygen therapy before epidural blockade increased median subcutaneous oxygen tension from 60 to 71 mmHg (P oxygen tension with oxygen therapy was 30 (15-55) min...... without epidural blockade and 15 (10-20) min with blockade (P oxygen tension with or without oxygen therapy after elective uncomplicated major abdominal surgery....

  7. Neuromuscular blockade: what was, is and will be.

    Science.gov (United States)

    Schepens, Tom; Cammu, Guy

    2014-01-01

    Non-depolarizing neuromuscular blocking agents (NMBAs) produce neuromuscular blockade by competing with acetylcholine at the neuromuscular junction, whereas depolarizing NMBAs open receptor channels in a manner similar to that of acetylcholine. Problems with NMBAs include malignant hyperthermia caused by succinylcholine, anaphylaxis with the highest incidence for succinylcholine and rocuronium, and residual neuromuscular blockade. To reverse these blocks, anticholinesterases can act indirectly by increasing the amount of acetylcholine in the neuromuscular junction; sugammadex is the only selective relaxant binding agent (SRBA) in clinical use. At all levels of blockade, recovery after sugammadex is faster than after neostigmine. Sugammadex potentially also has some other advantages over neostigmine that are related to neostigmine's increase in the amount of acetylcholine and the necessity of co-administering anticholinergics. However, hypersensitivity reactions, including anaphylaxis, have occurred in some patients and healthy volunteers after sugammadex and remain an issue for the FDA. In the near future, we may see the emergence of new SRBAs and of easier-to-use technologies that can routinely monitor neuromuscular transmissions in daily practice. The nature of the effect of sugammadex on freeing nicotinic acetylcholine receptors located outside the neuromuscular junction from NMBAs is unknown. Moreover, it is uncertain whether the full removal of the competing antagonists (by SRBAs) at the neuromuscular junction impacts the efficiency of acetylcholine transmission. In a recent pilot study in healthy volunteers, we demonstrated increased electromyographic diaphragm activity after sugammadex, compared to neostigmine. Further research is needed to elucidate the role of NMBAs and their reversal agents in the central control of breathing, respiratory muscle activity, and respiratory outcomes. PMID:25622380

  8. Coulomb Blockade in an Ultrathin Ti Nanowire at Room Temperature

    Institute of Scientific and Technical Information of China (English)

    CAIQiyu; YANGTao; CAIBingchu; YINYou; JIANGJianfei

    2003-01-01

    A scanning tunneling microscope operated in ambient air was employed to fabricate a~ 30nm-wide and ~ 700nm-long Ti nanowire connecting the source and drain electrodes on a 3nm-thick Ti film. The ultraflne but nonuniform Ti nanowire was well defined between two ox-idized lines. The gate electrode was capacitively coupled to the nanowire by a ~150nm-wide oxidized line. The electrical properties measured at room temperature of the Ti nanowire showed Coulomb blockade in highly nonlinear Ids-Vds characteristics and Coulomb oscillation in Ids - Vgs characteristics.

  9. Filtering single atoms from Rydberg blockaded mesoscopic ensembles

    CERN Document Server

    Petrosyan, David; Mølmer, Klaus

    2015-01-01

    We propose an efficient method to filter out single atoms from trapped ensembles with unknown number of atoms. The method employs stimulated adiabatic passage to reversibly transfer a single atom to the Rydberg state which blocks subsequent Rydberg excitation of all the other atoms within the ensemble. This triggers the excitation of Rydberg blockaded atoms to short lived intermediate states and their subsequent decay to untrapped states. Using an auxiliary microwave field to carefully engineer the dissipation, we obtain a nearly deterministic single-atom source. Our method is applicable to small atomic ensembles in individual microtraps and in lattice arrays.

  10. COULOMB BLOCKADE EFFECT IN SELF-ASSEMBLED GOLD QUANTUM DOTS

    Institute of Scientific and Technical Information of China (English)

    Shu-Fen Hu; Ru-Ling Yeh; Ru-Shi Liu

    2004-01-01

    Nanometer-scale Au quantum dots have been assembled on SiO2 by controlling the reaction of raw materials to form a citrate Au sol and an aminosilane/dithiol-treated patterned Si wafer. The detailed formation mechanism has been studied. Three gold colloidal particles (~15 nm), aligned in a chain to form a one-dimensional current path, was bridged across an 80-nm gap between source and drain metal electrodes. The device exhibited a Coulomb blockade effect at 33 K.

  11. CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage.

    Science.gov (United States)

    Chaturvedi, Vandana; Ertelt, James M; Jiang, Tony T; Kinder, Jeremy M; Xin, Lijun; Owens, Kathryn J; Jones, Helen N; Way, Sing Sing

    2015-04-01

    Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications. PMID:25751061

  12. Philosophical Intelligence: Letters, Print, and Experiment during Napoleon's Continental Blockade.

    Science.gov (United States)

    Watts, Iain P

    2015-12-01

    This essay investigates scientific exchanges between Britain and France from 1806 to 1814, at the height of the Napoleonic Wars. It argues for a picture of scientific communication that sees letters and printed texts not as separate media worlds, but as interconnected bearers of time-critical information within a single system of intelligence gathering and experimental practice. During this period, Napoleon Bonaparte's Continental System blockade severed most links between Britain and continental Europe, yet scientific communications continued--particularly on electrochemistry, a subject of fierce rivalry between Britain and France. The essay traces these exchanges using the archive of a key go-between, the English man of science Sir Charles Blagden. The first two sections look at Blagden's letter-writing operation, reconstructing how he harnessed connections with neutral American diplomats, merchants, and the State to get scientific intelligence between London and Paris. The third section, following Blagden's words from Britain to France to America, looks at how information in letters cross-fertilized with information in print. The final section considers how letters and print were used together to solve the difficult practical problem of replicating experiments across the blockade. PMID:27024935

  13. Assessment of Methods for the Intracellular Blockade of GABAA Receptors.

    Science.gov (United States)

    Atherton, Laura A; Burnell, Erica S; Mellor, Jack R

    2016-01-01

    Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4'-dinitro-stilbene-2,2'-disulphonic acid (DNDS) and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility. PMID:27501143

  14. Our experience on brachial plexus blockade in upper extremity surgery

    Directory of Open Access Journals (Sweden)

    Ömer Uslukaya

    2012-03-01

    Full Text Available Objective: Peripheral nerve blocks are usually used either alone or along with general anesthesia for postoperative analgesia. We also aimed to present the results and experiences.Materials and methods: This retrospective study was conducted to scan the files of patients who underwent orthopedic upper extremity surgery with peripheral nerve block between September 2009 and October 2010. After ethics committee approval was obtained, 114 patients who were ASA physical status I-III, aged 18-70, performed upper extremity surgery in the Orthopedics and Traumatology Clinic were included to study. Patients’ demographic data, clinical diagnoses, premedication status, peripheral block type, local anesthetic dose, stimuplex needle types, hemodynamic parameters at the during surgery, the first postoperative analgesic requirements, complications and patient satisfaction were recorded.Results: Demographic data were similar to each other. Brachial plexus block was commonly performed for the forearm surgery. Infraclavicular block was performed the most frequently to patients. As the classical methods in the supine position were preferred in 98.2% of patients, Stimuplex A needle (B. Braun, Melsungen AG, Germany have been used for blockage in 80.7% of patients. Also, in 54.4% of patients, 30 ml of local anesthetic solution composed of bupivacaine + prilocaine was used for blockade. Blocks applied to patients had provided adequate anesthesia.Conclusion: Since the brachial plexus blockade guided peripheral nerve stimulator for upper extremity surgery provide adequate depth of anesthesia and analgesia, it may be a good alternative to general anesthesia because of unwanted side effects

  15. Effects of VLA-1 Blockade on Experimental Inflammation in Mice.

    Science.gov (United States)

    Totsuka, Ryuichi; Kondo, Takaaki; Matsubara, Shigeki; Hirai, Midori; Kurebayashi, Yoichi

    2016-01-01

    VLA-1 (very late antigen-1) is implicated in recruitment, retention and activation of leukocytes and its blockade has been referred as a potential target of new drug discovery to address unmet medical needs in inflammatory disease area. In the present study, we investigate the effects of an anti-murine CD49a (integrin α subunit of VLA-1) monoclonal antibody (Ha31/8) on various experimental models of inflammatory diseases in mice. Pretreatment with Ha31/8 at an intraperitoneal dose of 250 µg significantly (P<0.01) reduced arthritic symptoms and joint tissue damage in mice with type II collagen-induced arthritis. In addition, Ha31/8 at an intraperitoneal dose of 100 µg significantly (P<0.01) inhibited airway inflammatory cell infiltration induced by repeated exposure to cigarette smoke. In contrast, Ha31/8 failed to inhibit oxazolone-induced chronic dermatitis and OVA-induced airway hyperresponsiveness at an intraperitoneal dose of 100 µg. These results show that VLA-1 is involved, at least partly, in the pathogenesis of type II collagen-induced arthritis and cigarette smoke-induced airway inflammatory cell infiltration in mice, indicating the therapeutic potential of VLA-1 blockade against rheumatoid arthritis and chronic occlusive pulmonary disease. PMID:27578034

  16. Cyclosporine preserves the anergic state of human T cells induced by costimulation blockade in vitro.

    NARCIS (Netherlands)

    Koenen, H.J.P.M.; Fasse, E.; Joosten, I.

    2005-01-01

    BACKGROUND: Costimulation blockade based tolerance-inducing therapies might be disrupted by adjunct conventional immunosuppressive drug use. In the current study, we evaluated the compatibility of various immunosuppressive agents on costimulation blockade-based immunosuppression and T-cell anergy in

  17. Epidural anaesthesia with levobupivacaine and ropivacaine : effects of age on the pharmacokinetics, neural blockade and haemodynamics

    NARCIS (Netherlands)

    Simon, Mischa J.G.

    2006-01-01

    Epidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and haemodynamics after epidural anaesthesia may be influenced by several factors, with age as the most impor

  18. Disentangling the effects of spin-orbit and hyperfine interactions on spin blockade

    NARCIS (Netherlands)

    Nadj-Perge, S.; Frolov, S.M.; Van Tilburg, J.W.W.; Danon, J.; Nazarov, Y.V.; Algra, R.; Bakkers, E.P.A.M.; Kouwenhoven, L.P.

    2010-01-01

    We have achieved the few-electron regime in InAs nanowire double quantum dots. Spin blockade is observed for the first two half-filled orbitals, where the transport cycle is interrupted by forbidden transitions between triplet and singlet states. Partial lifting of spin blockade is explained by spin

  19. Ultra-high-ohmic microstripline resistors for Coulomb blockade devices.

    Science.gov (United States)

    Lotkhov, Sergey V

    2013-06-14

    In this paper, we report on the fabrication and low-temperature characterization of ultra-high-ohmic microstripline resistors made of a thin film of weakly oxidized titanium. Nearly linear voltage-current characteristics were measured at temperatures down to T ~ 20 mK for films with sheet resistivities as high as ~7 kΩ, i.e. about an order of magnitude higher than our previous findings for weakly oxidized Cr. Our analysis indicates that such an improvement can help to create an advantageous high-impedance environment for different Coulomb blockade devices. Further properties of the Ti film addressed in this work show the promise of low-noise behavior of the resistors when applied in different realizations of the quantum standard of current. PMID:23670293

  20. Coulomb blockade in turnstile with multiple tunnel junctions

    CERN Document Server

    Lee, S C; Kang, D S; Kim, D C; Choi, C K; Ryu, J Y

    1999-01-01

    On the basis of the analytic solutions to the electrostatic problem of the multi-grated-small-junction systems, the stable domain for the Coulomb blockade of turnstile with multiple tunnel junctions at zero temperature has been analyzed as a function of the number of tunnel junction, the ratio of the gate capacitance to the junction capacitance, and the asymmetric factor. Our results show that domains form various shaped regions according to the asymmetric factor and their size depends on the number of junction and the ratio of the gate capacitance to the junction capacitance. In particular, it is shown that electrons can be transferred in positive and/or negative bias voltage depending on the asymmetric factor when an appropriate gate cycle is applied. Thus, the asymmetric factor plays an important role in determining the turnstile operation.

  1. Thermoelectric properties of Coulomb-blockaded fractional quantum Hall islands

    Directory of Open Access Journals (Sweden)

    Lachezar S. Georgiev

    2015-05-01

    Full Text Available We show that it is possible and rather efficient to compute at non-zero temperature the thermoelectric characteristics of Coulomb blockaded fractional quantum Hall islands, formed by two quantum point contacts inside of a Fabry–Pérot interferometer, using the conformal field theory partition functions for the chiral edge excitations. The oscillations of the thermopower with the variation of the gate voltage as well as the corresponding figure-of-merit and power factors, provide finer spectroscopic tools which are sensitive to the neutral multiplicities in the partition functions and could be used to distinguish experimentally between different universality classes sharing the same electric properties. We also propose a procedure for measuring the ratio r=vn/vc of the Fermi velocities of the neutral and charged edge modes for filling factor νH=5/2 from the power-factor data in the low-temperature limit.

  2. Edge-state blockade of transport in quantum dot arrays

    Science.gov (United States)

    Benito, Mónica; Niklas, Michael; Platero, Gloria; Kohler, Sigmund

    2016-03-01

    We propose a transport blockade mechanism in quantum dot arrays and conducting molecules based on an interplay of Coulomb repulsion and the formation of edge states. As a model we employ a dimer chain that exhibits a topological phase transition. The connection to a strongly biased electron source and drain enables transport. We show that the related emergence of edge states is manifest in the shot noise properties as it is accompanied by a crossover from bunched electron transport to a Poissonian process. For both regions we develop a scenario that can be captured by a rate equation. The resulting analytical expressions for the Fano factor agree well with the numerical solution of a full quantum master equation.

  3. Coulomb blockade and BLOCH oscillations in superconducting Ti nanowires.

    Science.gov (United States)

    Lehtinen, J S; Zakharov, K; Arutyunov, K Yu

    2012-11-01

    Quantum fluctuations in quasi-one-dimensional superconducting channels leading to spontaneous changes of the phase of the order parameter by 2π, alternatively called quantum phase slips (QPS), manifest themselves as the finite resistance well below the critical temperature of thin superconducting nanowires and the suppression of persistent currents in tiny superconducting nanorings. Here we report the experimental evidence that in a current-biased superconducting nanowire the same QPS process is responsible for the insulating state--the Coulomb blockade. When exposed to rf radiation, the internal Bloch oscillations can be synchronized with the external rf drive leading to formation of quantized current steps on the I-V characteristic. The effects originate from the fundamental quantum duality of a Josephson junction and a superconducting nanowire governed by QPS--the QPS junction.

  4. Cavity polaritons with Rydberg blockade and long-range interactions

    CERN Document Server

    Litinskaya, Marina; Pupillo, Guido

    2016-01-01

    We study interactions between polaritons, arising when photons strongly couple to collective excitations in an array of two-level atoms trapped in an optical lattice inside a cavity. We consider two types of interactions between atoms: Dipolar forces and atomic saturability, which ranges from hard-core repulsion to Rydberg blockade. We show that, in spite of the underlying repulsion in the subsystem of atomic excitations, saturability induces a broadband bunching of photons for two-polariton scattering states. We interpret this bunching as a result of interference, and trace it back to the mismatch of the quantization volumes for atomic excitations and photons. We examine also bound bipolaritonic states: These include states created by dipolar forces, as well as a gap bipolariton, which forms solely due to saturability effects in the atomic transition. Both types of bound states exhibit strong bunching in the photonic component. We discuss the dependence of bunching on experimentally relevant parameters.

  5. Abdominal compartment syndrome successfully treated with neuromuscular blockade

    Directory of Open Access Journals (Sweden)

    Kris T Chiles

    2011-01-01

    Full Text Available A 48 year old male admitted to the intensive care unit after a cardiac arrest complicated by a stroke intra-operatively during automatic implantable cardioverter defibrillator placement. He post-operatively developed a rigid abdomen, elevated peak and plateau pressures, hypoxia and renal insufficiency. He was diagnosed with abdominal compartment syndrome with an intra-abdominal compartment pressure of 40mmHg. The patient was administered 10 mg of intravenous cisatracuriumbesylate in preparation for bedside surgical abdominal decompression. Cisatracurium eliminated the patients need for surgical intervention by reducing his abdominal compartment pressures to normal and improving his hypoxia and renal function. This case illustrates that neuromuscular blockade should be attempted in patients with abdominal compartment syndrome prior to surgical intervention.

  6. Investigation of uncertainty components in Coulomb blockade thermometry

    Energy Technology Data Exchange (ETDEWEB)

    Hahtela, O. M.; Heinonen, M.; Manninen, A. [MIKES Centre for Metrology and Accreditation, Tekniikantie 1, 02150 Espoo (Finland); Meschke, M.; Savin, A.; Pekola, J. P. [Low Temperature Laboratory, Aalto University, Tietotie 3, 02150 Espoo (Finland); Gunnarsson, D.; Prunnila, M. [VTT Technical Research Centre of Finland, Tietotie 3, 02150 Espoo (Finland); Penttilä, J. S.; Roschier, L. [Aivon Oy, Tietotie 3, 02150 Espoo (Finland)

    2013-09-11

    Coulomb blockade thermometry (CBT) has proven to be a feasible method for primary thermometry in every day laboratory use at cryogenic temperatures from ca. 10 mK to a few tens of kelvins. The operation of CBT is based on single electron charging effects in normal metal tunnel junctions. In this paper, we discuss the typical error sources and uncertainty components that limit the present absolute accuracy of the CBT measurements to the level of about 1 % in the optimum temperature range. Identifying the influence of different uncertainty sources is a good starting point for improving the measurement accuracy to the level that would allow the CBT to be more widely used in high-precision low temperature metrological applications and for realizing thermodynamic temperature in accordance to the upcoming new definition of kelvin.

  7. Prorenin/Renin Receptor Blockade Promotes a Healthy Fat Distribution in Obese Mice

    Science.gov (United States)

    Tan, Paul; Blais, Carolane; Nguyen, Thi M.-D.; Schiller, Peter W.; Gutkowska, Jolanta; Lavoie, Julie L.

    2016-01-01

    Objective Administration of the handle region peptide (HRP), a (pro)renin receptor blocker, decreases body weight gain and visceral adipose tissue (VAT) in high-fat/high-carbohydrate (HF/HC) diet-fed mice. The objective of this study was to elucidate potential mechanisms implicated in these observations. Methods Mice were given a normal or a HF/HC diet along with saline or HRP for 10 weeks. Results In HF/HC-fed mice, HRP increased the expression of several enzymes implicated in lipogenesis and lipolysis in subcutaneous fat (SCF) while the expression of the enzyme implicated in the last step of lipogenesis decreased in VAT. A reduction was also observed in circulating free fatty acids in these animals which was accompanied by normalized adipocyte size in VAT and increased adipocyte size in SCF. “Beiging“ is the evolution of a white adipose tissue toward a brown-like phenotype characterized by an increased mitochondrial density and small lipid droplets. HRP increased the expression of’ “beiging” markers in SCF of HF/HC diet-fed mice. Conclusions HRP treatment may favor healthy fat storage in SCF by activating a triglyceride/free fatty acid cycling and “beiging,” which could explain the body weight and fat mass reduction. PMID:27458124

  8. Blockade of tolerance to morphine analgesia by cocaine.

    Science.gov (United States)

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  9. Differential blockade of rat α3β4 and α7 neuronal nicotinic receptors by ω-conotoxin MVIIC, ω-conotoxin GVIA and diltiazem

    Science.gov (United States)

    Herrero, Carlos J; García-Palomero, Esther; Pintado, Antonio J; García, Antonio G; Montiel, Carmen

    1999-01-01

    Rat α3β4 or α7 neuronal nicotinic acetylcholine receptors (AChRs) were expressed in Xenopus laevis oocytes, and the effects of various toxins and non-toxin Ca2+ channel blockers studied. Nicotinic AChR currents were elicited by 1 s pulses of dimethylphenylpiperazinium (DMPP, 100 μM) applied at regular intervals.The N/P/Q-type Ca2+ channel blocker ω-conotoxin MVIIC inhibited α3β4 currents with an IC50 of 1.3 μM; the blockade was non-competitive and reversible. The α7 currents were unaffected.At 1 μM, ω-conotoxin GVIA (N-type Ca2+ channel blocker) inhibited by 24 and 20% α3β4 and α7 currents, respectively. At 1 μM, ω-agatoxin IVA (a P/Q-type Ca2+ channel blocker) did not affect α7 currents and inhibited α3β4 currents by only 15%.L-type Ca2+ channel blockers furnidipine, verapamil and, particularly, diltiazem exhibited a preferential blocking activity on α3β4 nicotinic AChRs.The mechanism of α3β4 currents blockade by ω-conotoxins and diltiazem differed in the following aspects: (i) the onset and reversal of the blockade was faster for toxins; (ii) the blockade by the peptides was voltage-dependent, while that exerted by diltiazem was not; (iii) diltiazem promoted the inactivation of the current while ω-toxins did not.These data show that, at concentrations currently employed as Ca2+ channel blockers, some of these compounds also inhibit certain subtypes of nicotinic AChR currents. Our data calls for caution when interpreting many of the results obtained in neurons and other cell types, where nicotinic receptor and Ca2+ channels coexist. PMID:10455287

  10. Blockade of LFA-1 augments in vitro differentiation of antigen-induced Foxp3+ Treg cells

    OpenAIRE

    Verhagen, Johan; Wraith, David C.

    2014-01-01

    Adoptive transfer of antigen-specific, in vitro-induced Foxp3+ Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3+ iTreg cells at a purity of 90–95%, antigen-induced iTreg cells typically do not exceed a purity of 65–75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell dif...

  11. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

    Directory of Open Access Journals (Sweden)

    Willis Cynthia R

    2012-10-01

    Full Text Available Abstract Background Interleukin-7 (IL-7 acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. Methods We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. Results Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. Conclusions Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development

  12. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J;

    1992-01-01

    ) blockade. 2. During alpha-adrenoceptor blockade heart rate and cardiac output increased considerably and left ventricular ejection fraction increased because of increased contractility. Systemic vascular resistance fell both during alpha-adrenoceptor blockade alone and during combined blockade. The...... increase in calf blood flow was of the same magnitude after combined blockade and after alpha-adrenoceptor blockade alone, and was considerably higher than the fall in systemic vascular resistance. Plasma catecholamine concentrations increased after phentolamine, but the changes were blunted when...... propranolol and atropine were added. 3. These results indicate that peripheral vasoconstriction especially that exerted by alpha-adrenoceptor nervous tone in skeletal muscle restricts left ventricular emptying of the intact heart. During pharmacologic blockade of the sympathetic and parasympathetic nervous...

  13. Lentiviral Nef-mediated CD4 and CD28 downmodulation

    OpenAIRE

    Heilmann, Jessica

    2014-01-01

    Different properties allow HIV-1 and SIV to establish a chronic disease, e.g. genome insertion into long living quiescent T cells, high genome mutations and evasion of the immune system. The lentiviral Nef protein undertakes important functions of evading the immune system. One of these functions is the downregulation of CD4 receptors from infected cell surfaces. Downregulation of the main entry receptor of HIV-1 prevents superinfection and related cell death, enhances release and infectivity...

  14. Efficacy of regional renal nerve blockade in patients with chronic refractory heart failure

    Institute of Scientific and Technical Information of China (English)

    DAI Qi-ming; FEN Yi; LU Jing; MA Gen-shan

    2013-01-01

    Background Increased renal sympathetic nerve activity can result in diuretic resistance in patients with chronic congestive heart failure.We investigated the effect of regional renal nerve blockade on the patients with chronic refractory heart failure and diuretic resistance.Methods Eighteen patients with chronic refractory heart failure were enrolled (mean age (64±11) years).The patients were randomly divided into two groups (renal nerve blockade group and standard therapy group,n=9 each).Renal nerve blockade was performed by percutaneous injection of local anaesthetic under computed tomographic guidance.Heart rate,mean arterial blood pressure,plasma and urine electrolytes,neurohormones,factional excretion of sodium (FENa),24-hour urine volume were monitored at baseline and the first 24 hours after therapy.Dyspnea and oedema were also evaluated.The major adverse cardiovascular events (MACE),plasma brain natriuretic peptide (BNP) level and left ventricular ejection fraction (LVEF) were compared between the two groups during the 3-12 months follow-up period.Results No complication was observed during the acute phase of renal nerve blockade.After renal nerve blockade,the 24-hour urine volume and FENa were significantly increased,while the level of plasma rennin,angiotensin Ⅱ,aldosterone,BNP and atrial natriuretic peptide as well as dyspnea and oedema were significantly reduced in renal nerve blockade group compared with baseline and standard therapy group.During three to 12 months of follow-up,the rate of MACE and plasma BNP level were significantly lower,while LVEF was significantly higher in renal nerve blockade group than those in standard therapy group.Conclusion Regional renal nerve blockade may be a safe and effective treatment for patients with chronic refractory heart failure.

  15. Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy

    OpenAIRE

    Tzirogiannis, Konstantinos N; Kourentzi, Kalliopi T; Zyga, Sofia; Papalimneou, Vassiliki; Tsironi, Maria; Grypioti, Agni D; Protopsaltis, Ioannis; Panidis, Dimitrios; Panoutsopoulos, Georgios I

    2014-01-01

    Background Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by int...

  16. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng

    2016-01-01

    Full Text Available Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an

  17. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

    Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use ofmonotherapy, without applying any language restrictions.Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy,""dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc.Study Selection: The selected articles were carefully reviewed.We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin Ⅱ receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension.However, existing literature has presented mixed results, in particular, related to patient safety.In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility.Further trials are warranted to study the combination therapy as an evidence-based practice.

  18. Transfer of entangled state, entanglement swapping and quantum information processing via the Rydberg blockade

    Institute of Scientific and Technical Information of China (English)

    Deng Li; Chen Ai-Xi; Zhang Jian-Song

    2011-01-01

    We provide a scheme with which the transfer of the entangled state and the entanglement swapping can be realized in a system of neutral atoms via the Rydberg blockade.Our idea can be extended to teleport an unknown atomic state.According to the latest theoretical research of the Rydberg excitation and experimental reports of the Rydberg blockade effect in quantum information processing,we discuss the experimental feasibility of our scheme.

  19. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Directory of Open Access Journals (Sweden)

    Brian J. Ahn

    2013-11-01

    Full Text Available Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  20. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  1. Antithrombotic effects of beta2-adrenergic receptor blockade on top of beta1-receptor blockade in patients with acute coronary syndrome or heart failure : a systematic review

    NARCIS (Netherlands)

    De Peuter, O.R.; Lussana, F.; Peters, R.J.; Büller, H.R.; Kamphuisen, P.W.

    2009-01-01

    Background: Non-selective beta1 + 2 blockers may have specific antithrombotic effects not present in eta1-blockers, due to a eta2-specific effect on sympathetic activity. Our aim was to assess the influence of eta2-receptor suppression on top of selective beta1-receptor blockade on the occurrence of

  2. Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

    Science.gov (United States)

    Taniyama, Yoshiaki; Katsuragi, Naruto; Sanada, Fumihiro; Azuma, Junya; Iekushi, Kazuma; Koibuchi, Nobutaka; Okayama, Keita; Ikeda-Iwabu, Yuka; Muratsu, Jun; Otsu, Rei; Rakugi, Hiromi; Morishita, Ryuichi

    2016-02-01

    We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.

  3. GHRH excess and blockade in X-LAG syndrome.

    Science.gov (United States)

    Daly, Adrian F; Lysy, Philippe A; Desfilles, Céline; Rostomyan, Liliya; Mohamed, Amira; Caberg, Jean-Hubert; Raverot, Veronique; Castermans, Emilie; Marbaix, Etienne; Maiter, Dominique; Brunelle, Chloe; Trivellin, Giampaolo; Stratakis, Constantine A; Bours, Vincent; Raftopoulos, Christian; Beauloye, Veronique; Barlier, Anne; Beckers, Albert

    2016-03-01

    X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome. PMID:26671997

  4. Promoting long-term survival of insulin-producing cell grafts that differentiate from adipose tissue-derived stem cells to cure type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Shuzi Zhang

    Full Text Available BACKGROUND: Insulin-producing cell clusters (IPCCs have recently been generated in vitro from adipose tissue-derived stem cells (ASCs to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long-term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, β cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so. CONCLUSIONS/SIGNIFICANCE: Long-term survival of ASC-derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation.

  5. Effects of beta-adrenergic blockade on ventilation and gas exchange during incremental exercise.

    Science.gov (United States)

    Dodd, S; Powers, S; O'Malley, N; Brooks, E; Sommers, H

    1988-08-01

    Controversy exists concerning the effects of acute beta-adrenergic blockade on ventilation during exercise. Hence, the purpose of this study was to determine the effects of acute beta blockade on ventilation and gas exchange during incremental exercise. Nine male subjects underwent incremental exercise on a cycle ergometer (30 W.min-1) to exhaustion, with one trial being performed 60 min after the subject ingested propranolol hydrochloride (Inderal 1 mg.kg-1 BW) while the second test served as control. The treatment order was counterbalanced to preclude any ordering effect on the results, and 1 week separated the tests. Ventilation and gas exchange were monitored by open circuit techniques. No difference (p greater than 0.05) existed in VE, % Hb sat, VCO2, ventilatory threshold, and VE/VCO2 between treatments at the same exercise stage. VO2max was lowered from 3.82 to 3.26 l.min-1 (p less than 0.05) and HRmax was reduced from 190 to 150 bpm (p less than 0.05) as a result of beta blockade. These data suggested that acute beta blockade had no effect on exercise ventilation, but decreased HRmax at comparable work rates. In addition, VO2max and exercise time to exhaustion were hindered, probably due to beta blockade limitation of HRmax, and, thus, oxygen transport. PMID:3178619

  6. Spinal blockades of class I antiarrythmic drugs with bupivacaine by isobolographic analysis in rats.

    Science.gov (United States)

    Chen, Yu-Wen; Chu, Chin-Chen; Chen, Yu-Chung; Leung, Yuk-Man; Wang, Jhi-Joung

    2012-10-18

    Flecainide, quinidine, and mexiletine have been shown to be sodium channel blockers and local anesthetics. The purpose of this study was to examine the interaction of the traditional local anesthetic bupivacaine with flecainide, quinidine, or mexiletine on spinal blockades. To obtain the 50% effective dose (ED(50)) of drugs, dose-dependent responses of spinal blockades of motor and sensory functions with intrathecal flecainide, quinidine, mexiletine, and bupivacaine in rats were constructed. Using a continuum of different fixed drug dose ratios, the interactions of bupivacaine with drugs (flecainide, quinidine, or mexiletine) were evaluated by an isobolographic analysis. Our resulting data showed that flecainide, quinidine, and mexiletine, as well as local anesthetic bupivacaine produced dose-dependent spinal blockades in motor function and nociception. Flecainide had the most potent spinal antinociceptive effect (Pmexiletine displayed an additive effect on spinal blockades of motor function and nociception. We concluded that bupivacaine combined with flecainide, quinidine, or mexiletine exhibited an additive effect on spinal blockades of motor function and nociception. Using such a combination strategy to produce antinociception may potentially provide an improved therapeutic separation from myocardial toxicity occurred after spinal bupivacaine. PMID:22985507

  7. Quantum Interference Induced Photon Blockade in a Coupled Single Quantum Dot-Cavity System

    CERN Document Server

    Tang, Jing; Xu, Xiulai

    2015-01-01

    We propose an experimental scheme to implement a strong photon blockade with a single quantum dot coupled to a nanocavity. The photon blockade effect can be tremendously enhanced by driving the cavity and the quantum dot simultaneously with two classical laser fields. This enhancement of photon blockade is ascribed to the quantum interference effect to avoid two-photon excitation of the cavity field. Comparing with Jaynes-Cummings model, the second-order correlation function at zero time delay $g^{(2)}(0)$ in our scheme can be reduced by two orders of magnitude and the system sustains a large intracavity photon number. A red (blue) cavity-light detuning asymmetry for photon quantum statistics with bunching or antibunching characteristics is also observed. The photon blockade effect has a controllable flexibility by tuning the relative phase between the two pumping laser fields and the Rabi coupling strength between the quantum dot and the pumping field. Moreover, the photon blockade scheme based on quantum in...

  8. [The blockade of sphenopalatineganglionthrough the palatal approachin the present-day rhinological practice].

    Science.gov (United States)

    Borodulin, V G; Filimonov, S V

    2016-01-01

    This article deals with the application of the sphenopalatine ganglion blockade in the present-day rhinological practice. The blockade is known to arrest the propagation of pain impulses from the nose and break the rhinocardiac reflex arc. Moreover, it is involved in bleeding control during nasal surgery. The method for the blockade via the palatal route using the modern equipment and imaging techniques is described. The objective of the present study was to evaluate the effectiveness and safety of the blockade of sphenopalatine ganglionthrough the palatal approach in the patients who had undergone septoplasty under general and local anesthesia. It included a total of 105 patients divided into two groups one of which was treated with the use ofblockade of sphenopalatineganglionin addition to conventional anesthesia while the patients of the other group were treated under traditional anesthesia alone. The results of the study confirm the effectiveness of blockade of sphenopalatineganglionthrough the palatal approach as a method for the treatment of postoperative syndrome, bleeding control during nasal surgery, and reduction of parasympathetic influence on the cardiac rhythm. PMID:27500577

  9. Improvement of Chicken Primordial Germ Cell Maintenance In Vitro by Blockade of the Aryl Hydrocarbon Receptor Endogenous Activity.

    Science.gov (United States)

    Pérez Sáez, Juan M; Bussmann, Leonardo E; Barañao, J Lino; Bussmann, Ursula A

    2016-06-01

    Primordial germ cells (PGCs) are the undifferentiated progenitors of gametes. Germline competent PGCs can be developed as a cell-based system for genetic modification in chickens, which provides a valuable tool for transgenic technology with both research and industrial applications. This implies manipulation of PGCs, which, in recent years, encouraged a lot of research focused on the study of PGCs and the way of improving their culture. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that besides mediating toxic responses to environmental contaminants plays pivotal physiological roles in various biological processes. Since a novel compound that acts as an antagonist of this receptor has been reported to promote expansion of hematopoietic stem cells, we conducted the present study with the aim of determining whether addition of an established AHR antagonist to the standard culture medium used nowadays for in vitro chicken PGCs culture improves ex vivo expansion. We have found that addition of α-naphthoflavone in culture medium promotes the amplification of undifferentiated cells and that this effect is exerted by the blockade of AHR action. Our results constitute the first report of the successful use of a readily available AHR antagonist to improve avian PGCs expansion, and they further extend the knowledge of the effects of AHR modulation in undifferentiated cells.

  10. Two-Atom Rydberg Blockade using a Single-Photon Transition

    CERN Document Server

    Hankin, A M; Parazzoli, L P; Chou, C W; Armstrong, D J; Landahl, A J; Biedermann, G W

    2014-01-01

    We explore a single-photon approach to Rydberg state excitation and Rydberg blockade. Using detailed theoretical models, we show the feasibility of direct excitation, predict the effect of background electric fields, and calculate the required interatomic distance to observe Rydberg blockade. We then measure and control the electric field environment to enable coherent control of Rydberg states. With this coherent control, we demonstrate Rydberg blockade of two atoms separated by 6.6(3) {\\mu}m. When compared with the more common two-photon excitation method, this single-photon approach is advantageous because it eliminates channels for decoherence through photon scattering and AC Stark shifts from the intermediate state while moderately increasing Doppler sensitivity.

  11. A high fidelity Rydberg blockade entangling gate using shaped, analytic pulses

    CERN Document Server

    Theis, L S; Wilhelm, F K; Saffmann, M

    2016-01-01

    We show that the use of shaped pulses improves the fidelity of a Rydberg blockade two-qubit entangling gate by several orders of magnitude compared to previous protocols based on square pulses or optimal control pulses. Using analytical Derivative Removal by Adiabatic Gate (DRAG) pulses that reduce excitation of primary leakage states and an analytical method of finding the optimal Rydberg blockade we generate Bell states with a fidelity of $F>0.9999$ in a 300 K environment for a gate time of only $50\\;{\\rm ns}$, which is an order of magnitude faster than previous protocols. These results establish the potential of neutral atom qubits with Rydberg blockade gates for scalable quantum computation.

  12. Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models.

    Science.gov (United States)

    Silva, M M; Lemos, J M; Coito, A; Costa, B A; Wigren, T; Mendonça, T

    2014-01-01

    This paper addresses the local identifiability and sensitivity properties of two classes of Wiener models for the neuromuscular blockade and depth of hypnosis, when drug dose profiles like the ones commonly administered in the clinical practice are used as model inputs. The local parameter identifiability was assessed based on the singular value decomposition of the normalized sensitivity matrix. For the given input signal excitation, the results show an over-parameterization of the standard pharmacokinetic/pharmacodynamic models. The same identifiability assessment was performed on recently proposed minimally parameterized parsimonious models for both the neuromuscular blockade and the depth of hypnosis. The results show that the majority of the model parameters are identifiable from the available input-output data. This indicates that any identification strategy based on the minimally parameterized parsimonious Wiener models for the neuromuscular blockade and for the depth of hypnosis is likely to be more successful than if standard models are used.

  13. Water Mediates Recognition of DNA Sequence via Ionic Current Blockade in a Biological Nanopore.

    Science.gov (United States)

    Bhattacharya, Swati; Yoo, Jejoong; Aksimentiev, Aleksei

    2016-04-26

    Electric field-driven translocation of DNA strands through biological nanopores has been shown to produce blockades of the nanopore ionic current that depend on the nucleotide composition of the strands. Coupling a biological nanopore MspA to a DNA processing enzyme has made DNA sequencing via measurement of ionic current blockades possible. Nevertheless, the physical mechanism enabling the DNA sequence readout has remained undetermined. Here, we report the results of all-atom molecular dynamics simulations that elucidated the physical mechanism of ionic current blockades in the biological nanopore MspA. We find that the amount of water displaced from the nanopore by the DNA strand determines the nanopore ionic current, whereas the steric and base-stacking properties of the DNA nucleotides determine the amount of water displaced. Unexpectedly, we find the effective force on DNA in MspA to undergo large fluctuations, which may produce insertion errors in the DNA sequence readout. PMID:27054820

  14. Charge sensed Pauli blockade in a metal-oxide-semiconductor lateral double quantum dot.

    Science.gov (United States)

    Nguyen, Khoi T; Lilly, Michael P; Nielsen, Erik; Bishop, Nathan; Rahman, Rajib; Young, Ralph; Wendt, Joel; Dominguez, Jason; Pluym, Tammy; Stevens, Jeffery; Lu, Tzu-Ming; Muller, Richard; Carroll, Malcolm S

    2013-01-01

    We report Pauli blockade in a multielectron silicon metal-oxide-semiconductor double quantum dot with an integrated charge sensor. The current is rectified up to a blockade energy of 0.18 ± 0.03 meV. The blockade energy is analogous to singlet-triplet splitting in a two electron double quantum dot. Built-in imbalances of tunnel rates in the MOS DQD obfuscate some edges of the bias triangles. A method to extract the bias triangles is described, and a numeric rate-equation simulation is used to understand the effect of tunneling imbalances and finite temperature on charge stability (honeycomb) diagram, in particular the identification of missing and shifting edges. A bound on relaxation time of the triplet-like state is also obtained from this measurement. PMID:24199677

  15. Surgical Space Conditions During Low-Pressure Laparoscopic Cholecystectomy with Deep Versus Moderate Neuromuscular Blockade

    DEFF Research Database (Denmark)

    Staehr-Rye, Anne K; Rasmussen, Lars S.; Rosenberg, Jacob;

    2014-01-01

    described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with "optimal" surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy. METHODS......). RESULTS: Optimal surgical space conditions during the entire procedure were observed in 7 of 25 patients allocated to deep neuromuscular blockade and in 1 of 23 patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 4......%-43%). Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 of 25 and 8 of 23 patients in the deep and moderate group, respectively (95% confidence interval, -2% to 53%; P = 0.08). Surgical space conditions during dissection of the gallbladder assessed by use of the numeric rating scale were...

  16. Analgesia, sedation, and neuromuscular blockade during targeted temperature management after cardiac arrest.

    Science.gov (United States)

    Riker, Richard R; Gagnon, David J; May, Teresa; Seder, David B; Fraser, Gilles L

    2015-12-01

    The approach to sedation, analgesia, and neuromuscular blockade during targeted temperature management (TTM) remains largely unstudied, forcing clinicians to adapt previous research from other patient environments. During TTM, very little data guide drug selection, doses, and specific therapeutic goals. Sedation should be deep enough to prevent awareness during neuromuscular blockade, but titration is complex as metabolism and clearance are delayed for almost all drugs during hypothermia. Deeper sedation is associated with prolonged intensive care unit (ICU) and ventilator therapy, increased delirium and infection, and delayed wakening which can confound early critical neurological assessments, potentially resulting in erroneous prognostication and inappropriate withdrawal of life support. We review the potential therapeutic goals for sedation, analgesia, and neuromuscular blockade during TTM; the adverse events associated with that treatment; data suggesting that TTM and organ dysfunction impair drug metabolism; and controversies and potential benefits of specific monitoring. We also highlight the areas needing better research to guide our therapy. PMID:26670815

  17. Dynamical Coulomb blockade of the nonlocal conductance in normalmetal/superconductor hybrid structures

    International Nuclear Information System (INIS)

    In normalmetal/superconductor hybrid structures nonlocal conductance is determined by crossed Andreev reflection (CAR) and elastic cotunneling (EC). This was investigated recently both experimentally and theoretically. Dynamical Coulomb blockade of EC and CAR was predicted theoretically. Here we report on experimental investigations of these effects. We found signatures of dynamical Coulomb blockade in local and nonlocal conductance in the normal state. In the superconducting state, we find s-shaped nonlocal differential conductance curves as a function of bias applied on both contacts. These curves were observed for bias voltages both below and above the gap. We compare our results to theory.

  18. Renal and cardiac function during alpha1-beta-blockade in congestive heart failure

    DEFF Research Database (Denmark)

    Heitmann, M; Davidsen, U; Stokholm, K H;

    2002-01-01

    The kidney and the neurohormonal systems are essential in the pathogenesis of congestive heart failure (CHF) and the physiologic response. Routine treatment of moderate to severe CHF consists of diuretics, angiotensin-converting enzyme (ACE) inhibition and beta-blockade. The need for control...... of renal function during initiation of ACE-inhibition in patients with CHF is well known. The aim of this study was to investigate whether supplementation by a combined alpha1-beta-blockade to diuretics and ACE-inhibition might improve cardiac function without reducing renal function....

  19. Ultrasound Guided Intercostobrachial Nerve Blockade in Patients with Persistent Pain after Breast Cancer Surgery

    DEFF Research Database (Denmark)

    Wijayasinghe, Nelun; Duriaud, Helle M; Kehlet, Henrik;

    2016-01-01

    BACKGROUND: Persistent pain after breast cancer surgery (PPBCS) affects 25 - 60% of breast cancer survivors and damage to the intercostobrachial nerve (ICBN) has been implicated as the cause of this predominantly neuropathic pain. Local anesthetic blockade of the ICBN could provide clues...... determined the sonoanatomy of the ICBN and part 2 examined effects of the ultrasound-guided ICBN blockade in patients with PPBCS. SETTING: Section for Surgical Pathophysiology at Rigshospitalet, Copenhagen, Denmark. METHODS: Part 1: Sixteen unoperated, pain free breast cancer patients underwent systematic...

  20. Ultrasound guided intercostobrachial nerve blockade in patients with persistent pain after breast cancer surgery

    DEFF Research Database (Denmark)

    Wijayasinghe, Nelun; Duriaud, Helle M; Kehlet, Henrik;

    2016-01-01

    BACKGROUND: Persistent pain after breast cancer surgery (PPBCS) affects 25 - 60% of breast cancer survivors and damage to the intercostobrachial nerve (ICBN) has been implicated as the cause of this predominantly neuropathic pain. Local anesthetic blockade of the ICBN could provide clues...... determined the sonoanatomy of the ICBN and part 2 examined effects of the ultrasound-guided ICBN blockade in patients with PPBCS. SETTING: Section for Surgical Pathophysiology at Rigshospitalet, Copenhagen, Denmark. METHODS: Part 1: Sixteen unoperated, pain free breast cancer patients underwent systematic...

  1. Dynamical Coulomb blockade of the nonlocal conductance in normalmetal/superconductor hybrid structures

    Energy Technology Data Exchange (ETDEWEB)

    Kolenda, Stefan; Wolf, Michael J.; Beckmann, Detlef [Institut fuer Nanotechnologie, KIT, 76021 Karlsruhe (Germany)

    2013-07-01

    In normalmetal/superconductor hybrid structures nonlocal conductance is determined by crossed Andreev reflection (CAR) and elastic cotunneling (EC). This was investigated recently both experimentally and theoretically. Dynamical Coulomb blockade of EC and CAR was predicted theoretically. Here we report on experimental investigations of these effects. We found signatures of dynamical Coulomb blockade in local and nonlocal conductance in the normal state. In the superconducting state, we find s-shaped nonlocal differential conductance curves as a function of bias applied on both contacts. These curves were observed for bias voltages both below and above the gap. We compare our results to theory.

  2. The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy

    DEFF Research Database (Denmark)

    Nielsen, Stine; Rossing, Kasper; Hess, Georg;

    2012-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid-binding p......Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid...

  3. Cooperative Lifting of Spin Blockade in a Three-Terminal Triple Quantum Dot

    OpenAIRE

    Kobayashi, Takashi; Ota, Takeshi; Sasaki, Satoshi; Muraki, Koji

    2013-01-01

    We report measurements of multi-path transport through a triple quantum dot (TQD) in the few-electron regime using a GaAs three-terminal device with a separate lead attached to each dot. When two paths reside inside the transport window and are simultaneously spin-blockaded, the leak currents through both paths are significantly enhanced. We suggest that the transport processes in the two paths cooperate to lift the spin blockade. Fine structures in transport spectra indicate that different k...

  4. Continuous positive airway pressure breathing increases cranial spread of sensory blockade after cervicothoracic epidural injection of lidocaine.

    NARCIS (Netherlands)

    Visser, W.A.; Eerd, M.J. van; Seventer, R. van; Gielen, M.J.M.; Giele, J.L.P.; Scheffer, G.J.

    2007-01-01

    BACKGROUND: Continuous positive airway pressure (CPAP) increases the caudad spread of sensory blockade after low-thoracic epidural injection of lidocaine. We hypothesized that CPAP would increase cephalad spread of blockade after cervicothoracic epidural injection. METHODS: Twenty patients with an e

  5. The suprasacral parallel shift vs lumbar plexus blockade with ultrasound guidance in healthy volunteers - a randomised controlled trial

    DEFF Research Database (Denmark)

    Bendtsen, T F; Pedersen, E M; Haroutounian, S;

    2014-01-01

    Surgical anaesthesia with haemodynamic stability and opioid-free analgesia in fragile patients can theoretically be provided with lumbosacral plexus blockade. We compared a novel ultrasound-guided suprasacral technique for blockade of the lumbar plexus and the lumbosacral trunk with ultrasound......-guided blockade of the lumbar plexus. The objective was to investigate whether the suprasacral technique is equally effective for anaesthesia of the terminal lumbar plexus nerves compared with a lumbar plexus block, and more effective for anaesthesia of the lumbosacral trunk. Twenty volunteers were included...... in a randomised crossover trial comparing the new suprasacral with a lumbar plexus block. The primary outcome was sensory dermatome anaesthesia of L2-S1. Secondary outcomes were peri-neural analgesic spread estimated with magnetic resonance imaging, sensory blockade of dermatomes L2-S3, motor blockade, volunteer...

  6. GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade.

    Science.gov (United States)

    Gargett, Tessa; Yu, Wenbo; Dotti, Gianpietro; Yvon, Eric S; Christo, Susan N; Hayball, John D; Lewis, Ian D; Brenner, Malcolm K; Brown, Michael P

    2016-06-01

    Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.

  7. GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade.

    Science.gov (United States)

    Gargett, Tessa; Yu, Wenbo; Dotti, Gianpietro; Yvon, Eric S; Christo, Susan N; Hayball, John D; Lewis, Ian D; Brenner, Malcolm K; Brown, Michael P

    2016-06-01

    Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients. PMID:27019998

  8. Blockade of Mast Cell Activation Reduces Cutaneous Scar Formation

    OpenAIRE

    Lin Chen; Megan E Schrementi; Ranzer, Matthew J.; Wilgus, Traci A.; Luisa A DiPietro

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally...

  9. THE EFFECTS OF ALPHA-ADRENOCEPTOR BLOCKADE ON DOPAMINE-INDUCED RENAL VASODILATION AND NATRIURESIS

    NARCIS (Netherlands)

    SMIT, AJ; MEIJER, S; WESSELING, H; DONKER, AJM; REITSMA, WD

    1991-01-01

    To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pre-treatment with the selective postsynaptic alpha-1-adrenoceptor antagonist prazosin in normal volunteers an

  10. Reversal of profound neuromuscular blockade with sugammadex in an infant after bronchial foreign body removal.

    Science.gov (United States)

    Azizoglu, Mustafa; Birbicer, Handan; Memis, Suleyman; Taşkınlar, Hakan

    2016-09-01

    Sugammadex is a selective chemical agent that can reverse neuromuscular blockade induced by vecuronium and rocuronium. The aim of this report is to discuss the effectiveness of sugammadex in the reversal of neuromuscular blockade in children younger than 2 years. A 16-month-old boy, weighing 10 kg, was admitted to the pediatric emergency department due to choking, cyanosis, and severe respiratory distress that occurred while he was eating peanuts. In the emergency department, the patient's condition deteriorated, and he went into respiratory arrest. He was immediately intubated and taken to the operating room. A rigid bronchoscopy was performed under general anesthesia, with administration of intravenous pentothal (5 mg/kg), rocuronium (0.6 mg/kg), and fentanyl (0.5 μg/kg) in the operating room. The foreign body was removed within 6 minutes, and the profound neuromuscular blockade was reversed with a dose of 2 mg/kg sugammadex. He was extubated successfully after obtaining the spontaneous respiratory activity, and adequate breathing was restored. Clinical use of sugammadex in children younger than 2 years is not recommended because of the lack of clinical studies. In this case report, the profound neuromuscular blockade was successfully reversed with a dose of 2 mg/kg sugammadex in a 16-month-old boy. However, more prospective clinical studies are required for the safe use of this agent in children. PMID:27555184

  11. The efficacy of adductor canal blockade after minor arthroscopic knee surgery

    DEFF Research Database (Denmark)

    Espelund, M; Fomsgaard, J S; Haraszuk, J;

    2014-01-01

    BACKGROUND: Adductor canal blockade (ACB) has been demonstrated to be effective in the treatment of post-operative pain after major knee surgery. We hypothesised that the ACB would reduce pain and analgesic requirements after minor arthroscopic knee surgery. METHODS: Seventy-two patients schedule...

  12. The effect of neuromuscular blockade on canine laparoscopic ovariectomy: A double-blinded, prospective clinical trial

    NARCIS (Netherlands)

    van Goethem, B.; van Nimwegen, S.A.; Akkerdaas, L.C.; Murrell, J.C.; Kirpensteijn, J.

    2012-01-01

    The Effect of Neuromuscular Blockade on Canine Laparoscopic Ovariectomy: A Double-Blinded, Prospective Clinical Trial Bart Van Goethem, Diplomate ECVS, Sebastiaan Alexander van Nimwegen, PhD, Ies Akkerdaas, DVM, Joanna Claire Murrell, BVSc., PhD, Diplomate ECVAA, and Jolle Kirpensteijn, PhD, Diploma

  13. Improvement of Sodium Status to Optimize the Efficacy of Renin-Angiotensin System Blockade

    NARCIS (Netherlands)

    Laverman, Gozewijn D.; Navis, Gerjan

    2011-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) offers superior renoprotection in the treatment of patients with hypertension, but the efficacy of RAAS inhibition strongly depends on sodium status, presumably in relation to extracellular volume status. Because assessing volume status by

  14. Effect of axillary blockade on regional cerebral blood flow during static handgrip

    DEFF Research Database (Denmark)

    Friedman, D B; Friberg, L; Mitchell, J H;

    1991-01-01

    Regional cerebral blood flow (rCBF) was determined at rest and during static handgrip before and after regional blockade with lidocaine. A fast rotating single photon emission computer tomograph system with 133Xe inhalation was used at orbitomeatal plane (OM) +2.5 and +6.5 cm in eight subjects. M...

  15. Pumping of Vibrational Excitations in the Coulomb-Blockade Regime in a Suspended Carbon Nanotube

    NARCIS (Netherlands)

    Hüttel, A.K.; Witkamp, B.; Leijnse, M.; Wegewijs, M.R.; Van der Zant, H.S.J.

    2009-01-01

    Low-temperature transport spectroscopy measurements on a suspended few-hole carbon nanotube quantum dot are presented, showing a gate-dependent harmonic excitation spectrum which, strikingly, occurs in the Coulomb-blockade regime. The quantized excitation energy corresponds to the scale expected for

  16. Oxidative Stress Modulates DNA Methylation during Melanocyte Anchorage Blockade Associated with Malignant Transformation

    Directory of Open Access Journals (Sweden)

    Ana C.E. Campos

    2007-12-01

    Full Text Available Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenic melanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hey, an element in the methionine (universal methyl donor cycle. This alteration was accompanied by increase in glutathione (GSH levels and methylated DNA content. Furthermore, a significant increase in dnmti and 3b expression was identified along melan-a anchorage blockade. LG-Nitro-L-arginine methyl esther (L-NAME, known as a nitric oxide synthase (NOS inhibitor, and N-acetyl-L-cysteine (NAC prevented the increase in global DNA methylation, as well as the increase in dnmti and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.

  17. Gender differences in the long QT syndrome: Effects of β-adrenoceptor blockade

    NARCIS (Netherlands)

    Conrath, Chantal E; Wilde, Arthur A.M; Jongbloed, Rosalie J.E; Alders, Mariëlle; Van Langen, Irene M; Peter Van Tintelen, J.; Doevendans, Pieter A; Opthof, Tobias

    2002-01-01

    Background: Gender differences have been reported in patients with the congenital long QT syndrome (LQTS). We analyzed whether electrocardiographic differences existed in females, males, girls and boys in response to β-adrenoceptor blockade. Methods: 12-lead ECGs before and during β-adrenoceptor blo

  18. Sinus node function after autonomic blockade in normals and in sick sinus syndrome.

    Science.gov (United States)

    Sethi, K K; Jaishankar, S; Balachander, J; Bahl, V K; Gupta, M P

    1984-06-01

    Electrophysiologic studies were performed in 10 normals and 33 patients with sick sinus syndrome before and after total autonomic blockade with propranolol and atropine. In normals both corrected sinus node recovery time (SNRT) and sinoatrial conduction time (SACT) decreased significantly after autonomic blockade. In patients with sick sinus syndrome the corrected SNRT was abnormal (greater than 450 msec) in 16 (48.5%) cases before and 25 (76%) cases (greater than 285 msec) after autonomic ablation (P less than 0.02). Thirteen of 21 patients (62%) with normal intrinsic heart rate and all 12 cases with abnormally low intrinsic rate after autonomic blockade had abnormal corrected SNRT (greater than 285 msec). Mean SACT measured in 19 patients also shortened significantly following pharmacologic denervation. During control it was prolonged (greater than 226 msec) in 8 patients (44%). After autonomic blockade 2 of 13 patients with normal intrinsic heart rate and 3 of 6 with low intrinsic rate showed abnormal SACT (greater than 151 msec). The data suggest that the majority (76%) of patients with sick sinus syndrome have intrinsic abnormality of sinus node automaticity while in a minority (24%) disturbed autonomic regulation is the pathogenetic mechanism. Patients with normal intrinsic heart rate usually have normal intrinsic SACT, while a significant proportion of those with low intrinsic rate have abnormal perinodal conduction. Subjects with abnormal intrinsic heart rate have more severe disturbances of sinus node function than those with normal intrinsic rate.

  19. Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response

    Directory of Open Access Journals (Sweden)

    Jennifer M. Rojas

    2015-08-01

    Conclusions: The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

  20. CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial

    NARCIS (Netherlands)

    A.W.R. van Kuijk; C.E. Vergunst; D.M. Gerlag; B. Bresnihan; J.J. Gomez-Reino; R. Regine; P.C. Verschueren; C. van der Leij; M. Maas; M.C. Kraan; P.P. Tak

    2010-01-01

    Objective C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects o

  1. Fascia iliaca compartment blockade for acute pain control in hip fracture patients

    DEFF Research Database (Denmark)

    Foss, Nicolai B; Kristensen, Billy B; Bundgaard, Morten;

    2007-01-01

    Hip fracture patients are in severe pain upon arrival at the emergency department. Pain treatment is traditionally based on systemic opioids. No study has examined the effect of fascia iliaca compartment blockade (FICB) in acute hip fracture pain management within a double-blind, randomized setup....

  2. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G

    2012-02-01

    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  3. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G

    2010-07-01

    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  4. Optimized surgical space during low-pressure laparoscopy with deep neuromuscular blockade

    DEFF Research Database (Denmark)

    Staehr-Rye, Anne K; Rasmussen, Lars S; Rosenberg, Jacob;

    2013-01-01

    Laparoscopic cholecystectomy (LC) can be performed using low intra-abdominal pressure (space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mm......Hg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions....

  5. Photon Routing in Cavity QED: Beyond the Fundamental Limit of Photon Blockade

    CERN Document Server

    Rosenblum, Serge; Dayan, Barak

    2011-01-01

    The most simple and seemingly straightforward application of the photon blockade effect, in which the transport of one photon prevents the transport of others, would be to separate two incoming indistinguishable photons to different output ports. We show that time-energy uncertainty relations inherently prevent this ideal situation when the blockade is implemented by a two-level system. The fundamental nature of this limit is revealed in the fact that photon blockade in the strong coupling regime of cavity QED, resulting from the nonlinearity of the Jaynes-Cummings energy level structure, exhibits efficiency and temporal behavior identical to those of photon blockade in the bad cavity regime, where the underlying nonlinearity is that of the atom itself. We demonstrate that this limit can be exceeded, yet not avoided, by exploiting time-energy entanglement between the incident photons. Finally, we show how this limit can be circumvented completely by using a three-level atom coupled to a single-sided cavity, e...

  6. Photon routing in cavity QED: Beyond the fundamental limit of photon blockade

    Energy Technology Data Exchange (ETDEWEB)

    Rosenblum, Serge; Dayan, Barak [Department of Chemical Physics, Weizmann Institute of Science, Rehovot 76100 (Israel); Parkins, Scott [Department of Physics, University of Auckland, Private Bag 92019, Auckland (New Zealand)

    2011-09-15

    The most simple and seemingly straightforward application of the photon blockade effect, in which the transport of one photon prevents the transport of others, would be to separate two incoming indistinguishable photons to different output ports. We show that time-energy uncertainty relations inherently prevent this ideal situation when the blockade is implemented by a two-level system. The fundamental nature of this limit is revealed in the fact that photon blockade in the strong coupling regime of cavity QED, resulting from the nonlinearity of the Jaynes-Cummings energy level structure, exhibits efficiency and temporal behavior identical to those of photon blockade in the bad cavity regime, where the underlying nonlinearity is that of the atom itself. We demonstrate that this limit can be exceeded, yet not avoided, by exploiting time-energy entanglement between the incident photons. Finally, we show how this limit can be circumvented completely by using a three-level atom coupled to a single-sided cavity, enabling an ideal and robust photon routing mechanism.

  7. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    International Nuclear Information System (INIS)

    Highlights: → Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. → Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. → VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. → LPA-LPAR1/3 signaling regulated TGFβ1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. → LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGFβ1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the

  8. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Lu [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Xue, Jian-Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu (China); Li, Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Liu, De-Song [Department of Pediatrics, Sichuan Provincial Hospital of Women and Children, Chengdu (China); Ge, Yan; Ni, Pei-Yan; Deng, Lin [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Lu, You, E-mail: radyoulu@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Jiang, Wei, E-mail: wcumsjw72@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu (China)

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  9. Analgesic efficacy of the ultrasound-guided blockade of the transversus abdominis plane - a systematic review

    Directory of Open Access Journals (Sweden)

    Javier Ripollés

    2015-08-01

    Full Text Available BACKGROUND: The transverse abdominal plan blockade is a block of abdominal wall that has diffused rapidly in the clinical practice as part of a multimodal analgesia for abdominal surgery. The performance of the ultrasound-guided technique has allowed the lowering of potential complications, as well as new approaches that were carried out according to the descriptions, and the prospective studies would make it possible to utilize the transverse abdominal plan blockade in different surgical interventions; however, the results obtained in randomized clinical trials are inconsistent.OBJECTIVES: To prepare a systematic review aiming to determine the efficacy of the ultrasound-guided transverse abdominal plan blockade for different surgical interventions, as well as the indications according to the approaches and their influences.METHODS: Two research approaches, one manual, and the other in Pubmed returned 28 randomized clinical trials where intervention with ultrasound-guided transverse abdominal plan blockades was performed to compare the analgesic efficacy in contrast to another technique in adults, published between 2007 and October 2013, in English or Spanish, with Jadad score > 1, according to the inclusion criteria for this review. The authors analyzed independently all the randomized clinical trials.CONCLUSIONS: The transverse abdominal plan blockades have been shown to be an effective technique in colorectal surgery, cesarean section, cholecystectomy, hysterectomy, appendectomy, donor nephrectomy, retropubic prostatectomy, and bariatric surgery. However, the data found in randomized clinical trial are not conclusive, and as a result, it is necessary to develop new and well designed randomized clinical trial, with enough statistical power to compare different approaches, drugs, doses, and volumes for the same intervention, aiming to answer the current questions and their effects in the habitual clinical practice.

  10. Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Chen, Cheng-Lung; Liao, Jiunn-Wang; Hu, Oliver Yoa-Pu; Pao, Li-Heng

    2016-09-01

    Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI. PMID:26438401

  11. Metazoan promoters

    DEFF Research Database (Denmark)

    Lenhard, Boris; Sandelin, Albin Gustav; Carninci, Piero

    2012-01-01

    and their features, helping researchers who are investigating functional categories of promoters and their modes of regulation. Additional features of promoters that are being characterized include types of histone modifications, nucleosome positioning, RNA polymerase pausing and novel small RNAs. In this Review, we...

  12. Study of Rydberg blockade mediated optical non-linearity in thermal vapor using optical heterodyne detection technique

    CERN Document Server

    Bhowmick, Arup; Mohapatra, Ashok K

    2016-01-01

    We demonstrate the phenomenon of blockade in two-photon excitations to the Rydberg state in thermal vapor. A technique based on optical heterodyne is used to measure the dispersion of a probe beam far off resonant to the D2 line of rubidium in the presence of a strong laser beam that couples to the Rydberg state via two-photon resonance. Density dependent suppression of the dispersion peak is observed while coupling to the Rydberg state with principal quantum number, n = 60. The experimental observation is explained using the phenomenon of Rydberg blockade. The blockade radius is measured to be about 2.2 {\\mu}m which is consistent with the scaling due to the Doppler width of 2-photon resonance in thermal vapor. Our result promises the realization of single photon source and strong single photon non-linearity based on Rydberg blockade in thermal vapor.

  13. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

    Science.gov (United States)

    Dubin, Krista; Callahan, Margaret K; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G; Wolchok, Jedd D

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  14. Influence of pudendal nerve blockade on stress relaxation in the female urethra

    DEFF Research Database (Denmark)

    Thind, P; Bagi, P; Mieszczak, C;

    1996-01-01

    The urethral pressure decay following a sudden and sustained dilatation corresponds to stress relaxation. Urethral stress relaxation can be described by the equation Pt = Pequ + P alpha e-t/tau alpha + P beta e-t/tau beta, where Pt is the pressure at time t, Pequ is the equilibrium pressure after...... dilatation, P alpha and P beta are pressure decay, and tau alpha and tau beta are time constants. The time constants have previously proved independent of the way the dilatation is performed. The urethral stress relaxation obtained in 10 healthy women before and after pudendal nerve blockade was analysed...... by the mathematical model and the pressure parameters and time constants determined. The fast time constant, tau beta, was reduced by the nerve blockade, whereas tau alpha was unaffected, however, both P alpha and P beta were reduced. No single stress relaxation parameter can therefore be related to the muscle...

  15. Rydberg-Blockade Effects in Autler-Townes Spectra of Ultracold Strontium

    CERN Document Server

    DeSalvo, B J; Gaul, C; Pohl, T; Yoshida, S; Burgdörfer, J; Hazzard, K R A; Dunning, F B; Killian, T C

    2015-01-01

    We present a combined experimental and theoretical study of the effects of Rydberg interactions on Autler-Townes spectra of ultracold gases of atomic strontium. Realizing two-photon Rydberg excitation via a long-lived triplet state allows us to probe the thus far unexplored regime where Rydberg state decay presents the dominant decoherence mechanism. The effects of Rydberg interactions are observed in shifts, asymmetries, and broadening of the measured atom-loss spectra. The experiment is analyzed within a one-body density matrix approach, accounting for interaction-induced level shifts and dephasing through nonlinear terms that approximately incorporate correlations due to the Rydberg blockade. This description yields good agreement with our experimental observations for short excitation times. For longer excitation times, the loss spectrum is altered qualitatively, suggesting additional dephasing mechanisms beyond the standard blockade mechanism based on pure van der Waals interactions.

  16. Phonon blockade in a nanomechanical resonator resonantly coupled to a qubit

    CERN Document Server

    Xu, Xun-Wei; Liu, Yu-xi

    2016-01-01

    We study phonon statistics in a nanomechanical resonator (NAMR) which is resonantly coupled to a qubit. We find that there are two different mechanisms for phonon blockade in such a resonantly coupled NAMR-qubit system. One is due to the strong anharmonicity of the NAMR-qubit system with large coupling strength; the other one is due to the destructive interference between different paths for two-phonon excitation in the NAMR-qubit system with a moderate coupling strength. In order to enlarge the mean phonon number for strong phonon antibunching with a moderate NAMR-qubit coupling strength, we assume that two external driving fields are applied to the NAMR and qubit, respectively. In this case, we find that the phonon blockades under two mechanisms can appear at the same frequency regime by optimizing the strength ratio and phase difference of the two external driving fields.

  17. Quantum transport through a Coulomb blockaded quantum emitter coupled to a plasmonic dimer.

    Science.gov (United States)

    Goker, A; Aksu, H

    2016-01-21

    We study the electron transmission through a Coulomb blockaded quantum emitter coupled to metal nanoparticles possessing plasmon resonances by employing the time-dependent non-crossing approximation. We find that the coupling of the nanoparticle plasmons with the excitons results in a significant enhancement of the conductance through the discrete state with higher energy beyond the unitarity limit while the other discrete state with lower energy remains Coulomb blockaded. We show that boosting the plasmon-exciton coupling well below the Kondo temperature increases the enhancement adding another quantum of counductance upon saturation. Finite bias and increasing emitter resonance energy tend to reduce this enhancement. We attribute these observations to the opening of an additional transport channel via the plasmon-exciton coupling. PMID:26686761

  18. Split-dose atropine versus glycopyrrolate with neostigmine for reversal of gallamine-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Wetterslev, J; Jarnvig, I; Jørgensen, L N;

    1991-01-01

    The effects of a split-dose of atropine sulphate versus a single dose of glycopyrrolate given with neostigmine for the reversal of gallamine-induced neuromuscular blockade were studied in 55 patients undergoing gynaecological surgery. The patients were randomized to receive either a single dose of......, whereas none occurred in the glycopyrrolate group (P less than 0.05). It is concluded that a split-dose of atropine has similar chronotropic effects to a single dose of glycopyrrolate for the reversal of gallamine-induced neuromuscular blockade. However, the finding of a higher incidence of cardiac...... arrhythmias in the atropine group suggests that this reversal regime should be reserved for patients without cardiac disease....

  19. Photon-blockade as protection in photosynthesis Antenna with cyclic structures

    CERN Document Server

    Dong, Hui; Yi, Zhenhuan; Agarwal, Girish S; Scully, Marlan O

    2016-01-01

    Excess energy absorbed by the light-harvesting antennas could be potentially harmful to the photosynthesis complexes. The biological system has developed various mechanisms, e.g. non-photon chemical quenching, to prevent these damages by dissipating energy into the surrounding environment. In additional to this well-known mechanism, we hypothesise a new protection mechanism of suppressing the probability of double excitation in photosynthesis system, where pigment-protein complexes form cyclic structures with dipole-dipole interaction between adjacent chlorophylls. We also demonstrate robustness of the photon blockade against the disorder in the ring structures. The photon blockade can explain the recent observation on the suppression of simultaneous emission of two photons in natural photosynthetic antennas.

  20. Intrathecal amantadine for prolonged spinal blockade of sensory and motor functions in rats.

    Science.gov (United States)

    Tzeng, Jann-Inn; Kan, Chung-Dann; Wang, Jieh-Neng; Wang, Jhi-Joung; Lin, Heng-Teng; Hung, Ching-Hsia

    2016-08-01

    We aimed to compare the hypothesized local anesthetic action of amantadine (1-adamantanamine) with that of the known local anesthetic mepivacaine. Motor, proprioceptive, and nociceptive functions were evaluated in rats after intrathecal administration. Amantadine elicited spinal anesthesia in a dose-related fashion and produced a better sensory-selective action over motor blockade (P proprioceptive, and nociceptive block was mepivacaine > amantadine (P proprioception, and nociception. On an equipotent basis (ED25 , ED50 , and ED75 ), the duration of amantadine was longer (P proprioceptive, and nociceptive block. Our preclinical data demonstrated that amantadine was less potent than mepivacaine at producing spinal anesthesia. The spinal block duration produced by amantadine was greater than that produced by mepivacaine. Both amantadine and mepivacaine produced a markedly nociceptive-specific blockade. PMID:27011292

  1. Robust and High Fidelity Quantum Logic with the Rydberg-Dressed Blockade

    Science.gov (United States)

    Keating, Tyler; Cook, Robert; Deutsch, Ivan; Hankin, Aaron; Jau, Yuan-Yu; Biedermann, Grant

    2015-05-01

    We study a scheme for implementing a controlled-Z (CZ) gate between two neutral-atom qubits based on the Rydberg blockade mechanism in a manner that is robust to errors caused by atomic motion. By adiabatically dressing the ground electronic state, we can protect the gate from decoherence due to random phase errors that typically arise from atomic thermal motion. The adiabatic protocol also allows for a Doppler-free configuration with counterpropagating lasers in a σ+ /σ- orthogonal polarization geometry that further reduces motional errors due to Doppler shifts. The residual error is dominated by dipole-dipole forces acting on doubly-excited Rydberg atoms when the blockade is imperfect. For reasonable parameters, with qubits encoded into the clock states of 133Cs, we predict that our protocol could produce a CZ gate in logic.

  2. Combined androgen blockade in the treatment of advanced prostate cancer--an overview. The Scandinavian Prostatic Cancer Group

    DEFF Research Database (Denmark)

    Iversen, P

    1997-01-01

    The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed.......The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed....

  3. Magnetic Blockade Mechanism for Quantum Nucleation of Superconducting Vortex-Antivortex Pairs in Zero External Magnetic Field

    OpenAIRE

    Miller Jr, J. H.; Wijesinghe, A. I.

    2011-01-01

    We propose a magnetic dual of the Coulomb blockade effect for quantum nucleation of flux vortex pairs in high-Tc superconducting (HTS) films and grain boundaries in zero applied field. The magnetic blockade instability occurs at {\\theta} = {\\pi}, where {\\theta} is the "vacuum" or theta angle. The {\\theta} term has recently been discussed in the context of several other systems, including charge and spin density waves, topological insulators, the quantum Hall effect, and spontaneous CP violati...

  4. MFN Status, Trade Embargoes, Sanctions and Blockades: An Examination of Some Overlooked Property, Contract and Other Human Rights Issues

    OpenAIRE

    Robert W. McGee

    1998-01-01

    Most Favored Nation (MFN) status, trade embargoes and blockades have traditionally been used to entice nations to alter their behavior or to punish them for certain behavior. The intentions behind these policies are generally noble, at least on the surface. However, instituting these policies has side-effects. For example, FDR's blockade of raw materials against the Japanese in Manchuria in the 1930s arguably led to the bombing of Pearl Harbor, which got the United States involved in World Wa...

  5. PD-1/PD-L1 blockades in non-small-cell lung cancer therapy

    Directory of Open Access Journals (Sweden)

    Jing W

    2016-01-01

    Full Text Available Wang Jing,1,2,* Miaomiao Li,3,* Yan Zhang,2 Feifei Teng,2 Anqin Han,2 Li Kong,2 Hui Zhu2 1Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People’s Republic of China; 3Shandong Medical College, Jinan, Shandong Province, People’s Republic of China *Both these authors contributed equally to the work Abstract: Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1 receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy, and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients. Keywords: immunotherapy, checkpoint, PD-1, PD-L1, NSCLC

  6. Coulomb blockade in monolayer MoS2 single electron transistor

    Science.gov (United States)

    Lee, Kyunghoon; Kulkarni, Girish; Zhong, Zhaohui

    2016-03-01

    Substantial effort has been dedicated to understand the intrinsic electronic properties of molybdenum disulfide (MoS2). However, electron transport study on monolayer MoS2 has been challenging to date, especially at low temperatures due to large metal/semiconductor junction barriers. Herein, we report the fabrication and characterization of the monolayer MoS2 single-electron transistor. High performance devices are obtained through the use of low work function metal (zinc) contact and a rapid thermal annealing step. Coulomb blockade is observed at low temperatures and is attributed to single-electron tunneling via two tunnel junction barriers. The nature of Coulomb blockade is also investigated by temperature-dependent conductance oscillation measurement. Our results hold promise for the study of novel quantum transport phenomena in 2D semiconducting atomic layer crystals.Substantial effort has been dedicated to understand the intrinsic electronic properties of molybdenum disulfide (MoS2). However, electron transport study on monolayer MoS2 has been challenging to date, especially at low temperatures due to large metal/semiconductor junction barriers. Herein, we report the fabrication and characterization of the monolayer MoS2 single-electron transistor. High performance devices are obtained through the use of low work function metal (zinc) contact and a rapid thermal annealing step. Coulomb blockade is observed at low temperatures and is attributed to single-electron tunneling via two tunnel junction barriers. The nature of Coulomb blockade is also investigated by temperature-dependent conductance oscillation measurement. Our results hold promise for the study of novel quantum transport phenomena in 2D semiconducting atomic layer crystals. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08954a

  7. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis

    OpenAIRE

    Dubin, Krista; Callahan, Margaret K.; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G.; Wolchok, Jedd D.

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-med...

  8. Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma

    OpenAIRE

    J. Hu; Dong, A.; Fernandez-Ruiz, V. (Verónica); Shan, J.; Kawa, M. (Milosz); Martinez-Anso, E. (Eduardo); J. Prieto; Qian, C

    2009-01-01

    Aberrant activation of Wnt signaling plays an important role in hepatocarcinogenesis. In addition to direct effects on tumor cells, Wnt signaling might be involved in the organization of tumor microenvironment. In this study, we have explored whether Wnt signaling blockade by exogenous expression of Wnt antagonists could inhibit tumor angiogenesis and control tumor growth. Human Wnt inhibitory factor 1 (WIF1) and secreted frizzled-related protein 1 (sFRP1) were each fused with Fc fragment of ...

  9. Cardioprotection conferred by exercise training is blunted by blockade of the opioid system

    OpenAIRE

    Tatiana F.G. Galvão; Matos, Katt C; Brum, Patrícia C; Negrão, Carlos E.; Protásio Lemos da Luz; Chagas, Antônio Carlos P

    2011-01-01

    OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reper...

  10. Quantized current blockade and hydrodynamic correlations in biopolymer translocation through nanopores: evidence from multiscale simulations

    CERN Document Server

    Bernaschi, Massimo; Succi, Sauro; Fyta, Maria; Kaxiras, Efthimios

    2008-01-01

    We present a detailed description of biopolymer translocation through a nanopore in the presence of a solvent, using an innovative multi-scale methodology which treats the biopolymer at the microscopic scale as combined with a self-consistent mesoscopic description for the solvent fluid dynamics. We report evidence for quantized current blockade depending on the folding configuration and offer detailed information on the role of hydrodynamic correlations in speeding-up the translocation process.

  11. Universal Correlations of Coulomb Blockade Conductance Peaks and the Rotation Scaling in Quantum Dots

    OpenAIRE

    Alhassid, Y.; Attias, H.

    1996-01-01

    We show that the parametric correlations of the conductance peak amplitudes of a chaotic or weakly disordered quantum dot in the Coulomb blockade regime become universal upon an appropriate scaling of the parameter. We compute the universal forms of this correlator for both cases of conserved and broken time reversal symmetry. For a symmetric dot the correlator is independent of the details in each lead such as the number of channels and their correlation. We derive a new scaling, which we ca...

  12. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade

    OpenAIRE

    Huang, Jianzhong; Bae, Jae-O; Tsai, Judy P.; Kadenhe-Chiweshe, Angela; Papa, Joey; Lee, Alice; Zeng, Shan; Kornfeld, Z. Noah; Ullner, Paivi; Zaghloul, Nibal; Ioffe, Ella; Nandor, Sarah; Burova, Elena; Holash, Jocelyn; Thurston, Gavin

    2009-01-01

    Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signali...

  13. Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice

    OpenAIRE

    John Martin Barrett; Patrick Degenaar

    2015-01-01

    Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was ...

  14. The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

    OpenAIRE

    Eszter D Schoell; Ulrike Bingel; Falk Eippert; Juliana Yacubian; Kerrin Christiansen; Hilke Andresen; Arne May; Christian Buechel

    2010-01-01

    The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore...

  15. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  16. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.

    Directory of Open Access Journals (Sweden)

    Edward Seung

    Full Text Available An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012, with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8(+ T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8(+ T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.

  17. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

    OpenAIRE

    DiStefano, Youmna E.; Lazar, Michael D.

    2015-01-01

    Peripheral nerve blockade (PNB) is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR). Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD). Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year...

  18. BLOCKADE OF CENTRAL NICOTINE ACETYLCHOLINE RECEPTOR SIGNALING ATTENUATE GHRELIN-INDUCED FOOD INTAKE IN RODENTS

    OpenAIRE

    S.L. Dickson; Hrabovszky, E; Hansson, C.; Jerlhag, E.; Alvarez-Crespo, M.; Skibicka, K. P.; Molnar, C. S.; Liposits, Z; Engel, J. A.; Egecioglu, E.

    2010-01-01

    Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotinic cholinergic receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sou...

  19. Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock.

    Science.gov (United States)

    DeLano, Frank A; Schmid-Schönbein, Geert W

    2014-01-01

    Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance, but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 h) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution), and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat without enzyme blockade had significantly attenuated levels of insulin receptor density as compared with control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine led to a lesser decrease in insulin receptor density compared with controls without protease blockade. Glucose tolerance test indicates a significant increase in plasma glucose levels 2 h after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in

  20. Intralipid Therapy for Inadvertent Peripheral Nervous System Blockade Resulting from Local Anesthetic Overdose

    OpenAIRE

    Ihab Kamel; Gaurav Trehan; Rodger Barnette

    2015-01-01

    Although local anesthetics have an acceptable safety profile, significant morbidity and mortality have been associated with their use. Inadvertent intravascular injection of local anesthetics and/or the use of excessive doses have been the most frequent causes of local anesthetic systemic toxicity (LAST). Furthermore, excessive doses of local anesthetics injected locally into the tissues may lead to inadvertent peripheral nerve infiltration and blockade. Successful treatment of LAST with intr...

  1. Blockade of Ethanol Reward by the Kappa Opioid Receptor Agonist U50,488h

    OpenAIRE

    Logrip, Marian L.; Janak, Patricia H; Ron, Dorit

    2009-01-01

    Alcoholism is a pervasive social problem, and thus understanding factors which regulate alcohol (ethanol) reward is important for designing effective therapies. One putative regulatory system includes the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin. Previously we demonstrated that acute ethanol increased preprodynorphin expression via brain-derived neurotrophic factor (BDNF) in striatal neurons, and that blockade of the KOR attenuated decreases in ethanol intake observed ...

  2. Van der Waals Interactions and Dipole Blockade in a Cold Rydberg Gas Probed by Microwave Spectroscopy

    Science.gov (United States)

    Nguyen, Thanh Long; Celistrino Teixeira, Raul; Hermann Avigliano, Carla; Cantat Moltrecht, Tigrane; Raimond, Jean Michel; Haroche, Serge; Gleyzes, Sebastiens; Brune, Michel

    2016-05-01

    Dipole-dipole interactions between Rydberg atoms are a flourishing tool for quantum information processing and for quantum simulation of complex many-body problems. Microwave spectroscopy of a dense Rydberg gas trapped close to a superconducting atom chip in the strong dipole blockade regime reveals directly the many-body atomic interaction spectrum. We present here a direct measurement of the interaction energy distribution in the strong dipole blockade regime, based on microwave spectroscopy. We first apply this method to the observation of the excitation dynamics of the Rydberg gas, conditioned by dipole-dipole interactions, in either the strong blockade regime or the so-called facilitation regime. We also observe with this method the atomic cloud expansion driven by the repulsive Van der Waals interaction after excitation. This measurement, in good agreement with Monte Carlo simulations of the excitation process and of the cloud dynamics, reveals the limits of the frozen gas approximation. This method can help investigate self-organization and dynamical phase transitions in Rydberg-atom based quantum simulators. This study thus opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atom.

  3. Investigation of Prolactin Receptor Activation and Blockade Using Time-Resolved Fluorescence Resonance Energy Transfer

    Directory of Open Access Journals (Sweden)

    Estelle eTallet

    2011-09-01

    Full Text Available The prolactin receptor (PRLR is emerging as a therapeutic target in oncology. Knowledge-based drug design led to the development of a pure PRLR antagonist (Del1-9-G129R-hPRL that was recently shown to prevent PRL-induced mouse prostate tumorogenesis. In humans, the first gain-of-function mutation of the PRLR (PRLRI146L was recently identified in breast tumor patients. At the molecular level, the actual mechanism of action of these two novel players in the PRL system remains elusive. In this study, we addressed whether constitutive PRLR activation (PRLRI146L or PRLR blockade (antagonist involved alteration of receptor oligomerization and/or of inter-chain distances compared to unstimulated and PRL-stimulated PRLR. Using a combination of various biochemical and spectroscopic approaches (co-IP, blue-native electrophoresis, BRET1, we demonstrated that preformed PRLR homodimers are altered neither by PRL- or I146L-induced receptor triggering, nor by antagonist-mediated blockade. These findings were confirmed using a novel time-resolved fluorescence resonance energy transfer (TR-FRET technology that allows monitoring distance changes between cell-surface tagged receptors. This technology revealed that PRLR blockade or activation did not involve detectable distance changes between extracellular domains of receptor chains within the dimer. This study merges with our previous structural investigations suggesting that the mechanism of PRLR activation solely involves intermolecular contact adaptations leading to subtle intramolecular rearrangements.

  4. System identification of closed-loop cardiovascular control: effects of posture and autonomic blockade

    Science.gov (United States)

    Mullen, T. J.; Appel, M. L.; Mukkamala, R.; Mathias, J. M.; Cohen, R. J.

    1997-01-01

    We applied system identification to the analysis of fluctuations in heart rate (HR), arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize quantitatively the physiological mechanisms responsible for the couplings between these variables. We characterized two autonomically mediated coupling mechanisms [the heart rate baroreflex (HR baroreflex) and respiratory sinus arrhythmia (ILV-HR)] and two mechanically mediated coupling mechanisms [the blood pressure wavelet generated with each cardiac contraction (circulatory mechanics) and the direct mechanical effects of respiration on blood pressure (ILV-->ABP)]. We evaluated the method in humans studied in the supine and standing postures under control conditions and under conditions of beta-sympathetic and parasympathetic pharmacological blockades. Combined beta-sympathetic and parasympathetic blockade abolished the autonomically mediated couplings while preserving the mechanically mediated coupling. Selective autonomic blockade and postural changes also altered the couplings in a manner consistent with known physiological mechanisms. System identification is an "inverse-modeling" technique that provides a means for creating a closed-loop model of cardiovascular regulation for an individual subject without altering the underlying physiological control mechanisms.

  5. Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Jianbo He

    2015-01-01

    Full Text Available Diabetic retinopathy (DR is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1 blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ treatment or Insulin2 gene mutation (Akita in mice. Protein expression and localization were examined by western blots (WB and immunofluorescence (IF. mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [3H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC adhesion (or retinal leukostasis, expression of intercellular adhesion molecule- (ICAM- 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO- 1, and the cell adhesion protein vascular endothelial (VE cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR.

  6. Blockade of the SNARE protein syntaxin 1 inhibits glioblastoma tumor growth.

    Directory of Open Access Journals (Sweden)

    Fausto Ulloa

    Full Text Available Glioblastoma (GBM is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1 function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM.

  7. Durable antitumor responses to CD47 blockade require adaptive immune stimulation.

    Science.gov (United States)

    Sockolosky, Jonathan T; Dougan, Michael; Ingram, Jessica R; Ho, Chia Chi M; Kauke, Monique J; Almo, Steven C; Ploegh, Hidde L; Garcia, K Christopher

    2016-05-10

    Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy. PMID:27091975

  8. INCIDENCE OF RESIDUAL NEUROMUSCULAR BLOCKADE AT TRACHEAL EXTUBATION: COMPARISON OF ATRACURIUM WITH VECURONIUM

    Directory of Open Access Journals (Sweden)

    Shwetha S

    2015-11-01

    Full Text Available BACKGROUND: Occurrence of undetected residual neuromuscular blockade is a common event in the post anaesthesia care unit. AIM: To compare the incidence and degree of residual neuromuscular blockade with the use of intermediate acting neuromuscular blocking agents Atracurium and Vecuronium. METHODS: 360 patients satisfying the inclusion and exclusion criteria were enrolled in the study and randomly allocated into one of the two study groups of 180 each to receive either Atracurium or Vecuronium intraoperatively. The anaesthesiologist blinded from the study extubated the patient based on the standard clinical criteria and the corresponding Train of Four(TOF ratios were noted by a blinded research assistant using a TOF watch (TOF- Watch® SX Organon, Ireland Ltd., Dublin, Ireland. Residual neuromuscular blockade was defined as a TOF ratio of 0.9 thirty minutes after tracheal extubation. CONCLUSION: We conclude from our study that significant post-operative residual curarization (TOF < 0.9 exists in majority of patients at the time of tracheal extubation (54.4% incidence despite the use of intermediate acting neuromuscular blocking drugs. The incidence and degree of post-operative residual curarization is significantly greater with Vecuronium compared to Atracurium. Thus we suggest that quantitative neuromuscular monitoring is required to assure complete neuromuscular recovery.

  9. Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males.

    Science.gov (United States)

    Doh, Hyung-Woo; Stebbins, Charles L; Choi, Hyun-Min; Park, Joonsung; Nho, Hosung; Kim, Jong-Kyung

    2016-06-01

    Histamine is a potent vasodilator that has been found to increase during exercise. We tested the hypothesis that histamine would attenuate blood pressure (BP), cardiac output (CO), and vascular resistance responses to short-term, submaximal dynamic exercise during H2 receptor blockade. Fourteen healthy men (20-29 years of age) were studied. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) BP and heart rate (HR) were assessed at rest and during the last minute of 10 min of submaximal cycling exercise (60% of peak oxygen consumption) in the absence and presence of histamine H2 receptor blockade (ranitidine, 300 mg). Stroke volume (SV) (impedance cardiography) and plasma norepinephrine (NE) were measured, and CO, rate × pressure product (RPP), and total peripheral resistance (TPR) were calculated. Plasma levels of histamine were also measured. H2 blockade had no effects on any variables at rest. During exercise, SBP (184 ± 3 mm Hg vs. 166 ± 2 mm Hg), MAP (121 ± 2 mm Hg vs. 112 ± 5 mm Hg), and RPP (25.9 ± 0.8 × 10(3) mm Hg·beats/min vs. 23.5 ± 0.8 × 10(3) mm Hg/beats·min) were greater during blocked conditions (P < 0.05), and an interaction was observed for TPR. SV, DBP, HR, and NE levels were unaffected by blockade. Plasma histamine increased from 1.83 ± 0.14 ng/mL at rest to 2.33 ± 0.23 ng/mL during exercise (P < 0.05) and was not affected by H2 blockade (1.56 ± 0.23 ng/mL vs. 1.70 ± 0.24 ng/mL). These findings suggest that, during submaximal exercise, histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and that these effects occurred primarily in the vasculature and not in the myocardium. PMID:27191340

  10. Promoting Models

    Science.gov (United States)

    Li, Qin; Zhao, Yongxin; Wu, Xiaofeng; Liu, Si

    There can be multitudinous models specifying aspects of the same system. Each model has a bias towards one aspect. These models often override in specific aspects though they have different expressions. A specification written in one model can be refined by introducing additional information from other models. The paper proposes a concept of promoting models which is a methodology to obtain refinements with support from cooperating models. It refines a primary model by integrating the information from a secondary model. The promotion principle is not merely an academic point, but also a reliable and robust engineering technique which can be used to develop software and hardware systems. It can also check the consistency between two specifications from different models. A case of modeling a simple online shopping system with the cooperation of the guarded design model and CSP model illustrates the practicability of the promotion principle.

  11. Health Promotion

    DEFF Research Database (Denmark)

    Povlsen, Lene; Borup, I.

    2015-01-01

    In 1953 when the Nordic School of Public Health was founded, the aim of public health programmes was disease prevention more than health promotion. This was not unusual, since at this time health usually was seen as the opposite of disease and illness. However, with the Ottawa Charter of 1986......, the World Health Organization made a crucial change to view health not as a goal in itself but as the means to a full life. In this way, health promotion became a first priority and fundamental action for the modern society. This insight eventually reached NHV and in 2002 - 50 years after the foundation...

  12. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.

    Science.gov (United States)

    Noman, Muhammad Zaeem; Desantis, Giacomo; Janji, Bassam; Hasmim, Meriem; Karray, Saoussen; Dessen, Philippe; Bronte, Vincenzo; Chouaib, Salem

    2014-05-01

    Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.

  13. NMDA receptor blockade alters the intracellular distribution of neuronal nitric oxide synthase in the superficial layers of the rat superior colliculus

    Directory of Open Access Journals (Sweden)

    R.E. de Bittencourt-Navarrete

    2009-02-01

    Full Text Available Nitric oxide (NO is a molecular messenger involved in several events of synaptic plasticity in the central nervous system. Ca2+ influx through the N-methyl-D-aspartate receptor (NMDAR triggers the synthesis of NO by activating the enzyme neuronal nitric oxide synthase (nNOS in postsynaptic densities. Therefore, NMDAR and nNOS are part of the intricate scenario of postsynaptic densities. In the present study, we hypothesized that the intracellular distribution of nNOS in the neurons of superior colliculus (SC superficial layers is an NMDAR activity-dependent process. We used osmotic minipumps to promote chronic blockade of the receptors with the pharmacological agent MK-801 in the SC of 7 adult rats. The effective blockade of NMDAR was assessed by changes in the protein level of the immediate early gene NGFI-A, which is a well-known NMDAR activity-dependent expressing transcription factor. Upon chronic infusion of MK-801, a decrease of 47% in the number of cells expressing NGFI-A was observed in the SC of treated animals. Additionally, the filled dendritic extent by the histochemical product of nicotinamide adenine di-nucleotide phosphate diaphorase was reduced by 45% when compared to the contralateral SC of the same animals and by 64% when compared to the SC of control animals. We conclude that the proper intracellular localization of nNOS in the retinorecipient layers of SC depends on NMDAR activation. These results are consistent with the view that the participation of NO in the physiological and plastic events of the central nervous system might be closely related to an NMDAR activity-dependent function.

  14. Evaluation of the Effect of Bosentan-Mediated Endothelin Receptor Blockade on Flap Survival in Rats: An Experimental Study.

    Science.gov (United States)

    Görgülü, Tahsin; Guler, Ramazan; Olgun, Abdulkerim; Torun, Merve; Kargi, Eksal

    2016-08-01

    Local skin flaps are important tools for performing plastic surgery. Skin flaps are used for closure of defects after tumor excision or in tissue losses after trauma. However, problems associated with these flaps are commonly encountered, particularly in areas of marginal necrosis. Bosentan is a vasodilator that exerts its effect through endothelin receptor blockade, and has been shown to prevent ischemic tissue damage. However, no reports have addressed the effect of bosentan on skin flaps. The aim of the study was to investigate the effects of bosentan, which may be applied clinically to promote survival of ischemic skin flaps. A modified McFarlane flap was elevated in the dorsum of 20 Albino Wistar rats with a width-to-length ratio of 3 to 10 cm, respectively, with the caudal base. Perioperatively, 0.9% of physiologic NaCl and injectable distilled water of identical volume were injected into rats in Group 1 (n = 10), and 5 mg/kg bosentan was injected intraperitoneally into rats in Group 2 (n = 10). All of the rats were followed up for 7 days postoperatively. The surviving parts of the flaps were measured at the end of day 7. Acute and chronic inflammation, amount of granulation tissue, fibroblast maturation, amount of collagen, and amounts of reepithelialization and neovascularization present in the ischemic zones of the distal parts of the flaps were evaluated histopathologically, and results were compared statistically. The mean flap survivals were 61.1% in Group 1 and 91.1% in Group 2; the percentage of the surviving flap area in Group 2 was higher than that in Group 1 (p  0.005). Fibroblast maturation, amount of collagen, and amounts of reepithelialization and neovascularization investigated in Group 2 were statistically significantly higher than those in Group 1 (p skin flaps because it decreases ischemic necrosis distal to skin flaps, thus exerting favorable effects on flap survival. PMID:27494588

  15. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.

    Science.gov (United States)

    Bellocchio, Luigi; Soria-Gómez, Edgar; Quarta, Carmelo; Metna-Laurent, Mathilde; Cardinal, Pierre; Binder, Elke; Cannich, Astrid; Delamarre, Anna; Häring, Martin; Martín-Fontecha, Mar; Vega, David; Leste-Lasserre, Thierry; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat; Chaouloff, Francis; Pagotto, Uberto; Guzman, Manuel; Cota, Daniela; Marsicano, Giovanni

    2013-03-19

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.

  16. The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade.

    Science.gov (United States)

    Pamenter, Matthew E; Nguyen, Jetson; Carr, John A; Powell, Frank L

    2014-08-01

    Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839-1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7-9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a "cocktail" of the GluR antagonists MK-801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15-min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats.

  17. Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation.

    Science.gov (United States)

    Hernandez, Giovanni; Cossette, Marie-Pierre; Shizgal, Peter; Rompré, Pierre-Paul

    2016-01-01

    Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward. Blockade of VM NMDAR, however, enhances brain stimulation reward (BSR), the results can be explained by a reduction in the inhibitory drive on DA neurons that is also under the control of glutamate. In this study, we used fast-scan cyclic voltammetry (FSCV) in anesthetized animals to determine whether this enhancement is associated with a change in phasic DA release in the nucleus accumbens. Rats were implanted with a stimulation electrode in the dorsal-raphe (DR) and bilateral cannulae above the VM and trained to self-administer trains of electrical stimulation. The curve-shift method was used to evaluate the effect of a single dose (0.825 nmol/0.5 μl/side) of the NMDAR antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA), on reward. These animals were then anesthetized and DA release was measured during delivery of electrical stimulation before and after VM microinjection of the vehicle followed by PPPA. As expected, phasic DA release and operant responding depended similarly on the frequency of rewarding electrical stimulation. As anticipated, PPPA produced a significant reward enhancement. Unexpectedly, PPPA produced a decrease in the magnitude of DA transients at all tested frequencies. To test whether this decrease resulted from excessive activation of DA neurons, we injected apomorphine 20 min after PPPA microinjection. At a dose (100 μg s.c.) sufficient to reduce DA firing under control conditions, apomorphine restored electrical stimulation-induced DA transients. These findings show that combined electrical stimulation and VM NMDARs blockade induce DA inactivation, an effect that indirectly demonstrates that VM NMDARs blockade enhances reward by potentiating stimulation-induced excitation in the mesoaccumbens DA pathway. PMID:27616984

  18. Macroscopic quantum tunneling in Josephson tunnel junctions and Coulomb blockade in single small tunnel junctions

    International Nuclear Information System (INIS)

    Experiments investigating the process of macroscopic quantum tunneling in a moderately-damped, resistively shunted, Josephson junction are described, followed by a discussion of experiments performed on very small capacitance normal-metal tunnel junctions. The experiments on the resistively-shunted Josephson junction were designed to investigate a quantum process, that of the tunneling of the Josephson phase variable under a potential barrier, in a system in which dissipation plays a major role in the dynamics of motion. All the parameters of the junction were measured using the classical phenomena of thermal activation and resonant activation. Theoretical predictions are compared with the experimental results, showing good agreement with no adjustable parameters; the tunneling rate in the moderately damped (Q ∼ 1) junction is seen to be reduced by a factor of 300 from that predicted for an undamped junction. The phase is seen to be a good quantum-mechanical variable. The experiments on small capacitance tunnel junctions extend the measurements on the larger-area Josephson junctions from the region in which the phase variable has a fairly well-defined value, i.e. its wavefunction has a narrow width, to the region where its value is almost completely unknown. The charge on the junction becomes well-defined and is predicted to quantize the current through the junction, giving rise to the Coulomb blockade at low bias. I present the first clear observation of the Coulomb blockade in single junctions. The electrical environment of the tunnel junction, however, strongly affects the behavior of the junction: higher resistance leads are observed to greatly sharpen the Coulomb blockade over that seen with lower resistance leads. I present theoretical descriptions of how the environment influences the junctions; comparisons with the experimental results are in reasonable agreement

  19. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wei-guo HU; Tao LIU; Jiong-xin XIONG; Chun-you WANG

    2007-01-01

    Aim: To investigate the expression of sonic hedgehog (SHH) and epidermal growth factor receptor (EGFR) signal molecules in pancreatic cancer cells, and to assess the inhibitory effects through the blockade of the SHH and EGFR signaling path- ways by cyclopamine and Iressa, respectively. Methods: The expression of SHH and EGFR in pancreatic cancer cell lines (PANC-1, SUIT-2, and ASPC-1) was de-tected by RT-PCR and Western blot analysis. After treatment with different con-centrations of cyclopamine, alone or in combination with Iressa, the antiproliferative effect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazolium assays. A flow cytometry analysis was used to detect the cellular cycle distribu-tion and apoptosis of pancreatic cancer cells. Results: All of the 3 pancreatic cancer cell lines expressed SHH, Smoothened (SMO), and EGFR. Cyclopamine could downregulate the expression of EGFR in all cell lines. Cyclopamine or Iressa could induce a growth inhibitory effect in a dose-dependent manner. Moreover,the combined use of 2.5 μmol/L cyclopamine and 1 μmol/L Iressa induced an enhanced inhibitory effect and a greater apoptosis rate than any agent alone. The percentage of the cell population of the G0/G1 and sub-G1 phases was significantly increased along with the increasing dose of cyclopamine and/or Iressa. Conclusion: The blockade of the sonic hedgehog signal pathway enhances the antiproliferative effect of the EGFR inhibitor through the downregulation of its expression in pancreatic cancer cells. The simultaneous blockade of SHH and EGFR signaling represents possible targets of new treatment strategies for pan-creatic carcinoma.

  20. The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy

    Directory of Open Access Journals (Sweden)

    Alper Otunctemur

    2013-06-01

    Full Text Available Aim: Transrectal ultrasound (TRUS guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. Many different protocoles are applied to reduce the pain during the process. In this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respective- ly in addition to perianal intrarectal lidocaine gel on the pain control in prostate biop- sy by TRUS. Methods: 473 patients who underwent prostate biopsy guided TRUS between 2008-2012 were included in the study. 10-point linear visual analog pain scale(VAS was used to evaluate the pain during biopsy. The patients were divided into two groups according to anesthesia procedure. In Group 1, there were 159 patients who had perianal-intrarectal lidocaine gel, in Group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. The pain about probe manipulation was aseesed by VAS-1 and during the biopsy needle entries was evalu- ated by VAS-2. Results were compared with Mann-Whitney U and Pearson chi-square test. Results: Mean VAS-2 scores in Group 1 and Group 2 were 4.54 ± 1.02 and 2.06 ± 0.79 respectively. The pain score was determined significantly lower in the Group 2 (p = 0.001. In both groups there was no significant difference in VAS-1 scores, patient’s age, prostate volume, complication rate and PSA level. Conclusion: The combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel.

  1. Electromyographic monitoring of facial nerve under different levels of neuromuscular blockade during middle ear microsurgery

    Institute of Scientific and Technical Information of China (English)

    CAI Yi-rong; XU Jing; CHEN Lian-hua; CHI Fang-lu

    2009-01-01

    Background The evoked electromyography (EMG) is frequently used to identify facial nerve in order to prevent its damage during surgeries. Partial neuromuscular blockade (NMB) has been suggested to favor EMG activity and insure patients' safety. The aim of this study was to determine an adequate level of NMB correspondent to sensible facial nerve identification by evaluating the relationship between facial EMG responses and peripheral NMB levels during the middle ear surgeries.Methods Facial nerve evoked EMG and NMB monitoring were performed simultaneously in 40 patients who underwent tympanoplasty. Facial electromyographic responses were recorded by insertion of needle electrodes into the orbicularis oris and orbicularis oculi muscles after electrical stimulation on facial nerve. The NMB was observed objectively with the hypothenar muscle's twitching after electrical stimulation of ulnar nerve, and the intensity of blockade was adjusted at levels of 0, 25%, 50%, 75%, 90%, and 100% respectively with increased intravenous infusion of Rocuronium (muscle relaxant).Results All of the patients had detectable EMG responses at the levels of NMB ≤50%. Four out of forty patients had no EMG response at the levels of NMB ≥75%. A significant linear positive correlation was present between stimulation thresholds and NMB levels while a linear negative correlation was present between EMG amplitudes and NMB levels.Conclusions The facial nerve monitoring via facial electromyographic responses can be obtained when an intraoperative partial neuromuscular blockade is induced to provide an adequate immobilization of the patient. The 50% NMB should be considered as the choice of anesthetic management for facial nerve monitoring in otologic microsurgery based on the relationship of correlation.

  2. The effects of calcium channel blockade on agouti-induced obesity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Han; Moustaid, N.; Zemel, M.B. [Univ. of Tennessee, Knoxville, TN (United States)] [and others

    1996-12-01

    We have previously observed that obese viable yellow (A{sup vy}/a) mice exhibit increased intracellular Ca{sup 2+} ([Ca{sup 2+}]i) and fatty acid synthase (FAS) gene expression; further, recombinant agouti protein increases in cultured adipocytes and these effects are inhibited by Ca{sup 2+} channel blockade. Accordingly, we determined the effect of Ca{sup 2+} channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the agouti gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5 {+-} 0.6 vs. 27.3 {+-} 0.3 g; P<0.001) and exhibited a 0.81{degrees}C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensitivity (P,0.05), and transiently elevated core temperature in the transgenic mice, but was without effect in the control mice. These data suggest that agouti regulates FAS, fat storage, and possibly thermogenesis, at least partially, via a [Ca{sup 2+}]{sub i}-dependent mechanism, and that Ca{sup 2+} channel blockade may partially attenuate agouti-induced obesity. 42 refs., 4 figs., 1 tab.

  3. Effect of alpha and beta adrenergic blockade on epinephrine induced pulmonary insufficiency.

    Science.gov (United States)

    Berk, J L; Hagen, J F; Koo, R

    1976-04-01

    Recent studies demonstrated that epinephrine causes significant pulmonary A-V shunting. This study reports the effect of alpha and beta adrenergic blockade on this shunting. Sixty-three anesthetized mongrel dogs were ventilated with a mechanical respirator. Measurements of (1) the pulmonary shunt, (2) cardiac output, (3) mean pulmonary artery, pulmonary capillary wedge and systemic pressures, and (4) pulmonary and systemic vascular resistances were obtained at 5, 15 and 30 minute intervals during the first hour and hourly for 5 hours. Fifteen dogs received no treatment. All others received epinephrine hydrochloride, 2 mug/kg/min for 5 hours. Ten received epinephrine only. Ten were pretreated with propranolol hydrochloride, 250 mug/kg, 12 with phenoxybenzamine, 1 mg/kg, and 16 with phenoxybenzamine and propranolol. Propranolol significantly decreased the epinephrine induced pulmonary shunt at all times and was the most effective drug. Phenoxybenzamine decreased the early shunting, but less than propranolol, and did not decrease the late shunting. Blockade with propranolol and phenoxybenzamine was less effective than propranolol alone. Based on the observed hemodynamic changes it was suggested that beta blockade is effective in reducing epinephrine induced pulmonary insufficiency by favorably altering the flow and distribution of pulmonary blood flow which in turn decreases epinephrine induced ventilation-perfusion inequalities and capillary hypertension both of which result in shunting. Conversely phenoxybenzamine has an unfavorable effect on the pulmonary flow. These studies support previous work in animals and man which showed that beta adrenergic stimulation is important in the pathogenesis of pulmonary insufficiency. Because the amounts of epinephrine used produce blood levels observed in critical illness, these studies add support to a relationship between the increased catecholamine stimulation of critical illness and the associated and often unexplained

  4. Density functional theory of the Seebeck coefficient in the Coulomb blockade regime

    Science.gov (United States)

    Yang, Kaike; Perfetto, Enrico; Kurth, Stefan; Stefanucci, Gianluca; D'Agosta, Roberto

    2016-08-01

    The Seebeck coefficient plays a fundamental role in identifying the efficiency of a thermoelectric device. Its theoretical evaluation for atomistic models is routinely based on density functional theory calculations combined with the Landauer-Büttiker approach to quantum transport. This combination, however, suffers from serious drawbacks for devices in the Coulomb blockade regime. We show how to cure the theory through a simple correction in terms of the temperature derivative of the exchange correlation potential. Our results compare well with both rate equations and experimental findings on carbon nanotubes.

  5. Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases?

    DEFF Research Database (Denmark)

    Febbraio, M A; Rose-John, S; Pedersen, B K

    2010-01-01

    Interleukin-6 (IL-6) has been linked to a myriad of diseases associated with inflammation, including rheumatoid arthritis (RA), Crohn's disease, and several types of cancer. In 2009 the US Food and Drug Administration accepted a complete-response submission for the use of Actemra (tocilizumab), t......), the first humanized IL-6 receptor-inhibiting monoclonal antibody, for the treatment of RA. Although this treatment will certainly help in managing inflammatory disorders such as RA, we suggest that side effects of such blockade may be excess weight gain and hyperlipidemia....

  6. CTLA-4 blockade during dendritic cell based booster vaccination influences dendritic cell survival and CTL expansion

    DEFF Research Database (Denmark)

    Pedersen, Anders E; Ronchese, Franca

    2007-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells and critical for the priming of CD8+ T cells. Therefore the use of these cells as adjuvant cells has been tested in a large number of experimental and clinical vaccination studies, in particular cancer vaccine studies. A number of protocols....... We have previously reported that DCs loaded with specific antigens are eliminated by antigen specific CTLs in vivo and that this elimination affects the potential for in vivo CTL generation. We now show that CTLA-4 blockade increases the number of DC vaccine induced LCMV gp33 specific CTLs...

  7. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons.

    OpenAIRE

    Beurrier, Corinne; Bioulac, Bernard; Audin, Jacques; Hammond, Constance

    2001-01-01

    International audience The effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) was analyzed with patch-clamp techniques (whole cell configuration, current- and voltage-clamp modes) in rat STN slices in vitro. A brief tetanus, consisting of 100-micros bipolar stimuli at a frequency of 100--250 Hz during 1 min, produced a full blockade of ongoing STN activity whether it was in the tonic or bursting mode. This HFS-induced silence lasted around 6 min after the end of st...

  8. Transition from Coulomb Blockade to Resonant Transmission in a MoS2 Nanoribbon

    Science.gov (United States)

    Li, Yanjing; Mason, Nadya

    2014-03-01

    We have measured a side-gated nanoribbon of MoS2 at low temperature, and observed the transition from Coulomb blockade to resonant transmission when the Fermi level is tuned with a gate. We show that near the crossover between these regimes, the entire nanoribbon acts as a single quantum dot. Our findings may shed light on quasi-ballistic transport in the material. We also discuss the quantum dot formation in terms of a substrate-induced disorder potential, and consider other possible origins of disorder.

  9. Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice.

    Science.gov (United States)

    Chen, Bei-Yu; Zheng, Min-Hua; Chen, Yan; Du, Yan-Ling; Sun, Xiao-Long; Zhang, Xing; Duan, Li; Gao, Fang; Liang, Liang; Qin, Hong-Yan; Luo, Zhuo-Jing; Han, Hua

    2015-12-01

    The outcome of spinal cord injury (SCI) is determined by both neural cell-intrinsic survival pathways and tissue microenvironment-derived signals. Macrophages dominating the inflammatory responses in SCI possess both destructive and reparative potentials, according to their activation status. Notch signaling is involved in both cell survival and macrophage-mediated inflammation, but a comprehensive role of Notch signaling in SCI has been elusive. In this study, we compared the effects of general Notch blockade by a pharmaceutical γ-secretase inhibitor (GSI) and myeloid-specific Notch signal disruption by recombination signal binding protein Jκ (RBP-J) knockout on SCI. The administration of Notch signal inhibitor GSI resulted in worsened hind limb locomotion and exacerbated inflammation. However, mice lacking RBP-J, the critical transcription factor mediating signals from all four mammalian Notch receptors, in myeloid lineage displayed promoted functional recovery, attenuated glial scar formation, improved neuronal survival and axon regrowth, and mitigated inflammatory response after SCI. These benefits were accompanied by enhanced AKT activation in the lesion area after SCI. These findings demonstrate that abrogating Notch signal in myeloid cells ameliorates inflammation response post-SCI and promotes functional recovery, but general pharmaceutical Notch interception has opposite effects. Therefore, clinical intervention of Notch signaling in SCI needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

  10. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25.

    Science.gov (United States)

    Hannani, Dalil; Vétizou, Marie; Enot, David; Rusakiewicz, Sylvie; Chaput, Nathalie; Klatzmann, David; Desbois, Melanie; Jacquelot, Nicolas; Vimond, Nadège; Chouaib, Salem; Mateus, Christine; Allison, James P; Ribas, Antoni; Wolchok, Jedd D; Yuan, Jianda; Wong, Philip; Postow, Michael; Mackiewicz, Andrzej; Mackiewicz, Jacek; Schadendorff, Dirk; Jaeger, Dirk; Zörnig, Inka; Hassel, Jessica; Korman, Alan J; Bahjat, Keith; Maio, Michele; Calabro, Luana; Teng, Michele Wl; Smyth, Mark J; Eggermont, Alexander; Robert, Caroline; Kroemer, Guido; Zitvogel, Laurence

    2015-02-01

    The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma. PMID:25582080

  11. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

    Science.gov (United States)

    Sykes, David B; Kfoury, Youmna S; Mercier, François E; Wawer, Mathias J; Law, Jason M; Haynes, Mark K; Lewis, Timothy A; Schajnovitz, Amir; Jain, Esha; Lee, Dongjun; Meyer, Hanna; Pierce, Kerry A; Tolliday, Nicola J; Waller, Anna; Ferrara, Steven J; Eheim, Ashley L; Stoeckigt, Detlef; Maxcy, Katrina L; Cobert, Julien M; Bachand, Jacqueline; Szekely, Brian A; Mukherjee, Siddhartha; Sklar, Larry A; Kotz, Joanne D; Clish, Clary B; Sadreyev, Ruslan I; Clemons, Paul A; Janzer, Andreas; Schreiber, Stuart L; Scadden, David T

    2016-09-22

    While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML. PMID:27641501

  12. A mean field approach to Coulomb blockade for a disordered assembly of quantum dots

    Indian Academy of Sciences (India)

    Akashdeep Kamra; Praveen Pathak; Vijay A Singh

    2008-02-01

    The Coulomb blockade (CB) in quantum dots (QDs) is by now well documented. It has been used to guide the fabrication of single electron transistors. Even the most sophisticated techniques for synthesizing QDs (e.g. MOCVD/MBE) result in an assembly in which a certain amount of disorder is inevitable. On the other hand, theoretical approaches to CB limit themselves to an analysis of a single QD. In the present work we consider two types of disorders: (i) size disorder; e.g. QDs have a distribution of sizes which could be unimodal or bimodal in nature. (ii) Potential disorder with the confining potential assuming a variety of shapes depending on growth condition and external fields. We assume a Gaussian distribution in disorder in both size and potential and employ a simplified mean field theory. To do this we rely on the scaling laws for the CB (also termed as Hubbard ) obtained for an isolated QD [1]. We analyze the distribution in the Hubbard as a consequence of disorder and observe that Coulomb blockade is partially suppressed by the disorder. Further, the distribution in is a skewed Gaussian with enhanced broadening.

  13. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues.

    Science.gov (United States)

    Hamanishi, Junzo; Mandai, Masaki; Matsumura, Noriomi; Abiko, Kaoru; Baba, Tsukasa; Konishi, Ikuo

    2016-06-01

    Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment. PMID:26899259

  14. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    Science.gov (United States)

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  15. Bothrops jararacussu venom-induced neuromuscular blockade inhibited by Casearia gossypiosperma Briquet hydroalcoholic extract

    Directory of Open Access Journals (Sweden)

    TM Camargo

    2010-01-01

    Full Text Available The hydroalcoholic extract of Casearia gossypiosperma Briquet (Flacourtiaceae was standardized for the first time through quality control procedures including pharmacognostic methods, fingerprint chromatograms, defined amounts of marker substances and physicochemical characteristics. The pharmacological activity of C. gossypiosperma (Cg hydroalcoholic extract was assayed by a traditional in vitro test, which involved irreversible neuromuscular blockade induced by Bothrops jararacussu (Bjssu venom (60 µg/mL in mouse phrenic nerve-diaphragm preparations. Bjssu venom blocked muscle activity for 26 (± 2.0 minutes (n = 6. Cg extract (0.1 mg/mL induced changes on the baseline muscle activity without impairing the muscle function and inhibited 87.6% (± 1.8 (n = 6 of the Bjssu venom-induced blockade. Both flavonoids (0.624 g% and polyphenols (4.63 g% from the extract were spectrophotometrically quantified. Therefore, the present study confirms the antibothropic activity of Cg extract, supporting the ethnomedical use of Casearia sp. in the treatment of snakebite victims.

  16. Effect of alpha 1-adrenergic blockade on myocardial blood flow during exercise after myocardial infarction.

    Science.gov (United States)

    Herzog, C A; Dai, X Z; Bache, R J

    1991-08-01

    The effect of alpha 1-adrenergic blockade with prazosin on myocardial blood flow at rest and during two levels of treadmill exercise was assessed in 16 chronically instrumented dogs 9-14 days after myocardial infarction had been produced by occlusion of the left circumflex coronary artery. During resting conditions prazosin did not alter mean myocardial blood flow or the subendocardial-to-subepicardial flow ratio in either normally perfused or collateral-dependent myocardium. However, during exercise at comparable external work loads and comparable rate-pressure products, prazosin significantly increased blood flow to normally perfused (27% increase at the second level of exercise, P less than 0.001) and collateral-dependent myocardium (35% increase at the second level of exercise, P less than 0.001) compared with control. In addition, prazosin caused a small but significant decrease in the subendocardial-to-subepicardial flow ratio in both normal (1.27 +/- 0.04 to 1.19 +/- 0.04; P less than 0.01) and collateral-dependent myocardium (0.57 +/- 0.11 to 0.52 +/- 0.11; P less than 0.01) compared with control, reflecting a disproportionally greater increase in subepicardial flow in response to alpha 1-adrenergic blockade. These data demonstrate that alpha 1-adrenergic vasoconstriction inhibits coronary vasodilation during exercise, even in areas of collateral-dependent myocardium relatively early after coronary artery occlusion. PMID:1678929

  17. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    Energy Technology Data Exchange (ETDEWEB)

    Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.

    1984-02-01

    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of /sup 201/Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and /sup 201/Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of /sup 201/Tl uptake in non-occluded endocardium. Uptake of /sup 201/Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

  18. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    Elena eNosyreva

    2014-12-01

    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  19. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    Science.gov (United States)

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia. PMID:24865217

  20. TRANSRECTAL ULTRASOUND GUIDED PROSTATIC NERVE BLOCKADE FOR PAIN CONTROL DURING TRANSRECTAL PROSTATE BIOPSY

    Institute of Scientific and Technical Information of China (English)

    YANG Liu-ping; DENG Jun-hong; ZHONG Hong; HU Jian-bo; WEI Hong-ai; WANG Liang-sheng

    2005-01-01

    Objective: To assess the effect of transrectal ultrasound guided prostatic nerve blockade on the discomfort associated with systematic biopsy of the prostate. Methods: 73 patients receiving systematic 13 cores biopsy of the prostate were randomized into two groups. Group A(37 cases) received an injection of 5 ml 1% lidocaine into the prostatic neurovascular bundles on each side at the base of the prostate under ultrasound guidance and group B(36 cases) received 5 ml saline injection (0.9% sodium chloride) at the same site. Pain during biopsy was assessed by using a 10-point linear visual analog score (VAS) immediately after the biopsy. Results: The mean pain scores during transrectal prostate biopsy were significantly lower in group A than group B(1.1±0.6 versus 5.9±3.1, t=4.81, P<0.01). During this study no patient in either group had any adverse effect from the injection. Conclusion: Transcrectal ultrasound guided prostatic nerve blockade is a safe and efficacious method for providing satisfactory anesthesia in transrectal prostate biopsy. We recommend its routine administration in all patients during this procedure.

  1. Unexpected High Sensory Blockade during Continuous Spinal Anesthesiology (CSA in an Elderly Patient

    Directory of Open Access Journals (Sweden)

    R. Ketelaars

    2012-01-01

    Full Text Available A 98-year-old woman presented for a hemiarthroplasty of the left hip. Because of her age and cardiac and pulmonary co-existing diseases we decided to provide adequate regional anesthesia by continuous spinal anesthesia. Fragmented doses of isobaric bupivacaine 0.5% were administered through a system consisting of a spinal catheter connected to an antimicrobial filter. After an uneventful surgical procedure, prior to removal of the catheter, this system was flushed with 10 mL of normal saline in order to try to prevent post-dural-puncture headache. After arrival at the postanesthesia care unit and fifteen minutes after removal of the catheter the patient suffered an unexpected high thoracic sensory blockade and hypotension requiring treatment. The continuous spinal anesthesia technique can be used in selected cases to be able to administer local anesthetic agents in a slow and controlled manner to reach the desired effect. The risk of post-dural-puncture headache using this technique in elderly patients is very low and therefore precludes the need to try to prevent it. We have described a potentially dangerous complication of flushing a bupivacaine-filled system into the spinal canal of an elderly patient resulting in an undesirable high sensory blockade.

  2. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

    Directory of Open Access Journals (Sweden)

    Joanne O Davidson

    Full Text Available Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age. Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6 or vehicle infusion for controls (occlusion-vehicle group, n = 7. Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05, with reduced neuronal loss in the caudate and putamen (p<0.05, but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05 and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05, with a significant increase in proliferation (p<0.05. Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

  3. Neurolytic blockade of the obturator nerve in the treatment of idiopatic obturator neuralgia

    Directory of Open Access Journals (Sweden)

    Ćulafić Slobodan

    2008-01-01

    Full Text Available Introduction. Idiopathic obturator neuralgia is a rare chronic pain condition. It consists of pain radiating from the obturator nerve territory to the inner thigh. However, the symptomatic obturator neuralgia is commonly caused by the obturator canal bowel hernia that causes painful compressive neuropathy in more than 85% of the cases. Case report. A 61-year-old female who underwent right femoral amputation due to the occlusion of the aortofemoral vascular graft, complained of the pain characterized by its localization in the inguinal region and anterointernal side of the right inner thigh. Computer tomography and MRI findings excluded obturator canal herniation or lumbar plexopathy. A diagnosis of the obturator neuralgia was confirmed by an analgesic block of the obturator nerve. Thereafter, the neurolitic blockade of the right obturator nerve was done. The complete pain relief was achieved. Pain relief was complete in three-month follow-up period. Conclusion. Neurolitic blockade is an efficacious method in treating chronic pain caused by the idiopathic obturator neuralgia.

  4. Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans.

    Science.gov (United States)

    Kahnt, Thorsten; Weber, Susanna C; Haker, Helene; Robbins, Trevor W; Tobler, Philippe N

    2015-03-01

    The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs. PMID:25740537

  5. Blockade of S100A3 activity inhibits murine hair growth.

    Science.gov (United States)

    Guan, W; Deng, Q; Yu, X L; Yuan, Y S; Gao, J; Li, J J; Zhou, L; Xia, P; Han, G Y Q; Han, W; Yu, Y

    2015-10-28

    Using mouse gene expression microarray analysis, we obtained dynamic expression profiles of the whole genome in a depilation-induced hair growth mouse model. S100A3 expression increased during the anagen phase and returned to normal during the telogen phase. The effects of S100A3 blockade on the hair growth cycle were examined in mice after subcutaneous injection of an anti-mouse S100A3 antibody. Protein localization of S100A3 was confined to the hair shafts during the anagen phase and the sebaceous glands during the telogen phase. S100A3 blockade delayed hair follicle entry into the anagen phase, decreased hair elongation, and reduced the number of hair follicles in the subcutis, which correlated with the downregulated expression of hair growth induction-related genes in vivo. The present study demonstrates that anti-S100A3 antibody inhibits mouse hair growth, suggesting that S100A3 can be used as a target for hair loss treatment.

  6. Identification and specific blockade of two receptors for histamine in the cardiovascular system.

    Science.gov (United States)

    Powell, J R; Brody, M J

    1976-01-01

    Histamine caused a fall in blood pressure in anesthetized dogs and cats which was only partially attenuated by mepyramine (pyrilamine), a histamine type H1-receptor antagonist. Further treatment with burimide or metiamide, type H2-receptor antagonists, caused nearly complete attenuation of the response to histamine. Burimamide alone had no effect on vasodilatation produced by histamine in the dog gracilis muscle whereas mepyramine alone caused a partial attenuation. An H2-receptor agonist, 4-methylhistamine and an H1-receptor agonist, 2-(2-pyridyl)ethylamine, both produced vasodilatation which was blocked by metiamide and mepyramine, respectively. Constriction of the saphenous vein produced by histamine was found to involve interaction with H1-receptors only. In the intact dog, histamine increased heart rate and decreased left ventricular dp/dt through direct effects. Mepyramine prevented the increase in heart rate but did not affect the chronotropic actions of isoproterenol and glyceryl trinitrate. H1-receptor blockade did not alter inotropic effects whereas subsequent H2-receptor blockade prevented the negative inotropic effect of histamine. It is concluded that both peripheral vascular and cardiac responses to histamine are mediated through activation of H1- and H2-histamine receptors.

  7. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

    Science.gov (United States)

    Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

    2016-01-01

    A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours. PMID:27767031

  8. Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual neuromuscular blockade?

    DEFF Research Database (Denmark)

    Pedersen, T; Viby-Mogensen, J; Bang, U;

    1990-01-01

    The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one...... pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists...

  9. IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans[S

    OpenAIRE

    Müller, Nike; Schulte, Dominik M.; Türk, Kathrin; Freitag-Wolf, Sandra; Hampe, Jochen; Zeuner, Rainald; Johann O Schröder; Gouni-Berthold, Ioanna; Heiner K Berthold; Krone, Wilhelm; Rose-John, Stefan; Schreiber, Stefan; Laudes, Matthias

    2015-01-01

    Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans ha...

  10. Effects of a New Glutamic Acid Derivative on Myocardial Contractility of Stressed Animals under Conditions of Nitric Oxide Synthesis Blockade.

    Science.gov (United States)

    Tyurenkov, I N; Perfilova, V N; Sadikova, N V; Berestovitskaya, V M; Vasil'eva, O S

    2015-07-01

    Glufimet (glutamic acid derivative) in a dose of 28.7 mg/kg limited the reduction of the cardiac functional reserve in animals subjected to 24-h stress under conditions of nonselective NO synthase blockade with L-NAME (10 mg/kg). Adrenoreactivity and increased afterload tests showed that the increment of myocardial contraction/relaxation rates, left-ventricular pressure, and HR were significantly higher in glufimet-treated stressed animals with NO synthesis blockade than in animals which received no glufimet. The efficiency of glufimet was higher than that of phenibut (the reference drug). PMID:26205724

  11. Greater occipital nerve blockade in cervicogenic headache Bloqueio do nervo occipital maior na cefaléia cervicogênica

    OpenAIRE

    Maurice B Vincent; Renato A. Luna; DENISE SCANDIUZZI; Sérgio A. P. Novis

    1998-01-01

    Cervicocogenic headache (CeH) is a relatively common disorder. Although no ideal treatment is available so far, blockades in different structures and nerves may be temporarily effective. We studied the effects of 1-2 mL 0.5% bupivacaine injection at the ipsilateral greater occipital nerve (GON) in 41 CeH patients. The pain is significantly reduced both immediately and as long as 7 days after the blockade. The improvement is less marked during the first two days, a phenomenon we called "tilde ...

  12. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria.

    Science.gov (United States)

    Barnes, M J; Griseri, T; Johnson, A M F; Young, W; Powrie, F; Izcue, A

    2013-03-01

    Thymic induction of CD4(+)Foxp3(+) regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4(+) T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4(+) T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Foxp3 and maintenance of Foxp3 populations in the spleen and mesenteric lymph nodes, but their accumulation in the colon, where Treg cells specific for commensal bacteria accumulate, is impaired. In a T cell-transfer model of colitis, the two known CTLA-4 ligands, B7-1 and B7-2, had largely redundant roles in inducing inflammation and promoting Treg cell function. However, B7-2 proved more efficient than B7-1 in inducing Foxp3 in vitro and in vivo. Our data reveal an unappreciated role for CTLA-4 in establishing the Foxp3(+) compartment in the intestine. PMID:22910217

  13. CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

    Energy Technology Data Exchange (ETDEWEB)

    Datir, A., E-mail: apdatir@gmail.co [Jackson Memorial Hospital, Miami, FL (United States); Connell, D. [Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex (United Kingdom)

    2010-01-15

    Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

  14. The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects

    Directory of Open Access Journals (Sweden)

    Sathananthan M

    2014-07-01

    Full Text Available Matheni Sathananthan,1 Sayeed Ikramuddin,2 James M Swain,3,6 Meera Shah,1 Francesca Piccinini,4 Chiara Dalla Man,4 Claudio Cobelli,4 Robert A Rizza,1 Michael Camilleri,5 Adrian Vella1 1Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Division of General Surgery, University of Minnesota, Minneapolis, MN, USA; 3Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Information Engineering, University of Padua, Padua, Italy; 5Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA Purpose: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods: We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB. Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA to measure gastrointestinal transit. Insulin action and ß-cell responsivity indices were estimated using the minimal model. Results: Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose

  15. GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats.

    Science.gov (United States)

    Leung, L Stan; Shen, Bixia

    2007-01-01

    The participation of GABA(B) receptors in hippocampal EEG generation was studied by intracerebroventricular (icv) and intracerebral infusions of GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP35348) in freely behaving rats. During awake-immobility, icv CGP35348 induced a theta rhythm and increased gamma waves (30-100 Hz) in the hippocampus. The immobility theta peaked at 6-7 Hz and had a theta phase in CA1 stratum radiatum of approximately 160 degrees with reference to the theta at the alveus, when compared with approximately 130 degrees during walking. Immobility theta power peaks at 6-7 Hz was also found in normal rats, and it was detected in 27% of the EEG segments during immobility. Incidence of immobility theta increased to 87.5% after 480 nmol of CGP35348 icv. Muscarinic antagonist scopolamine (5 mg/kg, ip) suppressed the induction of immobility theta and the gamma power increase after icv CGP35348. CGP35348 icv did not significantly change the hippocampal theta power at 7-8 Hz during walking (theta fundamental), but it increased power at 12-15 Hz, at the second harmonic of theta. CGP35348 icv also increased 30-50 Hz gamma power during walking. Medial septal infusion of CGP35348 (12 nmol in 0.4 microl) increased the power and the frequency of the hippocampal theta second harmonic during walking, but did not increase gamma activity. Infusion of CGP35348 (8 nmol in 0.4 microl) in the hippocampus increased the local gamma activity at 30-100 Hz, but did not induce immobility theta or affect the walking theta rhythm. In conclusion, icv GABA(B) receptor blockade increased an atropine-sensitive input that generated an immobility theta rhythm, while GABA(B) receptor blockade of the medial septum increased atropine-resistant theta harmonics possibly generated by apical dendritic spikes. GABA(B) receptor blockade may enhance cognitive task performance by activating hippocampal theta and gamma rhythms in behaving rats.

  16. Muscle-type nicotinic receptor blockade by diethylamine, the hydrophilic moiety of lidocaine

    Directory of Open Access Journals (Sweden)

    Armando eAlberola-Die

    2016-02-01

    Full Text Available Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs, this work was aimed to determine the inhibitory effects of diethylamine (DEA, a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh in a dose-dependent manner (IC50 close to 70 μM, but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3 and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and

  17. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade

    DEFF Research Database (Denmark)

    Ablamunits, Vitaly; Henegariu, Octavian; Hansen, Jakob Bondo;

    2012-01-01

    Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1ß. We postulated that blockade of IL-1ß would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with...

  18. Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

    Science.gov (United States)

    Sobani, Zain A; Sawant, Ashwin; Jafri, Mikram; Correa, Amit Keith; Sahin, Ibrahim Halil

    2016-01-01

    Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade. PMID:27777877

  19. Human adipose tissue blood flow during prolonged exercise, III. Effect of beta-adrenergic blockade, nicotinic acid and glucose infusion

    DEFF Research Database (Denmark)

    Bülow, J

    1981-01-01

    acid, during acute i.v. beta-adrenergic blockade by propranolol, and during continuous i.v. infusion of glucose. The most pronounced lipid mobilization and utilization during work was seen in the control experiments where ATBF rose 3-fold on average from the initial rest period to the third hour...

  20. Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: A feasible strategy?

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Ger Jan; de Zeeuw, Dick

    2005-01-01

    Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strat

  1. Value of the addition of Amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade

    NARCIS (Netherlands)

    Dunselman, PHJM; Bouwens, LHM; Herweijer, AH; Bernink, PJLM

    1998-01-01

    Anginal patients who remain symptomatic despite optimally dosed beta blockade may also be given dihydropyridine calcium antagonists. This treatment regimen was examined in a double-blind parallel, randomized, controlled study in 147 patients with angina and positive bicycle exercise tests despite op

  2. Resolution of diarrhea in an immunocompromised patient with chronic norovirus gastroenteritis correlates with constitution of specific antibody blockade titer.

    Science.gov (United States)

    Knoll, Bettina M; Lindesmith, Lisa C; Yount, Boyd L; Baric, Ralph S; Marty, Francisco M

    2016-08-01

    Norovirus gastroenteritis in immunocompromised hosts can result in a serious and prolonged diarrheal illness. We present a case of chronic norovirus disease during rituximab-bendamustine chemotherapy for non-Hodgkin's lymphoma. We show for the first time a correlation between norovirus strain-specific antibody blockade titers and symptom improvement in an immunocompromised host. PMID:26825307

  3. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander".

    Science.gov (United States)

    Gelao, Lucia; Criscitiello, Carmen; Esposito, Angela; Goldhirsch, Aron; Curigliano, Giuseppe

    2014-03-01

    Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment. PMID:24594636

  4. Relevance of dorsal raphe nucleus firing in serotonin 5-HT2C receptor blockade-induced augmentation of SSRIs effects

    NARCIS (Netherlands)

    Sotty, Florence; Folgering, Joost H. A.; Brennum, Lise T.; Hogg, Sandra; Mork, Arne; Hertel, Peter; Cremers, Thomas I. F. H.

    2009-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT2C receptors signific

  5. CCR5 Blockade Suppresses Melanoma Development Through Inhibition of IL-6-Stat3 Pathway via Upregulation of SOCS3.

    Science.gov (United States)

    Tang, Qiu; Jiang, Jun; Liu, Jian

    2015-12-01

    In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, we found that chemokine receptor 5 (CCR5) neutralization resulted in reduced melanoma tumor size, decreased percentage of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs), and increased proportion of cluster of differentiation (CD)3+ T cells in tumor tissues. Suppressive activity of MDSCs on CD4+ T cells and CD8+ T cell proliferation is significantly inhibited by anti-CCR5 antibody. CCR5 blockade also suppresses interleukin (IL)-6 induction, which in turn deactivates signal transducer and activator of transcription 3 (Stat3) in tumors. Furthermore, the suppressed B16 tumor growth induced by CCR5 blockade is abolished with additional administration of recombinant IL-6. CCR5 blockade also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and anti-CCR5 antibody fails to suppress expression of phospho-Stat3 (p-Stat3), matrix metallopeptidase 9 (MMP9), and IL-6 in cells transfected with SOCS3 short-interfering RNA (SiRNA). All these data suggest that CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3.

  6. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Zhiqiang Guo

    Full Text Available The co-inhibitory receptor Programmed Death-1 (PD-1 curtails immune responses and prevent autoimmunity, however, tumors exploit this pathway to escape from immune destruction. The co-stimulatory receptor OX40 is upregulated on T cells following activation and increases their clonal expansion, survival and cytokine production when engaged. Although antagonistic anti-PD-1 or agonistic anti-OX40 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In the present study, we evaluated the antitumor effects and mechanisms of combinatorial PD-1 blockade and OX40 triggering in a murine ID8 ovarian cancer model. Although individual anti-PD-1 or OX40 mAb treatment was ineffective in tumor protection against 10-day established ID8 tumor, combined anti-PD-1/OX40 mAb treatment markedly inhibited tumor outgrowth with 60% of mice tumor free 90 days after tumor inoculation. Tumor protection was associated with a systemic immune response with memory and antigen specificity and required CD4(+ cells and CD8(+ T cells. The anti-PD-1/OX40 mAb treatment increased CD4(+ and CD8(+ cells and decreased immunosuppressive CD4(+FoxP3(+ regulatory T (Treg cells and CD11b(+Gr-1(+ myeloid suppressor cells (MDSC, giving rise to significantly higher ratios of both effector CD4(+ and CD8(+ cells to Treg and MDSC in peritoneal cavity; Quantitative RT-PCR data further demonstrated the induction of a local immunostimulatory milieu by anti-PD-1/OX40 mAb treatment. The splenic CD8(+ T cells from combined mAb treated mice produced high levels of IFN-γ upon tumor antigen stimulation and exhibited antigen-specific cytolytic activity. To our knowledge, this is the first study testing the antitumor effects of combined anti-PD-1/OX40 mAb in a murine ovarian cancer model, and our results provide a rationale for clinical trials evaluating ovarian cancer immunotherapy using this combination of mAb.

  7. Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jing [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); See, Alfred P.; Phallen, Jillian; Jackson, Christopher M.; Belcaid, Zineb; Ruzevick, Jacob [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Durham, Nicholas [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Meyer, Christian [Department of Oncology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Harris, Timothy J. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Albesiano, Emilia; Pradilla, Gustavo [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Ford, Eric; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Hammers, Hans-Joerg [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Mathios, Dimitris; Tyler, Betty; Brem, Henry [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Pardoll, Drew; Drake, Charles G. [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); and others

    2013-06-01

    Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized

  8. Efficient collisional blockade loading of single atom into a tight microtrap

    CERN Document Server

    Fung, Y H

    2015-01-01

    We show that controlled inelastic collisions can improve the single atom loading efficiency in the collisional blockade regime of optical microtraps. A collisional loss process where only one of the colliding atoms are lost, implemented during loading, enables us to kick out one of the atoms as soon as a second atom enters the optical microtrap. When this happens faster than the pair loss, which has limited the loading efficiency of previous experiments to about 50%, we experimentally observe an enhancement to 80%. A simple analytical theory predicts the loading dynamics. Our results opens up an efficient and fast route for loading individual atoms into optical tweezers and arrays of microtraps that are too tight for easy implementation of the method reported in [1,2]. The loading of tight traps with single atoms is a requirement for their applications in future experiments in quantum information processing and few-body physics.

  9. Overcoming blockade in producing doubly-excited dimers by a single intense pulse and their decay

    CERN Document Server

    Demekhin, Ph V; Jabbari, G; Kopelke, S; Kuleff, A I; Cederbaum, L S

    2012-01-01

    Excitation of two identical species in a cluster by the absorption of two photons of the same energy is strongly suppressed since the excitation of one subunit blocks the excitation of the other one due to the binding Coulomb interaction. Here, we propose a very efficient way to overcome this blockade in producing doubly-excited homoatomic clusters by a single intense laser pulse. For Ne$_2$ it is explicitly demonstrated that the optimal carrier frequency of the pulse is given by half of the energy of the target state, which allows one to doubly excite more than half of the dimers at moderate field intensities. These dimers then undergo ultrafast interatomic decay bringing one Ne to its ground state and ionizing the other one. The reported \\emph{ab initio} electron spectra present reliable predictions for future experiments by strong laser pulses.

  10. Implementation of an experimentally feasible controlled-phase gate on two blockaded Rydberg atoms

    Science.gov (United States)

    Müller, Matthias M.; Murphy, Michael; Montangero, Simone; Calarco, Tommaso; Grangier, Philippe; Browaeys, Antoine

    2014-03-01

    We investigate the implementation of a controlled-Z gate on a pair of Rydberg atoms in spatially separated dipole traps where the joint excitation of both atoms into the Rydberg level is strongly suppressed (the Rydberg blockade). We follow the adiabatic gate scheme of Jaksch et al. [D. Jaksch, J. I. Cirac, P. Zoller, S. L. Rolston, R. Côté, and M. D. Lukin, Phys. Rev. Lett. 85, 2208 (2000), 10.1103/PhysRevLett.85.2208], where the pair of atoms is coherently excited using lasers, and apply it to the experimental setup outlined by Gaëtan et al. [A. Gaëtan, Y. Miroshnychenko, T. Wilk, A. Chotia, M. Viteau, D. Comparat, P. Pillet, A. Browaeys, and P. Grangier, Nat. Phys. 5, 115 (2009), 10.1038/nphys1183]. We apply optimization to the experimental parameters to improve gate fidelity and consider the impact of several experimental constraints on the gate success.

  11. An all-silicon single-photon source by unconventional photon blockade

    CERN Document Server

    Flayac, H; Savona, V

    2015-01-01

    The lack of suitable quantum emitters in silicon and silicon-based materials has prevented the realization of room temperature, compact, stable, and integrated sources of single photons in a scalable on-chip architecture, so far. Current approaches rely on exploiting the enhanced optical nonlinearity of silicon through light confinement or slow-light propagation, and are based on parametric processes that typically require substantial input energy and spatial footprint to reach a reasonable output yield. Here we propose an alternative all-silicon device that employs a different paradigm, namely the interplay between quantum interference and the third-order intrinsic nonlinearity in a system of two coupled optical cavities. This unconventional photon blockade allows to produce antibunched radiation at extremely low input powers. We demonstrate a reliable protocol to operate this mechanism under pulsed optical excitation, as required for device applications, thus implementing a true single-photon source. We fin...

  12. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, Thomas

    2012-01-01

    Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular...... mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine......-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety...

  13. Postsynaptic blockade of inhibitory postsynaptic currents by plasmin in CA1 pyramidal cells of rat hippocampus.

    Science.gov (United States)

    Mizutani, A; Tanaka, T; Saito, H; Matsuki, N

    1997-06-27

    We have shown previously that plasmin facilitated the generation of long-term potentiation (LTP) in CA1 and dentate region of rat hippocampus. In the present study, we investigated the effects of plasmin on postsynaptic currents in CA1 pyramidal neurons of rat hippocampal slices. Plasmin (100 nM) had no effect on NMDA nor on non-NMDA receptor-mediated excitatory postsynaptic currents. However, plasmin significantly decreased GABA(A) receptor-mediated inhibitory postsynaptic currents. This effect of plasmin disappeared when intracellular Ca2+ was strongly chelated with BAPTA. Furthermore, plasmin attenuated the GABA-induced currents in CA1 pyramidal cells. These results suggest that the STP-enhancing effect of plasmin is due to a blockade of postsynaptic GABA(A) responses and that an increase in intracellular Ca2+ by plasmin may be involved in its mechanism.

  14. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

    Science.gov (United States)

    McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles

    2016-01-01

    As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

  15. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.

    Science.gov (United States)

    Cooper, Zachary A; Juneja, Vikram R; Sage, Peter T; Frederick, Dennie T; Piris, Adriano; Mitra, Devarati; Lo, Jennifer A; Hodi, F Stephen; Freeman, Gordon J; Bosenberg, Marcus W; McMahon, Martin; Flaherty, Keith T; Fisher, David E; Sharpe, Arlene H; Wargo, Jennifer A

    2014-07-01

    BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.

  16. Overcoming Barriers in Oncolytic Virotherapy with HDAC Inhibitors and Immune Checkpoint Blockade

    Directory of Open Access Journals (Sweden)

    Antonio Marchini

    2016-01-01

    Full Text Available Oncolytic viruses (OVs target and destroy cancer cells while sparing their normal counterparts. These viruses have been evaluated in numerous studies at both pre-clinical and clinical levels and the recent Food and Drug Administration (FDA approval of an oncolytic herpesvirus-based treatment raises optimism that OVs will become a therapeutic option for cancer patients. However, to improve clinical outcome, there is a need to increase OV efficacy. In addition to killing cancer cells directly through lysis, OVs can stimulate the induction of anti-tumour immune responses. The host immune system thus represents a “double-edged sword” for oncolytic virotherapy: on the one hand, a robust anti-viral response will limit OV replication and spread; on the other hand, the immune-mediated component of OV therapy may be its most important anti-cancer mechanism. Although the relative contribution of direct viral oncolysis and indirect, immune-mediated oncosuppression to overall OV efficacy is unclear, it is likely that an initial period of vigorous OV multiplication and lytic activity will most optimally set the stage for subsequent adaptive anti-tumour immunity. In this review, we consider the use of histone deacetylase (HDAC inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect. We also discuss an alternative approach, aimed at potentiating OV-elicited anti-tumour immunity through the blockade of immune checkpoints. We conclude by proposing a two-phase combinatorial strategy in which initial OV replication and spread is maximised through transient HDAC inhibition, with anti-tumour immune responses subsequently enhanced by immune checkpoint blockade.

  17. Anti-CD44-mediated blockade of leukocyte migration in skin-associated immune diseases.

    Science.gov (United States)

    Zöller, Margot; Gupta, Pooja; Marhaba, Rachid; Vitacolonna, Mario; Freyschmidt-Paul, Pia

    2007-07-01

    CD44 plays an important role in leukocyte extravasation, which is fortified in autoimmune diseases and delayed-type hypersensitivity (DTH) reactions. There is additional evidence that distinct CD44 isoforms interfere with the extravasation of selective leukocyte subsets. We wanted to explore this question in alopecia areata (AA), a hair-follicle centric autoimmune disease, and in a chronic eczema. The question became of interest because AA is treated efficiently by topical application of a contact sensitizer, such that a mild DTH reaction is maintained persistently. Aiming to support the therapeutic efficacy of a chronic eczema in AA by anti-CD44 treatment, it became essential to control whether a blockade of migration, preferentially of AA effector cells, could be achieved by CD44 isoform-specific antibodies. Anti-panCD44 and anti-CD44 variant 10 isoform (CD44v10) inhibited in vitro migration of leukocytes from untreated and allergen-treated, control and AA mice. In vivo, both antibodies interfered with T cell and monocyte extravasation into the skin; only anti-panCD44 prevented T cell homing into lymph nodes. Contributing factors are disease-dependent alterations in chemokine/chemokine receptor expression and a blockade of CD44 on endothelial cells and leukocytes. It is important that CD44 can associate with several integrins and ICAM-1. Associations depend on CD44 activation and vary with CD44 isoforms and leukocyte subpopulations. CD44 standard isoform preferentially associates with CD49d in T cells and CD44v10 with CD11b in monocytes. Accordingly, anti-panCD44 and anti-CD49d inhibit T cell, anti-CD11b, and anti-CD44v10 macrophage migration most efficiently. Thus, allergen treatment of AA likely can be supported by targeting AA T cells selectively via a panCD44-CD49d-bispecific antibody. PMID:17442857

  18. Viral vector-mediated selective and reversible blockade of the pathway for visual orienting in mice

    Directory of Open Access Journals (Sweden)

    Tadashi eIsa

    2013-10-01

    Full Text Available Recently, by using a combination of two viral vectors, we developed a technique for pathway-selective and reversible synaptic transmission blockade, and successfully induced a behavioral deficit of dexterous hand movements in macaque monkeys by affecting a population of spinal interneurons. To explore the capacity of this technique to work in other pathways and species, and to obtain fundamental methodological information, we tried to block the crossed tecto-reticular pathway, which is known to control orienting responses to visual targets, in mice. A neuron-specific retrograde gene transfer vector with the gene encoding enhanced tetanus neurotoxin (eTeNT tagged with enhanced green fluorescent protein (EGFP under the control of a tetracycline responsive element was injected into the left medial pontine reticular formation. 7–17 days later, an adeno-associated viral vector with a highly efficient Tet-ON sequence, rtTAV16, was injected into the right superior colliculus. 5–9 weeks later, the daily administration of doxycycline (Dox was initiated. Visual orienting responses toward the left side were impaired 1 - 4 days after Dox administration. Anti-GFP immunohistochemistry revealed that a number of neurons in the intermediate and deep layers of the right superior colliculus were positively stained, indicating eTeNT expression. After the termination of Dox administration, the anti-GFP staining returned to the baseline level within 28 days. A second round of Dox administration, starting from 28 days after the termination of the first Dox administration, resulted in the reappearance of the behavioral impairment. These findings showed that pathway-selective and reversible blockade of synaptic transmission causes behavioral effects also in rodents, and that the crossed tecto-reticular pathway surely controls visual orienting behaviors.

  19. Blockade of Rennin-Angiotensin system blunts the fibrotic response in experimental acute pyelonephritis

    Directory of Open Access Journals (Sweden)

    Singal A

    2005-01-01

    Full Text Available Aim: To study the impact of Renin-Angiotensin system blockade in experimental acute pyelonephritis, induced by a novel surgical approach via dorsal lumbotomy incision. Materials and Methods : 45 Adult female WISTAR rats aged 8-12 weeks, underwent direct inoculation of 0.1 ml of E.coli suspension into the parenchyma of the surgically exposed kidney. 3 groups of rats were studied: Group A - treated with antibiotics only; Group B- Captopril and antibiotics and Group C- Losartan and antibiotics. Changes of acute inflammation, parenchymal destruction and scarring were compared between the groups on histopathological sections. Kruskal-Wallis test was used for statistical analysis. Results : Changes consistent with acute pyelonephritis were seen in all the kidneys. Mean% scar area in Group A, Group B and Group C was 37.08±1.79, 24.40±1.88 and 24.68±1.32% respectively at end of six weeks. Mean tubular density in Group A, B and C was 17.26±1.92, 47.18±3.00 and 47.00±5.08-tubules/lac mm2 respectively. The differences between the control and the treated animals were significant, though the results did not differ between the losartan and captopril treated rats. Conclusions : Dorsal lumbotomy approach to the kidney provides a good exposure of the kidney. Induction of acute pyelonephritis by direct inoculation of bacteria into renal cortex produced a consistent scar at 6 weeks. Blockade of renin angiotensin system by either captopril or losartan decreased the renal scar area by almost 1/3 at 6 weeks.

  20. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    Science.gov (United States)

    Peppa, Dimitra; Micco, Lorenzo; Javaid, Alia; Kennedy, Patrick T F; Schurich, Anna; Dunn, Claire; Pallant, Celeste; Ellis, Gidon; Khanna, Pooja; Dusheiko, Geoffrey; Gilson, Richard J; Maini, Mala K

    2010-01-01

    NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright) NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade. PMID:21187913

  1. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    Directory of Open Access Journals (Sweden)

    Dimitra Peppa

    Full Text Available NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB, allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade.

  2. Blockade of beta-adrenoceptors enhances cAMP signal transduction in vivo

    Science.gov (United States)

    Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

    1998-01-01

    The aim of this study was to determine whether the blockade of beta-adrenoceptors would enhance cAMP-mediated signal transduction processes in vivo. The administration of the membrane permeable cAMP analogue, 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP, 10 micromol/kg, i.v.) produced an increase in heart rate (+27 +/- 2%, P < 0.05), a fall in mean arterial blood pressure (-21 +/- 3%, P < 0.05) and falls in hindquarter (-12 +/- 3%, P < 0.05) and mesenteric (-32 +/- 3%, P < 0.05) vascular resistances in pentobarbital-anesthetized rats. The beta-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.) lowered heart rate (-12 +/- 3%, P < 0.05) but did not affect mean arterial blood pressure or vascular resistances. The tachycardia, hypotension and vasodilation produced by 8-CPT-cAMP were exaggerated after administration of propranolol (P < 0.05 for all comparisons). The nitric oxide-donor, sodium nitroprusside (2 microg/kg, i.v.), produced falls in mean arterial blood pressure and vascular resistances of similar magnitude to those produced by 8-CPT-cAMP. These sodium nitroprusside-induced responses were unaffected by propranolol (P < 0.05 for all comparisons). Sodium nitroprusside also produced a minor increase in heart rate (+5 +/- 1%, P < 0.05) which was abolished by propranolol. These findings suggest that 8-CPT-cAMP directly increases heart rate and that blockade of beta-adrenoceptors enhances the potency of cAMP within the heart and vasculature.

  3. Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis.

    Science.gov (United States)

    Heppt, Markus V; Eigentler, Thomas K; Kähler, Katharina C; Herbst, Rudolf A; Göppner, Daniela; Gambichler, Thilo; Ulrich, Jens; Dippel, Edgar; Loquai, Carmen; Schell, Beatrice; Schilling, Bastian; Schäd, Susanne G; Schultz, Erwin S; Matheis, Fanny; Tietze, Julia K; Berking, Carola

    2016-08-01

    Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate. PMID:27294607

  4. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage.

    Science.gov (United States)

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-06-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.

  5. Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response

    Science.gov (United States)

    Rojas, Jennifer M.; Matsen, Miles E.; Mundinger, Thomas O.; Morton, Gregory J.; Stefanovski, Darko; Bergman, Richard N.; Kaiyala, Karl J.; Taborsky, Gerald J.; Schwartz, Michael W.

    2015-01-01

    Objective Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. Methods Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. Results Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if

  6. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise;

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function...

  7. Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

    OpenAIRE

    Lee, Hyung Eun; Lee, So Young; Kim, Ju Sun; Park, Se Jin; Kim, Jong Min; Lee, Young Woo; Jung, Jun Man; Kim, Dong hyun; Shin, Bum Young; Jang, Dae Sik; Kang, Sam Sik; Ryu, Jong Hoon

    2013-01-01

    In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activit...

  8. Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats.

    Science.gov (United States)

    Simmons, Steven J; Gentile, Taylor A; Mo, Lili; Tran, Fionya H; Ma, Sisi; Muschamp, John W

    2016-11-01

    Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated

  9. TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis

    DEFF Research Database (Denmark)

    Wedebye Schmidt, Esben Gjerløff; Larsen, Hjalte List; Kristensen, Nanna Ny;

    2013-01-01

    T helper (TH) 17 cells are believed to play a pivotal role in development of inflammatory bowel disease, and their contribution to intestinal inflammation has been studied in various models of colitis. TH17 cells produce a range of cytokines, some of which are potential targets for immunotherapy....... However, blockade of IL-17A alone with secukinumab was not effective in Crohn's disease. In this regard, the pathogenic impact of IL-17A versus IL-17F during intestinal inflammation is still unresolved....

  10. Angiotensin Receptor Blockade Increases Pancreatic Insulin Secretion and Decreases Glucose Intolerance during Glucose Supplementation in a Model of Metabolic Syndrome

    OpenAIRE

    Rodriguez, Ruben; Viscarra, Jose A.; Minas, Jacqueline N.; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M.

    2012-01-01

    Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT1) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test ...

  11. About the Need of Institutionalisation of Organisational Behaviour for Overcoming the Innovation Blockade in Poland and Ukraine

    Directory of Open Access Journals (Sweden)

    Teresa Bal-Woźniak

    2012-01-01

    Full Text Available On the example of Poland, paradoxes supporting the innovation blockade and limits of pro-innovation organisational behaviours are indicated in the article. Removing them requires reinstitutionalisation in the direction of subjective approach to innovativeness. The presented diagnosis concerning Poland may be used for defining conclusions in the sphere of actions intended for elimination of restrictions regarding proinnovation barriers of organisational behaviour also present in Ukraine.

  12. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

    OpenAIRE

    Phan, Giao Q.; Yang, James C.; Sherry, Richard M.; Hwu, Patrick; Topalian, Suzanne L.; Schwartzentruber, Douglas J.; Restifo, Nicholas P; Haworth, Leah R.; Seipp, Claudia A.; Freezer, Linda J.; Morton, Kathleen E.; Mavroukakis, Sharon A.; Duray, Paul H.; Steinberg, Seth M.; Allison, James P.

    2003-01-01

    Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c....

  13. Transforming growth factor-β inhibition and endothelin receptor blockade in rats with monocrotaline-induced pulmonary hypertension

    OpenAIRE

    Megalou, Aikaterini J; Glava, Chryssoula; Vilaeti, Agapi D.; Oikonomidis, Dimitrios L; Baltogiannis, Giannis G.; Papalois, Apostolos; Vlahos, Antonios P.; Kolettis, Theofilos M

    2012-01-01

    Transforming growth factor-β (TGF-β) inhibition is an investigational therapy for pulmonary arterial hypertension with promising results in experimental studies. The present work compared this approach with endothelin-receptor blockade and evaluated the effects of combined administration. Pulmonary arterial hypertension was induced by single monocrotaline injection (60 mg/kg) in 75 Wistar rats and 15 rats served as controls. Intervention groups consisted of treatment with an antibody against ...

  14. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell.

    Science.gov (United States)

    Bu, Lin-Lin; Zhao, Zhi-Li; Liu, Jian-Feng; Ma, Si-Rui; Huang, Cong-Fa; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2015-12-01

    Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. PMID:26556875

  15. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications.

    Science.gov (United States)

    De Rycke, L; Baeten, D; Kruithof, E; Van den Bosch, F; Veys, E M; De Keyser, F

    2005-01-01

    Since the first proof of efficacy of TNFalpha blockade, both the number of patients treated worldwide and the number of indications for treatment with TNFalpha blockers have grown steadily. Surprisingly, the profound immunomodulation induced by anti-TNFalpha therapy is associated with a relatively low incidence of immune-related complications such as lupus-like syndromes and demyelinating disease. This contrasts sharply with the prominent induction of autoantibodies such as antinuclear antibodies (ANA) and anti-dsDNA antibodies during TNFalpha blockade. Although this phenomenon has been recognized for several years, the clinical and biological implications are not yet fully understood. In this review, recent studies analysing the effect of TNFalpha blockade (infliximab and etanercept) on the ANA profile in autoimmune arthritis will be discussed. Taken together, these reports indicate that the prominent ANA and anti-dsDNA autoantibody response is 1) not a pure class effect of TNFalpha blockers, 2) independent of the disease background, 3) largely restricted to the induction of short-term IgM anti-dsDNA antibodies, and 4) not associated with other serological or clinically relevant signs of lupus. Nevertheless, a careful follow-up of patients treated with TNFalpha blockers remains mandatory, including monitoring for lupus-like characteristics.

  16. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade.

    Science.gov (United States)

    Xue, Wei; Metheringham, Rachael L; Brentville, Victoria A; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M; Durrant, Lindy G

    2016-06-01

    Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.

  17. The effect of subfornical organ lesions and ventricular blockade on drinking induced by angiotensin II.

    Science.gov (United States)

    Hoffman, W E; Phillips, M I

    1976-05-21

    The role of the subfornical organ (SFO) as the unique receptor site for the drinking behavior induced by intracranial injections of angiotensin II (AII) was investigated. It was found that: (1) drinking in response to intraventricular (IVT) injections of AII was reduced in 6 rats but was unchanged after 80-100% damage of the SFO in 4 cases; (2) reduction of drinking to lateral ventricular application of AII was seen with no apparent SFO damage in 4 rats; (3) recovery of the AII induced drinking deficit was consistently observed within a short time interval (14 days), even in those animals with complete SFO lesions: (4) the presence of ventricular debris was correlated with deficits in water intake to IVT angiotensin injections. In a second experiment artificial blockade of the ventricular space was produced by a plugging technique. Plugging the anterior third ventricle simulated the effects of SFO lesioning. It was concluded that the SFO is not a unique receptor area since the ventral anterior third ventricle is also sensitive for AII (IVT) induced drinking. If the SFO is a receptor site for AII circulating in the CSF it is probably not the only periventricular receptor site. Access of AII to the anterior ventral third ventricle appears to be essential for inducement of drinking. PMID:1276893

  18. Studies on neuromuscular blockade by boldine in the mouse phrenic nerve-diaphragm.

    Science.gov (United States)

    Kang, J J; Cheng, Y W; Fu, W M

    1998-02-01

    The effects of boldine [(S)-2,9-dihydroxyl-1,10-dimethoxy-aporphine], a major alkaloid in the leaves and bark of Boldo (Peumus boldus Mol.), on neuromuscular transmission were studied using a muscle phrenic-nerve diaphragm preparation. Boldine at concentrations lower than 200 microM preferentially inhibited, after an initial period of twitch augmentation, the nerve-evoked twitches of the mouse diaphragm and left the muscle-evoked twitches unaffected. The twitch inhibition could be restored by neostigmine or washout with Krebs solution. The twitches evoked indirectly and directly were both augmented initially, suggesting that the twitch augmentation induced by boldine was myogenic. Boldine inhibited the acetylcholine-induced contraction of denervated diaphragm dose-dependently with an IC50 value of 13.5 microM. At 50 microM, boldine specifically inhibited the amplitude of the miniature end plate potential. In addition, boldine was similar to d-tubocurarine in its action to reverse the neuromuscular blocking action of alpha-bungarotoxin. These results showed that the neuromuscular blockade by boldine on isolated mouse phrenic-nerve diaphragm might be due to its direct interaction with the postsynaptic nicotinic acetylcholine receptor. PMID:9541284

  19. Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

    Directory of Open Access Journals (Sweden)

    Sophie E. Broughton

    2014-07-01

    Full Text Available Interleukin-3 (IL-3 is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD, a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF, IL-5, and IL-13 receptors, adopting unique “open” and classical “closed” conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas “open-like” IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a “double hit” cytokine receptor blockade.

  20. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Hidehiro Sawa; Takashi Ueda; Yoshifumi Takeyama; Takeo Yasuda; Makoto Shinzeki; Takahiro Nakajima; Yoshikazu Kuroda

    2006-01-01

    AIM: To examine the effects of anti-high mobility group box 1 (HMGB1) neutralizing antibody in experimental severe acute pancreatitis (SAP).METHODS: SAP was induced by creating closed duodenal loop in C3H/HeN mice. SAP was induced immediately after intraperitoneal injection of anti-HMGB1 neutralizing antibody (200 μg). Severity of pancreatitis, organ injury (liver, kidney and lung), and bacterial translocation to pancreas was examined 12 h after induction of SAP.RESULTS: Anti-HMGB1 neutralizing antibody significantly improved the elevation of the serum amylase level and the histological alterations of pancreas and lung in SAP.Anti-HMGB1 antibody also significantly ameliorated the elevations of serum alanine aminotransferase and creatinine in SAP. However, anti-HMGB1 antibody worsened the bacterial translocation to pancreas.CONCLUSION: Blockade of HMGB1 attenuated the development of SAP and associated organ dysfunction,suggesting that HMGB1 may act as a key mediator for inflammatory response and organ injury in SAP.

  1. CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.

    Science.gov (United States)

    Lipina, Christopher; Vaanholt, Lobke M; Davidova, Anastasija; Mitchell, Sharon E; Storey-Gordon, Emma; Hambly, Catherine; Irving, Andrew J; Speakman, John R; Hundal, Harinder S

    2016-04-01

    The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant-mediated insulin sensitization in aged adipose tissue coincided with amelioration of low-grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging-related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging. PMID:26757949

  2. Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist.

    Science.gov (United States)

    Damond, Nicolas; Thorel, Fabrizio; Moyers, Julie S; Charron, Maureen J; Vuguin, Patricia M; Powers, Alvin C; Herrera, Pedro L

    2016-01-01

    Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced β-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of α-cells to reprogram into insulin production after extreme β-cell loss. α-to-β-cell conversion was improved in Gcgr(-/-) mice as a consequence of α-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future β-cell regeneration therapies relying upon α-cell reprogramming. PMID:27092792

  3. BLOCKADE OF PGE2, PGD2 RECEPTORS CONFERS PROTECTION AGAINST PREPATENT SCHISTOSOMIASIS MANSONI IN MICE.

    Science.gov (United States)

    Abdel-Ghany, Rasha; Rabia, Ibrahim; El-Ahwany, Eman; Saber, Sameh; Gamal, Rasha; Nagy, Faten; Mahmoud, Olaa; Hamad, Rabab Salem; Barakat, Walled

    2015-12-01

    Schistosomiasis is a chronic disease with considerable social impact. Despite the availability of affordable chemotherapy, drug treatment has not significantly reduced the overall number of disease cases. Among other mechanisms, the parasite produces PGE2 and PGD2 to evade host immune defenses. To investigate the role of PGE2 and PGD2 in schistosomiasis, we evaluated the effects of L-161,982, Ah6809 (PGE2 receptor antagonists alone of combined with each other) and MK-0524 (PGD2 receptor antagonist) during prepatent Schistosoma mansoni infection. Drugs were administered intraperitoneally an hour before and 24 hours after infection of C57BL/6 mice with 100 Schistosoma mansoni cercariae. L-161,982, Ah6809, their combination and MK-0524 caused partial protection against pre-patent S. mansoni infection which was mediated by biasing the immune response towards Th1 phenotype. These results showed that blockade of PGE2 and PGD2 receptors confers partial protection against pre-patent S. mansoni infection in mice and that they may be useful as adjunctive therapy to current anti-schistosomal drugs or vaccines. PMID:26939228

  4. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation

    Science.gov (United States)

    Seshasayee, Dhaya; Lee, Wyne P.; Zhou, Meijuan; Shu, Jean; Suto, Eric; Zhang, Juan; Diehl, Laurie; Austin, Cary D.; Meng, Y. Gloria; Tan, Martha; Bullens, Sherron L.; Seeber, Stefan; Fuentes, Maria E.; Labrijn, Aran F.; Graus, Yvo M.F.; Miller, Lisa A.; Schelegle, Edward S.; Hyde, Dallas M.; Wu, Lawren C.; Hymowitz, Sarah G.; Martin, Flavius

    2007-01-01

    Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses. PMID:18060034

  5. Enclosing resources on the islands of Kinmen and Xiamen: From war blockade to financializing natural heritage

    Directory of Open Access Journals (Sweden)

    Huei-Min Tsai

    2014-12-01

    Full Text Available The cultures of the islands of Kinmen and Xiamen, also respectively Quemoy and Amoy, are tightly interwoven with the South China coastal region of Fujian. Both archipelagos played important historical roles in coastal defense and have been home to many Overseas Chinese since the 19th Century. A decisive battle in the Chinese Civil War was fought on Kinmen in 1949, cutting off Kinmen’s connection with Xiamen and Fujian. Positioned on a critical frontier between the ‘free world’ and the ‘communist world’, self-sufficiency became militarily important in the event of a blockade. After 1979, Xiamen was designated as a special economic zone attracting large flows of foreign investment and experiencing rapid urban development. Since 2002 the scheduled ferries between Kinmen and Xiamen reopened connections between Kinmen and its neighbor cities in the People’s Republic of China. Renewed exchange highlighted the remarkable differences between the two archipelagos’ developmental paths that had developed over the course of the 53-year suspension of contact. This paper analyzes these divergent developmental paths through comparative case studies involving forms of enclosure. The wetland conservation at Tzi Lake in Kinmen as well as gentrified residential developments around Yuan-dan Lake in Xiamen are compared; changing relationships, the impact of the sudden re-opening of borders, new forms of enclosure under globalization; and regional flows of capitals are discussed.

  6. Blockade of glucocorticoid receptors improves cutaneous wound healing in stressed mice.

    Science.gov (United States)

    de Almeida, Taís Fontoura; de Castro Pires, Taiza; Monte-Alto-Costa, Andréa

    2016-02-01

    Stress is an important condition of modern life. The successful wound healing requires the execution of three major overlapping phases: inflammation, proliferation, and remodeling, and stress can disturb this process. Chronic stress impairs wound healing through the activation of the hypothalamic-pituitary-adrenal axis, and the glucocorticoids (GCs) hormones have been shown to delay wound closure. Therefore, the aim of this study was to investigate the effects of a GC receptor antagonist (RU486) treatment on cutaneous healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. Stressed and control animals were treated with RU486. A full-thickness excisional lesion was generated, and seven days later, lesions were recovered. The RU486 treatment improves wound healing since contraction takes place earlier in RU486-treated in comparison to non-treated mice, and the RU486 treatment also improves the angiogenesis in Stress+RU486 mice when compared to stressed animals. The Stress+RU486 group showed a decrease in inflammatory cell infiltration and in hypoxia-inducible factor-1α and inducible nitric oxide synthase expression; meanwhile, there was an increase in myofibroblasts quantity. In conclusion, blockade of GC receptors with RU486 partially ameliorates stress-impaired wound healing, suggesting that stress inhibits healing through more than one functional pathway.

  7. Functional capacity in healthy volunteers before and following beta-blockade with controlled-release metoprolol.

    Science.gov (United States)

    Rønnevik, P K; Nordrehaug, J E; von der Lippe, G

    1995-01-01

    The effects of the beta 1-selective beta-adrenergic blocker metoprolol on physiological responses, exercise capacity and gas exchange parameters were measured in healthy men using different graded bicycle exercise protocols on separate days before and following administration of 200 mg controlled-release metoprolol. Eleven men performed in randomised order maximal cardiopulmonary exercise testing on 50-W/6-min stage, 50-W/3-min stage and ramp (15-W/min-1) protocols. Peak heart rate and peak heart rate-blood pressure products were similar on all exercise protocols, and were significantly reduced by metoprolol. Submaximal and peak oxygen consumption were similar before and following beta-adrenoceptor blockade. Depending on the exercise protocol applied, an insignificant decrease of 4-10% in maximal cumulated exercise capacity (work-rate x time integral) was observed following administration of metoprolol. It is concluded that in healthy men evaluated with different exercise protocols the beta 1-selective controlled-release beta-adrenoceptor blocker metoprolol does not influence exercise capacity despite a marked reduction of heart rate and rate-pressure product. PMID:7589026

  8. Blockade of IL-36 receptor signaling does not prevent from TNF-induced arthritis.

    Directory of Open Access Journals (Sweden)

    Anja Derer

    Full Text Available INTRODUCTION: Interleukin (IL-36α is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R, its ligand IL-36α and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36α induces MAP-kinase and NFκB signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines. METHODS: To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36α signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36α was tested in murine and human osteoclast assays. RESULTS: Diseased mice showed an increased expression of IL-36R and IL-36α in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays. CONCLUSION: Thus we conclude that IL-36α does not affect the development of inflammatory arthritis.

  9. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    Science.gov (United States)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-02-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

  10. Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation.

    Science.gov (United States)

    Guinan, E C; Cole, G A; Wylie, W H; Kelner, R H; Janec, K J; Yuan, H; Oppatt, J; Brennan, L L; Turka, L A; Markmann, J

    2016-07-01

    Short-term outcomes of kidney transplantation have improved dramatically, but chronic rejection and regimen-related toxicity continue to compromise overall patient outcomes. Development of regulatory T cells (Tregs) as a means to decrease alloresponsiveness and limit the need for pharmacologic immunosuppression is an active area of preclinical and clinical investigation. Nevertheless, the immunomodulatory effects of end-stage renal disease on the efficacy of various strategies to generate and expand recipient Tregs for kidney transplantation are incompletely characterized. In this study, we show that Tregs can be successfully generated from either freshly isolated or previously cryopreserved uremic recipient (responder) and healthy donor (stimulator) peripheral blood mononuclear cells using the strategy of ex vivo costimulatory blockade with belatacept during mixed lymphocyte culture. Moreover, these Tregs maintain a CD3(+) CD4(+) CD25(+) CD127(lo) surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP3 Treg-specific demethylation region on allorestimulation with donor stimulator cells. These data support evaluation of this simple, brief Treg production strategy in clinical trials of mismatched kidney transplantation. PMID:26790369

  11. Effects of intraoperative magnetic resonance imaging on the neuromuscular blockade of vecuronium bromide in neurosurgery

    International Nuclear Information System (INIS)

    The effects of intraoperative magnetic resonance (iMR) imaging on the neuromuscular blockade of vecuronium bromide were investigated in neurosurgery. Fifty patients with American Society of Anesthesiologists grades I-II scheduled for craniotomy operation were divided into two groups (n=25 each) with no difference in demographic data: the iMR imaging group and control group. Train-of-four (TOF) stimulation through an accelerometer was used to monitor onset, maintenance, and recovery of muscle relaxation caused by vecuronium. Vecuronium bromide was intravenously injected after anesthesia induction. The dosage of vecuronium bromide in the iMR imaging group was larger than in the control group, but not significantly. Duration of vecuronium bromide administration and operation time were significantly longer in the iMR imaging group than in the control group. Time from drug discontinuation to operation termination, and to return to neurosurgery intensive care unit were not different. Time taken by first twitch (T1) in response to TOF stimulation to recover by 25%, and muscle relaxant recovery index were significantly greater in the control group than in the iMR imaging group. The body temperature of the patients increased gradually in the iMR imaging group but decreased in the control group. iMR imaging can prolong the operation time, increase the body temperature of the patient, and remarkably shorten the clinical action time and muscle relaxation recovery index of vecuronium. (author)

  12. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice.

    Science.gov (United States)

    González-Mariscal, Isabel; Krzysik-Walker, Susan M; Kim, Wook; Rouse, Michael; Egan, Josephine M

    2016-03-01

    The cannabinoid 1 receptor (CB1) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose-stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular cAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion. PMID:26724516

  13. [Effects of blockade of ionotropic glutamate receptors on the development of pentylenetetrazole kindling in mice].

    Science.gov (United States)

    Lukomskaia, N Ia; Lavrent'eva, V V; Starshinova, L A; Zhabko, E P; Gorbunova, L V; Tikhonova, T B; Gmiro, V E; Magazanik, L G

    2005-11-01

    Effects of mono- and dicationic derivatives of adamantane and phenylcyclohexyl on the petyleneterazole-induced (35 mg/kg i. p.) kindling were studied in the experiments on mice. Monocationic derivative of phenylcyclohexyl IEM-1921, effectively retarded the development of kindling beginning the dose 0.0001 microM/kg. Memantine: derivative of adamantane (derivative of adamatane) produced the same effect with 100-fold increased dose. Dicationic derivative ofphenylcyclohexyl: IEM-1925, is able to block equally the open channels of both NMDA and subtype of Ca-permeable AMPA receptors. Its effect on kindling differed markedly from selective NMDA antagonists (IEM-1921 and memantine) in more complicated dose-dependence. The retardation of kindling IEM-1925 was induced at 0.001 microM/kg. On the contrary, a 10-time lower dose: 0.0001 microM/kg, facilitated the development of kindling. The observed difference in the activity of selective NMDA antagonists and the drugs combining anti-NMDA and anti-AMPA potency indicates that both types of ionotropic glutamate receptors are involved in the mechanism of petyleneterazole-induced kindling. The integral effect of channel blockade evoked by drugs seems to be dependent not only upon the ratio of the receptor types but on the kinetics of drug action, too.

  14. The effect of opioid receptor blockade on the neural processing of thermal stimuli.

    Directory of Open Access Journals (Sweden)

    Eszter D Schoell

    Full Text Available The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

  15. Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders.

    Science.gov (United States)

    Zhong, Chunlong; Luo, Qizhong; Jiang, Jiyao

    2014-12-01

    The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.

  16. The effect of opioid receptor blockade on the neural processing of thermal stimuli.

    Science.gov (United States)

    Schoell, Eszter D; Bingel, Ulrike; Eippert, Falk; Yacubian, Juliana; Christiansen, Kerrin; Andresen, Hilke; May, Arne; Buechel, Christian

    2010-01-01

    The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone. PMID:20811582

  17. Comparison of electromyography and kinemyography during recovery from non-depolarising neuromuscular blockade.

    Science.gov (United States)

    Stewart, P A; Freelander, N; Liang, S; Heller, G; Phillips, S

    2014-05-01

    In this study, two commercially available quantitative neuromuscular function monitoring techniques, electromyography (EMG) and kinemyography (KMG), were compared with respect to repeatability and accuracy during late recovery from neuromuscular blockade. Train-of-four (TOF) ratios were recorded in 30 patients using KMG and EMG at the adductor pollicis muscle. Measurements were taken on the same hand using the Datex-Ohmeda NeuroMuscular Transmission monitor (GE Healthcare, Helsinki, Finland). Instrumental precision was evaluated using the coefficient of repeatability, while accuracy was assessed using the bias and limits of agreement. The coefficients of repeatability were similar for both techniques (0.035 for KMG and 0.043 for EMG), indicating a similar level of precision. KMG overestimated the TOF ratios measured with EMG with a bias of 0.11 (95% limits of agreement: -0.13 to 0.35). At a TOF ratio of 0.90 the bias was 0.08 (95% limits of agreement: -0.08 to 0.25). This means that at a TOF ratio of 0.90 measured with KMG will be approximately equivalent to a TOF ratio of 0.80 measured with EMG at the adductor pollicis muscle, but it may indeed be as low as 0.65 or as high as 1.00. Therefore, TOF ratios measured by KMG and EMG cannot be used interchangeably.

  18. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  19. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

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    Youmna E. DiStefano

    2015-01-01

    Full Text Available Peripheral nerve blockade (PNB is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR. Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD. Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year-old female undergoing TKR. A Humate-P intravenous infusion was started and the patient was positioned supinely. Using sterile technique with ultrasound guidance, a Contiplex 18 Gauge Tuohy needle was advanced in plane through the fascia iliaca towards the femoral nerve. A nerve catheter was threaded through the needle and secured without complications. Postoperatively, a levobupivacaine femoral catheter infusion was maintained, and twice daily Humate-P intravenous infusions were administered for 48 hours; enoxaparin thromboprophylaxis was initiated thereafter. The patient was discharged uneventfully on postoperative day 4. Given documentation of delayed, unheralded bleeding from PNB in coagulopathic patients, we recommend individualized PNB in vWD patients. Multidisciplinary team involvement is required to guide factor supplementation and thromboprophylaxis, as is close follow-up to elicit signs of bleeding throughout the delayed postoperative period.

  20. Immune checkpoint blockade therapy: The 2014 Tang prize in biopharmaceutical science

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    Ya-Shan Chen

    2015-02-01

    Full Text Available The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1 that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

  1. IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse

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    Kostek Matthew C

    2012-06-01

    Full Text Available Abstract Background IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse. Methods A monoclonal antibody against the IL-6 receptor (IL-6r mAb that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined. Results IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice. Conclusions These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.

  2. Use of beta adrenoceptor blockade during and after acute myocardial infarction.

    Science.gov (United States)

    Sleight, P

    1986-01-01

    In the last year, two large randomized controlled trials of metoprolol (MIAMI, almost 6,000 patients) and atenolol (ISIS 1, over 16,000 patients) given intravenously within 12 hours of the onset of acute myocardial infarction reduced mortality by about 15% in low-risk subjects. The reduction was significant for atenolol (2P = 0.04) but not for metoprolol, probably because of the smaller size of that trial. The reduction in mortality in both trials was nearly all in the first 36 hours, a finding that reduced the fears that the treatment might produce irreversible failure, shock, or heart block. Tolerance in these relatively low-risk subjects (control mortality about 5%) was good. Inotropes were used in 1-2% more subjects in the beta-blocked group but were effective in reversing the side effects without increasing mortality. No clear subgroups (age, sex, site, time from onset, initial blood pressure or heart rate) were found in which treatment was more beneficial. In the ISIS study, patients with higher heart rates were more likely to need inotropes after beta blockade and patients with long PR intervals at entry were more likely to develop block. Neither of these complications resulted in excess mortality in the blocked group, which suggests that these adverse effects were largely reversible. PMID:2871805

  3. Opioid receptor blockade and warmth-liking: effects on interpersonal trust and frontal asymmetry.

    Science.gov (United States)

    Schweiger, Desirée; Stemmler, Gerhard; Burgdorf, Christin; Wacker, Jan

    2014-10-01

    The emotion 'warmth-liking' (WL) associated with feelings of affection and acceptance is regularly activated in social contexts. WL has been suggested to be more closely related to the consummatory phase of post-goal attainment positive affect than to pre-goal attainment positive affect/approach motivation and to be partly mediated by brain opioids. To validate these assumptions we employed film/imagery to induce either a neutral emotional state or WL in female participants after intake of either placebo or the opioid antagonist naltrexone. Dependent variables were emotion self-report, interpersonal trust (TRUST, i.e. a behavioral indicator of WL) and frontal asymmetry (i.e. an electroencephalogram (EEG) indicator of approach motivation/behavioral activation). We found that participants reported more WL in the placebo/WL group than in the placebo/neutral group and both naltrexone groups. In addition, TRUST increased in the WL group after placebo, but not after naltrexone, and this pattern was reversed in the neutral control groups. Consequently, opioid blockade suppressed or even reversed the effects of the WL induction on the levels of self-report and behavior, respectively. In addition, we observed reduced relative left-frontal asymmetry in the WL (vs neutral) group, consistent with reduced approach motivation. Overall, these results suggest opioidergic influences on WL and TRUST and reduced approach motivation/behavioral activation for the positive emotion WL.

  4. Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson's disease.

    Science.gov (United States)

    Aidi-Knani, Sabrine; Regaya, Imed; Amalric, Marianne; Mourre, Christiane

    2015-02-01

    The striatum, a major input structure of basal ganglia, integrates glutamatergic cortical and thalamic inputs to control psychomotor behaviors. Nigrostriatal dopamine (DA) neurodegeneration in Parkinson's disease causes a loss of spinal and glutamatergic synapses in the striatal medium spiny neurons (MSNs). Adaptive responses, a form of homeostatic plasticity, to these changes are caused by a decrease in a potassium Kv4 channel-dependent inactivating A-type potassium (KIA) current that increases the intrinsic excitability of MSNs. Nevertheless, the functional outcome of these compensatory mechanisms does not allow adequate behavioral recovery in vivo. We thus addressed the question of whether further blockade of Kv4 activity could enhance the striatal responsiveness of MSNs to DA depletion and restore normal function in vivo. To test this hypothesis, we examined the effects of a selective blocker of Kv4 channels, AmmTX3, on the motor, cognitive, and emotional symptoms produced by 6-hydroxydopamine lesions of the nigrostriatal DA pathway in rats. Striatal infusion of AmmTX3 (0.2-0.4 μg) reduced motor deficits, decreased anxiety, and restored short-term social and spatial memories. These results underlie the importance of Kv4 channels as players in the homeostatic responses, and, more importantly, provide a potential target for adjunctive therapies for Parkinson's disease. PMID:25356731

  5. Blockade of TGF-β 1 Signalling Inhibits Cardiac NADPH Oxidase Overactivity in Hypertensive Rats

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    José Luis Miguel-Carrasco

    2012-01-01

    Full Text Available NADPH oxidases constitute a major source of superoxide anion (⋅O2 - in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-β 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-β 1 receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-β 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-β 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-β 1.

  6. Blockade in a silicon double quantum dot via the valley degree of freedom

    Science.gov (United States)

    Perron, Justin; Gullans, Michael J.; Taylor, Jacob M.; Stewart, M. D., Jr.; Zimmerman, Neil M.

    Measuring electrical transport through double quantum dots (DQDs) is a useful way of illuminating several aspects of the states of the carriers. We show transport measurements through a silicon DQD formed in a mesa etched nanowire. Comparing the data at positive and negative bias voltage we observe a size asymmetry in the region of allowed current typically associated with Pauli spin blockade (PSB). However, the qualitative features of the asymmetry in our data, including i) lack of odd/even filling, ii) same polarity of asymmetry across many bias triangles, iii) lack of systematic dependence on magnetic field, and iv) a dependence on gate voltages, are all in disagreement with the predictions of PSB. In contrast, we have developed a model based on the selective filling of valley states in the DQD and the conservation of the valley degree of freedom during tunneling that predicts all of the qualitative features in our data. Joint Quantum Institute, National Institute of Standards and Technology, Gaithersburg, Maryland 20899.

  7. Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model.

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    Zineb Belcaid

    Full Text Available BACKGROUND: Glioblastoma (GBM is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4 blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137 is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. METHODS: GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. RESULTS: Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. CONCLUSION: Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy

  8. Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

    OpenAIRE

    Stephen R Morairty; Revel, Florent G.; Pari Malherbe; Jean-Luc Moreau; Daniel Valladao; Wettstein, Joseph G; Kilduff, Thomas S.; Edilio Borroni

    2012-01-01

    The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexa...

  9. ICOS and CD28: similar or separate costimulators of T cells?

    NARCIS (Netherlands)

    Berkel, Elisabeth Anna Theodora van

    2006-01-01

    The human body contains an important mechanism to protect itself against pathogens like bacteria or viruses: the immune system. T cells are central cells of the immune system and are essential in the defence against these foreign invaders. When no bacteria or viruses are around, T cell circulate in

  10. Tongxinluo inhibits vascular inflammation and neointimal hyperplasia through blockade of the positive feedback loop between miR-155 and TNF-α.

    Science.gov (United States)

    Zhang, Ruo-nan; Zheng, Bin; Li, Li-min; Zhang, Jing; Zhang, Xin-hua; Wen, Jin-kun

    2014-08-15

    Tongxinluo (TXL), a traditional Chinese medicine, has multiple vasoprotective effects, including anti-inflammation. MicroRNA-155 (miR-155) is involved in vascular inflammation and atherosclerosis. However, a direct relationship between TXL and miR-155 in the development of vascular inflammation and remodeling had not yet been shown. The objective of the present study was to investigate whether TXL exerts an inhibitory effect on the vascular inflammatory response and neointimal hyperplasia by regulating miR-155 expression. Using the carotid artery ligation model in mice, we have shown that TXL dose dependently inhibited neointimal formation and reduced the vascular inflammatory response by inhibiting inflammatory cytokine production and macrophage infiltration. miR-155 was induced by carotid artery ligation, and neointimal hyperplasia was strongly reduced in miR-155(−/−) mice. In contrast, miR-155 overexpression partly reversed the inhibitory effect of TXL on neointimal hyperplasia. In bone marrow-derived macrophages, miR-155 and TNF-α formed a positive feedback loop to promote the inflammatory response, which could be blocked by TXL. Furthermore, TXL increased Akt1 protein expression and phosphorylation in TNF-α-stimulated marrow-derived macrophages, and knockdown of Akt1 abrogated the TXL-induced suppression of miR-155. In conclusion, TXL inhibits the vascular inflammatory response and neointimal hyperplasia induced by carotid artery ligation in mice. Suppression of miR-155 expression mediated by Akt1 and blockade of the feedback loop between miR-155 and TNF-α are important pathways whereby TXL exerts its vasoprotective effects. PMID:24951754

  11. Nonspecific blockade of vascular free radical signals by methylated arginine analogues

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    Pedro M.A.

    1998-01-01

    Full Text Available Methylated arginine analogues are often used as probes of the effect of nitric oxide; however, their specificity is unclear and seems to be frequently overestimated. This study analyzed the effects of NG-methyl-L-arginine (L-NMMA on the endothelium-dependent release of vascular superoxide radicals triggered by increased flow. Plasma ascorbyl radical signals measured by direct electron paramagnetic resonance spectroscopy in 25 rabbits increased by 3.8 ± 0.7 nmol/l vs baseline (28.7 ± 1.4 nmol/l, P<0.001 in response to papaverine-induced flow increases of 121 ± 12%. In contrast, after similar papaverine-induced flow increases simultaneously with L-NMMA infusions, ascorbyl levels were not significantly changed compared to baseline. Similar results were obtained in isolated rabbit aortas perfused ex vivo with the spin trap a-phenyl-N-tert-butylnitrone (N = 22. However, in both preparations, this complete blockade was not reversed by co-infusion of excess L-arginine and was also obtained by N-methyl-D-arginine, thus indicating that it is not related to nitric oxide synthase. L-arginine alone was ineffective, as previously demonstrated for NG-methyl-L-arginine ester (L-NAME. In vitro, neither L-arginine nor its analogues scavenged superoxide radicals. This nonspecific activity of methylated arginine analogues underscores the need for careful controls in order to assess nitric oxide effects, particularly those related to interactions with active oxygen species.

  12. Neuromuscular blockade in children Bloqueadores neuromusculares em crianças

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    João Fernando Lourenço de Almeida

    2000-06-01

    Full Text Available Neuromuscular blocking agents (NMBAs have been widely used to control patients who need to be immobilized for some kind of medical intervention, such as an invasive procedure or synchronism with mechanical ventilation. The purpose of this monograph is to review the pharmacology of the NMBAs, to compare the main differences between the neuromuscular junction in neonates, infants, toddlers and adults, and moreover to discuss their indications in critically ill pediatric patients. Continuous improvement of knowledge about NMBAs pharmacology, adverse effects, and the many other remaining unanswered questions about neuromuscular junction and neuromuscular blockade in children is essential for the correct use of these drugs. Therefore, the indication of these agents in pediatrics is determined with extreme judiciousness. Computorized (Medline 1990-2000 and active search of articles were the mechanisms used in this review.Os bloqueadores neuromusculares têm sido amplamente utilizados para controlar pacientes que necessitem imobilidade para algum tipo de intervenção médica, desde a realização de procedimentos invasivos até a obtenção de sincronismo com a ventilação mecânica. O objetivo básico desta monografia é revisar a farmacologia dos principais bloqueadores neuromusculares, analisar as diferenças existentes na junção neuromuscular de neonatos, lactentes, pré-escolares e adultos, além de discutir suas indicações em pacientes criticamente enfermos internados em unidade de terapia intensiva pediátrica. Revisão computadorizada da literatura (Medline 1990-2000 associado a busca ativa de artigos compuseram o mecanismo de busca dos dados desta revisão.

  13. Cardioprotection conferred by exercise training is blunted by blockade of the opioid system

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    Tatiana F. G Galvão

    2011-01-01

    Full Text Available OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reperfusion models. METHODS: Male Wistar rats (n = 76 were randomly assigned to 7 groups: (1 control; (2 exercise training; (3 morphine; (4 intermittent ischemia-reperfusion (three alternating periods of left anterior descending coronary occlusion and reperfusion; (5 exercise training+morphine; (6 naloxone (a non-selective opioid receptor blocker plus morphine; (7 naloxone before each exercise-training session. Myocardial infarction was established in all groups by left anterior descending coronary ligation. Exercise training was performed on a treadmill for 60 minutes, 5 times/week, for 12 weeks, at 60% peak oxygen (peak VO2. Infarct size was histologically evaluated. RESULTS: Exercise training significantly increased exercise capacity and ΔVO2 (VO2 peak - VO2 rest (p<0.01 vs. sedentary groups. Compared with control, all treatment groups except morphine plus naloxone and exercise training plus naloxone showed a smaller infarcted area (p<0.05. No additional decrease in infarct size occurred in the exercise training plus morphine group. No difference in myocardial capillary density (p = 0.88 was observed in any group. CONCLUSIONS: Exercise training, morphine, exercise training plus morphine and ischemia-reperfusion groups had a smaller infarcted area than the control group. The effect of chronic exercise training in decreasing infarct size seems to occur, at least in part, through the opioid receptor stimulus and not by increasing myocardial perfusion

  14. Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade.

    Science.gov (United States)

    Desposito, Dorinne; Chollet, Catherine; Taveau, Christopher; Descamps, Vincent; Alhenc-Gelas, François; Roussel, Ronan; Bouby, Nadine; Waeckel, Ludovic

    2016-01-01

    Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B1 and B2 receptors (B1R and B2R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B1R and B2R) and antagonist (B2R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1-2-fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B1R agonist had no effect on wound healing. In contrast, the B2R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B2R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B2R antagonist. Interestingly, in the two mouse models of diabetes, the B2R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor α) mRNAs. Thus stimulation of kinin B2 receptor impairs skin wound healing in mice. B2R activation occurs in the diabetic skin and delays wound healing. B2R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers.

  15. Evidence for improved cardiac performance after beta-blockade in patients with coronary artery disease.

    Science.gov (United States)

    Reale, A; Nigri, A; Gioffrè, P A

    1976-01-01

    The study was undertaken to investigate the acute haemodynamic effects of bunitrolol (0-2-hydroxy-3-(tert.butylamino)-propoxy)-bity. Right and left heart catheterization was performed in eleven patients with documented coronary artery disease. After bunitrolol (10 mg i.v.), there was a statistically significant decrease in left ventricular and aortic systolic pressures left ventricular end-diastolic pressure, aortic diastolic and mean pressures, pressure-rate product and compliance index (delta P/delta V). Left ventricular dp/dt, left ventricular dp/dt over isovolumic pressure, systemic resistance and heart rate tended to decrease, stroke volume and left ventricular stroke work index tended to increase, without statistical significance. Cardiac index showed individual variations, the mean values for the group being unchanged. Correlation of left ventricular end-diastolic pressure and left ventricular stroke work index showed a shift toward improved ventricular function curve in most cases, deterioration in no instance. Supine exercise was performed in ten patients. Angina occurred in nine patients; in five only before and in four before and after beta-blockade. Post-drug exercise heart rate, pressure-rate product and left ventricular end-diastolic pressure were significantly lower, the latter also in the four patients who still presented exercise angina. It is concluded that certain beta-blockers can improve cardiac performance at rest and during exercise in patients with coronary artery disease. This is explainable on the basis of a more favourable balance between oxygen supply and demand, together with a less marked negative inotropic effect due to the partial agonist activity of the agent used in the study. PMID:18374

  16. Effect of Acupuncture Signal after Brachial Plexus Blockade on Cerebral Blood Perfusion and Brain Cell Function

    Institute of Scientific and Technical Information of China (English)

    任永功; 郭长春; 贾少微

    2003-01-01

    Objective: Using single photon emission computed tomography (SPECT) to observe the influence of the up-transmitting of acupuncture signal into the brain in health volunteers whose nerve trunk was blocked by anesthetics. Methods: Thirty-one healthy volunteers were divided into two groups, the control group of 20 cases, and the brachial plexus blockade (BPB) group of 11 cases, with supraclavicular BPB route adopted. With the control group 2 acupoints were randomly selected (Hegu and Quchi of both sides), while with the BPB group Hegu and Quchi of anesthetic arm side were selected. Siemens ECAM/ICON SPECT system was used to conduct brain imaging using double imaging assay before acupuncture and 99mTc-ECD imaging agent during acupuncture for cerebral perfusion. The data were quantitatively analyzed by blood functional changing rate (BFCR%) mathematics model. Results: Before acupuncture, the control and BPB groups showed insignificant change by SPECT, but after electro-acupuncture (EA), the control group displayed improved motor and sensory cortex excitability in basal nuclei, contra-lateral thalamus, parietal and frontal lobe; while BPB group was characterized with reduction of the blood perfusion and cell function of contra-lateral thalamus of anesthetized arm. The difference between the two groups was significant (P<0.01). Conclusion: (1) After BPB, the up-transmitting of the acupuncture signal via upper limb into the brain, and its strength was impaired or blocked; (2) After BPB, the effect of acupuncture on cerebral perfusion and brain cell function of contra-lateral thalamus was impaired or blocked.

  17. The blockade of cyclooxygenases-1 and -2 reduces the effects of hypoxia on endothelial cells

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    Gloria M.A.

    2006-01-01

    Full Text Available Hypoxia activates endothelial cells by the action of reactive oxygen species generated in part by cyclooxygenases (COX production enhancing leukocyte transmigration. We investigated the effect of specific COX inhibition on the function of endothelial cells exposed to hypoxia. Mouse immortalized endothelial cells were subjected to 30 min of oxygen deprivation by gas exchange. Acridine orange/ethidium bromide dyes and lactate dehydrogenase activity were used to monitor cell viability. The mRNA of COX-1 and -2 was amplified and semi-quantified before and after hypoxia in cells treated or not with indomethacin, a non-selective COX inhibitor. Expression of RANTES (regulated upon activation, normal T cell expressed and secreted protein and the protective role of heme oxygenase-1 (HO-1 were also investigated by PCR. Gas exchange decreased partial oxygen pressure (PaO2 by 45.12 ± 5.85% (from 162 ± 10 to 73 ± 7.4 mmHg. Thirty minutes of hypoxia decreased cell viability and enhanced lactate dehydrogenase levels compared to control (73.1 ± 2.7 vs 91.2 ± 0.9%, P < 0.02; 35.96 ± 11.64 vs 22.19 ± 9.65%, P = 0.002, respectively. COX-2 and HO-1 mRNA were up-regulated after hypoxia. Indomethacin (300 µM decreased COX-2, HO-1, hypoxia-inducible factor-1alpha and RANTES mRNA and increased cell viability after hypoxia. We conclude that blockade of COX up-regulation can ameliorate endothelial injury, resulting in reduced production of chemokines.

  18. Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression

    Institute of Scientific and Technical Information of China (English)

    TIAN Xin-rui; TIAN Xin-li; BO Jian-ping; LI Shao-gang; LIU Zhuo-la; NIU Bo

    2011-01-01

    Background The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore,antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation.Methods In this study, we synthesized a 20-mer phosphorothioate antisense oligonucleotide (ASODN) overlapping the translation starting site of STAT6 and constructed STAT6 antisense RNA (pANTI-STAT6), then transfected them into murine spleen lymphocytes and analyzed the effects of antagonizing STAT6 function in vitro and in a murine model of asthma.Results In vitro, we showed suppression of STAT6 expression and interleukin (IL)-4 production of lymphocytes by STAT6 ASODN. This effect was more prominent when cells were cultured with pANTI-STAT6. In a murine model of asthma associated with allergic pulmonary inflammation in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate (FITC)-labeled STAT6 ASODN to DNA uptake in lung cells was accompanied by a reduction of intracellular STAT6 expression. Such intrapulmonary blockade of STAT6 expression abrogated signs of lung inflammation, infiltration of eosinophils and Th2 cytokine production.Conclusion These data suggest a critical role of STAT6 in the pathogenesis of asthma and the use of local delivery of STAT6 ASODN as a novel approach for the treatment of allergic airway inflammation such as in asthma.

  19. Effect of Intermittent Androgen Blockade on the Quality of Life of Patients with Advanced Prostate Carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    OBJECTIVE To investigate the effect of intermittent androgen blockade (IAB) on the quality of life (QOL) of patients with advanced prostatic carcinoma (APC).METHODS Investigations on the QOL of 51 APC patients receiving IAB treatment, totaling 3 times, i.e. 6 months before and after, and 12 months after treatment, were perform using the EORTC QLQ-C30 measuring scale and QLQ-PR25 scale.RESULTS Although IAB became an economic burden for the families, it was lessened during the intermission (P<0.05). The overall health status significantly improved 6 months after IAB treatment (P<0.01), especially during the intermission (P<0.05), with a total or local easement of pain (P<0.01) and an improvement of urinary function (P<0.01). Although there was impairment,to various degrees, in many functions of the patients on the 6th month of treatment, such as the physical function (P<0.05), role function (P<0.05), the emotional (P<0.01) and the social functions (P<0.01), with an enhancement of fatigue (P<0.01), these functions gradually recovered by the 12th month as the intermission started. Treatment-related symptoms such as flushing and mammary swelling significantly emerged on the 6th treatment month (P<0.01), and lessened on the 12th (P<0.01). During the treatment period,therewas an notable drop in sexual interest (P<0.01), with a deprivation of sex life, but revived to various degrees during the intermission (P<0.01).CONCLUSION Although IAB treatment of APC patients did impair the physiologic and psychologic status of patients to varying degrees, these were improved and restored during the intermission.

  20. Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice

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    John Martin Barrett

    2015-08-01

    Full Text Available Retinitis pigmentosa (RP is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA was recently shown to diminish RGC hyperactivity and improve the signal-to-noise ratio (SNR of RGC responses to light flashes and electrical stimulation in the rd10 mouse model of RP. We sought to extend these results to spatiotemporally patterned optogenetic stimulation in the faster-degenerating rd1 model and compare the effectiveness of a number of drugs known to disrupt rd1 hyperactivity.We crossed rd1 mice with a transgenic mouse line expressing the light-sensitive cation channel channelrhodopsin2 (ChR2 in RGCs, allowing them to be stimulated directly using high-intensity blue light. We used 60-channel ITO multielectrode arrays to record ChR2-mediated RGC responses from wholemount, ex-vivo retinas to full-field and patterned stimuli before and after application of MFA, 18-ß-glycyrrhetinic acid (18BGA, another gap junction blocker or flupirtine (Flu, a Kv7 potassium channel opener. All three drugs decreased spontaneous RGC firing, but 18BGA and Flu also decreased the sensitivity of RGCs to optogenetic stimulation. Nevertheless, all three drugs improved the SNR of ChR2-mediated responses. MFA also made it easier to discern motion direction of a moving bar from RGC population responses.Our results support the hypothesis that reduction of pathological RGC spontaneous activity characteristic in retinal degenerative disorders may improve the quality of visual responses in retinal prostheses and they provide insights into how best to achieve this for optogenetic

  1. Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice.

    Science.gov (United States)

    Barrett, John M; Degenaar, Patrick; Sernagor, Evelyne

    2015-01-01

    Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was recently shown to diminish RGC hyperactivity and improve the signal-to-noise ratio (SNR) of RGC responses to light flashes and electrical stimulation in the rd10 mouse model of RP. We sought to extend these results to spatiotemporally patterned optogenetic stimulation in the faster-degenerating rd1 model and compare the effectiveness of a number of drugs known to disrupt rd1 hyperactivity. We crossed rd1 mice with a transgenic mouse line expressing the light-sensitive cation channel channelrhodopsin2 (ChR2) in RGCs, allowing them to be stimulated directly using high-intensity blue light. We used 60-channel ITO multielectrode arrays to record ChR2-mediated RGC responses from wholemount, ex-vivo retinas to full-field and patterned stimuli before and after application of MFA, 18-β-glycyrrhetinic acid (18BGA, another gap junction blocker) or flupirtine (Flu, a Kv7 potassium channel opener). All three drugs decreased spontaneous RGC firing, but 18BGA and Flu also decreased the sensitivity of RGCs to optogenetic stimulation. Nevertheless, all three drugs improved the SNR of ChR2-mediated responses. MFA also made it easier to discern motion direction of a moving bar from RGC population responses. Our results support the hypothesis that reduction of pathological RGC spontaneous activity characteristic in retinal degenerative disorders may improve the quality of visual responses in retinal prostheses and they provide insights into how best to achieve this for optogenetic prostheses

  2. Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans.

    Science.gov (United States)

    Eippert, Falk; Bingel, Ulrike; Schoell, Eszter; Yacubian, Juliana; Büchel, Christian

    2008-05-21

    The endogenous opioid system is involved in fear learning in rodents, as opioid agonists attenuate and opioid antagonists facilitate the acquisition of conditioned fear. It has been suggested that an opioidergic signal, which is engaged through conditioning and acts inhibitory on unconditioned stimulus input, is the source of these effects. To clarify whether blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans, and to elucidate the neural underpinnings of such an effect, we used functional magnetic resonance imaging in combination with behavioral recordings and a double-blind pharmacological intervention. All subjects underwent the same classical fear-conditioning paradigm, but subjects in the experimental group received the opioid antagonist naloxone before and during the experiment, in contrast to subjects in the control group, who received saline. Blocking endogenous opioid neurotransmission with naloxone led to more sustained responses to the unconditioned stimulus across trials, evident in both behavioral and blood oxygen level-dependent responses in pain responsive cortical regions. This effect was likely caused by naloxone blocking conditioned responses in a pain-inhibitory circuit involving opioid-rich areas such as the rostral anterior cingulate cortex, amygdala, and periaqueductal gray. Most importantly, naloxone enhanced the acquisition of fear on the behavioral level and changed the activation profile of the amygdala: whereas the control group showed rapidly decaying conditioned responses across trials, the naloxone group showed sustained conditioned responses in the amygdala. Together, these results demonstrate that in humans the endogenous opioid system has an inhibitory role in the acquisition of fear. PMID:18495880

  3. Vasopressin responses to unloading arterial baroreceptors during cardiac nerve blockade in conscious dogs

    Science.gov (United States)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1992-01-01

    We examined the relative contributions of afferent input from the heart and from arterial baroreceptors in the stimulation of arginine vasopressin (AVP) secretion in response to hypotension caused by thoracic inferior vena caval constriction (TIVCC). Afferent input from cardiac receptors was reversibly blocked by infusing 2% procaine into the pericardial space to anesthetize the cardiac nerves. Acute cardiac nerve blockade (CNB) alone caused a rise in mean arterial pressure (MAP) of 24 +/- 3 mmHg but no change in plasma AVP. If the rise in MAP was prevented by TIVCC, plasma AVP increased by 39 +/- 15 pg/ml, and if MAP was allowed to increase and then was forced back to control by TIVCC, plasma AVP increased by 34 +/- 15 pg/ml. Thus the rise in MAP during CNB stimulated arterial baroreceptors, which in turn compensated for the loss of inhibitory input from cardiac receptors on AVP secretion. These results indicate that the maximum secretory response resulting from complete unloading of cardiac receptors at a normal MAP results in a mean increase in plasma AVP of 39 pg/ml in this group of dogs. When MAP was reduced 25% below control levels (from 95 +/- 5 to 69 +/- 3 mmHg) by TIVCC during pericardial saline infusion, plasma AVP increased by 79 +/- 42 pg/ml. However, the same degree of hypotension during CNB (MAP was reduced from 120 +/- 5 to 71 +/- 3 mmHg) led to a greater (P less than 0.05) increase in plasma AVP of 130 +/- 33 pg/ml. Because completely unloading cardiac receptors can account for an increase of only 39 pg/ml on average in this group of dogs, the remainder of the increase in plasma AVP must be due to other sources of stimulation. We suggest that the principal stimulus to AVP secretion after acute CNB in these studies arises from unloading the arterial baroreceptors.

  4. Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains.

    Directory of Open Access Journals (Sweden)

    Corinne Berthonneche

    Full Text Available We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the beta-adrenergic receptor blocker atenolol or under a low and a high dose of the beta-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H(2>0.7 and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to beta-stimulation and beta-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains.

  5. The effects of K+ channel blockade on eccentric and isotonic twitch and fatiguing contractions in situ

    Directory of Open Access Journals (Sweden)

    Michelle eMoyer

    2012-09-01

    Full Text Available K+ channel blockers like 3,4-diaminopyridine (DAP can double isometric muscle force. Functional movements require more complex concentric and eccentric contractions, however the effects of K+ channel blockade on these types of contractions in situ are unknown. Extensor digitorum longus (EDL muscles were stimulated in situ with and without DAP in anesthetized rats and fatigability was addressed using a series of either concentric or eccentric contractions. During isotonic protocols (5-100% load, DAP significantly shifted shortening- and maximum shortening velocity-load curves upward and to the right and increased power and work. Maximum shortening, maximum shortening velocity and power doubled while work increased by approximately 250% during isotonic contraction at 50% load. During isotonic fatigue, DAP significantly augmented maximum shortening, work, shortening velocity and power. During constant velocity eccentric protocols (2-12 mm/s, DAP increased muscle force during eccentric contractions at 6, 8, 10 and 12 mm/s. During eccentric contraction at a constant velocity of 6mm/s while varying the stimulation frequency, DAP significantly increased muscle force during 20, 40 and 70 Hz . The effects of DAP on muscle contractile performance during eccentric fatigue varied with level of fatigue. DAP-induced contractile increases during isotonic contractions were similar to those produced during previously studied isometric contractions, while the DAP effect during eccentric contractions was more modest. These findings are especially important in attempting to optimize functional electrical stimulation parameters for spinal cord injury patients while also preventing rapid fatigue of those muscles.

  6. Reversal of ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade.

    Science.gov (United States)

    Emanuele, M A; LaPaglia, N; Steiner, J; Jabamoni, K; Hansen, M; Kirsteins, L; Emanuele, N V

    1998-09-01

    Teenage drinking is a major problem in the United States, as well as abroad. Besides psychosocial implications, ethanol (EtOH) has detrimental effects on the reproductive system. Clinical problems associated with reduced reproductive hormones include osteoporosis, decreased muscle function, anemia, altered immune function, prostate involution, and decreased reproductive abilities. Education coupled with strategies aimed at preventing these deleterious consequences even in the face of continued EtOH intake is extremely important. We have tested the possibility that naltrexone, a drug currently used in patients to decrease alcohol craving, might also prevent the fall in the male hormone, testosterone, caused by EtOH exposure. Rats aged 35 days old (prepubertal), 45 days old (midpubertal), and 55 days old (late pubertal) were injected (intraperitoneally) with either saline, EtOH, naltrexone, or EtOH plus naltrexone. In the two older age groups, EtOH significantly suppressed testosterone, which was prevented by administration of naltrexone. In the youngest animals, there was no treatment effect presumably due to low basal levels of testosterone. EtOH similarly reduced luteinizing hormone (LH), but this suppression was not prevented by naltrexone. There was no consistent effect of any treatment on hypothalamic concentration of pro-LH releasing hormone (RH) (LHRH), LHRH, or on steady-state levels of LHRH mRNA. We conclude that, as animals progress through puberty, EtOH suppresses LH and testosterone. The testosterone decline can be prevented by opiate blockade with naltrexone, an effect primarily seen at gonadal level. Thus, naltrexone, a drug already used clinically to reduce EtOH intake, also has protective physiological effects on the endocrine system. PMID:9756033

  7. Reversal of chronic ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade.

    Science.gov (United States)

    Emanuele, N V; LaPaglia, N; Steiner, J; Kirsteins, L; Emanuele, M A

    1999-01-01

    Teenage drinking continues to be a significant problem in the U.S., as well as abroad. We have previously demonstrated that opiate blockade with naltrexone, a drug currently used in patients to diminish alcohol craving, prevented the fall in serum testosterone seen after acute ethanol (EtOH) exposure in young, peripubertal male rats. To follow-up on this reversal, a series of experiments was performed to determine if naltrexone would also prevent the testosterone suppression caused by chronic EtOH exposure. Peripubertal rats either 45 days old (mid-pubertal) or 55 days old (late pubertal) were fed an EtOH-containing liquid diet or pair-fed control diet for 14 days. Each animal was implanted with either a naltrexone containing or placebo pellet before starting the liquid diet. In each age group, EtOH alone significantly suppressed testosterone, whereas naltrexone prevented this fall, although it had no effect alone. Serum luteinizing hormone was also suppressed by EtOH; however, naltrexone did not abrogate this fall. In the 45-day-old animals, beta-luteinizing hormone mRNA levels rose significantly in the EtOH group, but not when naltrexone was coadministered with EtOH. There was no change in hypothalamic luteinizing hormone releasing hormone (LHRH) mRNA, pro-LHRH, or LHRH in any group at either age. Thus, naltrexone is able to partially prevent the EtOH-induced suppression of gonadal testosterone of young, adolescent male rats. This effect appears to be mediated directly at gonadal level, because hypothalamic and pituitary hormone changes were minor and nonsignificant. PMID:10029204

  8. Long-term but not short-term blockade of dopamine release in Drosophila impairs orientation during flight in a visual attention paradigm.

    Science.gov (United States)

    Ye, Yizhou; Xi, Wang; Peng, Yueqing; Wang, Yizheng; Guo, Aike

    2004-08-01

    Dopamine is a major neuromodulator in both vertebrates and invertebrates and has profound effects on many physiological processes, including the regulation of attention. Most studies of the functions of dopamine use models with long-term blockade of dopamine release and few effects of transient blockade have yet been reported. The goal of the present study was to determine the role of dopamine in attention-like behavior in Drosophila by taking advantage of the fly's orientation behavior during flight. The examination of several different transgenic flies in a single-target visual attention paradigm showed that flies lost their orientation ability if dopamine release was blocked from the beginning of the development of dopaminergic neurons. This is similar to the attention loss in mammals. However, if the blockade of dopamine release was induced during the experimental procedure, flies performed normally. Statistical analysis of the behavioral assessment showed a significant difference between long-term and transient blockade. Using the RNA interference approach, we generated flies with down-regulated J-domain protein, which is a potential cochaperone in synaptic vesicle release, to make an alternative form of long-term dopamine-blockade mutant. Behavioral assays revealed that flies with permanent J-domain protein down-regulation specifically in dopaminergic neurons have an attention defect similar to that induced by long-term blockade of dopamine release. Furthermore, dopamine depletion beginning at eclosion also caused an attention deficit. Our results indicate that prolonged but not transient blockade of dopamine release impairs visual attention-like behavior in Drosophila.

  9. Presynaptic snake beta-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm.

    Science.gov (United States)

    Wilson, H I; Nicholson, G M

    1997-11-01

    The present study investigated the ability of a number of presynaptic snake neurotoxins (snake beta-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and endplate potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake beta-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake beta-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. The 'non-neurotoxic' bovine pancreatic phospholipase A2 and the 'low-toxicity' phospholipase A2 from Naja naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake beta-neurotoxins is not responsible for the development of fade. Intracellular recording of endplate potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following incubation with all snake beta-neurotoxins except notexin. Again this run-down in EPP amplitude was confined to the final depressant phase of snake beta-neurotoxin action. However when EPP amplitude fell to near uniquantal levels (fade was reduced. Unlike postjunctional snake alpha-neurotoxins, prejunctional snake beta-neurotoxins interfere with acetylcholine release at the neuromuscular junction during the development of neuromuscular blockade. This study provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitude resulting from a prejunctional alteration of transmitter release rather than a use-dependent block of postjunctional nicotinic receptors.

  10. The Need for a Rational Approach to Vasoconstrictive Syndromes: Transcranial Doppler and Calcium Channel Blockade in Reversible Cerebral Vasoconstriction Syndrome

    Directory of Open Access Journals (Sweden)

    Elisabeth B. Marsh

    2016-07-01

    Full Text Available Introduction: Reversible cerebral vasoconstriction syndrome (RCVS typically affects young patients and left untreated can result in hemorrhage or ischemic stroke. Though the disorder has been well characterized in the literature, the most appropriate way to diagnose, treat, and evaluate therapeutic response remains unclear. In previous studies, transcranial Doppler ultrasound (TCD has shown elevated velocities indicative of vasospasm. This imaging modality is noninvasive and inexpensive; an attractive option for diagnosis and therapeutic monitoring if it is sensitive enough to detect changes in the acute setting given that RCVS often affects the distal vessels early in the course of disease. There is also limited data that calcium channel blockade may be effective in treating vasospasm secondary to RCVS, though the agent of choice, formulation, and dose are unclear. Methods: We report a small cohort of seven patients presenting with thunderclap headache whose vascular imaging was consistent with RCVS. All were treated with calcium channel blockade and monitored with TCD performed every 1–2 days. Results: On presentation, TCD correlated with standard neuroimaging findings of vasospasm (on MR, CT, and conventional angiography. TCD was also able to detect improvement in velocities in the acute setting that correlated well with initiation of calcium channel blockade. Long-acting verapamil appeared to have the greatest effect on velocities compared to nimodipine and shorter-acting calcium channel blockers. Conclusion: Though small, our cohort demonstrates potential utility of TCD to monitor RCVS, and relative superiority of extended-release verapamil over other calcium channel blockers, illustrating the need for larger randomized trials.

  11. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.

    Science.gov (United States)

    Misale, Sandra; Arena, Sabrina; Lamba, Simona; Siravegna, Giulia; Lallo, Alice; Hobor, Sebastijan; Russo, Mariangela; Buscarino, Michela; Lazzari, Luca; Sartore-Bianchi, Andrea; Bencardino, Katia; Amatu, Alessio; Lauricella, Calogero; Valtorta, Emanuele; Siena, Salvatore; Di Nicolantonio, Federica; Bardelli, Alberto

    2014-02-19

    Colorectal cancers (CRCs) that are sensitive to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) activation, which persisted after EGFR blockade. Inhibition of MEK1/2 alone failed to impair the growth of resistant cells in vitro and in vivo. An RNA interference screen demonstrated that suppression of EGFR, together with silencing of MEK1/2, was required to hamper the proliferation of resistant cells. Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells. Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti-EGFR antibodies. A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which reactivate ERK signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in CRC patients who become refractory to anti-EGFR therapies.

  12. Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system.

    Science.gov (United States)

    Yegla, B; Parikh, V

    2014-03-01

    Disruption in nerve growth factor (NGF) signaling via tropomyosin-related kinase A (trkA) receptors compromises the integrity of the basal forebrain (BF) cholinergic system, yielding cognitive, specifically attentional, impairments in Alzheimer's disease (AD). Although normal aging is considered a risk factor for AD, the mechanisms underlying the selective vulnerability of the aging cholinergic system to trkA disruption is not clear. The levels of proNGF, a proneurotrophin that possesses higher affinity for p75 receptors, increase in aging. The present study was designed to test the hypothesis that cholinergic and attentional dysfunction in aged rats with reduced BF trkA receptors occurs due to the overactivation of endogenous proNGF signaling. We employed a viral vector that produced trkA shRNA to suppress trkA receptors in the corticopetal cholinergic neurons of aged rats. BF trkA suppression impaired animals' performance on signal trials in both the sustained attention task (SAT) and the cognitively taxing distractor version of SAT (dSAT) and these deficits were normalized by chronic intracerebroventricular administration of proNGF antibody. Moreover, depolarization-evoked acetylcholine (ACh) release and the density of cortical cholinergic fibers were partially restored in these animals. However, SAT/dSAT scores reflecting overall performance did not improve following proNGF blockade in trkA knockdown rats due to impaired performance in non-signal trials. Sustained proNGF blockade alone did not alter baseline attentional performance but produced moderate impairments during challenging conditions. Collectively, our findings indicate that barring proNGF-p75 signaling may exert some beneficial effects on attentional capacities specifically when BF trkA signaling is abrogated. However, endogenous proNGF may also possess neurotrophic effects and blockade of this proneurotrophin may not completely ameliorate attentional impairments in AD and potentially hinder

  13. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.

    Science.gov (United States)

    Yuan, Jianda; Gnjatic, Sacha; Li, Hao; Powel, Sarah; Gallardo, Humilidad F; Ritter, Erika; Ku, Geoffrey Y; Jungbluth, Achim A; Segal, Neil H; Rasalan, Teresa S; Manukian, Gregor; Xu, Yinyan; Roman, Ruth-Ann; Terzulli, Stephanie L; Heywood, Melanie; Pogoriler, Evelina; Ritter, Gerd; Old, Lloyd J; Allison, James P; Wolchok, Jedd D

    2008-12-23

    Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.

  14. Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection.

    Science.gov (United States)

    Anderson, D J; Lo, D J; Leopardi, F; Song, M; Turgeon, N A; Strobert, E A; Jenkins, J B; Wang, R; Reimann, K A; Larsen, C P; Kirk, A D

    2016-05-01

    Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function-associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model. PMID:26602755

  15. Sequential maximum androgen blockade (MAB) in minimally symptomatic prostate cancer progressing after initial MAB:two case reports

    Institute of Scientific and Technical Information of China (English)

    Mohan Hingorani; Sanjay Dixit; Fahim Bashir; Mohammad Butt; Simon Hawkyard; Richard Khafagy; Andrew Robertson

    2014-01-01

    Te management of castrate-resistant prostate cancer progressing atfer maximum androgen blockade (MAB) has evolved in the last decade with the development of several novel therapeutic options. However, the initial therapeutic strategy in these patients usually involves withdrawal of anti-androgen that can be associated with biochemical response in approximately 20%of patients. Notably, we have observed evidence of sustained biochemical response in two patients following second-and third-line MAB using rechallenge schedule of previously administered anti-androgen atfer latent interval. hTe possibility of response following sequential MAB using the same anti-androgen agent has not yet been reported.

  16. Effect of serotonin receptor blockade on endocrine and cardiovascular responses to head-up tilt in humans

    DEFF Research Database (Denmark)

    Matzen, S; Secher, N H; Knigge, U;

    1993-01-01

    Effects of blockade of serotonin (5-HT) receptors on the integrated cardiovascular and endocrine adaptations during head-up tilt were investigated in normal men. In control experiments 50 degrees head-up tilt increased heart rate (HR), total peripheral resistance (TPR), plasma renin activity (PRA......) and sympathetic activity (plasma noradrenaline; NA). A moderate increase in pituitary-adrenal hormones (plasma ACTH, beta-END and cortisol) was observed. After a mean tilt time of 30 +/- 5 min (n = 20) presyncopal symptoms associated with decreases in HR, TPR and arterial pressure occurred. At this time pituitary...

  17. Universal quantum computation with electron spins in quantum dots based on superpositions of spacetime paths and Coulomb blockade

    CERN Document Server

    Lin, C C Y; Wu, Y Z; Zhang, W M; Lin, Cyrus C.Y.; Soo, Chopin; Wu, Yin-Zhong; Zhang, Wei-Min

    2004-01-01

    Using electrostatic gates to control the electron positions, we present a new controlled-NOT gate based on quantum dots. The qubit states are chosen to be the spin states of an excess conductor electron in the quantum dot; and the main ingredients of our scheme are the superpositions of space-time paths of electrons and the effect of Coulomb blockade. All operations are performed only on individual quantum dots and are based on fundamental interactions. Without resorting to spin-spin terms or other assumed interactions, the scheme can be realized with a dedicated circuit and a necessary number of quantum dots. Gate fidelity of the quantum computation is also presented.

  18. Sugammadex rescue following prolonged rocuronium neuromuscular blockade with ‘recurarisation’ in a patient with severe renal failure

    OpenAIRE

    Lobaz, Steven; Sammut, Mario; Damodaran, Anand

    2013-01-01

    We describe our experience of a 71-year-old patient with severe renal failure, who exhibited an unusually prolonged rocuronium-induced neuromuscular blockade (>4 h) and apparent recurarisation, following emergency rapid sequence induction (RSI). At the end of operation, 45 min post induction, train-of-four (TOF) testing had been 4/4 prior to wake up. No respiratory effort was seen 150 min postinduction, despite further neostigmine/glycopyrrolate and repeat TOF 4/4. The patient was resedated a...

  19. Lumbar paravertebral blockade as intractable pain management method in palliative care

    Directory of Open Access Journals (Sweden)

    Zaporowska-Stachowiak I

    2013-09-01

    Full Text Available Iwona Zaporowska-Stachowiak,1,2 Aleksandra Kotlinska-Lemieszek,3 Grzegorz Kowalski,3 Katarzyna Kosicka,4 Karolina Hoffmann,5 Franciszek Główka,4 Jacek Łuczak2 1Department of Pharmacology, 2Palliative Medicine In-patient Unit, University Hospital of Lord’s Transfiguration, 3Department of Palliative Care, 4Department of Physical Pharmacy and Pharmacokinetics, 5Department of Internal Medicine, Metabolic Disorders and Arterial Hypertension, Poznan University of Medical Sciences, Poznan, Poland Abstract: Optimal symptoms control in advanced cancer disease, with refractory to conventional pain treatment, needs an interventional procedure. This paper presents coadministration of local anesthetic (LA via paravertebral blockade (PVB as the alternative to an unsuccessful subcutaneous fentanyl pain control in a 71-year old cancer patient with pathological fracture of femoral neck, bone metastases, and contraindications to morphine. Bupivacaine in continuous infusion (0.25%, 5 mL · hour-1 or in boluses (10 mL of 0.125%–0.5% solution, used for lumbar PVB, resulted in pain relief, decreased demand for opioids, and led to better social interactions. The factors contributing to an increased risk of systemic toxicity from LA in the patient were: renal impairment; heart failure; hypoalbuminemia; hypocalcemia; and a complex therapy with possible drug–drug interactions. These factors were taken into consideration during treatment. Bupivacaine’s side effects were absent. Coadministered drugs could mask LA’s toxicity. Elevated plasma α1-acid glycoprotein levels were a protective factor. To evaluate the benefit-risk ratio of the PVB treatment in boluses and in constant infusion, bupivacaine serum levels were determined and the drug plasma half-lives were calculated. Bupivacaine’s elimination was slower when administered in constant infusion than in boluses (t½ = 7.80 hours versus 2.64 hours. Total drug serum concentrations remained within the safe

  20. Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

    Science.gov (United States)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1993-01-01

    The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

  1. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis.

    Science.gov (United States)

    Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta; Kolbinger, Frank; Moulin, Pierre; Brees, Dominique; Coleman, Bianca M; Mamo, Anna J; Garg, Abhishek V; Jaycox, Jillian R; Siebenlist, Ulrich; Kammüller, Michael; Gaffen, Sarah L

    2016-06-01

    Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency. PMID:26729813

  2. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis.

    Science.gov (United States)

    Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta; Kolbinger, Frank; Moulin, Pierre; Brees, Dominique; Coleman, Bianca M; Mamo, Anna J; Garg, Abhishek V; Jaycox, Jillian R; Siebenlist, Ulrich; Kammüller, Michael; Gaffen, Sarah L

    2016-06-01

    Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency.

  3. Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Abeer A.Mahmoud; Eman A.El-Sharawy; Mohamed M.El-Bassiouny; Ramy R.Ghali

    2014-01-01

    Objective: Maximum androgen blockade (MAB), consisting of an antiandrogen plus either a luteinizing hormone-releasing hormone agonist (LHRHA) or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB (orchiectomy or LHRHA “Goserelin”) and anti-androgen “Bicalutamide” with castration alone (orchiectomy or LHRHA) in previ-ously untreated metastatic prostate cancer patients.Methods: Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot.Results: During the period from January 2011 to January 2013, with a median folow up of 18 months (range 6 to 24 months), there were eight deaths (16%), in MAB arm and ten deaths (20%) in castration alone arm. At three months, there were 35 patients (70%) with prostate specific antigen (PSA) normalization (≤ 4 mg/dL) in MAB arm versus 17 patients (34%) with PSA normalization in castration alone arm (P = 0.001). The median progression free survival (PFS) times were 22.18 months (95% CI, 19.7 to 24.2 months) for MAB arm versus 22 months in castration alone arm (95% CI, 18 to 25.9 months;P = 0.045). The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm (P > 0.05). The median overal survival (OS) was not reached in either arm. Both hematological

  4. Promoting preschool reading

    OpenAIRE

    Istenič, Vesna

    2013-01-01

    The thesis titled Promoting preschool reading consists of a theoretiral and an empirical part. In the theoretical part I wrote about reading, the importance of reading, types of reading, about reading motivation, promoting reading motivation, internal and external motivation, influence of reading motivation on the child's reading activity, reading and familial literacy, the role of adults in promotion reading literacy, reading to a child and promoting reading in pre-school years, where I ...

  5. How Promotions Work

    OpenAIRE

    Robert C. Blattberg; Richard Briesch; Fox, Edward J.

    1995-01-01

    By synthesizing findings across the sales promotion literature, this article helps the reader understand how promotions work. We identify and explain empirical generalizations related to sales promotion; that is, effects that have been found consistently in multiple studies involving different researchers. We also identify issues which have generated conflicting findings in the research, as well as important sales promotion topics that have not yet been studied. This overview of the research ...

  6. What do health-promoting schools promote?

    DEFF Research Database (Denmark)

    Simovska, Venka

    2012-01-01

    -promotion interventions. Directly or indirectly the articles reiterate the idea that health promotion in schools needs to be linked with the core task of the school – education, and to the values inherent to education, such as inclusion, democracy, participation and influence, critical literacy and action competence...... for Health in Europe Research Group were invited to submit their work addressing processes and outcomes in school health promotion to this special issue of Health Education. Additionally, an open call for papers was published on the Health Education web site. Following the traditional double blind peer...... on the related processes and outcomes. Although diverse in focus and research methodology, the five contributions all emphasise that the question about the outcomes of the health-promoting schools cannot, and should not be limited to narrowly defined health outcomes achieved through single health...

  7. A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia

    DEFF Research Database (Denmark)

    Duvaldestin, Philippe; Kuizenga, Karel; Saldien, Vera;

    2010-01-01

    Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular...... blockade in patients induced and maintained under propofol anesthesia. However, sevoflurane anesthesia, unlike propofol, can prolong the effect of neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium.......Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular...

  8. Developing a Promotional Video

    Science.gov (United States)

    Epley, Hannah K.

    2014-01-01

    There is a need for Extension professionals to show clientele the benefits of their program. This article shares how promotional videos are one way of reaching audiences online. An example is given on how a promotional video has been used and developed using iMovie software. Tips are offered for how professionals can create a promotional video and…

  9. I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference?

    Science.gov (United States)

    Puddu, Paolo Emilio; Legrand, Jean-Christophe; Sallé, Laurent; Rouet, René; Ducroq, Joffrey

    2011-06-01

    The electrophysiological (standard intracellular microelectrode technique) and pro-arrhythmic (occurrence of early after-depolarization) effects of five class III agents acting on delayed rectifier current (I(K)), rapid (I(Kr)), and/or slow (I(Ks)) components have been studied in rabbit Purkinje fibers taken near the septum and submitted in vitro to reduced stimulation rate (from 1 to 0.5 Hz) in the absence or presence of epinephrine (10 nm) during normoxic conditions. There were two I(Kr) blockers (d-sotalol and dofetilide), two I(Ks) blockers (chromanol 293B and HMR 1556), and a non-selective I(K) blocker (azimilide). d-sotalol, dofetilide, and azimilide lengthened APD(60) and APD(90) in a concentration-dependent manner. Both d-sotalol and dofetilide showed pro-arrhythmia at highest concentrations and in the presence of epinephrine and lower stimulation rate. Despite azimilide markedly lengthened APD(90), it was globally less pro-arrhythmic than dofetilide. Thus, in normoxic rabbit Purkinje fibers, I(Kr) blockade prolonged action potential duration (APD) and increased the incidence of early after-depolarizations, particularly so in the presence of adrenergic stimulation and bradycardia, I(Ks) blockade did neither, and non-selective I(K) blockade (by azimilide) behaved principally as I(Kr) blockade. It is concluded that in normoxic rabbit Purkinje fibers, I(Ks) blockade was neutral, whereas I(Kr) blockade was pro-arrhythmic, which may make a difference worth exploration in more complex models.

  10. Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Takuya Kishi

    2015-01-01

    Full Text Available Abnormal blood pressure (BP elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP were treated with intracerebroventricular infusion (ICV of AT1R receptor blocker (ARB, oral administration of hydralazine (HYD, or ICV of vehicle (VEH. Telemetric averaged mean BP (MBP was measured at early morning (EM, after morning (AM, and night (NT. At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats.

  11. Humoral immune response induced by an engineered cell-based neuroblastoma vaccine with or without CD25 blockade

    Institute of Scientific and Technical Information of China (English)

    Jin Zheng; Rimas Orentas; Xiaofei Yan; Hongli Liu

    2011-01-01

    Neuroblastoma is the most common extracranial solid cancer in childhood and it can develop in the nerve tissue of the adrenal gland, neck, chest, or spinal cord A number of tumor-associated antigens(TAAs), which can elicit humoral immunity, have been identified in cancer patients. To investigate the humoral immunity during neuroblastoma development, we treated A/J mice with an aggressive clone of neuroblastoma(AGN2a)cells, then vaccinated the mice with cells expressing AGN2a-CD80/CD137L under the condihons with or without regulatory T cell blockade. Strong humoral immunity was induced by AGN2a-CD80/CD137L immunization in the context of regulatory T cell blockade. Sera from treated mice were used to screen an AGN2a cDNA expression library for identifying TAAs by SEREX(serological analysis of recombinant cDNA expression libraries). Clones were identified by sequencing and comparative analysis of gene pools. Further investigation of these gene products revealed that most of them play a role in the neuronal differentiation, cell metabolism, and are highly expressed in other types of malignancy. Asz1(ankyrin repeat, SAM, and basic leucine zipper domaincontaining protein)was found in all tumor-bearing groups. These results implicated that these candidates identified from tumor-bearing mice may be neuroblastoma-associated antigens, which can be used as biomarkers in early diagnosis of neuroblastoma, whereas those identified from vaccinated mice may be the potential therapeutic targets.

  12. [Surfactant and water balance of lung in intracerebral hemorrhage at conditions of capsaicin blockade of vagus nerve].

    Science.gov (United States)

    Urakova, M A; Bryndina, I G

    2015-03-01

    It is known that intracranial hemorrhage (ICH) is accompanied by the development of neurogenic pulmonary edema and insufficiency of surfactant function. The present study was undertaken for evaluation of the role of vagal afferents in the mechanisms of ICH effects on pulmonary surfactant and water balance of the lung. We explored the surface activity and biochemical composition of surfactant, as well as blood supply, total, intravascular and extravascular fluid content in lung after ICH, simulated by intraventricular administration of autologous blood against the background of bilateral blockade of capsaicin-sensitive vagal affere its. The blockade was caused by the capsaicin application (50 mcmol) on the cervical part of the nerves. Intracerebralhemorrhage was accompanied by the decrease of surfactant activity which appeared by the enhancement of minimal, maximal and static surface tension of bronchoalveolar lavage fluid (BAL), the reduction of total phospholipids including their main fraction phosphatidylcholine, the increase of lysophosphatidyicholine content and hyperhydration of the lung. The level of total proteins in BAL elevated, confirmed the enhanced permeability of the alveolar-blood barrier. The exhaustion of neuropeptides in capsaicin-sensitive vagal afferents led to the partial restoration of surface active properties of lung, normalization of phospholipids and protein contents and water balance parameters. The obtained results suggest that capsaicin-sensitive vagal afferents play a pivotal role in the disturbances of surfactant function and water balance of the lung after ICH. PMID:26016324

  13. Calibrating the impact of dual RAAS blockade on the heart and the kidney - balancing risks and benefits.

    Science.gov (United States)

    Ziff, O J; Covic, A; Goldsmith, D

    2016-07-01

    Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation. PMID:27278080

  14. Optimal point of insertion of the needle in neuraxial blockade using a midline approach: study in a geometrical model

    Science.gov (United States)

    Vogt, Mark; van Gerwen, Dennis J; van den Dobbelsteen, John J; Hagenaars, Martin

    2016-01-01

    Performance of neuraxial blockade using a midline approach can be technically difficult. It is therefore important to optimize factors that are under the influence of the clinician performing the procedure. One of these factors might be the chosen point of insertion of the needle. Surprisingly few data exist on where between the tips of two adjacent spinous processes the needle should be introduced. A geometrical model was adopted to gain more insight into this issue. Spinous processes were represented by parallelograms. The length, the steepness relative to the skin, and the distance between the parallelograms were varied. The influence of the chosen point of insertion of the needle on the range of angles at which the epidural and subarachnoid space could be reached was studied. The optimal point of insertion was defined as the point where this range is the widest. The geometrical model clearly demonstrated, that the range of angles at which the epidural or subarachnoid space can be reached, is dependent on the point of insertion between the tips of the adjacent spinous processes. The steeper the spinous processes run, the more cranial the point of insertion should be. Assuming that the model is representative for patients, the performance of neuraxial blockade using a midline approach might be improved by choosing the optimal point of insertion.

  15. Functional blockade of α5β1 integrin induces scattering and genomic landscape remodeling of hepatic progenitor cells

    Directory of Open Access Journals (Sweden)

    Lorenti Alicia

    2010-10-01

    Full Text Available Abstract Background Cell scattering is a physiological process executed by stem and progenitor cells during embryonic liver development and postnatal organ regeneration. Here, we investigated the genomic events occurring during this process induced by functional blockade of α5β1 integrin in liver progenitor cells. Results Cells treated with a specific antibody against α5β1 integrin exhibited cell spreading and scattering, over-expression of liver stem/progenitor cell markers and activation of the ERK1/2 and p38 MAPKs signaling cascades, in a similar manner to the process triggered by HGF/SF1 stimulation. Gene expression profiling revealed marked transcriptional changes of genes involved in cell adhesion and migration, as well as genes encoding chromatin remodeling factors. These responses were accompanied by conspicuous spatial reorganization of centromeres, while integrin genes conserved their spatial positioning in the interphase nucleus. Conclusion Collectively, our results demonstrate that α5β1 integrin functional blockade induces cell migration of hepatic progenitor cells, and that this involves a dramatic remodeling of the nuclear landscape.

  16. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses

    Directory of Open Access Journals (Sweden)

    Wujing Dai

    2016-01-01

    Full Text Available CD4+ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4+ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4+ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs. Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.

  17. THE EFFECTS OF ACUTE AND CHRONIC STRESS ON ERYTHROCYTE DYNAMIC IN COMBINATION WITH ß–ADRENERGIC RECEPTORS BLOCKADE IN RATS

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2005-08-01

    Full Text Available : 3 consecutive days propranolol hydrochloride administration (5 mg/kg b.w., subcutaneous injections under acute and chronic stress conditions causes changes of peripheral erythrocyte distribution in rats. The effects of acute stress and its combination with ȕ-adrenergic receptor blockade on erythrocyte dynamic were more pregnant beside the effects of chronic stress and its combination with ȕ-adrenergic receptor blockade, respectively. ȕ-adrenergic mechanisms were shown to be involved in regulation of erythrocyte dynamic in acute and chronic stress response.

  18. Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis.

    Science.gov (United States)

    Morfoisse, Florent; Tatin, Florence; Hantelys, Fransky; Adoue, Aurelien; Helfer, Anne-Catherine; Cassant-Sourdy, Stephanie; Pujol, Françoise; Gomez-Brouchet, Anne; Ligat, Laetitia; Lopez, Frederic; Pyronnet, Stephane; Courty, Jose; Guillermet-Guibert, Julie; Marzi, Stefano; Schneider, Robert J; Prats, Anne-Catherine; Garmy-Susini, Barbara H

    2016-08-01

    The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5' UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5'UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394-405. ©2016 AACR. PMID:27280395

  19. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points - An international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial

    DEFF Research Database (Denmark)

    Puhringer, F.K.; Rex, C.; Sielenkamper, A.W.;

    2008-01-01

    Background: Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evalua...

  20. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial

    DEFF Research Database (Denmark)

    Pühringer, Friedrich K; Rex, Christopher; Sielenkämper, Andreas W;

    2008-01-01

    Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evaluated....

  1. Deltamethrin, a type II pyrethroid insecticide, has neurotrophic effects on neurons with continuous activation of the Bdnf promoter.

    Science.gov (United States)

    Ihara, Daisuke; Fukuchi, Mamoru; Honma, Daisuke; Takasaki, Ichiro; Ishikawa, Mitsuru; Tabuchi, Akiko; Tsuda, Masaaki

    2012-02-01

    Pyrethroids, widely used insecticides with low acute toxicity in mammals, affect sodium channels in neurons. In a primary culture of rat cortical neurons, deltamethrin (DM), a type II pyrethroid, markedly enhanced the expression of brain-derived neurotrophic factor (BDNF) exon IV-IX (Bdnf eIV-IX) mRNA. In this study, we found that DM has a neurotrophic effect on cultured neurons and investigated the mechanisms responsible for it. One μM DM increased cell survival, neurite complexity and length. Neurite complexity and length were reduced not only by a blockade of cellular excitation with GABA or Ca(2+) influx via L-type voltage-dependent calcium channels with nicardipine, but also by a blockade of TrkB, a specific receptor for BDNF, with TrkB/Fc. These data indicate DM has neurotrophic actions. DM-induced Bdnf eIV-IX mRNA expression through the calcineurin and ERK/MAPK pathways, the increase of which was reduced by GABA(A) receptor activation. Using a promoter assay, we found that Ca(2+)-responsive elements including a CRE are involved in the DM-induced activation of the Bdnf promoter IV (Bdnf-pIV). The intracellular concentration of Ca(2+) and activation of Bdnf-pIV remained elevated for, at least, 1 and 24 h, respectively. Moreover, GABA(A) receptor activation or a blockade of Ca(2+) influx even after starting the incubation with DM reduced the elevated activity of Bdnf-pIV. These data demonstrated that the prolonged activation of Bdnf-pIV occurred because of this continuous increase in the intracellular Ca(2+) concentration. Thus, DM has neurotrophic effects on neurons, likely due to prolonged activation of Bdnf promoter in neurons. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  2. Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yu-ling; ZHOU Shu-xian; LEI Juan; YUAN Gui-yi; WANG Jing-feng

    2008-01-01

    Background It has been reported that osteopontin has an important role in cardiac fibrosis and remodeling.However,its direct mechanisms remain unclear.The purpose of this study was to investigate the role of angiotensin and aldosterone blockades in cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted (MI) rats.Methods Fifty SD rats that survived 24 hours after ligating left anterior descending coronary artery were randomly divided into three groups:Ml-saline group (n=15,5 ml/d),MI-perindopril group (n=18,perindopril 2 mg·kg-1·d-1) and MI-spironolacton (n=17,spironolacton 20 mg·kg-1.d-1).A sham operation group (n=15) was selected as non-infarcted control.At 6 weeks after treatment,hemodynamic pararmeters and left ventricular function were measured with catheterization,interstitial fibrosis infiltration and cardiomyocyte diameters were evaluated histologically.Myocardium osteopontin protein expression level in the non-infarcted myocardium was detected by Western blotting.Results No osteopontin protein was detected in the myocardium of sham-operation rats.High levels of osteopontin protein expression were detected in the MI-saline rats,but the levels were suppressed in the MI-perindopril and MI-spironolacton rats at 6 weeks following MI (P<0.01,respectively).Compared with the sham operation group,all rats in the MI group showed marked interstitial fibrosis infiltration in the non-infarction area,higher ventricular weight]body weight ratio,significantly increased cardiomyocyte diameter (P<0.01,respectively),and developed significant systolic and diastolic dysfunction as indicated by decreased left ventricular systolic pressure (LVSP) and ±dp/dt,as well as increased left ventricular end-diastolic pressure (LVEDP) (P<0.01,respectively).Angiotensin and aldosterone blockades partly prevented cardiac fibrosis and systolic and diastolic dysfunction (P<0.01,respectively).Conclusion Treatment with angiotensin and aldosterone blockades

  3. Lymphatic vessels growing apart from blood vessels in transplanted corneas after the blockade of vascular endothelial growth factor C

    Institute of Scientific and Technical Information of China (English)

    Ye Hui; Yan Hao; Zhong Lei; Wang Tao; Deng Juan; Ling Shi-qi

    2016-01-01

    BACKGROUND:Corneal lymphangiogenesis is beneficial to the transport of corneal antigenic materials, and accelerates the process of antigen presentation, thereby playing an important role in corneal immunity. However, due to the paral el outgrowth of corneal blood and lymphatic vessels in transplanted corneas, it is often difficult to accurately evaluate the role of corneal lymphatic vessels in allograft rejection. OBJECTIVE:To explore the development of corneal lymphangiogenesis and angiogenesis in transplanted rat corneas after the blockade of vascular endothelial growth factor C (VEGF-C). METHODS:130 rats used to establish corneal al ogenic transplantation models were equally randomized into two groups:the anti-VEGF-C group and the control group. VEGF-C was blocked in the anti-VEGF-C group by intraperitoneal injection of neutralizing monoclonal anti-VEGF-C antibody every other day for 2 consecutive weeks. Meanwhile, rats in control groups received intraperitoneal injections of saline. Corneal angiogenesis and lymphangiogenesis were characterized using whole mount immunofluorescence, and the immune rejection of the grafts was evaluated by scoring the rejection index (RI). In addition, the expression of VEGF-C was examined by real-time PCR. The relationship of corneal lymphangiogenesis and angiogenesis to RI in transplanted corneas was also characterized. RESULTS AND CONCLUSION:VEGF-C expression was markedly downregulated after VEGF-C blockade. Corneal lymphangiogenesis developed in parallel with corneal angiogenesis in the control group. While there was a mild reduction in blood vessel area (BVA) and a significant decrease in lymphatic vessel area (LVA) in the anti-VEGF-C group (P0.05). the graft survival time in the anti-VEGF-C group was significantly increased compared with that in the control group (P<0.05). Our results show that the outgrowth of lymphatic vessels is separated from that of blood vessels in transplanted corneas by blocking VEGF-C. The blockade

  4. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction

    OpenAIRE

    Weis, Sara; Shintani, Satoshi; Weber, Alberto; Kirchmair, Rudolf; Wood, Malcolm; Cravens, Adrianna; McSharry, Heather; Iwakura, Atsushi; Yoon, Young-Sup; Himes, Nathan; Burstein, Deborah; Doukas, John; Soll, Richard; Losordo, Douglas; Cheresh, David

    2004-01-01

    Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic o...

  5. Is Lamb Promotion Working?

    OpenAIRE

    Capps, Oral, Jr.; Williams, Gary W.

    2007-01-01

    This objective of this study is to determine whether the advertising and promotion dollars collected and spent by the American Lamb Board on lamb promotion since the inception of the Lamb Checkoff Program have effectively increased lamb consumption in the United States. The main conclusion is that program has resulted in roughly 7.6 additional pounds of total lamb consumption per dollar spent on advertising and promotion and $41.59 in additional lamb sales per dollar spent on advertising and ...

  6. Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation.

    Science.gov (United States)

    Hos, D; Dörrie, J; Schaft, N; Bock, F; Notara, M; Kruse, F E; Krautwald, S; Cursiefen, C; Bachmann, B O

    2016-05-01

    The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end of the 8 week observation period, whereas 38% of the grafts survived in the control group (p graft survival in low-risk corneal transplantation. PMID:26689751

  7. Health promotion in Brazil.

    Science.gov (United States)

    Buss, Paulo Marchiori; de Carvalho, Antonio Ivo

    2007-01-01

    The evolution of health promotion within the Brazilian health system is examined, including an assessment of the intersectoral and development policies that have influenced the process. Particular attention is paid to the legal characteristics of the Unified Health System. Human resources formation and research initiatives in health promotion are outlined, with a summary of the obstacles that need to be overcome in order to ensure the effective implementation of health promotion in the future. Up to the end of the 20th Century health promotion was not used as a term in the Brazilian public heath context. Health promoting activities were concentrated in the area of health education, although targeting the social determinants of health and the principle of intersectoral action were part of the rhetoric. The situation has changed during the last decade, with the publication of a national policy of health promotion, issued by the Ministry of Health and jointly implemented with the States and Municipals Health Secretaries. More recently there has been a re-emergence of the discourse on the social determinants of health and the formation of intersectoral public policies as the basis of a comprehensive health promotion. Health promotion infrastructure, particularly around human resources and financing, requires strengthening in order to ensure capacity and sustainability in health promotion practice.

  8. Analysis of promotions

    Directory of Open Access Journals (Sweden)

    V.V. Bozhkova

    2011-03-01

    Full Text Available Article describes the classification of promotions and determining the effectiveness of specific measures to stimulate sales (which isnt possible practically in most advertising companies.

  9. Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection

    DEFF Research Database (Denmark)

    Grgic, I; Wulff, H; Eichler, I;

    2009-01-01

    -lymphocyte activity. We investigated whether combined blockade of the T-cell K(+) channels K(Ca)3.1 and K(v)1.3, both of which regulate calcium signaling during lymphocyte activation, is effective in prevention of rejection of kidney allografts from Fisher rats to Lewis rats. All recipients were initially treated...

  10. Varying patterns of the antihypertensive and antialbuminuric response to higher doses of renin-angiotensin-aldosterone system blockade in albuminuric hypertensive type 2 diabetes mellitus patients

    DEFF Research Database (Denmark)

    Weir, Matthew R; Hollenberg, Norman K; Remuzzi, Giuseppe;

    2011-01-01

    In patients with type 2 diabetes mellitus (T2DM), blocking of the renin-angiotensin-aldosterone system (RAAS) has demonstrated efficacy in lowering blood pressure (BP) and urinary albumin excretion rate (UAER). Nonetheless, not all patients successfully respond to RAAS blockade with a reduction i...

  11. The Effect of Therapeutic Blockades of Dust Particles-Induced Ca2+ Signaling and Proinflammatory Cytokine IL-8 in Human Bronchial Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Ju Hee Yoon

    2015-01-01

    Full Text Available Bronchial epithelial cells are the first barrier of defense against respiratory pathogens. Dust particles as extracellular stimuli are associated with inflammatory reactions after inhalation. It has been reported that dust particles induce intracellular Ca2+ signal, which subsequently increases cytokines production such as interleukin- (IL- 8. However, the study of therapeutic blockades of Ca2+ signaling induced by dust particles in human bronchial epithelial cells is poorly understood. We investigated how to modulate dust particles-induced Ca2+ signaling and proinflammatory cytokine IL-8 expression. Bronchial epithelial BEAS-2B cells were exposed to PM10 dust particles and subsequent mediated intracellular Ca2+ signaling and reactive oxygen species signal. Our results show that exposure to several inhibitors of Ca2+ pathway attenuated the PM10-induced Ca2+ response and subsequent IL-8 mRNA expression. PM10-mediated Ca2+ signal and IL-8 expression were attenuated by several pharmacological blockades such as antioxidants, IP3-PLC blockers, and TRPM2 inhibitors. Our results show that blockades of PLC or TRPM2 reduced both of PM10-mediated Ca2+ signal and IL-8 expression, suggesting that treatment with these blockades should be considered for potential therapeutic trials in pulmonary epithelium for inflammation caused by environmental events such as seasonal dust storm.

  12. Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander”

    Directory of Open Access Journals (Sweden)

    Lucia Gelao

    2014-03-01

    Full Text Available Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific “immune-related adverse events” (irAEs. IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique “innocent bystander” effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment.

  13. TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade

    NARCIS (Netherlands)

    A.W.R. van Kuijk; C.A. Wijbrandts; M. Vinkenoog; T.S. Zheng; K.A. Reedquist; P.P. Tak

    2010-01-01

    Objective: To investigate the expression of tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) in the inflamed synovium of patients with arthritis, as TWEAK blockade has been observed to have a beneficial effect in an ani

  14. Quantum phase transition and Coulomb blockade effect in triangular quantum dots with interdot capacitive and tunnel couplings

    Institute of Scientific and Technical Information of China (English)

    熊永臣; 王为忠; 杨俊涛; 黄海铭

    2015-01-01

    The quantum phase transition and the electronic transport in triangular quantum dot system are investigated using the numerical renormalization group method. We concentrate on the interplay between the interdot capacitive coupling V and the interdot tunnel coupling t . For small t , three dots form a local spin doublet. As t increases, due to the competition between V and t , there exist two first-order transitions with phase sequence spin-doublet-magnetic frustration phase-orbital spin singlet. When t is absent, the evolutions of the total charge on the dots and the linear conductance are of the typical Coulomb-blockade features with increasing gate voltage. While for sufficient t , the antiferromagnetic spin correlation between dots is enhanced, and the conductance is strongly suppressed for the bonding state is almost doubly occupied.

  15. Effect of beta-adrenergic blockade on elevated arterial compliance and low systemic vascular resistance in cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Bendtsen, F; Henriksen, Jens Henrik Sahl

    2001-01-01

    beta-blockers, but the effect of this treatment on arterial compliance has not been investigated. The aim of the present study was therefore to assess the effects of propranolol on the arterial compliance of patients with cirrhosis. METHODS: Twenty patients with cirrhosis underwent a haemodynamic......) of 17.8 mmHg, and responded to beta-blocker treatment with a significant reduction in the HVPG (-16%; P < 0.001). Arterial compliance was elevated (1.27 versus controls 1.01 ml/mmHg; P < 0.001), but remained almost unchanged during beta-adrenergic blockade (1.27 versus 1.29 ml/mmHg, +2%, ns), whereas...... beta-blockers increases small vessel (arteriolar) vascular tone towards the normal level, but does not affect the elevated compliance of the larger arteries in patients with cirrhosis....

  16. Sugammadex 4.0 mg kg-1 reversal of deep rocuronium-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Yu, Buwei; Wang, Xiangrui; Hansen, Søren Helbo;

    2014-01-01

    of rocuronium, at a target blockade depth of 1-2 post-tetanic counts. The primary efficacy endpoint was time from sugammadex administration to recovery of the train-of-four (TOF) ratio to 0.9. Safety was also evaluated. Results: Overall, 115 Chinese and 36 Caucasian patients were treated. Geometric mean (95......% confidence interval) times to recovery of the TOF ratio to 0.9 were 2.3 (2.1 to 2.6) minutes and 1.4 (1.3 to 1.6) minutes in Chinese and Caucasian patients, respectively. Adverse events were reported in 57% of Chinese patients and 64% of Caucasian patients. Conclusion: This study demonstrates that sugammadex...

  17. Steady-state bistability and long-range order in optically driven Rydberg gases in the anti-blockade regime

    Science.gov (United States)

    Letscher, Fabian; Linzner, Dominik; Fleischhauer, Michael

    2016-05-01

    Motivated by recent experiments, we study spatial and temporal correlations of Rydberg excitations of optically driven ultra-cold atoms in the anti-blockade regime. In particular, we discuss the influence of dissipation on the excitation dynamics of a linear chain of atoms, described by the dissipative, transverse-field Ising model. Using t-DMRG simulations of the density matrix we identify parameter regimes with diverging correlation lengths in the coherent regime of weak dissipation. Correlation lengths remain short-ranged in the incoherent regime of strong dissipation, where classical rate equations can be employed. We discuss the different physical mechanisms determining the many-body dynamics in the two regimes and compare theoretical predictions with recent experimental results. In particular we discuss the formation of excitation cluster in the incoherent regime and explain the observed slow-down of the relaxation process due to cluster formation.

  18. Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

    DEFF Research Database (Denmark)

    Higginson, James; Wackerhage, Henning; Woods, Niall;

    2002-01-01

    Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin...... increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates...... slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state...

  19. Spin-blockade effect and coherent control of DNA-damage by free radicals: a proposal on bio-spintronics

    CERN Document Server

    Abolfath, Ramin M

    2011-01-01

    Coherent control of OH-free radicals interacting with the spin-triplet state of a DNA molecule is investigated. A model Hamiltonian for molecular spin singlet-triplet resonance is developed. We illustrate that the spin-triplet state in DNA molecules can be efficiently populated, as the spin-injection rate can be tuned to be orders of magnitudes greater than the decay rate due to small spin-orbit coupling in organic molecules. Owing to the nano-second life-time of OH free radicals, a non-equilibrium free energy barrier induced by the injected spin triplet state that lasts approximately longer than one-micro second in room temperature can efficiently block the initial Hydrogen abstraction and DNA damage. For a direct demonstration of the spin-blockade effect, a molecular simulation based on an {\\em ab-initio} Car-Parrinello molecular dynamics is deployed.

  20. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade.

    Science.gov (United States)

    Olson, Brian M; Jankowska-Gan, Ewa; Becker, Jordan T; Vignali, Dario A A; Burlingham, William J; McNeel, Douglas G

    2012-12-15

    Regulatory T cells play important roles in cancer development and progression by limiting the generation of innate and adaptive anti-tumor immunity. We hypothesized that in addition to natural CD4(+)CD25(+) regulatory T cells (Tregs) and myeloid-derived suppressor cells, tumor Ag-specific Tregs interfere with the detection of anti-tumor immunity after immunotherapy. Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed-type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses after immunization was prevented by the activity of PAP-specific regulatory cells. These regulatory cells were CD8(+)CTLA-4(+), and their suppression was relieved by blockade of CTLA-4, but not IL-10 or TGF-β. Moreover, Ag-specific CD8(+) Tregs were detected prior to immunization in the absence of PAP-specific effector responses. These PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion. Taken together, these findings suggest a novel population of CD8(+)CTLA-4(+) IL-35-secreting tumor Ag-specific Tregs arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of Ag-specific effector responses by an IL-35-dependent mechanism.

  1. Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease.

    Science.gov (United States)

    Hardwick, Jean C; Southerland, E Marie; Girasole, Allison E; Ryan, Shannon E; Negrotto, Sara; Ardell, Jeffrey L

    2012-11-01

    Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.

  2. Peribulbar anesthesia for cataract surgery: Effect of lidocaine warming and alkalinization on injection pain, motor and sensory nerve blockade

    Directory of Open Access Journals (Sweden)

    Jaichandran Venkatakrishnan

    2010-01-01

    Full Text Available Aim: To compare self-reported pain and efficacy of warmed, alkalinized, and warmed alkalinized lidocaine with plain 2% lidocaine at room temperature for peribulbar anesthesia in cataract surgery. Materials and Methods: Through a prospective, single-blinded, randomized, controlled clinical trial 200 patients were divided into four groups. They received either lidocaine at operating room temperature 18°C, control group (Group C, lidocaine warmed to 37°C (Group W, lidocaine alkalinized to a pH of 7.09 ± 0.10 (Group B or lidocaine at 37°C alkalinized to a pH of 6.94 ± 0.05 (Group WB. All solutions contained Inj. Hyaluronidase 50 IU/ml. Pain was assessed using a 10-cm visual analog score scale. Time of onset of sensory and motor blockade and time to onset of postoperative pain were recorded by a blinded observer. Results: Mean pain score was significantly lower in Group B and WB compared with Group C ( P < 0.001. Onset of analgesia was delayed in Group C compared with Group B ( P = 0.021 and WB ( P < 0.001. Mean time taken for the onset of complete akinesia and supplementation required for the block was significantly lower in Group B. Time of onset of pain after operation was significantly earlier in Group W compared with Group C ( P = 0.036. Conclusion: Alkalinized lidocaine with or without warming produced less pain than lidocaine injected at room temperature. Alkalinization enhances the effect of warming for sensory nerve blockade, but warming does not enhance alkalinization, in fact it reduces the efficacy of alkalinized solution for blocking the motor nerves in the eye.

  3. Anti- or profibrillatory effects of Na+ channel blockade depend on the site of application relative to gradients in repolarization

    Directory of Open Access Journals (Sweden)

    Ruben Coronel

    2010-06-01

    Full Text Available Introduction. Sodium channel blockers are associated with arrhythmic sudden death, although they are considered antiarrhythmic agents. The mechanism of these opposing effects is unknown. Methods. We used a model of induction of ventricular fibrillation (VF based on selective perfusion of the vascular beds of isolated porcine hearts (n=8. One bed was perfused with sotalol (220 µM, the adjacent bed with pinacidil (80 µM, leading to repolarization heterogeneity (late repolarization in the sotalol-, early in the pinacidil-area. Premature stimulation from the area with the short action potential was performed. Epicardial activation/repolarization mapping was done. Results. In 3 of the 8 hearts VF was inducible prior to infusion of flecainide. In those hearts the Fibrillation Factor (FF, the interval between the last activation of the premature beat (S2 in the late repolarizing (sotalol domain and the earliest S2 repolarization in the early repolarizing (pinacidil domain, was significantly shorter than in the hearts without VF (33+/-22 vs 93+/-11 ms, m+/-SEM, p<0.05. In the 3 hearts with VF flecainide was infused in the pinacidil domain after defibrillation. This led to shortening of the line of block, local delay of S2 activation and repolarization, an increase in FF and failure to induce VF. In the 5 hearts without VF, flecainide was subsequently infused in the sotalol domain. This led to a local delay of S2 activation, a shortening of FF (by 47+/- 3 ms and successful induction of VF in 3 hearts. In the 2 remaining hearts FF did not decrease enough (maximally 13 ms to allow reentry. Conclusions Sodium channel blockade applied to myocardium with a short refractory period is antifibrillatory whereas sodium channel blockade of myocardium with a long refractory period is profibrillatory. Our study provides a mechanistic basis for pro- and anti-arrhythmic effects of sodium channel blockers in the absence of structural heart disease.

  4. Anti- or Profibrillatory Effects of Na+ Channel Blockade Depend on the Site of Application Relative to Gradients in Repolarization

    Science.gov (United States)

    Coronel, Ruben; Wilms-Schopman, Francien J. G.; Janse, Michiel J.

    2010-01-01

    Sodium channel blockers are associated with arrhythmic sudden death, although they are considered antiarrhythmic agents. The mechanism of these opposing effects is unknown. We used a model of induction of ventricular fibrillation (VF) based on selective perfusion of the vascular beds of isolated porcine hearts (n = 8). One bed was perfused with sotalol (220 μM), the adjacent bed with pinacidil (80 μM), leading to repolarization heterogeneity (late repolarization in the sotalol-, early in the pinacidil-area). Premature stimulation from the area with the short action potential was performed. Epicardial activation/repolarization mapping was done. In three of the eight hearts VF was inducible prior to infusion of flecainide. In those hearts the Fibrillation Factor (FF), the interval between the earliest repolarization of the premature beat (S2) in the early repolarizing (pinacidil) domain, and the last S2-activation in the late repolarizing (sotalol) domain, was significantly shorter than in the hearts without VF (33 ± 22 vs 93 ± 11 ms, m ± SEM, p < 0.05). In the three hearts with VF flecainide was infused in the pinacidil domain after defibrillation. This led to shortening of the line of block, local delay of S2 activation and repolarization, an increase in FF and failure to induce VF. In the five hearts without VF, flecainide was subsequently infused in the sotalol domain. This led to a local delay of S2 activation, a shortening of FF (by 47 ± 3 ms) and successful induction of VF in three hearts. In the two remaining hearts FF did not decrease enough (maximally 13 ms) to allow re-entry. Sodium channel blockade applied to myocardium with a short refractory period is antifibrillatory whereas sodium channel blockade of myocardium with a long refractory period is profibrillatory. Our study provides a mechanistic basis for pro- and antiarrhythmic effects of sodium channel blockers in the absence of structural heart disease. PMID:21423353

  5. trans-Caryophyllene, a Natural Sesquiterpene, Causes Tracheal Smooth Muscle Relaxation through Blockade of Voltage-Dependent Ca2+ Channels

    Directory of Open Access Journals (Sweden)

    Jader Santos Cruz

    2012-10-01

    Full Text Available trans-Caryophyllene is a major component in the essential oils of various species of medicinal plants used in popular medicine in Brazil. It belongs to the chemical class of the sesquiterpenes and has been the subject of a number of studies. Here, we evaluated the effects of this compound in airway smooth muscle. The biological activities of trans-caryophyllene were examined in isolated bath organs to investigate the effect in basal tonus. Electromechanical and pharmacomechanical couplings were evaluated through the responses to K+ depolarization and exposure to acetylcholine (ACh, respectively. Isolated cells of rat tracheal smooth muscle were used to investigate trans-caryophyllene effects on voltage-dependent Ca2+ channels by using the whole-cell voltage-clamp configuration of the patch-clamp technique. trans-Caryophyllene showed more efficiency in the blockade of electromechanical excitation-contraction coupling while it has only minor inhibitory effect on pharmacomechanical coupling. Epithelium removal does not modify tracheal smooth muscle response elicited by trans-caryophyllene in the pharmacomechanical coupling. Under Ca2+-free conditions, pre-exposure to trans-caryophyllene did not reduce the contraction induced by ACh in isolated rat tracheal smooth muscle, regardless of the presence of intact epithelium. In the whole-cell configuration, trans-caryophyllene (3 mM, inhibited the inward Ba2+ current (IBa to approximately 50% of control levels. Altogether, our results demonstrate that trans-caryophyllene has anti-spasmodic activity on rat tracheal smooth muscle which could be explained, at least in part, by the voltage-dependent Ca2+ channels blockade.

  6. Therapeutic synergy and complementarity for ischemia/reperfusion injury: β1-adrenergic blockade and phosphodiesterase-3 inhibition.

    Science.gov (United States)

    Huang, Ming-He; Poh, Kian-Keong; Tan, Huay-Cheem; Welt, Frederick G P; Lui, Charles Y

    2016-07-01

    The β1-blocker when administered before reperfusion activates myocyte prosurvival signaling via β2-adrenergic receptor (β2-AR) and protein kinase A (PKA)-dependent mechanism during ischemia/reperfusion (I/R). The heart is endowed with powerful self-protective ability executed by endogenous β2-adrenopeptide receptor activation. I/R triggers cardiac epinephrine and neuropeptide calcitonin gene-related peptide (CGRP) release. Cardiac β1- and β2-AR stimulation mediates pro- and anti-apoptotic cell signaling, respectively. Removal of myocardial β1-AR-derived proapoptotic force with β1-AR blockade unmasks the dominance of β2-AR mediated prosurvival cell signaling through the well-defined PKA-Akt dependent mechanism. This review focuses on recent clinical and experimental findings including intrinsic cardiac β2-adrenopeptide neuroparacrine signaling mechanisms involved in I/R injury protection. While β2-adrenopeptide-mediated cardioprotection is important, age-related β2-adrenopeptide receptor decoupling can result in their ineffectiveness in response to the receptor-specific therapies. Accordingly, direct activation of receptor-coupled upstream PKA-dependent signaling may serve as a therapeutic alternative to achieve cardioprotection bypassing adrenopeptidergic receptor decoupling accompanied with aging. Phosphodiesterase-3 (PDE3) inhibitor reduces infarct-size via cAMP-dependent PKA signaling. Non-β1-AR-mediated PKA activation activates multiple prosurvival signaling pathways eventually leading to Akt activation. Combination therapy with β1-blocker esmolol and PDE3 inhibitor milrinone additively reduced infarct-size in preclinical studies. Concurrent β1-AR blockade and PDE3 inhibition provides complementary synergy with promising therapeutic potential in patients with acute myocardial infarction and beyond. PMID:27085132

  7. Genetic blockade of the dopamine D3 receptor enhances hippocampal expression of PACAP and receptors and alters their cortical distribution.

    Science.gov (United States)

    Marzagalli, R; Leggio, G M; Bucolo, C; Pricoco, E; Keay, K A; Cardile, V; Castorina, S; Salomone, S; Drago, F; Castorina, A

    2016-03-01

    Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R(-/-)) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R(-/-) mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R(-/-) mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R(-/-) mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R(-/-) mice. PMID:26718601

  8. Blockade of 4-1BB/4-1BB ligand interactions prevents acute rejection in rat liver transplantation

    Institute of Scientific and Technical Information of China (English)

    QIN Lei; GUAN Hong-geng; ZHOU Xiao-jun; YIN Jun; LAN Jing; QIAN Hai-xin

    2010-01-01

    Background Blocking the 4-1BB/4-1BB ligand (4-1BBL) signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1 BBL monoclonal antibody (mAB) in acute rejection of rat orthotopic liver transplantation. Methods The orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase (AST), alanine aminotransferase (ALT), and bilirubin (BIL), was assayed. The concentrations of interleukin (IL)-2, IL-10 and interferon (IFN)- γ in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope. Results Isotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver allografts, and a mean graft survival time (MST) of 10.9 days. Administration of anti 4-1 BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-γ. The histological grade of rejection on day 7 decreased and MST (17.3 days) increased substantially.Conclusions These results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.

  9. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    Science.gov (United States)

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  10. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.

    Science.gov (United States)

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-11-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  11. Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons.

    Science.gov (United States)

    Beske, Phillip H; Bradford, Aaron B; Grynovicki, Justin O; Glotfelty, Elliot J; Hoffman, Katie M; Hubbard, Kyle S; Tuznik, Kaylie M; McNutt, Patrick M

    2016-02-01

    Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A-G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays. PMID:26615023

  12. Antisense oligonucleotides-induced local blockade of T-bet expression leads to airway inflammation in rats

    Institute of Scientific and Technical Information of China (English)

    Gang WANG; Chun-tao LIU; Zeng-li WANG; Li-li JIANG; Cuniang YAN; Feng-min LUO

    2006-01-01

    Aim: To explore whether local blockade of T-box expressed in T cells (T-bet) expression in the 1ungs could lead to airway inflammation. Methods: Twenty-four rats were randomly divided into 4 groups: saline group, ovalbumin (OVA)-sensitized group, nonsense group, and the antisense group. The OVA-sensitized rats were sensitized and challenged with OVA, and the rats in the nonsense and antisense groups were subjected to an aerosol delivery of the nonsense and antisense oligonucleotides (AS-ODN)of T-bet(0.1%, w/v). The levels of interferon-γ(IFN-γ), interleukin-4(IL-4), and IL-5 in the bronchoalveolar lavage fluid (BALF) were detected by ELISA, and the mRNA and the protein expression of T-bet and GATA-3 genes were examined by in situ hybridization and Western blot analysis, respectively. Results: The expression of T-bet mRNA and protein in the lungs of the rats in the antisense group were inhibited effectively. The lungs of the rats in the antisense and OVA-sensitized groups showed eosinophil and lymphocyte inflammatory infiltration, and eosinophilia located predominantly around the airways. The number of GATA-3 mRNA-positive cells and the level of GAllA-3 protein in the 1ungs of the rats in the antisense and the OVA-sensitized groups significantly increased. The level of IL-4 and IL-5 in the BALF in the antisense and OVA-sensitized groups were elevated, but the level of IFN-γ decreased markedly. Conclusion: Antisense ODN-induced local blockade of T-bet expression leads to airway inflammation with a selective alteration in patterns of cytokine expression and recruitment of eosinophil cells similar to that in the OVA-sensitized

  13. Train-of-four fade during neuromuscular blockade induced by tubocurarine, succinylcholine or alpha-bungarotoxin in the rat isolated hemidiaphragm.

    Science.gov (United States)

    Cheah, L S; Gwee, M C

    1988-12-01

    1. Nerve-evoked maximal twitches (T1, T2, T3, T4) of the rat isolated hemidiaphragm to train-of-four (TOF) stimulation (2 Hz X 2 s) were recorded continuously in the absence or presence of tubocurarine (1.5 mumol/l), succinylcholine (40 mumol/l) or alpha-bungarotoxin (1 mumol/l). The T1 and T4 response-time profiles for the three drugs were analysed with respect to amplitude depression and the TOF ratio (T4/T1) during the development of and recovery from neuromuscular blockade. 2. Tubocurarine produced T1 block accompanied by intense TOF fade; for the same degree of T1 block, the TOF ratio was lower during the recovery from blockade after washing out tubocurarine from the bath than during the onset of blockade. There was also a correspondingly slower recovery of the TOF ratio from 90% T1 block to control levels when compared with the time for complete T1 recovery. Fade and twitch tension depression were shown clearly to be separate responses, each with its own response-time profile. Fade is therefore not simply a consequence of postjunctional cholinoceptor blockade. 3. Succinylcholine produced T1 block with only moderate TOF fade; similar recovery rates from 90% T1 block to control levels were obtained for T1 and the TOF ratio. 4. alpha-Bungarotoxin produced irreversible and complete neuromuscular blockade during which TOF fade was virtually absent. 5. The results obtained in this study closely resemble those from other similar studies in animals and in humans and clearly demonstrate that the rat isolated hemidiaphragm is a suitable in vitro model for time course studies on TOF fade.

  14. Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles.

    Science.gov (United States)

    Stone, Audrey J; Copp, Steven W; Kim, Joyce S; Kaufman, Marc P

    2015-12-01

    In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs. PMID:26472871

  15. Promoter reuse in prokaryotes

    NARCIS (Netherlands)

    Nijveen, H.; Matus-Garcia, M.; Passel, van M.W.J.

    2012-01-01

    Anecdotal evidence shows promoters being reused separate from their downstream gene, thus providing a mechanism for the efficient and rapid rewiring of a gene’s transcriptional regulation. We have identified over 4000 groups of highly similar promoters using a conservative sequence similarity search

  16. Bloqueo tricompartimental del hombro doloroso: estudio preliminar Tricompartmental blockade of painful shoulder: A preliminary study

    Directory of Open Access Journals (Sweden)

    D. Abejón

    2009-10-01

    shoulder is one of the most common reasons for consulting in primary care and affects between 7% and 34% of the general adult population. The most frequent etiology is rotator cuff dysfunction, accounting for over 70% of cases, including tendinitis, bursitis and rupture of the rotator cuff or any of its components. Various treatments have been proposed for painful shoulder. The aim of this study was to present a new technique for patients refractory to conventional treatments. Material and methods: We analyzed the efficacy of the technique using a visual analog scale (VAS, administered to patients at baseline and 1 month later. In the same period, we evaluated patient satisfaction and the percentage of improvement. Finally, we analyzed complications, if any, and the patients were asked if they would repeat the process or not. Results: The technique was performed in 12 patients. The mean baseline VAS was 8.5 ± 1, which decreased to 5.5 ± 3 after the procedure. In patients who benefitted from the procedure, the decrease in VAS score was close to 5 points with respect to baseline. The technique seemed to be more effective in patients with arthrosis than in those mainly with soft tissue involvement. The mean improvement in the entire sample was 45.83 ± 42.05. Seven patients reported they would repeat the technique compared with five who reported they would not. No complications resulted from the procedure. Conclusions: Tricompartmental blockade of the shoulder seems to be a promising technique in the treatment of shoulder pain, especially when the underlying disease is degenerative.

  17. Health Promotion Education

    DEFF Research Database (Denmark)

    Lehn-Christiansen, Sine

    The paper discusses the implications of health promotion in education. The paper is based on my PhD project entitled “Health promotion education seen through a power/knowledge and subjectification perspective” (in prep). The PhD project explores how professional health promotion skills...... self-technology that requires the subject to take on the ideology and practices prescribed by health promotion in order to conduct themselves and others to better health. But where there is power and attempted government, there is also resistance. The paper will investigate and discuss the resistance...... are conceived in a specific educational setting; namely the Danish social and health education programme. Here, health promotion is formally conceived as a qualification aimed at citizens and patients - and not at the students themselves. However, as the paper will demonstrate, conceptions of student...

  18. Blockade of MerTK Activation by AMPK Inhibits RPE Cell Phagocytosis.

    Science.gov (United States)

    Qin, Suofu

    2016-01-01

    Timely removal of shed photoreceptor outer segments by retinal pigment epithelial cells (RPE) plays a key role in biological renewal of these highly peroxidizable structures and in maintenance of retina health. How environmental stress cause RPE cell dysfunction is undefined however. AMP-activated protein kinase (AMPK), a heterotrimer of a catalytic α subunit and regulatory β and γ subunits, maintains energy homeostasis by limiting energy utilization and/or promoting energy production when energy supply is compromised. Intriguingly, AMPK has been shown to be important in functions of RPE cells. In this mini-review, the role and mechanisms of AMPK in controlling RPE cell phagocytosis are discussed. PMID:26427488

  19. CCR5 blockade for neuroinflammatory diseases--beyond control of HIV.

    Science.gov (United States)

    Martin-Blondel, Guillaume; Brassat, David; Bauer, Jan; Lassmann, Hans; Liblau, Roland S

    2016-02-01

    Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within tissues. Among them, the chemokine (C-C motif) receptor 5 (CCR5) can be targeted by maraviroc, a readily available and well-tolerated drug that was developed for the treatment of HIV. Correlative evidence implicates the CCR5-chemokine axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders. On the basis of this evidence, we postulate in this Review that CCR5 antagonists, such as maraviroc, offer neuroprotective benefits in settings in which CCR5 promotes deleterious neuroinflammation, particularly in diseases in which CD8(+) T cells seem to play a pivotal role.

  20. Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice.

    Science.gov (United States)

    Lei, Kelly; Wegner, Scott A; Yu, Ji-Hwan; Hopf, F Woodward

    2016-11-01

    Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 μM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin + quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs. PMID:27523303