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Sample records for ankara exerts potent

  1. A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts

    PubMed Central

    Swarnkar, Gaurav; Sharan, Kunal; Siddiqui, Jawed A; Mishra, Jay Sharan; Khan, Kainat; Khan, Mohd Parvez; Gupta, Varsha; Rawat, Preeti; Maurya, Rakesh; Dwivedi, Anil K; Sanyal, Sabyasachi; Chattopadhyay, Naibedya

    2012-01-01

    BACKGROUND AND PURPOSE Naringenin and its derivatives have been assessed in bone health for their oestrogen-‘like’ effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action. EXPERIMENTAL APPROACH Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC. KEY RESULTS NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin. CONCLUSIONS AND IMPLICATIONS NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability. PMID:21864313

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

    PubMed

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

    2014-03-01

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

  3. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma.

    PubMed

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-02-02

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.

  4. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma

    PubMed Central

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-01-01

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma. PMID:26830149

  5. Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo

    PubMed Central

    Jain, Chetan Kumar; Pradhan, Bhola Shankar; Banerjee, Sukdeb; Mondal, Nirup Bikash; Majumder, Subeer S.; Bhattacharyya, Madhumita; Chakrabarti, Saikat; Roychoudhury, Susanta; Majumder, Hemanta Kumar

    2015-01-01

    DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy. PMID:26189912

  6. Berteroin Present in Cruciferous Vegetables Exerts Potent Anti-Inflammatory Properties in Murine Macrophages and Mouse Skin

    PubMed Central

    Jung, Yoo Jin; Jung, Jae In; Cho, Han Jin; Choi, Myung-Sook; Sung, Mi-Kyung; Yu, Rina; Kang, Young-Hee; Park, Jung Han Yoon

    2014-01-01

    Berteroin (5-methylthiopentyl isothiocyanate) is a sulforaphane analog present in cruciferous vegetables, including Chinese cabbage, rucola salad leaves, and mustard oil. We examined whether berteroin exerts anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin inflammation models. Berteroin decreased LPS-induced release of inflammatory mediators and pro-inflammatory cytokines in Raw 264.7 macrophages. Berteroin inhibited LPS-induced degradation of inhibitor of κBα (IκBα) and nuclear factor-κB p65 translocation to the nucleus and DNA binding activity. Furthermore, berteroin suppressed degradation of IL-1 receptor-associated kinase and phosphorylation of transforming growth factor β activated kinase-1. Berteroin also inhibited LPS-induced phosphorylation of p38 MAPK, ERK1/2, and AKT. In the mouse ear, berteroin effectively suppressed TPA-induced edema formation and down-regulated iNOS and COX-2 expression as well as phosphorylation of AKT and ERK1/2. These results demonstrate that berteroin exhibits potent anti-inflammatory properties and suggest that berteroin can be developed as a skin anti-inflammatory agent. PMID:25393510

  7. Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways

    PubMed Central

    Liao, Xin-Hua; Zhang, Arina Li; Zheng, Min; Li, Mei-Qing; Chen, Champ Peng; Xu, Huijuan; Chu, Qing-Song; Yang, Dayun; Lu, Wenxian; Tsai, Ting-Fen; Liu, Hekun; Zhou, Xiao Zhen; Lu, Kun Ping

    2017-01-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC. PMID:28262728

  8. Affinity-purified respiratory syncytial virus antibodies from intravenous immunoglobulin exert potent antibody-dependent cellular cytotoxicity.

    PubMed

    Gupta, Nimesh; LeGoff, Jerome; Chamat, Soulaima; Mercier-Delarue, Severine; Touzelet, Olivier; Power, Ultan F; Kazatchkine, Michel D; Simon, Francois; Lacroix-Desmazes, Sebastien; Bayry, Jagadeesh; Kaveri, Srinivas V

    2013-01-01

    Mixed infections are one of the major therapeutic challenges, as the current strategies have had limited success. One of the most common and widespread conditions of mixed infection is respiratory syncytial virus-mediated pathology of the respiratory tract in children. There is a dire need for the development of novel therapeutic approaches during mixed infections. Therapeutic intravenous immunoglobulin preparations, obtained from plasma pools of healthy donors have been used in immune deficiencies. This study was thus designed to characterize the functional efficacy of RSV-specific antibodies in IVIg. To explore the functional ability of these affinity-purified RSV-specific antibodies, the antibody-dependent and complement dependent cytotoxicity was determined using peripheral cells of healthy donors. This study demonstrates the existence of highly potent RSV-specific antibodies in IVIg preparations and provides the basis for the use of IVIg as broad-spectrum protective shield to RSV-infected children during mixed infections.

  9. Affinity-Purified Respiratory Syncytial Virus Antibodies from Intravenous Immunoglobulin Exert Potent Antibody-Dependent Cellular Cytotoxicity

    PubMed Central

    Gupta, Nimesh; LeGoff, Jerome; Chamat, Soulaima; Mercier-Delarue, Severine; Touzelet, Olivier; Power, Ultan F.; Kazatchkine, Michel D.; Simon, Francois; Lacroix-Desmazes, Sebastien; Bayry, Jagadeesh; Kaveri, Srinivas V.

    2013-01-01

    Mixed infections are one of the major therapeutic challenges, as the current strategies have had limited success. One of the most common and widespread conditions of mixed infection is respiratory syncytial virus-mediated pathology of the respiratory tract in children. There is a dire need for the development of novel therapeutic approaches during mixed infections. Therapeutic intravenous immunoglobulin preparations, obtained from plasma pools of healthy donors have been used in immune deficiencies. This study was thus designed to characterize the functional efficacy of RSV-specific antibodies in IVIg. To explore the functional ability of these affinity-purified RSV-specific antibodies, the antibody-dependent and complement dependent cytotoxicity was determined using peripheral cells of healthy donors. This study demonstrates the existence of highly potent RSV-specific antibodies in IVIg preparations and provides the basis for the use of IVIg as broad-spectrum protective shield to RSV-infected children during mixed infections. PMID:23894466

  10. AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells.

    PubMed

    Yao, Ting-Jing; Zhu, Jin-Hai; Peng, De-Feng; Cui, Zhen; Zhang, Chao; Lu, Pei-hua

    2015-07-01

    Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.

  11. The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo.

    PubMed

    Dong, Yang-Yang; Zhuang, Yi-Huang; Cai, Wen-Jie; Liu, Yan; Zou, Wen-Bing

    2016-11-01

    The development of novel anti-pancreatic cancer agents is extremely important. Here, we investigated the anti-pancreatic cancer activity by NPC-26, a novel mitochondrion interfering compound. We showed that NPC-26 was anti-proliferative and cytotoxic to human pancreatic cancer cells, possibly via inducing caspase-9-dependent cell apoptosis. Pharmacological inhibition or shRNA-mediated silence of caspase-9 attenuated NPC-26-induced pancreatic cancer cell death and apoptosis. Further, NPC-26 treatment led to mitochondrial permeability transition pore (mPTP) opening in the cancer cells, which was evidenced by mitochondrial depolarization, ANT-1(adenine nucleotide translocator-1)-Cyp-D (cyclophilin-D) association and oxidative phosphorylation disturbance. mPTP blockers (cyclosporin and sanglifehrin A) or shRNA-mediated knockdown of key mPTP components (Cyp-D and ANT-1) dramatically attenuated NPC-26-induced pancreatic cancer cell apoptosis. Importantly, we showed that NPC-26, at a low concentration, potentiated gemcitabine-induced mPTP opening and subsequent pancreatic cancer cell apoptosis. In vivo, NPC-26 intraperitoneal injection significantly suppressed the growth of PANC-1 xenograft tumors in nude mice. Meanwhile, NPC-26 sensitized gemcitabine-mediated anti-pancreatic cancer activity in vivo. In summary, the results of this study suggest that NPC-26, alone or together with gemcitabine, potently inhibits pancreatic cancer cells possibly via disrupting mitochondrion.

  12. siRNA targeting vaccinia virus double-stranded RNA binding protein [E3L] exerts potent antiviral effects.

    PubMed

    Dave, Rajnish S; McGettigan, James P; Qureshi, Tazeen; Schnell, Matthias J; Nunnari, Giuseppe; Pomerantz, Roger J

    2006-05-10

    The Vaccinia virus gene, E3L, encodes a double-stranded RNA [dsRNA]-binding protein. We hypothesized that, owing to the critical nature of dsRNA in triggering host innate antiviral responses, E3L-specific small-interfering RNAs [siRNAs] should be effective antiviral agents against pox viruses, for which Vaccinia virus is an appropriate surrogate. In this study, we have utilized two human cell types, namely, HeLa and 293T, one which responds to interferon [IFN]-beta and the other produces and responds to IFN-beta, respectively. The antiviral effects were equally robust in HeLa and 293T cells. However, in the case of 293T cells, several distinct features were observed, when IFN-beta is activated in these cells. Vaccinia virus replication was inhibited by 97% and 98% as compared to control infection in HeLa and 293T cells transfected with E3L-specific siRNAs, respectively. These studies demonstrate the utility of E3L-specific siRNAs as potent antiviral agents for small pox and related pox viruses.

  13. Pd@Ag Nanosheets in Combination with Amphotericin B Exert a Potent Anti-Cryptococcal Fungicidal Effect

    PubMed Central

    Wang, Guizhen; Fang, Wei; Ye, Chen; Hu, Hanhua; Fa, Zhenzong; Yi, Jiu; Liao, Wan-qing

    2016-01-01

    Silver nanoparticles have received considerable interest as new “nanoantibiotics” with the potential to kill drug-resistant microorganisms. Recently, a class of new core-shell nanostructures, Pd@Ag nanosheets (Pd@Ag NSs), were created using deposition techniques and demonstrated excellent inhibitory effects on various bacteria in vitro. In this study, we evaluated the antifungal activity of Pd@Ag NSs against common invasive fungal pathogens. Among these organisms, Cryptococcus neoformans complex species was most susceptible to Pd@Ag NSs, which exhibited potent antifungal activity against various molecular types or sources of cryptococcal strains including fluconazole-resistant isolates. The anticryptococcal activity of Pd@Ag NSs was significantly greater than fluconazole and similar to that of amphotericin B (AmB). At relatively high concentrations, Pd@Ag NSs exhibited fungicidal activity against Cryptococcus spp., which can likely be attributed to the disruption of cell integrity, intracellular protein synthesis, and energy metabolism. Intriguingly, Pd@Ag NSs also exhibited strong synergistic anti-cryptococcal fungicidal effects at low concentrations in combination with AmB but exhibited much better safety in erythrocytes than AmB, even at the minimal fungicidal concentration. Therefore, Pd@Ag NSs may be a promising adjunctive agent for treating cryptococcosis, and further investigation for clinical applications is required. PMID:27271376

  14. A recombinantly tailored β-defensin that displays intensive macropinocytosis-mediated uptake exerting potent efficacy against K-Ras mutant pancreatic cancer

    PubMed Central

    Du, Yue; Shang, Bo-yang; Sheng, Wei-jin; Zhang, Sheng-hua; Li, Yi; Miao, Qing-fang; Zhen, Yong-su

    2016-01-01

    K-Ras mutant pancreatic cancer cells display intensive macropinocytosis, indicating that this process may be exploited in the design of anticancer targeted therapies. In this study, we constructed a macropinocytosis-oriented recombinantly tailored defensin (DF-HSA) which consists of human β-defensin-2 (DF) and human serum albumin (HSA). The macropinocytosis intensity and cytotoxicity of DF-HSA were investigated in K-Ras mutant MIA PaCa-2 cells and wild-type BxPC-3 cells. As found, the DF-HSA uptake in MIA PaCa-2 cells was much higher than that in wild-type BxPC-3 cells. Correspondingly, the cytotoxicity of DF-HSA to MIA PaCa-2 cells was more potent than that to BxPC-3 cells. In addition, the cytotoxicity of DF-HSA was much stronger than that of β-defensin HBD2. DF-HSA suppressed cancer cell proliferation and induced mitochondrial pathway apoptosis. Notably, DF-HSA significantly inhibited the growth of human pancreatic carcinoma MIA PaCa-2 xenograft in athymic mice at well tolerated dose. By in vivo imaging, DF-HSA displayed a prominent accumulation in the tumor. The study indicates that the recombinantly tailored β-defensin can intensively enter into the K-Ras mutant pancreatic cancer cells through macropinocytosis-mediated process and exert potent therapeutic efficacy against the pancreatic carcinoma xenograft. The novel format of β-defensin may play an active role in macropinocytosis-mediated targeting therapy. PMID:27517152

  15. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma

    PubMed Central

    2013-01-01

    Background The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. Methods NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. Results The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. Conclusions The anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies. PMID:24305507

  16. The novel trisubstituted pyran derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-like activity in rodents

    PubMed Central

    Dutta, Aloke K.; Gopishetty, Bhaskar; Gogoi, Sanjib; Ali, Solav; Zhen, Juan; Reith, Maarten

    2011-01-01

    Major depression disorder is a significant health problem with 10-20% of all adults suffering from this disease. The underlying causes of depression are still unclear and 15% of depressed patients are resistant to all known therapies. Monoamine therapies have so far been the most successful approach for treating depression. Triple monoamine reuptake inhibitors have recently been implicated in generation of potent antidepressant activity while possibly exhibiting a low side-effect profile in addition to treating anhedonia. The additional, previously under-appreciated involvement of dopaminergic systems in depression prompted our efforts to develop novel asymmetric trisubstituted and disubstituted pyran derivatives as triple reuptake inhibitors. One of the lead compounds, D-142, exhibited uptake inhibition (Ki) values of 29.3 nM, 14.7 nM and 37.4 nM for norepinephrine, serotonin and dopamine transporters, respectively. Its affinity for serotonin transporter was comparable to fluoxetine , a well known SSRI. In the rat forced swimming test, compound D-142 exhibited potent antidepressant activity in the dose range tested (2.5, 5 and 10 mg/kg) and was far more efficacious than the reference compound imipramine. In the mouse tail suspension test, compound D-142 reduced immobility in a dose (2.5, 5 and 10 mg/kg) dependent manner, indicating a potent antidepressant effect. In locomotor activity tests, compound D-142 did not exhibit any stimulation in the same dose ranges. In the extended CNS receptors screening assay this molecule exhibited little or no non-specific interaction in the CNS, indicating high specificity for monoamine transporters. These results advance D-142 as a potential potent antidepressant. PMID:21963455

  17. The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.

    PubMed

    Baker, Adele; Gregory, Gareth P; Verbrugge, Inge; Kats, Lev; Hilton, Joshua J; Vidacs, Eva; Lee, Erwin M; Lock, Richard B; Zuber, Johannes; Shortt, Jake; Johnstone, Ricky W

    2016-03-01

    Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

  18. The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs

    PubMed Central

    Siddiqi, Faraz; Atmadibrata, Bernard; Telfer, Thomas J.; Sun, Yuting; Zhang, Lihong; Yu, Denise; Mccarroll, Joshua; Liu, Bing; Yang, Rui H.; Guo, Xiang Y.; Tee, Andrew E.; Itoh, Ken; Wang, Jenny; Kavallaris, Maria; Haber, Michelle; Norris, Murray D.; Cheung, Belamy B.; Byrne, Jennifer A.; Ziegler, David S.; Marshall, Glenn M.; Dinger, Marcel E.; Codd, Rachel; Zhang, Xu D.; Liu, Tao

    2016-01-01

    BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2. Treatment with JQ1 blocked the recruitment of Nrf2 to the antioxidant responsive elements at Nrf2 target gene promoters, and JQ1 exerted synergistic anticancer effects with nanaomycin by blocking the Nrf2-antioxidant signaling pathway. JQ1 and vincristine synergistically induced neuroblastoma cell cycle arrest at the G2/M phase, aberrant mitotic spindle assembly formation and apoptosis, but showed no effect on cell survival in normal non-malignant cells. Importantly, co-treatment with JQ1 and vincristine synergistically suppressed tumor progression in neuroblastoma-bearing mice. These results strongly suggest that patients treated with BET bromodomain inhibitors in clinical trials should be co-treated with vincristine. PMID:27764794

  19. KU135, a Novel Novobiocin-Derived C-Terminal Inhibitor of the 90-kDa Heat Shock Protein, Exerts Potent Antiproliferative Effects in Human Leukemic Cells

    PubMed Central

    Shelton, Shary N.; Shawgo, Mary E.; Matthews, Shawna B.; Lu, Yuanming; Donnelly, Alison C.; Szabla, Kristen; Tanol, Mehmet; Vielhauer, George A.; Rajewski, Roger A.; Matts, Robert L.; Blagg, Brian S. J.

    2009-01-01

    The 90-kDa heat shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Consequently, there is considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90. Here, we investigated the extent to which a novel novobiocin-derived C-terminal Hsp90 inhibitor, designated KU135, induced antiproliferative effects in Jurkat T-lymphocytes. The results indicated that KU135 bound directly to Hsp90, caused the degradation of known Hsp90 client proteins, and induced more potent antiproliferative effects than the established N-terminal Hsp90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG). Closer examination of the cellular response to KU135 and 17-AAG revealed that only 17-AAG induced a strong up-regulation of Hsp70 and Hsp90. In addition, KU135 caused wild-type cells to undergo G2/M arrest, whereas cells treated with 17-AAG accumulated in G1. Furthermore, KU135 but not 17-AAG was found to be a potent inducer of mitochondria-mediated apoptosis as evidenced, in part, by the fact that cell death was inhibited to a similar extent by Bcl-2/Bcl-xL overexpression or the depletion of apoptotic protease-activating factor-1 (Apaf-1). Together, these data suggest that KU135 inhibits cell proliferation by regulating signaling pathways that are mechanistically different from those targeted by 17-AAG and as such represents a novel opportunity for Hsp90 inhibition. PMID:19741006

  20. C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

    PubMed Central

    Aoki, Manabu; Hayashi, Hironori; Yedidi, Ravikiran S.; Martyr, Cuthbert D.; Takamatsu, Yuki; Aoki-Ogata, Hiromi; Nakamura, Teruya; Nakata, Hirotomo; Das, Debananda; Yamagata, Yuriko; Ghosh, Arun K.

    2015-01-01

    ABSTRACT We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRVRP51); the three compounds remained active against HIV-1DRVRP51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. IMPORTANCE Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRVR) has recently been observed in vivo and in

  1. Novel octahedral Pt(IV) complex with di-n-propyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoato ligand exerts potent immunomodulatory effects.

    PubMed

    Miljković, Djordje; Poljarević, Jelena M; Petković, Filip; Blaževski, Jana; Momčilović, Miljana; Nikolić, Ivana; Saksida, Tamara; Stošić-Grujičić, Stanislava; Grgurić-Šipka, Sanja; Sabo, Tibor J

    2012-01-01

    We have recently reported that a novel octahedral Pt(IV) complex with di-n-propyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoato ligand has a potent cytotoxic effect on glioma, melanoma and fibrosarcoma cell lines. In this work, we investigated the influence of the Pt(IV) compound on immune cells. We determined its effect on the viability of spleen cells and lymph node cells and on their capability to produce interferon (IFN)-γ and interleukin (IL)-17. Also, we researched the compound's impact on peritoneal macrophages and generation of NO in these cells. Our results show that the complex has limited influence on cell viability of immune cells, but profound inhibitory effect on the production of examined immune mediators. These results are valuable as they show that the novel Pt(IV) complex applied in concentrations which are effective against tumor cells do not affect immune cell viability. Moreover, they also imply that the complex has immunomodulatory properties.

  2. New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

    PubMed Central

    Altaf, Muhammad; Monim-ul-Mehboob, Muhammad; Kawde, Abdel-Nasser; Corona, Giuseppe; Larcher, Roberto; Ogasawara, Marcia; Casagrande, Naike; Celegato, Marta; Borghese, Cinzia; Siddik, Zahid H.; Aldinucci, Donatella; Isab, Anvarhusein A.

    2017-01-01

    We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes. PMID:27888799

  3. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells

    PubMed Central

    2013-01-01

    cleaved caspase-3 in the tumor tissues. Conclusions The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted. PMID:24215614

  4. CWF-145, a novel synthetic quinolone derivative exerts potent antimitotic activity against human prostate cancer: Rapamycin enhances antimitotic drug-induced apoptosis through the inhibition of Akt/mTOR pathway.

    PubMed

    Hung, Chao-Ming; Lin, Ying-Chao; Liu, Liang-Chih; Kuo, Sheng-Chu; Ho, Chi-Tang; Way, Tzong-Der

    2016-12-25

    CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU-145 and LNCap. It had a very low IC50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin at the colchicine-binding site then disrupted microtubule polymerization. Furthermore, the damaged microtubule affected the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our data showed that CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. The increased cyclin B1 and securin arrested cell cycle at G2/M phase. Moreover, we showed that Akt activation markedly increased resistance to microtubule-directed agents, including CWF-145, colchicine, and paclitaxel. Interestingly, rapamycin inhibited Akt-mediated therapeutic resistance, indicating that these effects were dependent on mTOR. Taken together, these observations suggest that activation of the Akt/mTOR signaling pathway can promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data may provide insight into potentially synergistic combinations of anticancer therapies.

  5. The potent synthetic androgens, dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone, do not require 5α-reduction to exert their maximal androgenic effects.

    PubMed

    Attardi, Barbara J; Hild, Sheri A; Koduri, Sailaja; Pham, Trung; Pessaint, Laurent; Engbring, Jean; Till, Bruce; Gropp, David; Semon, Anne; Reel, Jerry R

    2010-10-01

    Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent androgens in development for hormonal therapy in men. As 5α-reduced androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats

  6. The Potent Synthetic Androgens, Dimethandrolone (7α,11β-Dimethyl-19-Nortestosterone) and 11β-Methyl-19-Nortestosterone, Do Not Require 5α-Reduction to Exert their Maximal Androgenic Effects*

    PubMed Central

    Attardi, Barbara J.; Hild, Sheri A.; Koduri, Sailaja; Pham, Trung; Pessaint, Laurent; Engbring, Jean; Till, Bruce; Gropp, David; Semon, Anne; Reel, Jerry R.

    2010-01-01

    Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent androgens in development for hormonal therapy in men. As 5α-reduced androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22 day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least 3-fold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was 4- to 8-fold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T + DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats, whereas

  7. Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development.

    PubMed

    Volz, A; Sutter, G

    2017-01-01

    Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology.

  8. Urban Heat Island ın Ankara

    NASA Astrophysics Data System (ADS)

    Yılmaz, Erkan

    2016-04-01

    In this study, the seasonal variation of the surface temperature of Ankara urban area and its enviroment have been analyzed by using Landsat 7 image. The Landsat 7 images of each month from 2007 to 2011 have been used to analyze the annually changes of the surface temperature. The land cover of the research area was defined with supervised classification method on the basis of the satellite image belonging to 2008 July. After determining the surface temperatures from 6-1 bands of satellite images, the monthly mean surface temperatures were calculated for land cover classification for the period between 2007 and 2011. According to the results obtained, the surface temperatures are high in summer and low in winter from the airtemperatures. all satellite images were taken at 10:00 am, it is found that urban areas are cooler than rural areas at 10:00 am. Regarding the land cover classification, the water surfaces are the coolest surfaces during the whole year.The warmest areas are the grasslands and dry farming areas. While the parks are warmer than the urban areas during the winter, during the summer they are cooler than artificial land covers. The urban areas with higher building density are the cooler surfaces after water bodies.

  9. A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors

    PubMed Central

    Favreau, Philippe; Benoit, Evelyne; Hocking, Henry G; Carlier, Ludovic; D' hoedt, Dieter; Leipold, Enrico; Markgraf, René; Schlumberger, Sébastien; Córdova, Marco A; Gaertner, Hubert; Paolini-Bertrand, Marianne; Hartley, Oliver; Tytgat, Jan; Heinemann, Stefan H; Bertrand, Daniel; Boelens, Rolf; Stöcklin, Reto; Molgó, Jordi

    2012-01-01

    BACKGROUND AND PURPOSE The µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH µ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS Synthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC50= 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked NaV1.4 (IC50= 1.3 nM) and NaV1.2 channels in a long-lasting manner. Cardiac NaV1.5 and DRG-specific NaV1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the α3β2 nAChR subtype (IC50= 450 nM) and, to a lesser extent, on the α7 and α4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to α-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS µ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels. PMID:22229737

  10. Nanoliposomal Nitroglycerin Exerts Potent Anti-Inflammatory Effects

    NASA Astrophysics Data System (ADS)

    Ardekani, Soroush; Scott, Harry A.; Gupta, Sharad; Eum, Shane; Yang, Xiao; Brunelle, Alexander R.; Wilson, Sean M.; Mohideen, Umar; Ghosh, Kaustabh

    2015-11-01

    Nitroglycerin (NTG) markedly enhances nitric oxide (NO) bioavailability. However, its ability to mimic the anti-inflammatory properties of NO remains unknown. Here, we examined whether NTG can suppress endothelial cell (EC) activation during inflammation and developed NTG nanoformulation to simultaneously amplify its anti-inflammatory effects and ameliorate adverse effects associated with high-dose NTG administration. Our findings reveal that NTG significantly inhibits human U937 cell adhesion to NO-deficient human microvascular ECs in vitro through an increase in endothelial NO and decrease in endothelial ICAM-1 clustering, as determined by NO analyzer, microfluorimetry, and immunofluorescence staining. Nanoliposomal NTG (NTG-NL) was formulated by encapsulating NTG within unilamellar lipid vesicles (DPhPC, POPC, Cholesterol, DHPE-Texas Red at molar ratio of 6:2:2:0.2) that were ~155 nm in diameter and readily uptaken by ECs, as determined by dynamic light scattering and quantitative fluorescence microscopy, respectively. More importantly, NTG-NL produced a 70-fold increase in NTG therapeutic efficacy when compared with free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses. Thus, these findings, which are the first to reveal the superior therapeutic effects of an NTG nanoformulation, provide the rationale for their detailed investigation for potentially superior vascular normalization therapies.

  11. Nanoliposomal Nitroglycerin Exerts Potent Anti-Inflammatory Effects

    PubMed Central

    Ardekani, Soroush; Scott, Harry A.; Gupta, Sharad; Eum, Shane; Yang, Xiao; Brunelle, Alexander R.; Wilson, Sean M.; Mohideen, Umar; Ghosh, Kaustabh

    2015-01-01

    Nitroglycerin (NTG) markedly enhances nitric oxide (NO) bioavailability. However, its ability to mimic the anti-inflammatory properties of NO remains unknown. Here, we examined whether NTG can suppress endothelial cell (EC) activation during inflammation and developed NTG nanoformulation to simultaneously amplify its anti-inflammatory effects and ameliorate adverse effects associated with high-dose NTG administration. Our findings reveal that NTG significantly inhibits human U937 cell adhesion to NO-deficient human microvascular ECs in vitro through an increase in endothelial NO and decrease in endothelial ICAM-1 clustering, as determined by NO analyzer, microfluorimetry, and immunofluorescence staining. Nanoliposomal NTG (NTG-NL) was formulated by encapsulating NTG within unilamellar lipid vesicles (DPhPC, POPC, Cholesterol, DHPE-Texas Red at molar ratio of 6:2:2:0.2) that were ~155 nm in diameter and readily uptaken by ECs, as determined by dynamic light scattering and quantitative fluorescence microscopy, respectively. More importantly, NTG-NL produced a 70-fold increase in NTG therapeutic efficacy when compared with free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses. Thus, these findings, which are the first to reveal the superior therapeutic effects of an NTG nanoformulation, provide the rationale for their detailed investigation for potentially superior vascular normalization therapies. PMID:26584637

  12. Ozone profiles and structure of lamination in Ankara, Turkey

    NASA Astrophysics Data System (ADS)

    Kahya, C.; Demirhan, D.; Topcu, S.; Incecik, S.

    2003-04-01

    The existence of the laminar layers with depleted and enhanced ozone mixing ratios in the vertical profiles of ozone has been received scientific attention. Due to the influences of the dynamic processes on the ozone mixing ratio in the lower stratosphere, laminar features are used in relation to the filaments of air shed from the dynamic processes. Stratospheric ozone observations are based on ozonesonde flown from Ankara (40^oN; 33^oE) by Turkish State Meteorological Service. Measurements of the ozone profile using ECC balloon-borne ozonesonde have been made since January 1994 at Ankara, Turkey weekly or twice in month. In this study, about 151 soundings in the measured program (Jan.1994- Dec.2001) were used for the analysis. The total ozone characteristics of Ankara are similar to the stations of located in mid-latitudes of Eastern Europe. The average value of total column ozone amount by ozone sounding is found with a 320 DU ± 43 in the period of 1994-2001 in Ankara. The laminae features in Ankara reflect the similar characteristics obtained in European mid-latitude stations. The seasonal distributions of laminae at Ankara show a peak occurrence in Spring. The numbers of laminae are found as 45, 58, 17 and 18 for winter, spring, summer and fall seasons respectively. The most of the laminae are found below 13 km. Frequency distribution magnitudes of laminae indicates 21% in 26-30 nb class. The mean magnitude and depth of the laminae is found as 45 nb and 1.1km respectively. In order to understand the influence of tropopause heights on the laminae structure, the number of laminae has been grouped according to high and low tropopause heights. The frequency of laminae for both lower and higher tropopause groups for winter and spring seasons are close. However the laminae disappearances in both summer and fall seasons for only in case of the lower tropopause. The days with the maximum laminae which are mostly occurred in winter and spring seasons have been examined

  13. Exertional Rhabdomyolysis after Spinning

    PubMed Central

    Jeong, Youjin; Oh, Eun-Jung; Ahn, Ah-Leum; Choi, Jae-Kyung; Cho, Dong-Yung

    2016-01-01

    Any strenuous muscular exercise may trigger rhabdomyolysis. We report an episode of clinically manifested exertional rhabdomyolysis due to stationary cycling, commonly known as spinning. Reports of spinning-related rhabdomyolysis are rare in the English literature, and the current case appears to be the first such case reported in South Korea. A previously healthy 21-year-old Asian woman presented with severe thigh pain and reddish-brown urinary discoloration 24–48 hours after attending a spinning class at a local gymnasium. Paired with key laboratory findings, her symptoms were suggestive of rhabdomyolysis. She required hospital admission to sustain renal function through fluid resuscitation therapy and fluid balance monitoring. Because exertional rhabdomyolysis may occur in any unfit but otherwise healthy individual who indulges in stationary cycling, the potential health risks of this activity must be considered. PMID:27900075

  14. Determination of Coleoptera fauna on carcasses in Ankara province, Turkey.

    PubMed

    Ozdemir, Senem; Sert, Osman

    2009-01-10

    In this study, 40 species from Staphylinidae, Histeridae, Dermestidae, Silphidae, Nitidulidae and Cleridae families of Coleoptera which were found in 12 pig (Sus scrofa L.) carcasses were identified and recorded during a one-year period at the Hacettepe University Beytepe Campus located in Ankara, Turkey. According to the duration of their presence on the carcasses, 22 of these species were accepted to be important in decomposition. Their distribution over the months and the duration of their presence in the various decomposition stages over the seasons were determined.

  15. Recombinant modified vaccinia virus Ankara-based malaria vaccines.

    PubMed

    Sebastian, Sarah; Gilbert, Sarah C

    2016-01-01

    A safe and effective malaria vaccine is a crucial part of the roadmap to malaria elimination/eradication by the year 2050. Viral-vectored vaccines based on adenoviruses and modified vaccinia virus Ankara (MVA) expressing malaria immunogens are currently being used in heterologous prime-boost regimes in clinical trials for induction of strong antigen-specific T-cell responses and high-titer antibodies. Recombinant MVA is a safe and well-tolerated attenuated vector that has consistently shown significant boosting potential. Advances have been made in large-scale MVA manufacture as high-yield producer cell lines and high-throughput purification processes have recently been developed. This review describes the use of MVA as malaria vaccine vector in both preclinical and clinical studies in the past 5 years.

  16. Ambulance times of Ankara emergency aid and rescue services' ambulance system.

    PubMed

    Altintaş, K H; Bilir, N

    2001-03-01

    The aim of this study was to determine various times related to the ambulance activities of Ankara Emergency Aid and Rescue Services (EARS) and if necessary contribute to the improvement of them. A descriptive study was planned to determine various times related to the ambulance activities of Ankara EARS. The data was collected by one of the researchers. The study was conducted between 1 October 1995 and 30 September 1996. The variables of the study were: delay time, response time, time at the scene (scene time), round trip time, transport time and total run time of Ankara EARS ambulance activities. Ankara EARS Emergency Call Registry Forms (5638 forms) were evaluated for the above stated variables. The computer program EPI-INFO 5.0 was used in the study. The median response time of Ankara EARS was found to be 9 minutes. In the research year, the median delay time was 2 minutes. Median arrival to patient contact time of Ankara EARS was 2 minutes. Median time at the scene was 7 minutes. Median round trip time of the system was 44 minutes. The median time to arrive at the scene from the ambulance station was 8 minutes. The median transport time was 10 minutes. The median total run time was 30 minutes. As the median response time was found to be 9 minutes it is concluded that there should be more ambulance vehicles to improve this time of Ankara EARS. Due to financial problems, times were recorded manually by the ambulance crew and dispatchers of Ankara EARS. If digital and electronic recording systems are used, these times might be more precise.

  17. Electrocution fatalities in military personnel in Ankara, Turkey

    PubMed Central

    Tugcu, Harun; Ozsoy, Sait; Balandiz, Huseyin

    2015-01-01

    Objectives: To investigate various cases of death caused by electrical injuries among Turkish military personnel. Methods: We retrospectively reviewed fatality cases of military personnel between 1994 and 2013 at the Department of Forensic Medicine, Gulhane Military Medical Academy, School of Medicine, Ankara, Turkey, the only forensic medicine center for the Turkish Armed Forces. Medical records and autopsy reports of cases of electrical fatalities were reviewed and analyzed in terms of age and gender-specific incidence, voltage, contact details, body region distribution, location, and season of incident, site, and severity of injuries sustained, and histopathological and toxicological findings. Results: Sixteen (3.5%) out of the 450 autopsy cases involved electrocution. All deaths were accidental and most frequently occurred outdoors (75%). Eight (50%) died due to high voltage while 6 (37.5%) died due to low voltage. The entry and exit lesions were determined most frequently in cases with high voltage injury. The low voltage deaths commonly occurred at the scene of the event (66.6%), while almost all high voltage deaths occurred in the hospital (87.5%, p=0.03). Electrical burns were most commonly detected in the upper extremities (32.6%, n=14). Conclusion: The present study shows that deaths due to high voltage electrocution are more frequent than low voltage electrocution among military personnel. PMID:25630009

  18. Effects of urbanization on climate of İstanbul and Ankara

    NASA Astrophysics Data System (ADS)

    Karaca, Mehmet; Tayanç, Mete; Toros, Hüseyi˙n.

    The purpose of this work is to study regional climate change and investigate the effects of urbanization on climates of two largest cities in Turkey: İstanbul and Ankara. Air temperature (mean, maximum and minimum) data of İstanbul and Ankara are analyzed to study regional climate change and to understand the possible effects of urbanization on the climate of these regions owing to industrialization and large flux of migration from rural parts of the country. For the trend analysis, linear regression and the sequential version of the Mann-Kendall test is used. A significant upward trend is found in the urban temperatures of southern İstanbul, which is the most highly populated and industrialized part of the city compared to its rural parts. Northern stations do not show any warming trend; instead, they have a cooling trend. Urbanization and industrialization in the southern part of İstanbul has a negative effect on regional cooling. In spite of Ankara's urban geometry and air pollution problem, the urban station in Ankara does not show any warming trend. A significant urban heat island intensity ( urban-rural) is not observed in Ankara.

  19. When exercise causes exertional rhabdomyolysis.

    PubMed

    Furman, Janet

    2015-04-01

    Exertional rhabdomyolysis is a clinical condition caused by intense, repetitive exercise or a sudden increase in exercise in an untrained person, although rhabdomyolysis can occur in trained athletes. In many cases, the presentation of early, uncomplicated rhabdomyolysis is subtle, but serious complications such as renal failure, compartment syndrome, and dysrhythmias may arise if severe exertional rhabdomyolysis is undiagnosed or untreated. Management is further complicated by the lack of concrete management guidelines for treating rhabdomyolysis and returning patients to activity.

  20. Determination of formaldehyde levels in 100 furniture workshops in Ankara.

    PubMed

    Vaizoğlu, Songül Acar; Aycan, Sefer; Akin, Levent; Koçdor, Pelin; Pamukçu, Gül; Muhsinoğlu, Orkun; Ozer, Feyza; Evci, E Didem; Güler, Cağatay

    2005-10-01

    One of the airborne pollutants in wood products industry is formaldehyde, which may pose some health effects. Therefore this study is conducted to determine formaldehyde levels in 100 furniture-manufacturing workshops in Ankara and also to determine the symptoms, which may be related with formaldehyde exposure among the workers. Indoor formaldehyde levels ranged from 0.02 ppm to 2.22 ppm with a mean of 0.6 +/- 0.3 ppm. Outdoor formaldehyde levels also ranged from 0.0 ppm to 0.08 ppm with a mean of 0.03 +/- 0.03 ppm. Formaldehyde levels were higher in workplaces located at basement than in workplaces located at or above ground level (p < 0.01). An association was found between indoor formaldehyde levels and the types of fuel used (p < 0.05). The levels were higher in workplaces where only sawdust was used for heating, than in workplaces where wood, coal, and sawdust are used (p = 0.02). An association was found between runny nose and indoor formaldehyde levels (p = 0.03). Formaldehyde levels were lower in workplaces where employees had no symptoms than in those where employees had 4 or more symptoms (p = 0.02). Of 229 employees 57 subjects (24.9%) work under the formaldehyde levels of 0.75 ppm and above. Thus, approximately one fourth of the employees in workplaces are working in environments with formaldehyde levels exceeding those permitted by Occupational Safety and Health Administration (OSHA). The employees working in small-scale furniture workshops are at risk of formaldehyde exposure. Measures, such as improved ventilation, have to be taken in these workplaces, in order to decrease the formaldehyde levels.

  1. Air pollution forecasting in Ankara, Turkey using air pollution index and its relation to assimilative capacity of the atmosphere.

    PubMed

    Genc, D Deniz; Yesilyurt, Canan; Tuncel, Gurdal

    2010-07-01

    Spatial and temporal variations in concentrations of CO, NO, NO(2), SO(2), and PM(10), measured between 1999 and 2000, at traffic-impacted and residential stations in Ankara were investigated. Air quality in residential areas was found to be influenced by traffic activities in the city. Pollutant ratios were proven to be reliable tracers to differentiate between different sources. Air pollution index (API) of the whole city was calculated to evaluate the level of air quality in Ankara. Multiple linear regression model was developed for forecasting API in Ankara. The correlation coefficients were found to be 0.79 and 0.63 for different time periods. The assimilative capacity of Ankara atmosphere was calculated in terms of ventilation coefficient (VC). The relation between API and VC was investigated and found that the air quality in Ankara was determined by meteorology rather than emissions.

  2. Exertional Rhabdomyolysis in the Athlete

    PubMed Central

    Tietze, David C.; Borchers, James

    2014-01-01

    Context: Exertional rhabdomyolysis is a relatively uncommon but potentially fatal condition affecting athletes that requires prompt recognition and appropriate management. Evidence Acquisition: A search of the PubMed database from 2003 to 2013 using the term exertional rhabdomyolysis was performed. Further evaluation of the bibliographies of articles expanded the evidence. Study Design: Clinical review. Level of Evidence: Level 3. Results: Exertional rhabdomyolysis (ER) is a relatively uncommon condition with an incidence of approximately 29.9 per 100,000 patient years but can have very serious consequences of muscle ischemia, cardiac arrhythmia, and death. The athlete will have pain, weakness, and swelling in the muscles affected as well as significantly elevated levels of creatine kinase (CK). Hydration is the foundation for any athlete with ER; management can also include dialysis or surgery. Stratifying the athlete into high- or low-risk categories can determine if further workup is warranted. Conclusion: Exertional rhabdomyolysis evaluation requires a history, physical examination, and serology for definitive diagnosis. Treatment modalities should include rest and hydration. Return to play and future workup should be determined by the risk stratification of the athlete. Strength-of-Recommendation Taxonomy (SORT): C. PMID:24982707

  3. Pesticide poisoning cases in Ankara and nearby cities in Turkey: an 11-year retrospective analysis.

    PubMed

    Kır, M Ziya; Öztürk, Gülfer; Gürler, Mukaddes; Karaarslan, Bekir; Erden, Gönül; Karapirli, Mustafa; Akyol, Ömer

    2013-05-01

    Since they are available in open markets and pharmacies, pesticides have been widely used all over the country. (Un)intentional poisoning with these compounds is one of the most common causes of chemical poisoning, especially in rural agricultural areas. Pesticide poisonings reported by various countries showed that it is a worldwide health problem with 250,000-370,000 associated deaths each year. In this study, medico-legal deaths between the years 2001 and 2011 in Ankara and nearby cities in Turkey were investigated retrospectively. The autopsies were partly carried out by Ankara Branch of Council of Forensic Medicine. Data were collected from reports of the Morgue Department whose toxicological analyses were performed in the Chemistry Department. The data revealed that 70 cases out of 10,720 autopsied ones had been attributed to fatal pesticide poisoning. The age range was 1-80 years (mean ± SD, 41.33 ± 17.42 years). Most of the cases (60%) were reported from Ankara. Insecticides were the most common (94%) cause of fatal pesticide poisonings, most of them (63%) being organophosphate insecticides. The percentages of pesticide-induced deaths are quite high in our society and should therefore not be underestimated. Accordingly, intensive efforts to reduce occupational and intentional pesticide poisonings are urgently needed in Ankara and nearby cities.

  4. Modified Vaccinia Ankara Virus Vaccination Provides Long-Term Protection against Nasal Rabbitpox Virus Challenge.

    PubMed

    Jones, Dorothy I; McGee, Charles E; Sample, Christopher J; Sempowski, Gregory D; Pickup, David J; Staats, Herman F

    2016-07-01

    Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. This study was performed to determine if MVA vaccination provides long-term protection against rabbitpox virus (RPXV) challenge, an animal model of smallpox. Two doses of MVA provided 100% protection against a lethal intranasal RPXV challenge administered 9 months after vaccination.

  5. Middle School Students' Perceptions of the Quality of School Life in Ankara

    ERIC Educational Resources Information Center

    Eres, Figen; Bilasa, Pinar

    2016-01-01

    The aim of this research is to measure the perception of middle school students in Ankara regarding the quality of school life. According to the findings obtained, the students have moderate level perceptions about the quality of school life. Their perceptions about sub-dimensions vary. While the students have the highest perceptions about…

  6. Service Quality of State Universities in Turkey: The Case of Ankara

    ERIC Educational Resources Information Center

    Eres, Figen

    2011-01-01

    The aim of this study is determine the service quality perceptions of students being educated at state universities in Ankara. The sample of the study is composed of final grade students of faculties of Economics and Administrative Sciences. The sample of the study is composed of a total of randomly selected students. There were 416 returned…

  7. Internet Use Habits of Students of the Department of Information Management, Hacettepe University, Ankara

    ERIC Educational Resources Information Center

    Ucak, Nazan Ozenc

    2007-01-01

    The frequency and other characteristics of Internet use of students studying at the Department of Information Management at Hacettep University in Ankara, Turkey, are examined. According to the findings, students prefer electronic media to printed media, they find the easy accessibility of the information more important than the other qualities,…

  8. Image of Turkish Basic Schools: A Reflection from the Province of Ankara

    ERIC Educational Resources Information Center

    Eres, Figen

    2011-01-01

    The purpose of this study was to investigate the organizational image of basic schools in Turkey, a rapidly developing nation that has been investing significantly in education. Participants were 730 residents of Ankara province in the Golbasi district. The participants were selected using a cluster sampling methodology. Data were collected…

  9. Perspectives on ... An Evaluation of Faculty Use of the Digital Library at Ankara University, Turkey

    ERIC Educational Resources Information Center

    Atilgan, Dogan; Bayram, Ozlem

    2006-01-01

    New consortial buying models have dramatically increased the availability of online resources, particularly journal articles, in the universities and technical institutes of developing countries. The degree of acceptance and pattern of use of such materials is of great interest to library collection development. Ankara University surveyed faculty…

  10. Modified Vaccinia Ankara Virus Vaccination Provides Long-Term Protection against Nasal Rabbitpox Virus Challenge

    PubMed Central

    Jones, Dorothy I.; McGee, Charles E.; Sample, Christopher J.; Sempowski, Gregory D.; Pickup, David J.

    2016-01-01

    Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. This study was performed to determine if MVA vaccination provides long-term protection against rabbitpox virus (RPXV) challenge, an animal model of smallpox. Two doses of MVA provided 100% protection against a lethal intranasal RPXV challenge administered 9 months after vaccination. PMID:27146001

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

    PubMed

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

    2017-01-27

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

  12. Transduction of human dendritic cells with a recombinant modified vaccinia Ankara virus encoding MUC1 and IL-2.

    PubMed

    Trevor, K T; Hersh, E M; Brailey, J; Balloul, J M; Acres, B

    2001-10-01

    The epithelial mucin MUC1 is considered an opportune target antigen for cancer immunotherapy, as it is over-expressed and exhibits aberrant glycosylation in malignant cells. Because dendritic cells (DC) are powerful initiators of immune responses, efforts have focused on tumor antigen-bearing DC as potent cancer vaccines. In this study we have characterized the transduction of monocyte-derived DC with a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] encoding human MUC1 and the immunostimulatory cytokine IL-2. Analysis of transduced DC cultures generated from a number of donors revealed MUC1 expression in the range of 27-54% of the cells and a co-regulated secretion of bioactive IL-2. As shown by FACS analysis with MUCI-specific antibodies, the MVA-MUC1/IL-2-transduced DC predominantly expressed the fully processed glycoform of MUC1, typical of that displayed by normal epithelia. Over a 3-day period after transduction, transgene expression declined concurrent with an increase in MVA-induced cytopathic effects. The transduced DC stimulated allogeneic lymphocyte proliferation, indicating that DC immunostimulatory function is not impaired by vector transduction. In the presence of IL-2, MVA-transduced DC were able to enhance autologous lymphocyte proliferation. Also, vector expression was analyzed in DC cultures treated with TNF-alpha, a known DC maturation factor. As indicated by the up-regulation of several DC maturation markers, neither virus infection nor transgene expression influenced the maturation capacity of the cells. The MVA-MUC1/IL-2 vector effectively transduced both immature and TNF-alpha-matured DC. Overall, our results are encouraging for the clinical application of MVA-MUC1/IL-2-transduced DC.

  13. Prevalence of restless legs syndrome in Ankara, Turkey: an analysis of diagnostic criteria and awareness.

    PubMed

    Yilmaz, Nesrin Helvaci; Akbostanci, Muhittin Cenk; Oto, Aycan; Aykac, Ozlem

    2013-09-01

    The aim of this study was threefold: (1) to investigate the prevalence of restless legs syndrome (RLS), in Ankara, Turkey; (2) to determine the predictive values of diagnostic criteria; and (3) to determine the frequency of physician referrals and the frequency of getting the correct diagnosis. A total of 815 individuals, from randomly selected addresses, above the age of 15, were reached using the questionnaire composed of the four diagnostic criteria. Individuals who responded by answering 'yes' for at least one question were interviewed by neurologists for the diagnosis of RLS. Frequency of physician referrals and frequency of getting the correct diagnosis of RLS were also determined for patients getting the final diagnoses of RLS. Prevalence of RLS in Ankara was 5.52 %; 41.0 % of the individuals diagnosed with RLS had replied 'yes' to either one, two or three questions asked by interviewers. However, only 21.3 % of individuals who replied 'yes' to all four questions received the diagnosis of RLS. Among the patients who had the final diagnosis of RLS, 25.7 % had referred to a physician for the symptoms and 22.2 % got the correct diagnosis. The RLS prevalence in Ankara was somewhere between Western and Far East countries compatible with the geographical location. Diagnostic criteria may not be fully predictive when applied by non-physician pollsters. Physician's probability of correctly diagnosing RLS is still low.

  14. Sensitization to Alternaria and Cladosporium in patients with respiratory allergy and outdoor counts of mold spores in Ankara atmosphere, Turkey.

    PubMed

    Bavbek, Sevim; Erkekol, Ferda Oner; Ceter, Talip; Mungan, Dilşad; Ozer, Faruk; Pinar, Münevver; Misirligil, Zeynep

    2006-08-01

    Sensitization to Alternaria and Cladosporium has been reported to be 3% to 30% in European countries. However, in Turkey, there is limited data about the prevalence of sensitization to these molds and the intensity of the two mold spores in Ankara atmosphere. This study was designed to evaluate the sensitization to Alternaria and Cladosporium in patients with respiratory allergy in Ankara and also the concentration of the two molds in Ankara atmosphere. Allergic rhinitis and asthma patients living in Ankara were included in the study. Demographic and diagnostic data of the patients were recorded. A skin prick test with extracts supplied by three different laboratories was used to evaluate the sensitization to Alternaria and Cladosporium. Mold spores were measured using a Burkard 7-day recording volumetric spore trap in Ankara atmosphere during a year. Overall sensitization to the two molds was found to be 14.8%, and isolated Alternaria or Cladosporiumsensitization was 3%. Considering the positive reaction to at least one of the three suppliers, the sensitization rate was 11.9% and 8.1% for Alternaria and Cladosporium, respectively. Cochran's Q homogenization test demonstrated that the positive and negative reaction were not homogeneous among three laboratories. The total number of mold spores in Ankara atmosphere was 429,264 spores/m3 of which 75.5% and 6% were constituted by Cladosporium and Alternaria, respectively. The prevalence of Cladosporium and Alternaria sensitization in respiratory allergy patients is quite similar to European countries; however, our data indicate that commercial mold extracts should be standardized to establish the real sensitization rates. Additionally, considering the great numbers of these mold spores in Ankara atmosphere, long-term follow-up studies are needed to evaluate the relationship between the mold load and sensitization patterns.

  15. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

    PubMed Central

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-01-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells. PMID:25864732

  16. Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo.

    PubMed

    Lee, Misu; Minaskan, Ninelia; Wiedemann, Tobias; Irmler, Martin; Beckers, Johannes; Yousefi, Behrooz H; Kaissis, Georgios; Braren, Rickmer; Laitinen, Iina; Pellegata, Natalia S

    2017-01-01

    Pheochromocytomas (PCCs) are mostly benign tumors, amenable to complete surgical resection. However, 10-17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify the effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual-PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers and non-invasively by functional imaging (diffusion-weighted magnetic resonance imaging) in vivo Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo-identified potential mediators of therapy response were performed. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression in PCC cell lines (MPC) also. Studies of a BEZ235-resistant derivative of the MPC cell line confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression after BEZ235 treatment in vivo could be monitored by positron emission tomography (PET) using a tracer targeting NET. Altogether, here we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy.

  17. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling.

    PubMed

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-07-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells.

  18. Prevalence of Obesity and Associated Risk Factors Among Adolescents in Ankara, Turkey

    PubMed Central

    Ercan, Sırma; Dallar, Yıldız Bilge; Önen, Serdar; Engiz, Özlem

    2012-01-01

    Objective: The purpose of this study was to investigate the prevalence of and the risk factors associated with obesity among adolescents in Ankara, Turkey. Methods: The study was conducted in 26 schools in Ankara during the time period from September 2010 to March 2011. A total of 8848 adolescents aged 11-18 years were chosen using a population-based stratified cluster sampling method. Body mass index (BMI) of the participants was compared with the BMI references for Turkish children and adolescents to estimate the prevalence of overweight and obesity. A standardized questionnaire aiming to determine the sociodemographic characteristics, computer use, television (TV) watching, physical activity, and presence of obesity in the family was applied to the study group. Results: The results showed that the overall prevalence of obesity among adolescents was 7.7% (8.4 % for females and 7.0% for males). It was observed that BMI increased as computer use increased. A greater proportion of the overweight and obese adolescents watched TV and use computer for more than 2 hours/day as compared to their normal-weight counterparts. The normal-weight subjects were found to show a higher participation in regular physical activity. Obesity prevalence among the families of obese adolescents was 56.5%. Conclusions: The prevalence of adolescent obesity in Ankara, Turkey is lower as compared to many European countries and to the United States. Computer use, watching TV, physical activity and family factors are important risk factors for obesity. Conflict of interest:None declared. PMID:23149433

  19. Protective Efficacy of Recombinant Modified Vaccinia Virus Ankara Delivering Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein.

    PubMed

    Volz, Asisa; Kupke, Alexandra; Song, Fei; Jany, Sylvia; Fux, Robert; Shams-Eldin, Hosam; Schmidt, Jörg; Becker, Christin; Eickmann, Markus; Becker, Stephan; Sutter, Gerd

    2015-08-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease in humans. We tested a recombinant modified vaccinia virus Ankara (MVA) vaccine expressing full-length MERS-CoV spike (S) glycoprotein by immunizing BALB/c mice with either intramuscular or subcutaneous regimens. In all cases, MVA-MERS-S induced MERS-CoV-specific CD8(+) T cells and virus-neutralizing antibodies. Vaccinated mice were protected against MERS-CoV challenge infection after transduction with the human dipeptidyl peptidase 4 receptor. This MERS-CoV infection model demonstrates the safety and efficacy of the candidate vaccine.

  20. Effects of physical environment on the stress levels of hemodialysis nurses in Ankara Turkey.

    PubMed

    Uğur, Sultan; Acuner, Ahmet M; Göktaş, Bayram; Senoğlu, Birdal

    2007-08-01

    This study has been planned and executed as a field study for identifying the effect of physical environment on the stress levels of hemodialysis nurses who work in the official and private hemodialysis centers in the capital city of Turkey, Ankara (n=161). According to the results obtained from the study, it has been seen that "education level" and "institution of employment" of the hemodialysis nurses are significantly related with the stress levels of the hemodialysis nurses. Nurses' age, marital status, number of children, occupational seniority, years of working, employment status, husbands' occupation and husbands' educational levels are not significantly related with their stress levels.

  1. A test of Hirschi's social bonding theory: juvenile delinquency in the high schools of Ankara, Turkey.

    PubMed

    Ozbay, Ozden; Ozcan, Yusuf Ziya

    2006-12-01

    Travis Hirschi's social bonding theory has mostly been tested in the West. In this study, the theory is tested on juvenile delinquency in a developing country, Turkey. Data were gathered from 1,710 high school students in Ankara by using two-stage stratified cluster sampling. Factor analysis was employed to determine the dimensions of juvenile delinquency (assault, school delinquency, and public disturbance), and regression analysis was used to test the theory. Similar to some other traditional societies, the social bonding theory plays an important role in the explanation of juvenile delinquency in Turkey.

  2. The seroprevalences of HBs Ag and anti-HCV in pregnant women in Ankara.

    PubMed

    Altinbas, Sibel; Erdogan, Mine; Danişman, Nuri

    2010-02-01

    In the previous decade, the prevalence of HBs-Ag positivity and the anti-HCV positivity declined in Turkey. We aimed to investigate the prevalences of HBs Ag and anti-HCV positivity in pregnant women in Ankara, the capital city of Turkey, while the vertical transmission should be important way of HBV and HCV transmission. HBs-Ag positivity was determined 2.8% (102) out of 4,700 pregnant women, and 0.1% (6) out of them were positive for anti-HCV. The prevalences of HBs Ag and anti-HCV were both similar to the rate of that seen in western region of Turkey.

  3. Discrimination against teenagers in the mall environment: a case from Ankara, Turkey.

    PubMed

    Mugan, Guliz; Erkip, Feyzan

    2009-01-01

    Teenagers spend much of their leisure time at shopping malls which is a result of factors such as parental constraints due to the incivility of the streets, financial dependence, and limited financial resources. Migros, a shopping mall in Ankara was chosen as the site for this research with the main purpose of studying discrimination patterns against teenagers in the mall environment. The research was carried out through observation and in-depth interviews with 104 teenagers. Results indicate that, although they have some complaints, most of the teenagers do not perceive discrimination in the mall, unlike their foreign counterparts.

  4. Feasibility and acceptability of a text messaging-based smoking cessation program in ankara, Turkey.

    PubMed

    Ybarra, Michele L; Holtrop, Jodi S; Bağci Bosi, A Tülay; Bilir, Nazmi; Korchmaros, Josephine D; Salih Emri, A K

    2013-08-01

    Data from high-income countries suggest that cell phone-based smoking cessation programs have the potential to affect cessation rates. There is a paucity of research, however, about the feasibility of cell phone-based smoking cessation programs in lower income countries that have higher smoking prevalence rates. A one-arm feasibility and acceptability pilot study of SMS Turkey, a text messaging-based smoking cessation program, was conducted in Ankara, the capital of Turkey. The authors recruited 75 daily smokers who were seriously thinking about quitting in the subsequent 30 days into the 6-week SMS Turkey program. Recruitment was completed in 4 months. Participant retention was high: Almost all (96%) completed the program, and 84% provided 12-week follow-up data. Most (89%) of the respondents who completed the 4-week follow-up measures (n = 38, 51%) said that the text messages were easy to understand and referred to what they were experiencing and feeling during the quitting process (78%). On the basis of intention to treat, 13% of participants (n = 10) reported, at 12-week follow-up, continuous abstinence since their quit date, confirmed by carbon monoxide readings. The cell phone text messaging-based smoking cessation intervention appears feasible and acceptable in Ankara, Turkey.

  5. Levels and sources of polychlorinated biphenyls in Ankara creek sediments, Turkey.

    PubMed

    Ozyürek, Nazan Akduman; Gedik, Kadir; Siltu, Esra; Imamoğlu, Ipek

    2013-01-01

    The spatial distribution, degree of pollution and major sources of polychlorinated biphenyls (PCBs) were evaluated in surficial sediments of Ankara Creek, located in the capital of Turkey and serving as one of the tributaries in the third largest watershed in Turkey. Sediment ΣPCB concentrations analyzed on Aroclor and congener basis (seven indicator congeners) range from 5.5 to 777.6 ng g(-1) and 3.7 to 743.3 ng g(-1) dw as Aroclor and congener based concentrations, respectively. High concentrations of ΣPCBs were observed in the samples located at the downstream sections of the Creek, after discharge from Ankara municipal wastewater treatment plant. Using a chemical mass balance receptor model (CMB), major sources of PCBs affecting the sediments were investigated. The CMB model identified Aroclor 1254 and 1260 to be the major PCB sources affecting sediments. The potential sources for the PCBs were briefly discussed in terms of their use in various industrial applications.

  6. Sensitivity and specificity of Ankara University Cerebral Dominance Inventory in comparison with the Wada test.

    PubMed

    Yılmaz, Nesrin Helvacı; Bingol, Ayse Petek

    2014-03-01

    We aimed to examine the sensitivity and specificity of the Ankara University Cerebral Dominance Inventory (AUCDI) in determining left cerebral dominance compared with the Wada test. The AUCDI and Wada test were applied to 49 patients referred to Ankara University for epilepsy surgery. Hand, foot and 'total' preference scores were specified according to the results of the inventory. Thirty-eight of the patients had left cerebral dominance and 11 had atypical cerebral dominance for language. 86 % of the patients were right-handed and 43 % were right-footed. When compared with the results of the Wada test, the sensitivity of the AUCDI for each 'total preference', and hand and foot preference was 90, 95 and 50 % and specificity was 46, 46 and 82 %, respectively. The percentage of right-footed patients was low when compared with the other studies. This difference might result from the method used for assessing foot preference by the actual demonstration of the task rather than just asking about the performance. The AUCDI was found to be sensitive in terms of 'total preference' and hand preference, and specific in terms of foot preference for determining the left hemisphere dominance in patients preferring the right side. It was a cheap and noninvasive alternative to the Wada test, appropriate for clinical bedside evaluation.

  7. Tectonic Evolution of the Çayirhan Neogene Basin (Ankara), Central Turkey

    NASA Astrophysics Data System (ADS)

    Behzad, Bezhan; Koral, Hayrettin; İşb&idot; l, Duygu; Karaaǧa; ç, Serdal

    2016-04-01

    Çayırhan (Ankara) is located at crossroads of the Western Anatolian extensional region, analogous to the Basin and Range Province, and suture zone of the Neotethys-Ocean, which is locus of the North Anatolian Transform since the Late Miocene. To the north of Çayırhan (Ankara), a Neogene sedimentary basin comprises Lower-Middle Miocene and Upper Miocene age formations, characterized by swamp, fluvial and lacustrine settings respectively. This sequence is folded and transected by neotectonic faults. The Sekli thrust fault is older than the Lower-Middle Miocene age formations. The Davutoǧlan fault is younger than the Lower-Middle Miocene formations and is contemporaneous to the Upper Miocene formation. The Çatalkaya fault is younger than the Upper Miocene formation. The sedimentary and tectonic features provide information on mode, timing and evolution of this Neogene age sedimentary basin in Central Turkey. It is concluded that the region underwent a period of uplift and erosion under the influence of contractional tectonics prior to the Early-Middle Miocene, before becoming a semi-closed basin under influence of transtensional tectonics during the Early-Middle Miocene and under influence of predominantly extensional tectonics during the post-Late Miocene times. Keywords: Tectonics, Extension, Transtension, Stratigraphy, Neotectonic features.

  8. 2-Aminoresorcinol is a potent alpha-glucosidase inhibitor.

    PubMed

    Gao, Hong; Kawabata, Jun

    2008-01-15

    A series of aminoresorcinols and related compounds were tested for rat intestinal alpha-glucosidase inhibition and these results suggested that the 2-aminoresorcinol moiety of 6-amino-5,7-dihydroxyflavone (2) is important to exert the intestinal alpha-glucosidase inhibitory activity and 2-aminoresorcinol (4), itself, is a potent alpha-glucosidase inhibitor and inhibited sucrose-hydrolyzing activity of rat intestinal alpha-glucosidase uncompetitively.

  9. 78 FR 76821 - Executive-Led U.S.-Turkey Healthcare Trade Mission to Ankara, Istanbul, and Izmir

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-19

    ...The United States Department of Commerce, International Trade Administration is amending the Notice published at 78 FR 18318 (March 26, 2013), regarding the Executive-Led U.S.-Turkey Healthcare Trade Mission to Ankara, Istanbul, and Izmir to extend the date of the application deadline to February 6, 2014, and to amend the selection criteria for the applications received from midnight December......

  10. Environmental Attitudes of the 6th Grade Students from Rural and Urban Areas: A Case Study for Ankara

    ERIC Educational Resources Information Center

    Tuncer, Gaye; Sungur, Semra; Tekkaya, Ceren; Ertepinar, Hamide

    2004-01-01

    This study investigated environmental attitude of 6th grade students living in rural and urban areas in Ankara. Hundred and thirty-eight students were selected from four schools located in these areas. A 45-item questionnaire consisting of four dimensions was used to measure students' environmental attitude. Results of the study revealed that,…

  11. Reflections on the Design of Exertion Games.

    PubMed

    Mueller, Florian Floyd; Altimira, David; Khot, Rohit Ashot

    2015-02-01

    The design of exertion games (i.e., digital games that require physical effort from players) is a difficult intertwined challenge of combining digital games and physical effort. To aid designers in facing this challenge, we describe our experiences of designing exertion games. We outline personal reflections on our design processes and articulate analyses of players' experiences. These reflections and analyses serve to highlight the unique opportunities of combining digital games and physical effort. The insights we seek aim to enhance the understanding of exertion game design, contributing to the advancement of the field, and ultimately resulting in better games and associated player experiences.

  12. Toxoplasma gondii RH Ankara: production of evolving tachyzoites using a novel cell culture method.

    PubMed

    Değirmenci, Aysu; Döşkaya, Mert; Caner, Ayşe; Ciçek, Candan; Korkmaz, Metin; Gürüz, Yüksel; Uner, Ahmet

    2011-05-01

    Toxoplasma gondii is one of the most researched parasite due to its easy growth both in vitro and in vivo. Tachyzoites, derived from mouse or rat peritoneum encounters ethical and economical problems when used for research or diagnostic purposes. Currently, research has focused on determining the most suitable cell culture environment to reach highest amount of viable tachyzoites with least host cell contamination. However, gene expression changes that take place throughout the adaptation of evolving T. gondii strains to continuous cell cultures appear as a problem. The present study aimed to determine a novel cell culture strategy for T. gondii RH Ankara strain tachyzoites to harvest abundant tachyzoites with least host cell contamination and minimal antigenic variation at predetermined dates to use as an antigen source in serological assays that will facilitate reduction in animal use. To achieve this purpose, T. gondii RH Ankara strain tachyzoites were incubated with HeLa cell at different ratios for two or three days. In all flasks incubated for two days, viability rate reached to 100% and HeLa cell contamination decreased to levels between 0.12-0.5×10(6)/ml. In the flasks with HeLa-tachyzoite ratio 1/8, the tachyzoite yield and viability ratio were 3×10(6)/ml and 100%, respectively, with accompanying 10 fold decrease (0.12×10(6)/ml) in HeLa contamination. During continuous production, highest tachyzoite yield was obtained from the first passage (3.55×10(6)/ml) and until the end of third subculture viability rates and HeLa cell contaminations were between 98.2-99.4% and 0.31-0.37×10(6)/ml, respectively. ELISA, IFA and Western blot analyses showed that the quality, specificity and sensitivity of the antigen harvested from the first passage of cell culture performed at two days intervals were comparable to the antigen harvested from mice and decreased in the following subcultures. Overall, these results demonstrated that T. gondii RH Ankara strain is still

  13. Neonatal outcomes of Syrian refugees delivered in a tertiary hospital in Ankara, Turkey.

    PubMed

    Büyüktiryaki, Mehmet; Canpolat, Fuat Emre; Alyamaç Dizdar, Evrim; Okur, Nilüfer; Kadıoğlu Şimşek, Gülsüm

    2015-01-01

    We retrospectively reviewed the medical records of all Syrian immigrants from the TurkishSyrian border who delivered the Zekai Tahir Burak Maternity and Teaching Hospital Neonatal Intensive Care Unit (NICU) in Ankara, Turkey. Between January 2013 and December 2014 a total of 36,346 women gave birth at this center. Of these, 457 women were Syrian immigrants, comprising 1.2 % (457/36,346) of all deliveries. The number of births among Syrian refugees in Turkey appears to be increasing. Further research is needed to understand the relative morbidity of babies born to Syrian refugees compared to the local population, as well as the economic impact on facilities treating these cases.

  14. Emergency peripartum hysterectomy: experience of a major referral hospital in Ankara, Turkey.

    PubMed

    Danisman, N; Baser, E; Togrul, C; Kaymak, O; Tandogan, M; Gungor, T

    2015-01-01

    The objective of this study was to report and discuss the incidence, clinical characteristics and outcomes of emergency peripartum hysterectomies (EPH) performed at a tertiary referral hospital in Ankara, Turkey. The labour and delivery unit database was retrospectively analysed for emergency peripartum hysterectomies (EPH) performed between January 2008 and January 2013, at the Zekai Tahir Burak Women's Health Training and Research Hospital. A total of 92,887 deliveries were accomplished within the study period. EPH was performed in 48 cases, and the incidence was 0.51 in 1,000. Abnormal placentation was the most common indication for EPH. Most common complications were blood product transfusion and postoperative fever. None of the cases resulted in maternal mortality. Serious maternal complication rates were relatively low in our study. In cases that are unresponsive to initial conservative measures, EPH should be performed without delay and a multidisciplinary team approach should be conducted whenever possible.

  15. Non-plaque-forming virions of Modified Vaccinia virus Ankara express viral genes.

    PubMed

    Lülf, Anna-Theresa; Freudenstein, Astrid; Marr, Lisa; Sutter, Gerd; Volz, Asisa

    2016-12-01

    In cell culture infections with vaccinia virus the number of counted virus particles is substantially higher than the number of plaques obtained by titration. We found that standard vaccine preparations of recombinant Modified Vaccinia virus Ankara produce only about 20-30% plaque-forming virions in fully permissive cell cultures. To evaluate the biological activity of the non-plaque-forming particles, we generated recombinant viruses expressing fluorescent reporter proteins under transcriptional control of specific viral early and late promoters. Live cell imaging and automated counting by fluorescent microscopy indicated that virtually all virus particles can enter cells and switch on viral gene expression. Although most of the non-plaque-forming infections are arrested at the level of viral early gene expression, we detected activation of late viral transcription in 10-20% of single infected cells. Thus, non-plaque-forming particles are biologically active, and likely contribute to the immunogenicity of vaccinia virus vaccines.

  16. Environmental Risk Assessment of Clinical Trials Involving Modified Vaccinia Virus Ankara (MVA)-Based Vectors

    PubMed Central

    Goossens, Martine; Pauwels, Katia; Willemarck, Nicolas; Breyer, Didier

    2013-01-01

    The modified vaccinia virus Ankara (MVA) strain, which has been developed as a vaccine against smallpox, is since the nineties widely tested in clinical trials as recombinant vector for vaccination or gene therapy applications. Although MVA is renowned for its safety, several biosafety aspects need to be considered when performing the risk assessment of a recombinant MVA (rMVA). This paper presents the biosafety issues and the main lessons learned from the evaluation of the clinical trials with rMVA performed in Belgium. Factors such as the specific characteristics of the rMVA, the inserted foreign sequences/transgene, its ability for reconversion, recombination and dissemination in the population and the environment are the main points of attention. Measures to prevent or manage identified risks are also discussed. PMID:24397528

  17. Generation and evaluation of a recombinant modified vaccinia virus Ankara vaccine for rabies.

    PubMed

    Weyer, Jacqueline; Rupprecht, Charles E; Mans, Janet; Viljoen, Gerrit J; Nel, Louis H

    2007-05-22

    Modified vaccinia virus Ankara (MVA) has become a vaccine vector of choice for recombinant vaccine development. A MVA-based rabies vaccine would be advantageous for use as a vaccine for dogs (and wildlife), particularly if it proves innocuous and efficacious by the oral route. Here, the generation and immunological testing of a recombinant MVA expressing a rabies virus glycoprotein gene is described. In a murine model, higher dosages of recombinant MVA were needed to induce equivocal immune responses as with Vaccinia Copenhagen or Vaccinia Western Reserve recombinants, when administered by a parenteral route. The MVA recombinant was not immunogenic or efficacious when administered per os in naïve mice. The ability of the recombinant MVA to induce anamnestic responses in dogs and raccoons was also investigated. Recombinant MVA boosted humoral immune responses in these animals when administered peripherally, but not when administered orally.

  18. Prevalence of Toxocara spp. eggs in the soil of public parks in Ankara, Turkey.

    PubMed

    Oge, S; Oge, H

    2000-02-01

    One hundred and seventy soil samples from forty-six public parks in Ankara area were examined to determine the level of contamination with Toxocara spp. eggs. 30.6% of the 170 soil samples were contaminated with Toxocara spp. eggs. The number of eggs in the positive soil samples varied from 1 to 10. A high proportion of the eggs was fully embryonated. The findings demonstrate the common occurrence of these eggs in locations likely to be important in the transmission of visceral larva migrans. Of 19 fecal collected, 5 (26.3%) contained Toxocara spp. eggs. Eggs of Ancylostomidae, Toxascaris leonina, Trichuris spp., Taenia spp. and Enterobius vermicularis were also recovered from 17.6, 4.1, 2.4, 1.8 and 1.2% of soil samples, respectively.

  19. Lean Body Mass as a Predictive Value of Hypertension in Young Adults, in Ankara, Turkey

    PubMed Central

    VAZIRI, Yashar; BULDUK, Sidika; SHADMAN, Zhaleh; BULDUK, Emre Ozgur; HEDAYATI, Mehdi; KOC, Haluk; ER, Fatmanur; ERDOGAN, Ceren Suveren

    2015-01-01

    Background: The aim of this study was to assess the predictive capacity of body composition estimated by bioelectrical impedance analysis (BIA) to identify abnormal blood pressure in physical education and sport teaching students in the city of Ankara. Methods: Data for this cross-sectional study were obtained in the city of Ankara in 2014. A total of 133 students aged 20–35 yr participated in this study. Anthropometric measurements were measured. Body composition was assessed by BIA. Physical activity level (PAL) and usual dietary intake were assessed. Pre-hypertension and hypertension were defined, respectively, as BP ≥120 and/or 80, and ≥140 and /or 90 mmHg. Results: More overweight students showed abnormal BP especially SBP (P=0.005 and 0.002, respectively). Age adjusted regression showed significant association between arm circumference (β= 0.176, P 0.044), mid arm muscle circumference (MAMC) (β= 0.235, P 0.007), lean body mass (LBM) (β= 0.238, P 0.006), basal metabolism rate (BMR) (β= 0.219, P 0.012) and SBP and, also, MAMC (β= 0.201, P 0.022), LBM (β= 0.203, P 0.021), BMR (β= 0.189, P 0.030) and DBP. Fat intake was associated with DBP (β= 0.14, P =0.040). Multivariate regression models adjusted for age, BMI, WC and fat intake/kg body weight showed positive association of SBP with MAMC, BMR and LBM (P<0.05). Conclusion: The relationship between blood pressure and body composition in young adults may be associated to LBM and MAMC. LBM or MAMC in this population may be indirect indicators of heart muscle mass and heart pumping power. PMID:26811815

  20. Chemical and stable-radiogenic isotope compositions of Polatlı-Haymana thermal waters (Ankara, Turkey)

    NASA Astrophysics Data System (ADS)

    Akilli, Hafize; Mutlu, Halim

    2016-04-01

    Complex tectono-magmatic evolution of the Anatolian land resulted in development of numerous geothermal areas through Turkey. The Ankara region in central Anatolia is surrounded by several basins which are filled with upper Cretaceous-Tertiary sediments. Overlying Miocene volcanics and step faulting along the margins of these basins played a significant role in formation of a number of low-enthalpy thermal waters. In this study, chemical and isotopic compositions of Polatlı and Haymana geothermal waters in the Ankara region are investigated. The Polatlı-Haymana waters with a temperature range of 24 to 43 °C are represented by Ca-(Na)-HCO3 composition implying derivation from carbonate type reservoir rocks. Oxygen-hydrogen isotope values of the waters are conformable with the Global Meteoric Water Line and point to a meteoric origin. The carbon isotopic composition in dissolved inorganic carbon (DIC) of the studied waters is between -21.8 and -1.34 permil (vs. VPDB). Marine carbonates and organic rocks are the main sources of carbon. There is a high correlation between oxygen (3.7 to 15.0 permil; VSMOW) and sulfur (-9.2 to 19.5 permil; VCDT) isotope compositions of sulfate in waters. The mixing of sulfate from dissolution of marine carbonates and terrestrial evaporite units is the chief process behind the observed sulfate isotope systematics of the samples. 87Sr/86Sr ratios of waters varying from 0.705883 to 0.707827 are consistent with those of reservoir rocks. The temperatures calculated by SO4-H2O isotope geothermometry are between 81 and 138 °C nearly doubling the estimates from chemical geothermometers.

  1. Pollen counts and their relationship to meteorological factors in Ankara, Turkey during 2005-2008

    NASA Astrophysics Data System (ADS)

    Kizilpinar, Ilginc; Civelek, Ersoy; Tuncer, Ayfer; Dogan, Cahit; Karabulut, Erdem; Sahiner, Umit M.; Yavuz, S. Tolga; Sackesen, Cansin

    2011-07-01

    Pollen plays an important role in the development and exacerbation of allergic diseases. We aimed to investigate the days with highest counts of the most allergenic pollens and to identify the meteorological factors affecting pollen counts in the atmosphere of Ankara, Turkey. Airborne pollen measurements were carried out from 2005 to 2008 with a Burkard volumetric 7-day spore trap. Microscope counts were converted into atmospheric concentrations and expressed as pollen grains/m3. Meteorological parameters were obtained from the State Meteorological Service. All statistical analyses were done with pollen counts obtained from March to October for each year. The percentages of tree, grass and weed pollens were 72.1% ( n = 24,923), 12.8% ( n = 4,433) and 15.1% ( n = 5,219), respectively. The Pinaceae family from tree taxa (39% to 57%) and the Chenopodiaceae/Amaranthaceae family from weed taxa, contributed the highest percentage of pollen (25% to 43%), while from the grass taxa, only the Poaceae family was detected from 2005 to 2008. Poaceae and Chenopodiaceae/Amaranthaceae families, which are the most allergenic pollens, were found in high numbers from May to August in Ankara. In multiple logistic regression analysis, wind speed (OR = 1.18, CI95% = 1.02-1.36, P = 0.023) for tree pollen, daily mean temperature (OR = 1.10, CI95% = 1.04-1.17, P = 0.001) and sunshine hours (OR = 1.15, CI95% = 1.01-1.30, P = 0.033) for grass pollen, and sunshine hours (OR = 3.79, CI95% = 1.03-13.92, P = 0.044) for weed pollen were found as significant risk factors for high pollen count. The pollen calendar and its association with meteorological factors depend mainly on daily temperature, sunshine hours and wind speed, which may help draw the attention of physicians and allergic patients to days with high pollen counts.

  2. Arthropod repellency, especially tick (Ixodes ricinus), exerted by extract from Artemisia abrotanum and essential oil from flowers of Dianthus caryophyllum.

    PubMed

    Tunón, H; Thorsell, W; Mikiver, A; Malander, I

    2006-06-01

    A toluene extract of southernwood (Artemisia abrotanum) and the essential oil from flowers of carnation (Dianthus caryophyllum ) exerted pronounced a repellent effect both against ticks (nymphs of Ixodes ricinus) and yellow fever mosquitoes (Aedes aegypti). The most potent repellents found were coumarin and thujyl alcohol from A. abrotanum and phenylethanol from D. caryophyllum where coumarin and thujyl alcohol were also detected.

  3. Screening of quinolone antibiotic residues in chicken meat and beef sold in the markets of Ankara, Turkey.

    PubMed

    Er, Buket; Onurdag, Fatma Kaynak; Demirhan, Burak; Ozgacar, Selda Özgen; Oktem, Aysel Bayhan; Abbasoglu, Ufuk

    2013-08-01

    This study aimed to find the effects of quinolone antibiotics in chicken and beef used in Ankara, Turkey. Total number of 127 chicken and 104 beef meat samples were collected randomly from local markets for analysis. Extraction and determination of quinolones were made by ELISA procedure. One hundred eighteen of 231 (51.1%) examined chicken meat and beef samples were found to contain quinolone antibiotic residue. Among the chicken meat and beef samples, 58 (45.7%) of chicken meat samples and 60 (57.7%) of beef meat samples were positive for quinolones, respectively. The mean levels (±SE) of quinolones were found to be 30.81 ± 0.45 µg/kg and 6.64 ± 1.11 µg/kg in chicken and beef samples, respectively. This study indicated that some chicken and beef meat sold in Ankara contains residues of quinolone antibiotics.

  4. International Conference on Beam-Solid Interactions Held in Ankara, Turkey on April 24-28, 1989

    DTIC Science & Technology

    1989-04-01

    Army RDSG (UK) 16:45-%NumericalModels in-t’aser Processing of’Semiconductors~ A. Aydinli * US Navy ONR (UK) April 26, 1989 Wednesday " British...talks, all being experimental in nature except one theoretical on Numerical Models in Laser Processing of Semiconductors by Prof. A. Aydinli . The...tr Dog. Dr. Atilla Aydinli Hacettepe Cniversitesi Fizik MUhendisliji B61UmU Beytepe, Ankara Phone +90(4)223-0391 Prof.Dr. Giorgio Benedek Univ. degli

  5. A proton irradiation test facility for space research in Ankara, Turkey

    NASA Astrophysics Data System (ADS)

    Gencer, Ayşenur; Yiǧitoǧlu, Merve; Bilge Demirköz, Melahat; Efthymiopoulos, Ilias

    2016-07-01

    Space radiation often affects the electronic components' performance during the mission duration. In order to ensure reliable performance, the components must be tested to at least the expected dose that will be received in space, before the mission. Accelerator facilities are widely used for such irradiation tests around the world. Turkish Atomic Energy Authority (TAEA) has a 15MeV to 30MeV variable proton cyclotron in Ankara and the facility's main purpose is to produce radioisotopes in three different rooms for different target systems. There is also an R&D room which can be used for research purposes. This paper will detail the design and current state of the construction of a beamline to perform Single Event Effect (SEE) tests in Ankara for the first time. ESA ESCC No.25100 Standard Single Event Effect Test Method and Guidelines is being considered for these SEE tests. The proton beam kinetic energy must be between 20MeV and 200MeV according to the standard. While the proton energy is suitable for SEE tests, the beam size must be 15.40cm x 21.55cm and the flux must be between 10 ^{5} p/cm ^{2}/s to at least 10 ^{8} p/cm ^{2}/s according to the standard. The beam size at the entrance of the R&D room is mm-sized and the current is variable between 10μA and 1.2mA. Therefore, a defocusing beam line has been designed to enlarge the beam size and reduce the flux value. The beam line has quadrupole magnets to enlarge the beam size and the collimators and scattering foils are used for flux reduction. This facility will provide proton fluxes between 10 ^{7} p/cm ^{2}/s and 10 ^{10} p/cm ^{2}/s for the area defined in the standard when completed. Also for testing solar cells developed for space, the proton beam energy will be lowered below 10MeV. This project has been funded by Ministry of Development in Turkey and the beam line construction will finish in two years and SEE tests will be performed for the first time in Turkey.

  6. Elements in the Development of a Production Process for Modified Vaccinia Virus Ankara.

    PubMed

    Jordan, Ingo; Lohr, Verena; Genzel, Yvonne; Reichl, Udo; Sandig, Volker

    2013-11-01

    The production of several viral vaccines depends on chicken embryo fibroblasts or embryonated chicken eggs. To replace this logistically demanding substrate, we created continuous anatine suspension cell lines (CR and CR.pIX), developed chemically-defined media, and established production processes for different vaccine viruses. One of the processes investigated in greater detail was developed for modified vaccinia virus Ankara (MVA). MVA is highly attenuated for human recipients and an efficient vector for reactogenic expression of foreign genes. Because direct cell-to-cell spread is one important mechanism for vaccinia virus replication, cultivation of MVA in bioreactors is facilitated if cell aggregates are induced after infection. This dependency may be the mechanism behind our observation that a novel viral genotype (MVA-CR) accumulates with serial passage in suspension cultures. Sequencing of a major part of the genomic DNA of the new strain revealed point mutations in three genes. We hypothesize that these changes confer an advantage because they may allow a greater fraction of MVA-CR viruses to escape the host cells for infection of distant targets. Production and purification of MVA-based vaccines may be simplified by this combination of designed avian cell line, chemically defined media and the novel virus strain.

  7. Assessment of traumatic deaths in a level one trauma center in Ankara, Turkey.

    PubMed

    Arslan, E D; Kaya, E; Sonmez, M; Kavalci, C; Solakoglu, A; Yilmaz, F; Durdu, T; Karakilic, E

    2015-06-01

    Trauma management shows significant progress in last decades. Determining the time and place of deaths indicate where to focus to improve our knowledge about trauma. We conducted this retrospective study from data of trauma victims who were brought to a major tertiary hospital which is a level one trauma center in Ankara, Turkey, and died even if during transport or in the hospital between 1 March 2010 and 1 March 2013. The patients' demographic characteristics, trauma mechanisms, time frames and causes of deaths determined by physicians were recorded. Traumas were grouped as "high energy trauma" (HET) and "low energy trauma" (LET). Falls from ground level were defined as LET. 209 traumatic deaths due to trauma or trauma-related conditions were found in the study period. 161 of 209 (78 %) patients suffered from HET. Motor vehicle collisions (MVC) (56 %) were the most common mechanism of trauma followed by burns (16 %), falls (11 %), gunshots (9 %) and stabs (6 %) in this group and traumatic brain injuries (TBI) (41 %) were the most common cause of death followed by circulatory collapse (22 %) and multi-organ failure (20 %). 36 % of deaths occurred before arrival at hospital, 25 % in the first 24 h of admission, 18 % between 2nd and 7th day and 21 % after first week. Trimodal distribution of traumatic deaths was not valid for all types of injuries and the most important factor to decrease traumatic deaths is still prevention. Also we have to keep on searching to improve our knowledge about trauma management.

  8. Sex and the capital city: the political framing of syphilis and prostitution in early republican Ankara.

    PubMed

    Evered, Emine Ö; Evered, Kyle T

    2013-04-01

    In its initial years, the nascent Turkish republic established the Ministry of Health and Social Assistance in order to promote public health. Beyond simply facilitating its modernizing agenda for the emergent nation-state as it sought to define itself against an Ottoman past, this institution was also geared toward remedying a self-defined population crisis by prioritizing and confronting particular diseases and health conditions. One of the maladies of utmost concern was syphilis. Based upon an analysis of official primary sources, this article engages with how the developing republic distinguished and consequently politically constructed-or framed-the syphilis problem from the vantage of its new forward capital, Ankara. Integral to this project of confronting this sexually transmitted disease, public health officials projected upon both this ailment and their understanding of the suitable means for its treatment their own views of what constituted appropriate sexual practices and relations. In doing so, certain subgroups of the population, especially prostitutes, were particularized as targets for surveillance and policing through regimes of licensing and compulsory medical examinations. Stemming from the state's framing of the disease-and its definition of appropriate sexual practices-this article also examines the subsequent legislative and public health education projects that followed.

  9. A Review of the Scientific Misconduct Inquiry Process, Ankara Chamber of Medicine, Turkey.

    PubMed

    Gökçay, Banu; Arda, Berna

    2016-11-28

    The aim of this study is to review the inquiry process used in scientific misconduct cases in the Ankara Chamber of Medicine between the years 1998 and 2012. The violations of the "Disciplinary Regulations of the Turkish Medical Association" have been examined by keeping the names of the people, institutions, associations and journals secret. In total, 31 files have been studied and 11 of these files have been identified as related to scientific misconduct. The methods of inquiry, the decisions about the need for an investigation process, the types of scientific misconduct, and the adjudication processes have all been reported. Furthermore, the motives of researchers who made allegations, the study approaches of investigators, and the objections to the decisions about guilt and innocence have also been examined. Based on the findings obtained, the reasons for scientific misconduct and the distribution of responsibilities among the people in the inquiry process have been discussed. A major conclusion is the need to standardize the process of conducting inquiries about scientific misconduct cases for the regional chambers of medicine in Turkey.

  10. Seasonal prevalence of Toxocara ova in soil samples from public parks in Ankara, Turkey.

    PubMed

    Avcioglu, H; Burgu, A

    2008-06-01

    This survey was conducted to determine prevalence of Toxocara spp. eggs and seasonal variation of this prevalence in public parks in Ankara, Turkey. A total of 259 sand samples were collected from May 2005 to April 2006 in 40 public parks for determining prevalence. To attain seasonal variation, a total of 696 sand samples were collected from five public parks regularly throughout year. Prevalence of Toxocara spp. and combination of Toxascaris leonina and Taenia spp. was 15.05% and 0.38%. Overall, 45% of public parks were contaminated. There was a seasonal variation in prevalence. Prevalence of Toxocara spp., Toxascaris leonina, and Taenia spp. eggs during summer (4.21%) was lower than during spring (12.64%), autumn (13.21%), and winter (9.77%; p < 0.05). Average number of Toxocara spp. eggs was 2.57 per 50 g of sand, with average dimension of 70.1 mum. In conclusion, prevalence data are consistent with international data reported in other metropolitans. Our results indicate that the public parks in surveyed areas may be a source of toxocariasis. Effective preventive measures should be established.

  11. Factors Controlling Sediment Load in The Central Anatolia Region of Turkey: Ankara River Basin.

    PubMed

    Duru, Umit; Wohl, Ellen; Ahmadi, Mehdi

    2017-01-18

    Better understanding of the factors controlling sediment load at a catchment scale can facilitate estimation of soil erosion and sediment transport rates. The research summarized here enhances understanding of correlations between potential control variables on suspended sediment loads. The Soil and Water Assessment Tool was used to simulate flow and sediment at the Ankara River basin. Multivariable regression analysis and principal component analysis were then performed between sediment load and controlling variables. The physical variables were either directly derived from a Digital Elevation Model or from field maps or computed using established equations. Mean observed sediment rate is 6697 ton/year and mean sediment yield is 21 ton/y/km² from the gage. Soil and Water Assessment Tool satisfactorily simulated observed sediment load with Nash-Sutcliffe efficiency, relative error, and coefficient of determination (R²) values of 0.81, -1.55, and 0.93, respectively in the catchment. Therefore, parameter values from the physically based model were applied to the multivariable regression analysis as well as principal component analysis. The results indicate that stream flow, drainage area, and channel width explain most of the variability in sediment load among the catchments. The implications of the results, efficient siltation management practices in the catchment should be performed to stream flow, drainage area, and channel width.

  12. [Antimicrobial resistance of Neisseria gonorrhoeae strains isolated from sex workers in Ankara].

    PubMed

    Zarakolu, Pinar; Sakizligil, Bülent; Unal, Serhat

    2006-01-01

    The prevalence of gonococcal infections among sexually transmitted infections is decreasing particularly in developed countries, but the increase in antimicrobial resistance of Neisseria gonorrhoeae is an emerging issue. There is lack of data about the epidemiology and the resistance pattern of the pathogen in our country. Gonococcal infections are recently included among the reportable diseases in Turkey. The specific laboratory tests are difficult, expensive and seldomly used for diagnosis in our country. The infection is usuallly treated empirically. In this study, 30 N. gonorrhoeae strains isolated from clinical samples (endocervical, rectal and urethral swabs) obtained from registered/unregistered sex workers admitted to Ankara Municipiality Hospital of Dermatology and Venereal Diseases were tested for beta-lactamase production and the susceptibility to various antimicrobials. The susceptibility testing was performed by agar dilution method, and the results were evaluated according to Clinical and Laboratory Standards Institute (CLSI) recommendations. Of the isolates, 70% was found resistant to penicilin and beta-lactamase production was observed in 48% of them. The susceptibility rates of the isolates to ceftriaxone, cefixime, ciprofloxacin, and tetracycline were found as 100%, 100%, 97%, and 40%, respectively.

  13. Transparent 3D Visualization of Archaeological Remains in Roman Site in Ankara-Turkey with Ground Penetrating Radar Method

    NASA Astrophysics Data System (ADS)

    Kadioglu, S.

    2009-04-01

    Transparent 3D Visualization of Archaeological Remains in Roman Site in Ankara-Turkey with Ground Penetrating Radar Method Selma KADIOGLU Ankara University, Faculty of Engineering, Department of Geophysical Engineering, 06100 Tandogan/ANKARA-TURKEY kadioglu@eng.ankara.edu.tr Anatolia has always been more the point of transit, a bridge between West and East. Anatolia has been a home for ideas moving from all directions. So it is that in the Roman and post-Roman periods the role of Anatolia in general and of Ancyra (the Roman name of Ankara) in particular was of the greatest importance. Now, the visible archaeological remains of Roman period in Ankara are Roman Bath, Gymnasium, the Temple of Augustus of Rome, Street, Theatre, City Defence-Wall. The Caesar Augustus, the first Roman Emperor, conquered Asia Minor in 25 BC. Then a marble temple was built in Ancyra, the administrative capital of province, today the capital of Turkish Republic, Ankara. This monument was consecrated to the Empreror and to the Goddess Rome. This temple is supposed to have built over an earlier temple dedicated to Kybele and Men between 25 -20 BC. After the death of the Augustus in 14AD, a copy of the text of "Res Gestae Divi Augusti" was inscribed on the interior of the pronaos in Latin, whereas a Greek translation is also present on an exterior wall of the cella. In the 5th century, it was converted in to a church by the Byzantines. The aim of this study is to determine old buried archaeological remains in the Augustus temple, Roman Bath and in the governorship agora in Ulus district. These remains were imaged with transparent three dimensional (3D) visualization of the ground penetrating radar (GPR) data. Parallel two dimensional (2D) GPR profile data were acquired in the study areas, and then a 3D data volume were built using parallel 2D GPR data. A simplified amplitude-colour range and appropriate opacity function were constructed and transparent 3D image were obtained to activate buried

  14. The force exerted by a fireball

    SciTech Connect

    Makrinich, G.; Fruchtman, A.

    2014-02-15

    The force exerted by a fireball was deduced both from the change of the equilibrium position of a pendulum and from the change in the pendulum oscillation period. That measured force was found to be several times larger than the force exerted by the ions accelerated across the double layer that is assumed to surround the fireball. The force enhancement that is expected by ion-neutral collisions in the fireball is evaluated to be too small to explain the measured enhanced force. Gas pressure increase, due to gas heating through electron-neutral collisions, as recently suggested [Stenzel et al., J. Appl. Phys. 109, 113305 (2011)], is examined as the source for the force enhancement.

  15. Exertional leg pain: teasing out arterial entrapments.

    PubMed

    Pham, Thomas T; Kapur, Rahul; Harwood, Marc I

    2007-12-01

    Vascular causes of exertional lower extremity pain are relatively rare, but may be the answer in athletes refractory to treatment for the more common overuse syndromes of the lower extremities. It is important to differentiate these vascular causes from chronic exertional compartment syndrome (CECS), medial tibial stress syndrome (MTSS), and stress fractures in order to develop appropriate treatment plans, avoid complications, and return athletes to play expeditiously. Important vascular etiologies to be considered are popliteal artery entrapment syndrome (PAES), endofibrotic disease, popliteal artery aneurysm, cystic adventitial disease, and peripheral arterial dissections. The diagnostic workup involves angiography or noninvasive vascular studies such as Doppler ultrasound or magnetic resonance angiography in both the neutral and provocative positions. Treatment of these vascular abnormalities typically involves surgical correction of the vascular anomaly.

  16. Future River Flow Estimations of Gerede-Ulusu River, Ankara, Turkey

    NASA Astrophysics Data System (ADS)

    Kentel, E.

    2009-12-01

    Increase in population, industrialization and urbanization causes water demand to increase. However, due to unplanned water resources utilization and environmental factors such as global warming, the increasing water demand can not be supplied by the available sources. Ankara, Turkey experienced this situation in the past years which resulted in water shortages in the city in 2007. As a temporary solution to this problem, a water transmission line was installed from Hirfanli Dam and water was pumped to Camlidere Dam reservoir. However, the authorities believe this is not a permanent solution; thus alternative water resources need to be investigated and included in the future management plans. As an alternative, transmitting water from Gerede-Ulusu River to Camlidere Dam is being considered. To be able to identify safe amount of water that will be available for transmission to Camlidere Dam, future river flow regime of Gerede-Ulusu River need to be assessed. An artificial neural network model is developed to estimate future monthly flow values of Gerede-Ulusu River. Past precipitation and river flow data, and the associated month are used to predict future river flows. One critical issue in water resources planning and management is determination of the reliability of the estimates. One of the major weaknesses of artificial neural network models is that they may fail to generate good estimates for extreme events, i.e. events that do not occur at all or often enough in the training set. If reliable estimates can be distinguished from unreliable ones, the former can be used with greater confidence in planning and management of the water resources. A fuzzy c-means algorithm is used in this study to cluster the estimates of the artificial neural networks into reliable and less-reliable river flow values. Key words: River flow estimation; Artificial Neural Network; fuzzy c-means clustering

  17. The impact of anti-smoking laws on high school students in Ankara, Turkey

    PubMed Central

    Demir, Melike; Karadeniz, Gulistan; Demir, Fikri; Karadeniz, Cem; Kaya, Halide; Yenibertiz, Derya; Taylan, Mahsuk; Yilmaz, Sureyya; Sen, Velat

    2015-01-01

    ABSTRACT OBJECTIVE: To determine the factors affecting the smoking habits of high school students, their thoughts about changes resulting from anti-smoking laws, and how they are affected by those laws. METHODS: In this cross-sectional study, 11th-grade students at eight high schools in Ankara, Turkey, were invited to complete a questionnaire. RESULTS: A total of 1,199 students completed the questionnaire satisfactorily. The mean age of the respondents was 17.0 ± 0.6 years; 56.1% were female, of whom 15.3% were smokers; and 43.9% were male, of whom 43.7% were smokers (p < 0.001). The independent risk factors for smoking were male gender, attending a vocational school, having a sibling who smokes, having a friend who smokes, and poor academic performance. Of the respondents, 74.7% were aware of the content of anti-smoking laws; 81.8% approved of the restrictions and fines; and 8.1% had quit smoking because of those laws. According to the respondents, the interventions that were most effective were the (television) broadcast of films about the hazards of smoking and the ban on cigarette sales to minors. The prevalence of smoking was highest (31.5%) among students attending vocational high schools but lowest (7.5%) among those attending medical vocational high schools. Although 57.1% of the smokers were aware of the existence of a smoking cessation helpline, only 3.7% had called, none of whom had made any attempt to quit smoking. CONCLUSIONS: Although most of the students evaluated were aware of the harmful effects of smoking and approved of the anti-smoking laws, only a minority of those who smoked sought professional help to quit. PMID:26785961

  18. Determination of Uniaxial Compressive Strength of Ankara Agglomerate Considering Fractal Geometry of Blocks

    NASA Astrophysics Data System (ADS)

    Coskun, Aycan; Sonmez, Harun; Ercin Kasapoglu, K.; Ozge Dinc, S.; Celal Tunusluoglu, M.

    2010-05-01

    The uniaxial compressive strength (UCS) of rock material is a crucial parameter to be used for design stages of slopes, tunnels and foundations to be constructed in/on geological medium. However, preparation of high quality cores from geological mixtures or fragmented rocks such as melanges, fault rocks, coarse pyroclastic rocks, breccias and sheared serpentinites is often extremely difficult. According to the studies performed in literature, this type of geological materials may be grouped as welded and unwelded birmocks. Success of preparation of core samples from welded bimrocks is slightly better than unwelded ones. Therefore, some studies performed on the welded bimrocks to understand the mechanical behavior of geological mixture materials composed of stronger and weaker components (Gokceoglu, 2002; Sonmez et al., 2004; Sonmez et al., 2006; Kahraman, et al., 2008). The overall strength of bimrocks are generally depends on strength contrast between blocks and matrix; types and strength of matrix; type, size, strength, shape and orientation of blocks and volumetric block proportion. In previously proposed prediction models, while UCS of unwelded bimrocks may be determined by decreasing the UCS of matrix considering the volumetric block proportion, the welded ones can be predicted by considering both UCS of matrix and blocks together (Lindquist, 1994; Lindquist and Goodman, 1994; Sonmez et al., 2006 and Sonmez et al., 2009). However, there is a few attempts were performed about the effect of blocks shape and orientation on the strength of bimrock (Linqduist, 1994 and Kahraman, et al., 2008). In this study, Ankara agglomerate, which is composed of andesite blocks and surrounded weak tuff matrix, was selected as study material. Image analyses were performed on bottom, top and side faces of cores to identify volumetric block portions. In addition to the image analyses, andesite blocks on bottom, top and side faces were digitized for determination of fractal

  19. Are Physicians Healthy When They Are Aged and Retired? A Survey of the Ankara Chamber of Medicine and the Turkish Geriatrics Society.

    PubMed

    Aslan, D; Gökçe-Kutsal, Y; Kanuncu, S

    2013-01-01

    In literature, there is a lack of knowledge about clinical and lifestyle characteristics of retired physicians. Aim of the study is to describe the health profile of older physicians registered to the Ankara Chamber of Medicine (Ankara, Turkey). Two hundred and seventy four registered physicians agreed to participate to a survery. Most of them (76.6%) were men. Mean age was 74.9 (standard deviation 6.3) years. More than 85% of the participants presented at least one chronic disease. High scores were reported for the role-physical component of the SF-36, differently from the general health section of it scoring low. The results of the present survey pose the basis for collaborative efforts from the Ankara Chamber of Medicine and the Turkish Geriatrics Society collaboratively to improve the design and development of services for local older physicians.

  20. Cold thermoregulatory responses following exertional fatigue.

    PubMed

    Castellani, John W; Sawka, Michael N; DeGroot, David W; Young, Andrew J

    2010-06-01

    Participants in prolonged, physically demanding cold-weather activities are at risk for a condition called "thermoregulatory fatigue". During cold exposure, the increased gradient favoring body heat loss to the environment is opposed by physiological responses and clothing and behavioral strategies that conserve body heat stores to defend body temperature. The primary human physiological responses elicited by cold exposure are shivering and peripheral vasoconstriction. Shivering increases thermogenesis and replaces body heat losses, while peripheral vasoconstriction improves thermal insulation of the body and retards the rate of heat loss. A body of scientific literature supports the concept that prolonged and/or repeated cold exposure, fatigue induced by sustained physical exertion, or both together, can impair the shivering and vasoconstrictor responses to cold ("thermoregulatory fatigue"). The mechanisms accounting for this thermoregulatory impairment are not clear, but there is evidence to suggest that changes in central thermoregulatory control or peripheral sympathetic responsiveness to cold lead to thermoregulatory fatigue and increased susceptibility to hypothermia.

  1. [Pandemic influenza A (H1N1)v vaccination status and factors affecting vaccination: Ankara and Diyarbakır 2009 data from Turkey].

    PubMed

    Ertek, Mustafa; Sevencan, Funda; Kalaycıoğlu, Handan; Gözalan, Ayşegül; Simşek, Ciğdem; Culha, Gönül; Dorman, Vedat; Ozlü, Ahmet; Arıkan, Füsun; Aktaş, Dilber; Akın, Levent; Korukluoğlu, Gülay; Sevindi, Demet Furkan

    2011-10-01

    In this study, it was aimed to determine the frequency of the symptoms of influenza-like illness during influenza A (H1N1)v pandemic in two provinces where sentinel influenza surveillance was conducted and also to obtain opinions about H1N1 influenza and vaccination, H1N1 vaccination status and factors affecting vaccination. This cross-sectional study was conducted in the provinces of Ankara (capital city, located at Central Anatolia) and Diyarbakır (located at southeastern Anatolia). It was planned to include 455 houses in Ankara and 276 houses in Diyarbakır. The household participation rate in the study was 78.9% and 53.6% for Ankara and Diyarbakır, respectively. Our study was carried out between January-February 2010, with 1164 participants from Ankara and 804 from Diyarbakır, including every household subjects except for infants younger than 11 months and patients with primary/secondary immunodeficiency diseases. Data was collected by site teams consisting of a physician and a healthcare staff with informed consent. Of the participants 45.5% from Ankara and 35.3% from Diyarbakır stated that they had gone through an influenza-like illness. The most frequently indicated clinical symptoms were fatigue/weakness, rhinitis, sore throat and cough. The rates of admission to a physician with influenza like illness complaints were 50.6% and 58.7%; rates of hospitalization due to influenza-like illness were 1% and 1.5%, and rates of antiviral drug use were 3.8% and 1.9%, in Ankara ve Diyarbakır participants, respectively. The rate of personal precautions taken by the subjects for prevention from pandemic influenza were 59% and 53.3%, in Ankara and Diyarbakır, respectively. These precautions most frequently were "hand washing" and "avoiding crowded public areas". H1N1 influenza vaccine was applied in 9.3% of the participants in Ankara and in 3.7% of the participants in Diyarbakır. Vaccination rate was higher in both of the provinces in adults over 25 years old than

  2. The Ankara Mélange: an indicator of Tethyan evolution of Anatolia

    NASA Astrophysics Data System (ADS)

    Çakir, Üner; Üner, Tijen

    2016-08-01

    The Ankara Mélange is a complex formed by imbricated slices of limestone block mélanges (Karakaya and Hisarlıkaya Formations), Neotethyan ophiolites (Eldivan, Ahlat and Edige ophiolites), post-ophiolitic cover units (Mart and Kavak formations) and Tectonic Mélange Unit (Hisarköy Formation or Dereköy Mélange). The Karakaya and Hisarlıkaya formations are roughly similar and consist mainly of limestone block mélange. Nevertheless, they represent some important geological differences indicating different geological evolution. Consequently, the Karakaya and Hisarlıkaya formations are interpreted as Eurasian and Gondwanian marginal units formed by fragmentation of the Gondwanian carbonate platform during the continental rifting of the Neotethys in the Middle Triassic time. During the latest Triassic, Neotethyan lithosphere began to subduct beneath the Eurasian continent and caused intense deformation of the marginal units. The Eldivan, Ahlat and Edige ophiolites represent different fragments of the Neotethyan oceanic lithosphere emplaced onto the Gondwanian margin during the Albian-Aptian, middle Turonian and middle Campanian, respectively. The Eldivan Ophiolite is a NE-SW trending and a nearly complete assemblage composed, from bottom to top, of a volcanic-sedimentary unit, a metamorphic unit, peridotite tectonites, cumulates and sheeted dykes. The Eldivan Ophiolite is unconformably covered by Cenomanian-Lower Turonian sedimentary unit. The Eldivan Ophiolite is overthrust by the Ahlat Ophiolite in the north and Edige Ophiolite in the west. The Ahlat ophiolite is an east-west oriented assemblage comprised of volcanic-sedimentary unit, metamorphic unit, peridotite tectonites and cumulates. The Edige Ophiolite consists of a volcanic-sedimentary unit, peridotite tectonites, dunite, wherlite, pyroxenite and gabbro cumulates. The Tectonic Mélange Unit is a chaotic formation of various blocks derived from ophiolites, from the Karakaya and Hisarlıkaya formations and

  3. Recognition of cigarette brand names and logos by primary schoolchildren in Ankara, Turkey

    PubMed Central

    Emri, S.; Bagci, T.; Karakoca, Y.; Baris, E.

    1998-01-01

    OBJECTIVE—To assess the smoking behaviour of primary schoolchildren and their ability to recognise brand names and logos of widely advertised cigarettes, compared with other commercial products intended for children.
DESIGN—Cross-sectional survey in classroom settings using a questionnaire designed to measure attitudes towards smoking and the recognition of brand names and logos for 16 food, beverage, cigarette, and toothpaste products.
SETTING—Ankara, Turkey.
SUBJECTS—1093 children (54.6% boys, 44.4% girls) aged 7-13 years (mean = 10, SD = 1), from grades 2-5. The student sample was taken from three primary schools—one school in each of three residential districts representing high, middle, and low income populations.
MAIN OUTCOME MEASURES—Prevalence of ever-smoking, recognition of brand names and logos.
RESULTS—Prevalence of ever-smoking was 11.7% overall (13.9% among boys and 9.1% among girls; p<0.05). Children aged eight years or less had a higher prevalence of ever-smoking (19.6%) than older children (p<0.002). Ever-smoking prevalence did not differ significantly across the three school districts. Ever-smoking prevalence was higher among children with at least one parent who smoked (15.3%) than among those whose parents did not (4.8%) (p<0.001). Brand recognition rates ranged from 58.1% for Chee-tos (a food product) to 95.2% for Samsun (a Turkish cigarette brand). Recognition rates for cigarette brand names and logos were 95.2% and 80.8%, respectively, for Samsun; 84.0% and 90.5%, respectively, for Camel; and 92.1% and 69.5%, respectively, for Marlboro. The Camel logo and the Samsun and Marlboro brand names were the most highly recognised of all product logos and brand names tested.
CONCLUSIONS—The high recognition of cigarette brand names and logos is most likely the result of tobacco advertising and promotion. Our results indicate the need to implement comprehensive tobacco control measures in Turkey

  4. Differentiated Ratings of Perceived Exertion during Physical Exercise

    DTIC Science & Technology

    1982-01-01

    MEDICINE AND SCIENCE IN SPORTS AND EXERCISE VOl 14, No 5. Pp 397-405. 1982 -1982 Differentiated ratings of perceived exertion during physical ...that PANDOLF, KENT B. Differentiated ratings of perceived exertion utilizes differentiated ratings of perceived exertion (RPE) during physical exercise ...in the eval- Specific instructions and procedures for the utilization uation of effort sensations during physical exercise . Ekblom and Goldbarg (17

  5. Exercise Device Would Exert Selectable Constant Resistance

    NASA Technical Reports Server (NTRS)

    Smith, Damon C.

    2003-01-01

    An apparatus called the resistive exercise device (RED) has been proposed to satisfy a requirement for exercise equipment aboard the International Space Station (ISS) that could passively exert a selectable constant load on both the outward and return strokes. The RED could be used alone; alternatively, the RED could be used in combination with another apparatus called the treadmill with vibration isolation and stabilization (TVIS), in which case the combination would be called the subject load device (SLD). The basic RED would be a passive device, but it could incorporate an electric motor to provide eccentric augmentation (augmentation to make the load during inward movement greater than the load during outward movement). The RED concept represents a unique approach to providing a constant but selectable resistive load for exercise for the maintenance and development of muscles. Going beyond the original ISS application, the RED could be used on Earth as resistive weight training equipment. The advantage of the RED over conventional weight-lifting equipment is that it could be made portable and lightweight.

  6. Negative radiation pressure exerted on kinks

    SciTech Connect

    Forgacs, Peter; Lukacs, Arpad; Romanczukiewicz, Tomasz

    2008-06-15

    The interaction of a kink and a monochromatic plane wave in one dimensional scalar field theories is studied. It is shown that in a large class of models the radiation pressure exerted on the kink is negative, i.e. the kink is pulled towards the source of the radiation. This effect has been observed by numerical simulations in the {phi}{sup 4} model, and it is explained by a perturbative calculation assuming that the amplitude of the incoming wave is small. Quite importantly the effect is shown to be robust against small perturbations of the {phi}{sup 4} model. In the sine-Gordon (SG) model the time-averaged radiation pressure acting on the kink turns out to be zero. The results of the perturbative computations in the SG model are shown to be in full agreement with an analytical solution corresponding to the superposition of a SG kink with a cnoidal wave. It is also demonstrated that the acceleration of the kink satisfies Newton's law.

  7. Hansenula polymorpha expressed heat shock protein gp96 exerts potent T cell activation activity as an adjuvant.

    PubMed

    Li, Yang; Song, Haolei; Li, Jin; Wang, Yanzhong; Yan, Xiaoli; Zhao, Bao; Zhang, Xiaojun; Wang, Saifeng; Chen, Lizhao; Qiu, Bingsheng; Meng, Songdong

    2011-02-20

    Previous studies together with ours showed that heat shock protein gp96 as an adjuvant induces antigen specific T cell responses against cancer and infectious diseases. However, at present there is no efficient method to obtain high amount of full-length gp96 by in vitro expression. Here, we used the yeast Hansenula polymorpha as an efficient host for gp96 recombinant protein production. The transformant clones with highly expressed recombinant proteins were screened and selected by measuring the halo size which indicates enzymatic hydrolysis of starch in the medium. High-level production of gp96 (around 150mg/mL) was achieved by using high-cell density fed-batch cultivations. We showed that peptide binding of the recombinant protein has similar specificity and intrinsic binding parameters as that of the native gp96. We next examined the self-assembly properties and high-order structures of the recombinant protein. Moreover, the H. polymorpha expressed recombinant gp96 can effectively induce HBV-specific CTL response in immunized mice while Escherichia coli-expressed gp96 cannot. Our results therefore may provide bases for structure and functional studies of gp96 and thereby potentially expedite the development of gp96-based vaccines for immunotherapy of cancer or infectious diseases.

  8. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.

    PubMed

    Ghosh, Arnab; Smith, Melody; James, Scott E; Davila, Marco L; Velardi, Enrico; Argyropoulos, Kimon V; Gunset, Gertrude; Perna, Fabiana; Kreines, Fabiana M; Levy, Emily R; Lieberman, Sophie; Jay, Hillary V; Tuckett, Andrea Z; Zakrzewski, Johannes L; Tan, Lisa; Young, Lauren F; Takvorian, Kate; Dudakov, Jarrod A; Jenq, Robert R; Hanash, Alan M; Motta, Ana Carolina F; Murphy, George F; Liu, Chen; Schietinger, Andrea; Sadelain, Michel; van den Brink, Marcel R M

    2017-02-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.

  9. Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells.

    PubMed

    Tabolacci, Claudio; Cordella, Martina; Turcano, Lorenzo; Rossi, Stefania; Lentini, Alessandro; Mariotti, Sabrina; Nisini, Roberto; Sette, Giovanni; Eramo, Adriana; Piredda, Lucia; De Maria, Ruggero; Facchiano, Francesco; Beninati, Simone

    2015-09-05

    Aim of this study was to extend the knowledge on the antineoplastic effect of aloe-emodin (AE), a natural hydroxyanthraquinone compound, both in metastatic human melanoma cell lines and in primary stem-like cells (melanospheres). Treatment with AE caused reduction of cell proliferation and induction of SK-MEL-28 and A375 cells differentiation, characterized by a marked increase of transamidating activity of transglutaminase whose expression remained unmodified. In vitro antimetastatic property of AE was evaluated by adhesion and Boyden chamber invasion assays. The effect of AE on melanoma cytokines/chemokines production was determined by a multiplex assay: interestingly AE showed an immunomodulatory activity through GM-CSF and IFN-γ production. We report also that AE significantly reduced the proliferation, stemness and invasive potential of melanospheres. Moreover, AE treatment significantly enhanced dabrafenib (a BRAF inhibitor) antiproliferative activity in BRAF mutant cell lines. Our results confirm that AE possesses remarkable antineoplastic properties against melanoma cells, indicating this anthraquinone as a promising agent for differentiation therapy of cancer, or as adjuvant in chemotherapy and targeted therapy. Further, its mechanisms of action support a potential efficacy of AE treatment to counteract resistance of BRAF-mutated melanoma cells to target therapy.

  10. Cucurbitacin-I, a natural cell-permeable triterpenoid isolated from Cucurbitaceae, exerts potent anticancer effect in colon cancer.

    PubMed

    Kim, Hyeon Jin; Park, Jung Han Yoon; Kim, Jin-Kyung

    2014-08-05

    Cucurbitacin-I is a triterpenoids found in medicinal plants and have diverse pharmacological and biological activities. In this study, the antitumor effects of cucurbitacin-I on colon cancer and possible roles in apoptosis and cell cycle arrest were investigated. Treatment of SW480 cells, a human colon cancer cells, with cucurbitacin-I decreased cell viability and cell proliferation in a concentration-dependent manner. Also, cucurbitacin-I induced G2/M phase cell cycle arrest in SW480 cells with a decreased expression of cell cycle proteins including cyclin B1, cyclin A, CDK1, and CDC25C. Moreover, cucurbitacin-I induced increased cleavage of caspase-3, -7, -8, -9, and poly ADP ribose polymerase. When we examined the inhibitory effect of cucurbitacin-I on tumor growth in vivo, cucurbitacin-I effectively inhibited the tumorigenicity and growth of CT-26 cells in syngenic BALB/c mice. In summary, the present study showed that cucurbitacin-I reduced colon cancer cell proliferation by enhancing apoptosis and causing cell cycle arrest at the G2/M phase.

  11. Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart.

    PubMed

    Lim, Yi-Cheng; Budin, Siti Balkis; Othman, Faizah; Latip, Jalifah; Zainalabidin, Satirah

    2016-07-11

    Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dt max, suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca(2+) channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

  12. Jurassic-Paleogene intraoceanic magmatic evolution of the Ankara Mélange, north-central Anatolia, Turkey

    NASA Astrophysics Data System (ADS)

    Sarifakioglu, E.; Dilek, Y.; Sevin, M.

    2014-02-01

    Oceanic rocks in the Ankara Mélange along the Izmir-Ankara-Erzincan suture zone (IAESZ) in north-central Anatolia include locally coherent ophiolite complexes (∼ 179 Ma and ∼ 80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 256.9 ± 8.0 Ma, 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma indicating northern Tethys during the late Paleozoic through Cretaceous, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (∼ 67-63 Ma). All but the arc rocks occur in a shale-graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the middle to late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant large ion lithophile elements (LILE) enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syenodioritic plutons exhibit high-K shoshonitic to medium- to high-K calc-alkaline compositions with strong enrichment in LILE, rare earth elements (REE) and Pb, and initial ɛNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syenodioritic plutons) in the southern part. The late Permian, Early to Late Jurassic, and Late Cretaceous amphibole-epidote schist, epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the northern

  13. Jurassic-Paleogene intra-oceanic magmatic evolution of the Ankara Mélange, North-Central Anatolia, Turkey

    NASA Astrophysics Data System (ADS)

    Sarifakioglu, E.; Dilek, Y.; Sevin, M.

    2013-11-01

    Oceanic rocks in the Ankara Mélange along the Izmir-Ankara-Erzincan suture zone (IAESZ) in North-Central Anatolia include locally coherent ophiolite complexes (~179 Ma and ~80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (~67-63 Ma). All but the arc rocks occur in a shaly-graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the Middle to Late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant LILE enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syeno-dioritic plutons exhibit high-K shoshonitic to medium-to high-K calc-alkaline compositions with strong enrichment in LILE, REE and Pb, and initial ϵNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syeno-dioritic plutons) in the southern part. The Early to Late Jurassic and Late Cretaceous epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the Northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the Northern Neotethys was an open ocean with its MORB-type oceanic lithosphere by the Early Triassic. The Latest Cretaceous-Early Paleocene island arc volcanic, dike and plutonic rocks with

  14. Myristoylation increases the CD8+T-cell response to a GFP prototype antigen delivered by modified vaccinia virus Ankara.

    PubMed

    Marr, Lisa; Lülf, Anna-Theresa; Freudenstein, Astrid; Sutter, Gerd; Volz, Asisa

    2016-04-01

    Activation of CD8(+)T-cells is an essential part of immune responses elicited by recombinant modified vaccinia virus Ankara (MVA). Strategies to enhance T-cell responses to antigens may be particularly necessary for broadly protective immunization against influenza A virus infections or for candidate vaccines targeting chronic infections and cancer. Here, we tested recombinant MVAs that targeted a model antigen, GFP, to different localizations in infected cells. In vitro characterization demonstrated that GFP accumulated in the nucleus (MVA-nls-GFP), associated with cellular membranes (MVA-myr-GFP) or was equally distributed throughout the cell (MVA-GFP). On vaccination, we found significantly higher levels of GFP-specific CD8(+)T-cells in MVA-myr-GFP-vaccinated BALB/c mice than in those immunized with MVA-GFP or MVA-nls-GFP. Thus, myristoyl modification may be a useful strategy to enhance CD8(+)T-cell responses to MVA-delivered target antigens.

  15. Protective and disease-enhancing immune responses induced by recombinant modified vaccinia Ankara (MVA) expressing respiratory syncytial virus proteins.

    PubMed

    Olszewska, Wieslawa; Suezer, Yasemin; Sutter, Gerd; Openshaw, Peter J M

    2004-11-25

    Modified vaccinia Ankara (MVA) recombinants expressing single or multiple RSV surface proteins (F or G) are promising potential vaccines. We studied humoral and cellular responses induced by MVA-F and MVA-G in mice, comparing them to a formalin inactivated RSV preparation (FI-RSV) known to increase disease severity. MVA-F or MVA-G vaccination enhanced weight loss during RSV challenge, but did not show the lung eosinophilia seen after FI-RSV vaccination. FI-RSV induced a stronger total RSV IgG response than the MVA recombinants, but very little IgG2a. MVA recombinants induced cytokine responses biased towards IFNgamma and IL-12, while FI-RSV induced strong IL-4/5 responses in the lungs during RSV challenge. Thus, MVA vaccines induce a favourable immune profile in RSV disease but retain the potential to enhance disease.

  16. The Effect of Exertion on Heart Rate and Rating of Perceived Exertion in Acutely Concussed Individuals

    PubMed Central

    Hinds, Andrea; Leddy, John; Freitas, Michael; Czuczman, Natalie; Willer, Barry

    2016-01-01

    Objective Research suggests that one physiological effect of concussion is a disruption in regulation of autonomic nervous system control that affects the balance between parasympathetic and sympathetic output. While changes in heart rate after concussion have been observed, the nature of the heart rate change during progressive exercise has not been well evaluated in acutely symptomatic patients. Additionally, little is known about the relationship between HR and RPE in this population. Methods We compared changes in heart rate and perceived effort during graded treadmill exertion in recently concussed patients to elucidate the effect of brain injury on cardiovascular response to exercise. Resting HR, HR on exercise initiation, and changes in HR and RPE during the Buffalo Concussion Treadmill Test (BCTT) were compared on two test visits: When patients were symptomatic (acute) and after recovery. Results were compared with the test-retest results obtained from a control group consisting of healthy, non-concussed individuals. Results Patients had a significantly lower HR at onset of exercise when acutely concussed as compared to when recovered and reported greater perceived exertion at every exercise intensity level when symptomatic, despite exercising at lower workloads, than when recovered. Sympathetic response to increased exertion was not affected by concussion - HR increased in response to exercise at a comparable rate in both tests. These differences observed in response to exercise between the first BCTT and follow-up evaluation in initially concussed patients were not present in non-concussed individuals. Conclusion Our results suggest that during the acute phase after concussion, acutely concussed patients demonstrated an impaired ability to shift from parasympathetic to sympathetic control over heart rate at the onset of exercise. Changes in the autonomic nervous system after concussion may be more complex than previously reported. Continued evaluation of

  17. Adrenomedullin - new perspectives of a potent peptide hormone.

    PubMed

    Schönauer, Ria; Els-Heindl, Sylvia; Beck-Sickinger, Annette G

    2017-02-02

    Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  18. Using Ratings of Perceived Exertion in Physical Education

    ERIC Educational Resources Information Center

    Lagally, Kristen M.

    2013-01-01

    Ratings of perceived exertion have been shown to be a valid method of monitoring physical activity intensity for both adults and children. As such, this subjective method may serve as an alternative to objective measurements for assessing students' performance on national standards 2 and 4. The OMNI-Child perceived exertion scales were…

  19. Exertional Rhabdomyolysis: What Is It and Why Should We Care?

    ERIC Educational Resources Information Center

    Thomas, David Q.; Carlson, Kelli A.; Marzano, Amy; Garrahy, Deborah

    2012-01-01

    Exertional rhabdomyolysis gained increased attention recently when 13 football players from the University of Iowa developed this condition after an especially demanding practice session and were hospitalized. Exertional rhabdomyolysis may lead to severe kidney stress, kidney failure, and even sudden death. Anyone who does physical exercise at a…

  20. 20 CFR 220.135 - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... limitations. (a) General. The claimant's impairment(s) and related symptoms, such as pain, may cause... as pain, are exertional, nonexertional, or a combination of both. (b) Exertional limitations. When... pain, affect only the claimant's ability to meet the strength demands of jobs (sitting,...

  1. 20 CFR 220.135 - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... limitations. (a) General. The claimant's impairment(s) and related symptoms, such as pain, may cause... as pain, are exertional, nonexertional, or a combination of both. (b) Exertional limitations. When... pain, affect only the claimant's ability to meet the strength demands of jobs (sitting,...

  2. 20 CFR 220.135 - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... limitations. (a) General. The claimant's impairment(s) and related symptoms, such as pain, may cause... as pain, are exertional, nonexertional, or a combination of both. (b) Exertional limitations. When... pain, affect only the claimant's ability to meet the strength demands of jobs (sitting,...

  3. 20 CFR 220.135 - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... limitations. (a) General. The claimant's impairment(s) and related symptoms, such as pain, may cause... as pain, are exertional, nonexertional, or a combination of both. (b) Exertional limitations. When... pain, affect only the claimant's ability to meet the strength demands of jobs (sitting,...

  4. Force Exertion Capacity Measurements in Haptic Virtual Environments

    ERIC Educational Resources Information Center

    Munih, Marko; Bardorfer, Ales; Ceru, Bojan; Bajd, Tadej; Zupan, Anton

    2010-01-01

    An objective test for evaluating functional status of the upper limbs (ULs) in patients with muscular distrophy (MD) is presented. The method allows for quantitative assessment of the UL functional state with an emphasis on force exertion capacity. The experimental measurement setup and the methodology for the assessment of maximal exertable force…

  5. Exertional myopathy in whooping cranes (Grus americana) with prognostic guidelines.

    PubMed

    Hanley, Christopher S; Thomas, Nancy J; Paul-Murphy, Joanne; Hartup, Barry K

    2005-09-01

    Exertional myopathy developed in three whooping cranes (Grus americana) secondary to routine capture, handling, and trauma. Presumptive diagnosis of exertional myopathy was based on history of recent capture or trauma, clinical signs, and elevation of aspartate aminotransferase, alanine aminotransferase, creatine kinase, lactate dehydrogenase, and serum potassium. Treatments were attempted in each case, but ultimately were not successful. Gross and microscopic lesions at necropsy confirmed the diagnosis in each case, with the leg musculature most severely affected. Guidelines for determining prognosis of exertional myopathy in cranes have been included based on the analysis of these cases and others in the literature. As treatment is largely unrewarding, prevention remains the key in controlling exertional myopathy. Identification of predisposing factors and proper handling, immobilization, and transportation techniques can help prevent development of exertional myopathy in cranes.

  6. Exertional myopathy in whooping cranes (Grus americana) with prognostic guidlelines

    USGS Publications Warehouse

    Hanley, C.S.; Thomas, N.J.; Paul-Murphy, P.; Hartup, B.K.

    2005-01-01

    Exertional myopathy developed in three whooping cranes (Grus americana) secondary to routine capture, handling, and trauma. Presumptive diagnosis of exertional myopathy was based on history of recent capture or trauma, clinical signs, and elevation of aspartate aminotransferase, alanine aminotransferase, creatine kinase, lactate dehydrogenase, and serum potassium. Treatments were attempted in each case, but ultimately were not successful. Gross and microscopic lesions at necropsy confirmed the diagnosis in each case, with the leg musculature most severely affected. Guidelines for determining prognosis of exertional myopathy in cranes have been included based on the analysis of these cases and others in the literature. As treatment is largely unrewarding, prevention remains the key in controlling exertional myopathy. Identification of predisposing factors and proper handling, immobilization, and transportation techniques can help prevent development of exertional myopathy in cranes.

  7. Acute exertional anterior compartment syndrome in an adolescent female.

    PubMed

    Fehlandt, A; Micheli, L

    1995-01-01

    Acute compartment syndromes usually occur as a complication of major trauma. While the chronic exertional anterior tibial compartment syndrome is well described in the sports medicine literature, reports of acute tibial compartment syndromes due to physical exertion, or repetitive microtrauma, are rare. The case of an adolescent female who developed an acute anterior compartment syndrome from running in a soccer game is described in this report. Failure to recognize the onset of an acute exertional compartment syndrome may lead to treatment delay and serious complications. Whereas the chronic exertional anterior compartment syndrome is characterized by pain that diminishes with the cessation of exercise, the onset of the acute exertional anterior compartment syndrome is heralded by pain that continues, or increases, after exercise has stopped. Compartment pressure measurement confirms the clinical diagnosis and helps guide treatment. True compartment syndromes require urgent fasciotomy.

  8. An evaluation on levels of knowledge, attitude and behavior of people at 65 years and above about alternative medicine living in Ankara.

    PubMed

    Ozer, Ozlem; Santaş, Fatih; Yıldırım, Hasan Hüseyin

    2012-01-01

    The aim was to determine the knowledge, attitude and behavioral levels of people at and above 65 years of age, living in Ankara (Turkey) about alternative medicine. The study was carried out between March - April 2010 through survey application of 200 participants by selective random sampling from the population. Data obtained as a result of the survey were analyzed by SPSS program. The study revealed that 83.5% of the participants believed in alternative therapy methods but 16.5% of them did not. It is concluded that herbal therapy methods are the most frequently used methods with a 63% rate among other alternative therapy methods. When status of the participants was analyzed it was found that it was found that 69% received the information about alternative medicines from their family while 53.5% received it from television This study revealed that alternative medicine is profoundly used by people above 65 years of age in Ankara.

  9. Coenzyme Q10 Administration Increases Brain Mitochondrial Concentrations and Exerts Neuroprotective Effects

    NASA Astrophysics Data System (ADS)

    Matthews, Russell T.; Yang, Lichuan; Browne, Susan; Baik, Myong; Flint Beal, M.

    1998-07-01

    Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.

  10. [Tuberculosis Laboratory Surveillance Network (TuLSA) study group. The first step for national tuberculosis laboratory surveillance: Ankara, 2011].

    PubMed

    Sezen, Figen; Albayrak, Nurhan; Özkara, Şeref; Karagöz, Alper; Alp, Alpaslan; Duyar Ağca, Filiz; İnan Süer, Asiye; Müderris, Tuba; Ceyhan, İsmail; Durmaz, Rıza; Ertek, Mustafa

    2015-04-01

    The most effective method for monitoring country-level drug resistance frequency and to implement the necessary control measures is the establishment of a laboratory-based surveillance system. The aim of this study was to summarize the follow up trend of the drug-resistant tuberculosis (TB) cases, determine the load of resistance and evaluate the capacities of laboratories depending on laboratory quality assurance system for the installation work of National Tuberculosis Laboratory Surveillance Network (TuLSA) which has started in Ankara in 2011. TuLSA studies was carried out under the coordination of National Tuberculosis Reference Laboratory (NRL) with the participation of TB laboratories and dispensaries. Specimens of TB patients, reported from health institutions, were followed in TB laboratories, and the epidemiological information was collected from the dispensaries. One isolate per patient with the drug susceptibility test (DST) results were sent to NRL from TB laboratories and in NRL the isolates were rechecked with the genotypical (MTBDRplus, Hain Lifescience, Germany) and phenotypical (MGIT 960, BD, USA) DST methods. Molecular epidemiological analysis were also performed by spoligotyping and MIRU/VNTR. Second-line DST was applied to the isolates resistant to rifampin. A total of 1276 patients were reported between January 1st to December 31th 2011, and 335 cases were defined as "pulmonary TB from Ankara province". The mean age of those patients was 43.4 ± 20 years, and 67.5% were male. Three hundred seventeen (94.6%) patients were identified as new cases. The average sample number obtained from pulmonary TB cases was 3.26 ± 2.88, and 229 (68.3%) of them was culture positive. DST was applied to all culture positive isolates; 90.4% (207/229) of cases were susceptible to the five drugs tested (ethambutol, isoniazid, pyrazinamide, rifampicin, streptomycin). Eight (3.5%) of the isolates were multidrug-resistant (MDR-TB), while no extensively drug

  11. MiRNA regulation of TRAIL expression exerts selective cytotoxicity to prostate carcinoma cells.

    PubMed

    Huo, Wei; Jin, Ning; Fan, Li; Wang, Weihua

    2014-03-01

    Prostate carcinoma is the most common cancer for men and among the leading cancer-related causes. Many evidences have shown that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) potently induces apoptosis in cancer cells, and thus, is a promising biologic agent for prostate carcinoma therapy. However, TRAIL expression mediated by the current vectors lacks tumor specificity, thereby exerting cytotoxicity to normal cells. To solve this problem, we inserted miRNA response elements (MREs), miR-143 and miR-145, expression levels of which were reduced in prostate carcinoma, as well as that of miR-122, which is specifically expressed in hepatic cells, into adenoviral vectors to control TRAIL expression (Ad-TRAIL-M3). qPCR data confirmed that miR-143, miR-145, and miR-122 levels were all decreased in prostate carcinoma cell lines and prostate cancer samples from patients. Luciferase assays showed that MREs-regulated luciferase expression was potently suppressed in normal cells, but not in prostate cancer cells. Ad-TRAIL-M3, which expresses TRAIL in a MREs-regulated manner, produced high level of TRAIL and suppressed the survival of prostate cancer cells by inducing apoptosis, while Ad-TRAIL-M3 had no TRAIL expression in normal cells and thus exerted no cytotoxicity to them. The studies on PC-3 tumor xenograft in mice further confirmed that Ad-TRAIL-M3 was able to inhibit the growth of tumors and possessed high biosafety. In conclusion, we successfully generated an adenoviral vector that expresses TRAIL in miRNA-regulated mechanism. This miRNA-based gene therapy may be promising for prostate carcinoma treatment.

  12. Chickenpox complications, incidence and financial burden in previously healthy children and those with an underlying disease in Ankara in the pre-vaccination period.

    PubMed

    Ozdemir, Halil; Candir, Mehmet Onur; Karbuz, Adem; Belet, Nurşen; Tapisiz, Anil; Ciftçi, Ergin; Ince, Erdal

    2011-01-01

    The aim of this study was to determine the complications, financial burden and mortality caused by chickenpox using the data of Ankara, Turkey in the pre-vaccination period. The study was conducted as a retrospective sectional study. Of the 65 patients admitted to our hospital, 34 (52.3%) had been previously healthy, 10 (15.4%) had previous chronic disease and 21 (32.3%) were immunocompromised. The most common complications of chickenpox in those patient groups were skin and soft tissue infections (41.2%), hematological complications (50%) and gastrointestinal complications (38.1%), respectively. We found 10.6/100,000 and 8.7/100,000 rates of hospitalization due to chickenpox in Ankara for all children and for previously healthy children, respectively. The chickenpox-related mortality rate for the 0-17 age group was 3.03/1,000,000 in Ankara. In conclusion, we feel that a national vaccination program for chickenpox will lead to a significant decrease in the overall cost to our country.

  13. Prior Acute Mental Exertion in Exercise and Sport

    PubMed Central

    Silva-Júnior, Fernando Lopes e; Emanuel, Patrick; Sousa, Jordan; Silva, Matheus; Teixeira, Silmar; Pires, Flávio; Machado, Sérgio; Arias-Carrion, Oscar

    2016-01-01

    Introduction: Mental exertion is a psychophysiological state caused by sustained and prolonged cognitive activity. The understanding of the possible effects of acute mental exertion on physical performance, and their physiological and psychological responses are of great importance for the performance of different occupations, such as military, construction workers, athletes (professional or recreational) or simply practicing regular exercise, since these occupations often combine physical and mental tasks while performing their activities. However, the effects of implementation of a cognitive task on responses to aerobic exercise and sports are poorly understood. Our narrative review aims to provide information on the current research related to the effects of prior acute mental fatigue on physical performance and their physiological and psychological responses associated with exercise and sports. Methods: The literature search was conducted using the databases PubMed, ISI Web of Knowledge and PsycInfo using the following terms and their combinations: “mental exertion”, “mental fatigue”, “mental fatigue and performance”, “mental exertion and sports” “mental exertion and exercise”. Results: We concluded that prior acute mental exertion affects effectively the physiological and psychophysiological responses during the cognitive task, and performance in exercise. Conclusion: Additional studies involving prior acute mental exertion, exercise/sports and physical performance still need to be carried out in order to analyze the physiological, psychophysiological and neurophysiological responses subsequently to acute mental exertion in order to identify cardiovascular factors, psychological, neuropsychological associates. PMID:27867415

  14. [A case of cutaneous leishmaniasis caused by Leishmania infantum in a non-endemic province (Ankara) of Turkey].

    PubMed

    Dinçer, Didem; Arca, Ercan; Koç, Erol; Topal, Yusuf; Taylan Özkan, Ayşegül; Celebi, Bekir

    2012-07-01

    Southeastern Anatolia and the Mediterranean regions of Turkey are known as endemic areas for cutaneous leishmaniasis (CL). In this report, a 64 years-old male patient with CL caused by Leishmania infantum has been presented. The patient who was inhabiting in Ankara (Central Anatolia region, Turkey) complained from a lesion on his right ring finger for the last six months. He has a cat and has been engaged with gardening. Overall, he was healthy with the exception of hypertension and glucose intolerance. The patient had not left Ankara since the last seven months, however, he had previously been to the Aegean coast during his summer holiday. The examination of the 4th phalanx of his right hand revealed the presence of a 3 x 3 cm erythematous, slightly swollen lesion, at the center of which 1.5 x 1.5 cm ulcerative area covered with a hemorrhagic crust, was detected. Neither axillary or cervical lymphadenopathy, nor hepatosplenomegaly could be observed. The routine examinations, including complete blood count, serum biochemistry, chest X-ray and abdominal ultrasonography were within normal limits. Giemsa stained smears prepared from aspiration of the lesion revealed amastigote-like organisms and leishmania promastigotes were grown in NNN media. PCR amplification of the specimen indicated the presence of a positive DNA band of 420 bp specific for Leishmania spp. The serum sample of the patient revealed positivity for leishmaniasis by the rapid rK39 test and immunofluorescence antibody (IFAT) test. The organism was identified as L.infantum by PCR-RFLP applied to the cultivated organism. The examination of his cat's serum for leishmaniasis by IFAT and PCR, were negative. The exact way of transmission had not been confirmed for the patient. However, when long incubation period of CL was considered, the transmission might probably occurred during his summer stay in the Aegean coast. This case was presented to withdraw attention to a delayed diagnosis of CL which developed

  15. Asthma and allergic diseases in schoolchildren: third cross-sectional survey in the same primary school in Ankara, Turkey.

    PubMed

    Demir, Ahmet U; Karakaya, Gül; Bozkurt, Bülent; Sekerel, Bülent E; Kalyoncu, Ali F

    2004-12-01

    We investigated prevalence and determinants of asthma and allergic diseases in a cross-sectional survey of schoolchildren aged 6-14 in 2002. This was the third of a series of cross-sectional surveys, conducted in 1992 and 1997, in the same school in Ankara, Turkey. Questionnaire including information on house characteristics, dietary habits, past and current exposures and diseases were distributed to 1064 children (523 boys, 541 girls) and filled by the parents at home. Percentage of children having a pet was significantly higher (1992: 7.9, 1997: 22.9, 2002: 21), but that of passive smoking was significantly lower (1992: 74, 1997: 64, 2002: 64.1) in 1997 and 2002 when compared with 1992. Current prevalence percentage of asthma (1992: 8.3, 1997: 9.8, 2002: 6.4), wheeze (1992: 11.9, 1997: 13.3, 2002: 6.4), hay fever (1992: 15.4, 1997: 14.1, 2002: 7.2), and eczema (1992: 4, 1997: 4.3, 2002: 1.8) were significantly lower in 2002 compared with 1992. Multiple logistic regression analysis model for current wheeze included ingestion of cow's milk (no regular ingestion: reference, ORs and 95% CIs, <1 glass/day: 0.5, 0.3-1.0; at least 1 glass/day: 0.3, 0.2-0.7), ingestion of red meat (2.2, 1.2-3.8), and currently holding a dog (6.1, 1.6-23.4). Multiple logistic regression analysis model for current hay fever included ingestion of red meat (1.8, 1.1-2.9) and father's education (none of the parents finished secondary school: reference, secondary school to university: 0.5, 0.2-1.0). Our findings suggested that current prevalence of asthma and allergic diseases decreased among schoolchildren in Ankara, in the last 10 yr, and ingestion of milk and red meat could have a role in the occurrence of asthma and hay fever. Detailed assessment of dietary habits is required to test this hypothesis.

  16. Modified Vaccinia Virus Ankara (MVA) as Production Platform for Vaccines against Influenza and Other Viral Respiratory Diseases

    PubMed Central

    Altenburg, Arwen F.; Kreijtz, Joost H. C. M.; de Vries, Rory D.; Song, Fei; Fux, Robert; Rimmelzwaan, Guus F.; Sutter, Gerd; Volz, Asisa

    2014-01-01

    Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses. PMID:25036462

  17. Mineralogical, geochemical and micromorphological evaluation of the Plio-Quaternary paleosols and calcretes from Karahamzall, Ankara (Central Turkey)

    NASA Astrophysics Data System (ADS)

    Küçükuysal, Ceren; Kapur, Selim

    2014-06-01

    We present the mineralogical, micromorphological, and geochemical characteristics of the paleosols and their carbonates from Karahamzall, Ankara (Central Turkey). The paleosols include calcretes of powdery to nodular forms and alternate with channel deposits. The presence of pedofeatures, such as clay cutans, floating grains, circumgranular cracks, MnO linings, secondary carbonate rims, traces of past bioturbation and remnants of root fragments are all the evidence of pedogenesis. Bw is the most common soil horizon showing subangular-angular blocky to granular or prismatic microstructures. Calcretes, on the other hand, are evaluated as semi-mature massive, nodular, tubular or powdery forms. The probable faunal and floral passages may also imply the traces of life from when these alluvial deposits were soil. The presence of early diagenetic palygorskite and dolomite together with high salinization, high calcification and low chemical index of alteration values are evidence of the formation of calcretes under arid and dry conditions. δ13C compositions of the carbonates ranging from -7.11 ‰ to -7.74 ‰ VPDB are comformable with the world pedogenic carbonates favouring the C4 vegetation; likely δ18O compositions of the carbonates are between -3.97 ‰ and -4.91 ‰ which are compatible with the paleosols formed under the influence of meteroic water in the vadose zone

  18. Sensitivity analyses for the DTMs derived from Unmanned Aerial Vehicle (UAV) in gully erosion mapping: Nallihan badland area (Ankara, Turkey)

    NASA Astrophysics Data System (ADS)

    Avdan, Ugur; Gorum, Tolga; Comert, Resul; Nefeslioglu, Hakan

    2015-04-01

    The main purpose of this study is to evaluate the spatial resolutions for the Digital Terrain Models (DTMs) derived from Unmanned Aerial Vehicle (UAV) in gully erosion mapping. For the purpose, Nallihan badland area (Ankara, Turkey) was selected to be the experimental site. The investigations were carried out in 3 stages; (i) production of the DTMs having 3 cm and 9 cm spatial resolutions by using the orthophoto imagery acquired from the UAV at 97.5 m and 292.4 m altitudes, respectively, (ii) Terrestrial Laser Scanning (TLS) of the experimental site and production of the DTMs derived from the TLS data resampled at 3 cm and 9 cm spatial resolutions, and (iii) spatial and profile comparisons of the derived data. The average altitude differences were obtained on the intervals (-0.1, 0.1) m and (-0.2, 0.2) m for the comparisons between TLS-3cm and UAV-3cm, and TLS-9cm and UAV-9cm data, respectively. Additionally, considering the profile comparisons, it is revealed that depending on the decreasing of spatial resolution, the erosion rates calculated from the DTMs increase artificially.

  19. Generation of Recombinant Modified Vaccinia Virus Ankara Encoding VP2, NS1, and VP7 Proteins of Bluetongue Virus.

    PubMed

    Marín-López, Alejandro; Ortego, Javier

    2016-01-01

    Modified Vaccinia Virus Ankara (MVA) is employed widely as an experimental vaccine vector for its lack of replication in mammalian cells and high expression level of foreign/heterologous genes. Recombinant MVAs (rMVAs) are used as platforms for protein production as well as vectors to generate vaccines against a high number of infectious diseases and other pathologies. The portrait of the virus combines desirable elements such as high-level biological safety, the ability to activate appropriate innate immune mediators upon vaccination, and the capacity to deliver substantial amounts of heterologous antigens. Recombinant MVAs encoding proteins of bluetongue virus (BTV), an Orbivirus that infects domestic and wild ruminants transmitted by biting midges of the Culicoides species, are excellent vaccine candidates against this virus. In this chapter we describe the methods for the generation of rMVAs encoding VP2, NS1, and VP7 proteins of bluetongue virus as a model example for orbiviruses. The protocols included cover the cloning of VP2, NS1, and VP7 BTV-4 genes in a transfer plasmid, the construction of recombinant MVAs, the titration of virus working stocks and the protein expression analysis by immunofluorescence and radiolabeling of rMVA infected cells as well as virus purification.

  20. Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine.

    PubMed

    Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja; Nabi, Rafiq; Kozlowski, Pamela A; Montefiori, David C; LaBranche, Celia C; Wrammert, Jens; Keele, Brandon F; Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Santra, Sampa; Basu, Rahul; Moss, Bernard; Robinson, Harriet L; Amara, Rama Rao

    2016-01-01

    Background.  In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods.  The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results.  Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5)α-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions.  The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques.

  1. EPS production and bioremoval of heavy metals by mixed and pure bacterial cultures isolated from Ankara Stream.

    PubMed

    Kiliç, Nur Koçberber; Kürkçü, Güliz; Kumruoğlu, Durna; Dönmez, Gönül

    2015-01-01

    This study is focused on isolation of Ni(II), Cu(II) and Cr(VI) resistant bacteria to assess their exopolysaccharide (EPS) production and related bioremoval capacities. Mixed cultures had higher heavy metal removal capacity in media with molasses (MAS) than the control cultures lacking this carbon (AS) containing 50 mg/l of heavy metal. The yields were 32%, 75.7%, and 51.1% in MAS, while the corresponding values were 29%, 55.1%, and 34.5% in AS, respectively. Purification of the strains 1, 5 and 6 present in the mixed cultures decreased the bioremoval capacities of the mixed culture samples, although these strains produced higher EPS amounts in MAS agar. Strain 5 had the highest Cu(II) (69.1%) and Cr(VI) (43.1%) removal rates at 25 mg/l initial concentration of each pollutant with EPS amounts of 0.74 g/l and 1.05 g/l, respectively. This strain was identified as Stenotrophomonas maltophilia. The presented data show that especially mixed and also pure cultures of bacterial strains isolated from Ankara Stream could be assessed as potential bioremoval agents in the treatment of Cu(II) or Cr(VI) containing wastewaters.

  2. Immunogenicity and protective efficacy of recombinant Modified Vaccinia virus Ankara candidate vaccines delivering West Nile virus envelope antigens.

    PubMed

    Volz, Asisa; Lim, Stephanie; Kaserer, Martina; Lülf, Anna; Marr, Lisa; Jany, Sylvia; Deeg, Cornelia A; Pijlman, Gorben P; Koraka, Penelope; Osterhaus, Albert D M E; Martina, Byron E; Sutter, Gerd

    2016-04-07

    West Nile virus (WNV) cycles between insects and wild birds, and is transmitted via mosquito vectors to horses and humans, potentially causing severe neuroinvasive disease. Modified Vaccinia virus Ankara (MVA) is an advanced viral vector for developing new recombinant vaccines against infectious diseases and cancer. Here, we generated and evaluated recombinant MVA candidate vaccines that deliver WNV envelope (E) antigens and fulfil all the requirements to proceed to clinical testing in humans. Infections of human and equine cell cultures with recombinant MVA demonstrated efficient synthesis and secretion of WNV envelope proteins in mammalian cells non-permissive for MVA replication. Prime-boost immunizations in BALB/c mice readily induced circulating serum antibodies binding to recombinant WNV E protein and neutralizing WNV in tissue culture infections. Vaccinations in HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice elicited WNV E-specific CD8+ T cell responses. Moreover, the MVA-WNV candidate vaccines protected C57BL/6 mice against lineage 1 and lineage 2 WNV infection and induced heterologous neutralizing antibodies. Thus, further studies are warranted to evaluate these recombinant MVA-WNV vaccines in other preclinical models and use them as candidate vaccine in humans.

  3. Determining the agent factors related with time management of responsible doctors and nurses in clinics at Ankara University hospitals.

    PubMed

    Acuner, Ahmet Munir; Nilgun, Sarp; Cifteli, F Gulay

    2006-01-01

    This research has been planned and conducted as a descriptive scanning model field study in order to determine the agent factors related with time management of doctors and nurses in positions of responsibility at Ankara University hospitals. As data collection instruments; the "Personal Information Form" which has been developed to determine the socio-demographical characteristics of the research group, the questionnaire of "Determining the Time Management Attitudes and Behaviour of Managers, Time Management Opportunities of the Managers, Prodcutive Working Times of the Managers and the Factors Causing Them to Lose Time", developed by Erdem has been used. It has been determined that the time management attitudes and behaviour of doctors, nurses and nurse assistants responsible for clinics are all different. It was found that nurse assistants graduated from pre-undergraduate or high schools are the least conscious of time management. In particular, nurse assistants of 36 years old and over with 21 years of work experience and 11 years of management experience show little awareness of time management. The time losing factors of the research group were found to be unnecessary visitors, lack of materials and the excessive amount of time spent on obtaining the necessary equipment.

  4. Modified vaccinia virus ankara (MVA) as production platform for vaccines against influenza and other viral respiratory diseases.

    PubMed

    Altenburg, Arwen F; Kreijtz, Joost H C M; de Vries, Rory D; Song, Fei; Fux, Robert; Rimmelzwaan, Guus F; Sutter, Gerd; Volz, Asisa

    2014-07-17

    Respiratory viruses infections caused by influenza viruses, human parainfluenza virus (hPIV), respiratory syncytial virus (RSV) and coronaviruses are an eminent threat for public health. Currently, there are no licensed vaccines available for hPIV, RSV and coronaviruses, and the available seasonal influenza vaccines have considerable limitations. With regard to pandemic preparedness, it is important that procedures are in place to respond rapidly and produce tailor made vaccines against these respiratory viruses on short notice. Moreover, especially for influenza there is great need for the development of a universal vaccine that induces broad protective immunity against influenza viruses of various subtypes. Modified Vaccinia Virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform. MVA can encode one or more foreign antigens and thus functions as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. However, there are some practical and regulatory issues that need to be addressed in order to develop MVA-based vaccines on short notice at the verge of a pandemic. In this review, we discuss promising novel influenza virus vaccine targets and the use of MVA for vaccine development against various respiratory viruses.

  5. [Modified vaccinia virus ankara (MVA)--development as recombinant vaccine and prospects for use in veterinary medicine].

    PubMed

    Volz, Asisa; Fux, Robert; Langenmayer, Martin C; Sutter, Gerd

    2015-01-01

    Poxviruses as expression vectors are widely used in medical research for the development of recombinant vaccines and molecular therapies. Here we review recent accomplishments in vaccine research using recombinant modified vaccinia virus ankara (MVA). MVA is a highly attenuated vaccinia virus strain that originated from serial tissue culture passage in chicken embryo fibroblasts more than 40 years ago. Growth adaptation to avian host cells caused deletions and mutations in the viral genome affecting about 15% of the original genetic information. In consequence, MVA is replication-deficient in cells of mammalian origin and fails to produce many of the virulence factors encoded by conventional vaccinia virus. Because of its safety for the general environment MVA can be handled under conditions of biosafety level one. Non-replicating MVA can enter any target cell and activate its molecular life cycle to express all classes of viral and recombinant genes. Therefore, recombinant MVA have been established as an extremely safe and efficient vector system for vaccine development in medical research. By now, various recombinant MVA vaccines have been found safe and immunogenic when used for phase I/II clinical testing in humans, and suitable for industrial scale production following good practice of manufacturing. Thus, there is an obvious usefulness of recombinant MVA vaccines for novel prophylactic and therapeutic approaches also in veterinary medicine. Results from first studies in companion and farm animals are highly promising.

  6. Cross-protective immunity against multiple influenza virus subtypes by a novel modified vaccinia Ankara (MVA) vectored vaccine in mice.

    PubMed

    Brewoo, Joseph N; Powell, Tim D; Jones, Jeremy C; Gundlach, Nancy A; Young, Ginger R; Chu, Haiyan; Das, Subash C; Partidos, Charalambos D; Stinchcomb, Dan T; Osorio, Jorge E

    2013-04-03

    Development of an influenza vaccine that provides cross-protective immunity remains a challenge. Candidate vaccines based on a recombinant modified vaccinia Ankara (MVA) viral vector expressing antigens from influenza (MVA/Flu) viruses were constructed. A vaccine candidate, designated MVA/HA1/C13L/NP, that expresses the hemagglutinin from pandemic H1N1 (A/California/04/09) and the nucleoprotein (NP) from highly pathogenic H5N1 (A/Vietnam/1203/04) fused to a secretory signal sequence from vaccinia virus was highly protective. The vaccine elicited strong antibody titers to homologous H1N1 viruses while cross-reactive antibodies to heterologous viruses were not detectable. In mice, this MVA/HA1/C13L/NP vaccine conferred complete protection against lethal challenge with A/Vietnam/1203/04 (H5N1), A/Norway/3487-2/09 (pandemic H1N1) or A/Influenza/Puerto Rico/8/34 (seasonal H1N1) and partial protection (57.1%) against challenge with seasonal H3N2 virus (A/Aichi/68). The protective efficacy of the vaccine was not affected by pre-existing immunity to vaccinia. Our findings highlight MVA as suitable vector to express multiple influenza antigens that could afford broad cross-protective immunity against multiple subtypes of influenza virus.

  7. Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

    PubMed Central

    Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja; Nabi, Rafiq; Kozlowski, Pamela A.; Montefiori, David C.; LaBranche, Celia C.; Wrammert, Jens; Keele, Brandon F.; Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Santra, Sampa; Basu, Rahul; Moss, Bernard; Robinson, Harriet L.; Amara, Rama Rao

    2016-01-01

    Background. In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods. The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results. Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5)α-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions. The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques. PMID:27006959

  8. Musical agency reduces perceived exertion during strenuous physical performance

    PubMed Central

    Fritz, Thomas Hans; Hardikar, Samyogita; Demoucron, Matthias; Niessen, Margot; Demey, Michiel; Giot, Olivier; Li, Yongming; Haynes, John-Dylan; Villringer, Arno; Leman, Marc

    2013-01-01

    Music is known to be capable of reducing perceived exertion during strenuous physical activity. The current interpretation of this modulating effect of music is that music may be perceived as a diversion from unpleasant proprioceptive sensations that go along with exhaustion. Here we investigated the effects of music on perceived exertion during a physically strenuous task, varying musical agency, a task that relies on the experience of body proprioception, rather than simply diverting from it. For this we measured psychologically indicated exertion during physical workout with and without musical agency while simultaneously acquiring metabolic values with spirometry. Results showed that musical agency significantly decreased perceived exertion during workout, indicating that musical agency may actually facilitate physically strenuous activities. This indicates that the positive effect of music on perceived exertion cannot always be explained by an effect of diversion from proprioceptive feedback. Furthermore, this finding suggests that the down-modulating effect of musical agency on perceived exertion may be a previously unacknowledged driving force for the development of music in humans: making music makes strenuous physical activities less exhausting. PMID:24127588

  9. Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

    PubMed Central

    Scalco, Renata S; Snoeck, Marc; Quinlivan, Ros; Treves, Susan; Laforét, Pascal; Jungbluth, Heinz; Voermans, Nicol C

    2016-01-01

    Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed. PMID:27900193

  10. A case of mitochondrial cytopathy with exertion induced dystonia

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor

    2015-01-01

    Paroxysmal dystonias are a group of relatively benign hyperkinetic childhood movement disorders of varied etiology. Mitochondrial diseases are well known to produce persistent dystonias as sequelae, but paroxysmal exertion induced dystonia has been reported in only one case to the best of our knowledge. Two siblings born to consanguineous parents presented with early-onset exertion induced dystonia, which was unresponsive to diphenylhydantoin and carbamazepine. A trial with valproate in one of the siblings turned fatal within 24 h. Based on this clue, the second child was investigated and found to suffer from complex I deficiency with a paternally inherited dominant nuclear DNA mutation, which is responsive to the mitochondrial cocktail. Exertion induced dystonia can be a rare manifestation of complex I deficiency. PMID:26557169

  11. Safety and immunogenicity of mammalian cell derived and Modified Vaccinia Ankara vectored African swine fever subunit antigens in swine.

    PubMed

    Lopera-Madrid, Jaime; Osorio, Jorge E; He, Yongqun; Xiang, Zuoshuang; Adams, L Garry; Laughlin, Richard C; Mwangi, Waithaka; Subramanya, Sandesh; Neilan, John; Brake, David; Burrage, Thomas G; Brown, William Clay; Clavijo, Alfonso; Bounpheng, Mangkey A

    2017-03-01

    A reverse vaccinology system, Vaxign, was used to identify and select a subset of five African Swine Fever (ASF) antigens that were successfully purified from human embryonic kidney 293 (HEK) cells and produced in Modified vaccinia virus Ankara (MVA) viral vectors. Three HEK-purified antigens [B646L (p72), E183L (p54), and O61R (p12)], and three MVA-vectored antigens [B646L, EP153R, and EP402R (CD2v)] were evaluated using a prime-boost immunization regimen swine safety and immunogenicity study. Antibody responses were detected in pigs following prime-boost immunization four weeks apart with the HEK-293-purified p72, p54, and p12 antigens. Notably, sera from the vaccinees were positive by immunofluorescence on ASFV (Georgia 2007/1)-infected primary macrophages. Although MVA-vectored p72, CD2v, and EP153R failed to induce antibody responses, interferon-gamma (IFN-γ(+)) spot forming cell responses against all three antigens were detected one week post-boost. The highest IFN-γ(+) spot forming cell responses were detected against p72 in pigs primed with MVA-p72 and boosted with the recombinant p72. Antigen-specific (p12, p72, CD2v, and EP153R) T-cell proliferative responses were also detected post-boost. Collectively, these results are the first demonstration that ASFV subunit antigens purified from mammalian cells or expressed in MVA vectors are safe and can induce ASFV-specific antibody and T-cell responses following a prime-boost immunization regimen in swine.

  12. A Technique for Establishing True Levels of Muscle Strength Exertion

    DTIC Science & Technology

    1980-01-01

    performed -"aximal or submaximal isometric strength exertions. The exertions tested were elbow flexion, finger flexion, knee flexion and knee...190.1 167.11 17.3350 Buttock-Knee Length (cm) 54.1 66.7 59.29 3.2106 Knee Height, sitting (cm) 46.5 58.7 52.91 2.8737 Shoulder- Elbow Length (cm) 29.3...propped the elbow of the right arm on the arm rest, extended the fore- arm directly forward so that the cuff was exactly above the load cell, with

  13. Species distribution and detection of Crimean Congo Hemorrhagic Fever Virus (CCHFV) in field-collected ticks in Ankara Province, Central Anatolia, Turkey.

    PubMed

    Hekimoglu, Olcay; Ozer, Nurdan; Ergunay, Koray; Ozkul, Aykut

    2012-01-01

    Ticks may act as vectors for a number of infectious diseases including Crimean Congo Hemorrhagic Fever (CCHF). The causative agent is Crimean Congo Hemorrhagic Fever Virus (CCHFV), a member of Bunyaviridae, causing extensive ecchymosis, visceral bleeding and hepatic dysfunction with a high fatality rate in the affected individuals. CCHF was initially recognized in Turkey in 2002 and the current number of reported cases exceeds 4,400. This study was conducted to confirm the presence of tick species established as potential CCHFV vectors and investigate CCHFV activity in ticks at Ankara province, Turkey's second most-densely populated province, where CCHF cases were demonstrated. A total of 1,196 adult ticks, collected from various animals and vegetation in 12 sites located in 5 counties of Ankara during April-July 2010 were identified to species level. Twenty-two tick pools from county K2 were also evaluated for the presence of CCHFV RNA via a one-step real-time RT-PCR assay and reactive results were further confirmed by an in house nested RT-PCR assay. Nine tick species were identified: Rhipicephalus bursa (44.9%), R. sanguineus (18.9%), R. turanicus (18.1%), Haemaphysalis parva (8.3%), Hyalomma marginatum marginatum (5.4%), H. aegyptium (1.4%), H. anatolicum excavatum (1.3%), Hae. punctata (0.3%) and Dermacentor marginatus (0.2%). A total of five tick pools (22.7%) were reactive in real-time and nested RT-PCR assays. The pools included R. bursa, H. m. marginatum and Hae. parva ticks, collected from mammal hosts from two villages in one county. This is the first documentation of CCHFV activity in ticks from Ankara province, which indicates requirement for detailed surveillance to predict high risk zones in the region.

  14. The Age and Geodynamic Evolution of the Metamorphic sole rocks from Izmir-Ankara-Erzıncan suture zone (Northern-Turkey)

    NASA Astrophysics Data System (ADS)

    Melih Çörtük, Rahmi; Faruk Çelik, Ömer; Özkan, Mutlu; Sherlock, Sarah C.; Marzoli, Andrea; Altıntaş, İsmail Emir; Topuz, Gültekin

    2016-04-01

    The İzmir-Ankara-Erzincan suture zone in northern Turkey is one of the major tectonic zones separating the Pontides to the North from the Anatolide-Tauride block and Kı rşehir Massif to the South. The accretionary complex of the İzmir-Ankara-Erzincan suture zone, near Artova, is composed mainly of peridotites with varying degree serpentinization, metamorphic rocks, basalt, sandstones, pelagic and neritic limestones. The metamorphic rocks are represented by amphibolite, garnet micaschit, calc-schist and marble. The metamorphic rocks were interpreted as the metamorphic sole rocks. Because; (i) They are tectonically located beneath the serpentinized peridotites. (ii) Foliation planes of both the amphibolites and mantle tectonites are parallel to each other. (iii) The metamorphic rocks are crosscut by non-metamorphic dolerite dikes which exhibite Nb and Ta depletion relative to Th enrichment on the N-MORB normalized multi-element spider diagram. The dolerite dikes display flat REE patterns (LaN/YbN=0.85-1.24). These geochemical signatures of the dolerite dikes are indicative of subduction component during their occurrences. Geochemical observations of the amphibolites suggest E-MORB- and OIB-like signatures (LaN/SmN= 1.39-3.14) and their protoliths are represented by basalt and alkali basaltic rocks. Amphiboles from the amphibolites are represented by calcic amphiboles (magnesio-hornblende, tchermakite and tremolite) and they yielded 40Ar-39Ar ages between 157.8 ± 3.6 Ma and 139 ± 11 Ma. These cooling ages were interpreted to be the intra-oceanic subduction/thrusting time of the İzmir-Ankara-Erzincan oceanic domain. This study was funded by TÜBİTAK (Project no: 112Y123).

  15. Design and synthesis of 4-substituted quinazolines as potent EGFR inhibitors with anti-breast cancer activity.

    PubMed

    Ahmed, Marwa; Magdy, Naja

    2016-09-23

    Cancer is a major health problem to human beings around the world. Many quinazoline derivatives were reported to have potent cytotoxic activity. Our aim in this work is the discovery of potent epidermal growth factor receptor (EGFR) inhibitors with anti-breast cancer activity containing 4-substituted quinazoline pharmacophore. Novel series of 4-substituted 6,8-dibromo-2-(4-chlorophenyl)-quinazoline derivatives have been designed and synthesized. New derivatives were tested against MCF-7 (human breast carcinoma cell line) and screened for their inhibition activity against epidermal growth factor receptor tyrosine kinase (EGFR-TK). Most of the tested compounds show potent antiproliferative activity and EGFR-TK inhibitory activity. Compounds VIIIc and VIIIb exerted powerful cytotoxic activity (IC50 3.1 and 6.3 µM) with potent inhibitory percent (91.1 and 88.4%) against EGFR-TK. Compounds IX, VIIa, X, VIIb, VIc, V, IV, VIa and VIb showed promising cytotoxic effects with IC50 range (12-79 µM) with good activity against EGFR-TK with the inhibitory percent (85.4-60.8%). On the other hand, compounds VIIc, VIIIa exerted low cytotoxic effects as revealed from their IC50 value (124 and 144 µM) with low activity against EGFR-TK with inhibitory percent 30.6 and 29.1% respectively.

  16. Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals.

    PubMed

    Parrino, Janie; McCurdy, Lewis H; Larkin, Brenda D; Gordon, Ingelise J; Rucker, Steven E; Enama, Mary E; Koup, Richard A; Roederer, Mario; Bailer, Robert T; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S

    2007-02-09

    Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax in vaccinia-naïve and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax challenge at 3 months. Two or more doses of MVA prior to Dryvax reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax vaccinia-specific CD8(+) T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses.

  17. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  18. Phenyltriazolinones as potent factor Xa inhibitors.

    PubMed

    Quan, Mimi L; Pinto, Donald J P; Rossi, Karen A; Sheriff, Steven; Alexander, Richard S; Amparo, Eugene; Kish, Kevin; Knabb, Robert M; Luettgen, Joseph M; Morin, Paul; Smallwood, Angela; Woerner, Francis J; Wexler, Ruth R

    2010-02-15

    We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

  19. 20 CFR 404.1567 - Physical exertion requirements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Physical exertion requirements. 404.1567 Section 404.1567 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  20. 20 CFR 404.1567 - Physical exertion requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 2 2014-04-01 2014-04-01 false Physical exertion requirements. 404.1567 Section 404.1567 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  1. 20 CFR 404.1569a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Exertional and nonexertional limitations. 404.1569a Section 404.1569a Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  2. 20 CFR 404.1567 - Physical exertion requirements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 2 2012-04-01 2012-04-01 false Physical exertion requirements. 404.1567 Section 404.1567 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  3. 20 CFR 404.1569a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 2 2014-04-01 2014-04-01 false Exertional and nonexertional limitations. 404.1569a Section 404.1569a Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  4. 20 CFR 404.1567 - Physical exertion requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 2 2013-04-01 2013-04-01 false Physical exertion requirements. 404.1567 Section 404.1567 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Determining Disability and Blindness Vocational Considerations §...

  5. Perceived Exertion: An Old Exercise Tool Finds New Applications.

    ERIC Educational Resources Information Center

    Monahan, Terry

    1988-01-01

    Perceived exertion scales, based on subjective perception of energy output, are gaining respect as prescribing and monitoring tools for individual exercise programs. A review of recent literature indicates growing research interest in applications for individuals who are elderly, inactive, or subject to medical conditions such as angina. (IAH)

  6. 20 CFR 416.969a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... or restrictions imposed by your impairment(s) and related symptoms, such as pain, are exertional... imposed by your impairment(s) and related symptoms, such as pain, affect only your ability to meet...

  7. 20 CFR 404.1569a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... impairment(s) and related symptoms, such as pain, are exertional, nonexertional, or a combination of both. (b... symptoms, such as pain, affect only your ability to meet the strength demands of jobs (sitting,...

  8. 20 CFR 416.969a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... or restrictions imposed by your impairment(s) and related symptoms, such as pain, are exertional... imposed by your impairment(s) and related symptoms, such as pain, affect only your ability to meet...

  9. 20 CFR 404.1569a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... impairment(s) and related symptoms, such as pain, are exertional, nonexertional, or a combination of both. (b... symptoms, such as pain, affect only your ability to meet the strength demands of jobs (sitting,...

  10. 20 CFR 416.969a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... or restrictions imposed by your impairment(s) and related symptoms, such as pain, are exertional... imposed by your impairment(s) and related symptoms, such as pain, affect only your ability to meet...

  11. 20 CFR 404.1569a - Exertional and nonexertional limitations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., such as pain, may cause limitations of function or restrictions which limit your ability to meet... impairment(s) and related symptoms, such as pain, are exertional, nonexertional, or a combination of both. (b... symptoms, such as pain, affect only your ability to meet the strength demands of jobs (sitting,...

  12. Are the Measurements of Attention Allocation and Perceived Exertion Trustworthy?

    ERIC Educational Resources Information Center

    Meir, Gily; Hutchinson, Jasmin C.; Habeeb, Christine M.; Boiangin, Nataniel M.; Shaffer, Cory; Basevitch, Itay; Tenenbaum, Gershon

    2015-01-01

    Two studies examined the trustworthiness of commonly used measurement scales for ratings of perceived exertion (RPE) and state attentional focus (SAF) during exercise. In Study 1, participants (N = 24, 14 female) performed a treadmill graded-exercise test. The order of scale presentation during the task was manipulated (i.e., RPE followed by SAF…

  13. Perception of Forces Exerted by Objects in Collision Events

    ERIC Educational Resources Information Center

    White, Peter A.

    2009-01-01

    Impressions of force are commonplace in the visual perception of objects interacting. It is proposed that these impressions have their source in haptically mediated experiences of exertion of force in actions on objects. Visual impressions of force in interactions between objects occur by a kind of generalization of the proprioceptive impression…

  14. Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques

    PubMed Central

    Iyer, Smita S.; Gangadhara, Sailaja; Victor, Blandine; Shen, Xiaoying; Chen, Xuemin; Nabi, Rafiq; Kasturi, Sudhir P.; Sabula, Michael J.; Labranche, Celia C.; Reddy, Pradeep B. J.; Tomaras, Georgia D.; Montefiori, David C.; Spearman, Paul; Pulendran, Bali; Kozlowski, Pamela A.

    2016-01-01

    ABSTRACT The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations with DNA (D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the second MVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of seven DNA/MVA and VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control. IMPORTANCE The development of an effective HIV vaccine remains a global necessity for preventing HIV

  15. Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content

    PubMed Central

    Kaur, Suneet; Srivastava, Gautam; Sharma, Amar Nath; Jolly, Ravinder S

    2015-01-01

    Background and Purpose Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. Experimental Approach Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. Key Results CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21CIP1/WAF1. The effect of CaeA on cell proliferation was reversible. Conclusions and Implications CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron. PMID:25537422

  16. Oxytocin microinjected into the central amygdaloid nuclei exerts anti-aggressive effects in male rats.

    PubMed

    Calcagnoli, Federica; Stubbendorff, Christine; Meyer, Neele; de Boer, Sietse F; Althaus, Monika; Koolhaas, Jaap M

    2015-03-01

    We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain OXT levels induces potent anti-aggressive and pro-social explorative effects during social challenges. However, the exact anatomical location in the brain where OXT exerts its action is still elusive. In the present study, we targeted two critical brain areas, i.e. the central amygdala (CeA) and the dorsal raphe (DR), both containing high levels of OXT receptors (OXTRs) and constituting important nodes of the neural circuitry related to aggression. Behavioral effects of local micro-infusion of OXT and OXTR antagonist, L368.899, (alone and combined) were evaluated in resident male rats during confrontations with an unfamiliar male intruder. Our results show that OXT microinjected into the CeA markedly reduced resident's offensive behavior and facilitated social exploration, without affecting other non-aggressive behaviors. The receptor specificity of the behavioral effects was verified when a micro-infusion of a selective OXTR antagonist nullified the changes. Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous OXT within the CeA does not play a major inhibitory role on offensiveness. Anatomical specificity was also supported by the absence of relevant behavioral effects when OXT was microinjected into more medial sub-regions of the amygdala. Likewise, within the DR neither OXT nor OXTR exerted significant effects on offensive aggression, while microinjection of the 5-HT1A autoreceptor agonist in this region significantly suppressed aggression. In conclusion, our results point at the CeA as an important brain site of action for the anti-aggressive and pro-social explorative effects induced by exogenous enhancement of brain OXT levels.

  17. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters.

    PubMed

    Hofmaier, Tina; Luf, Anton; Seddik, Amir; Stockner, Thomas; Holy, Marion; Freissmuth, Michael; Ecker, Gerhard F; Schmid, Rainer; Sitte, Harald H; Kudlacek, Oliver

    2014-07-01

    Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30μM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect "fades out" the levamisole/aminorex effect "kicks in".

  18. C5-C12 volatile organic compounds at roadside, residential, and background locations in Ankara, Turkey: temporal and spatial variations and sources.

    PubMed

    Kuntasal, Oznur Oğuz; Kilavuz, Seda Aslan; Karman, Deniz; Wang, Daniel; Tuncel, Gürdal

    2013-10-01

    Concentrations of 91 volatile organic compounds (VOCs) ranging from C5 to C12 were measured at three sites in Ankara, the capital of Turkey, in the summer of 2003 and winter of 2004. Samples were collected at roadside, residential and background stations at consecutive 4-hr intervals over a 24-hr period for six weeks in each season. Air samples were collected onto cartridges packed with Tenax TA and Carbopack B resins and analyzed by thermal desorption, followed by gas chromatography coupled to a mass selective detector (GC/MSD). Time resolved data provided information on ambient levels, temporal and spatial variations and sources of VOCs in Ankara. Toluene is the most abundant compound at all sites with and average concentration of 13.1 ?g m(-3). The mean concentrations of benzene are 12.6, 5.2, and 2.4 ?g m(-3) during winter at roadside, residential and background stations, respectively. Diurnal variation in the data together with toluene to benzene concentration ratio (T:B) that is close to 2.0 indicated the influence of traffic related emissions at residential and roadside stations during winter season. Higher T:B ratio observed at residential and background stations during summer period and correlation analysis indicated additional VOC sources. Temporal variations and low m,p-xylene to ethylbenzene ratio (mpX:E) indicated that transported air mass is the major VOC source influencing VOC concentrations measured at the background station.

  19. Broad Protection against Avian Influenza Virus by Using a Modified Vaccinia Ankara Virus Expressing a Mosaic Hemagglutinin Gene

    PubMed Central

    Kamlangdee, Attapon; Kingstad-Bakke, Brock; Anderson, Tavis K.; Goldberg, Tony L.

    2014-01-01

    ABSTRACT A critical failure in our preparedness for an influenza pandemic is the lack of a universal vaccine. Influenza virus strains diverge by 1 to 2% per year, and commercially available vaccines often do not elicit protection from one year to the next, necessitating frequent formulation changes. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. We have constructed a recombinant modified vaccinia virus Ankara (MVA) that expresses an H5N1 mosaic hemagglutinin (H5M) (MVA-H5M). This mosaic was generated in silico using 2,145 field-sourced H5N1 isolates. A single dose of MVA-H5M provided 100% protection in mice against clade 0, 1, and 2 avian influenza viruses and also protected against seasonal H1N1 virus (A/Puerto Rico/8/34). It also provided short-term (10 days) and long-term (6 months) protection postvaccination. Both neutralizing antibodies and antigen-specific CD4+ and CD8+ T cells were still detected at 5 months postvaccination, suggesting that MVA-H5M provides long-lasting immunity. IMPORTANCE Influenza viruses infect a billion people and cause up to 500,000 deaths every year. A major problem in combating influenza is the lack of broadly effective vaccines. One solution from the field of human immunodeficiency virus vaccinology involves a novel in silico mosaic approach that has been shown to provide broad and robust protection against highly variable viruses. Unlike a consensus algorithm which picks the most frequent residue at each position, the mosaic method chooses the most frequent T-cell epitopes and combines them to form a synthetic antigen. These studies demonstrated that a mosaic influenza virus H5 hemagglutinin expressed by a viral vector can elicit full protection against diverse H5N1 challenges as well as induce broader immunity than a wild-type hemagglutinin. PMID:25210173

  20. Afforestation areas defined by GIS in Gölbaşi specially protected area Ankara/Turkey.

    PubMed

    Dilek, E Figen; Sahin, Sükran; Yilmazer, Ilyas

    2008-09-01

    This paper concentrates on determining the areas for afforestation and the development of conservation strategies and actions in the case where there is high demand for the conservation of a particular land area. The analysis of hydrological landscape structure and of erodibility was prerequisite in the methodological design considering the site-specific natural landscape characteristics of the study area. The Gölbaşi Specially Protected Area (SPA) being the case area has many local environmental disturbances, especially with respect to its hydrological system, and the area is beset by increasing demands for its use by the burgeoning human population. It is obviously clear that the present intensive demand for recreational use will be forecasted further increase in the future. The count of rural residences is estimated to increase by 50% over the next decade. This intensive demand shall further strain the carrying capacity of the ecological milieu, which has already suffered to a significant degree because of the present urban and rural activities. The Gölbaşi district is located only 20 km from the city center of Ankara, and its surroundings were legally designated to be a Specially Protected Area primarily for the existence of lacustral and fluvial systems where two interconnected lakes exist: Mogan and Eğmir Lakes. Essentially, the continuity of the lacustral and fluvial system of Lakes Mogan and Eğmir depends on the preservation and improvement of the water sources. However, interconnected surface water bodies of these lakes are actually quite contaminated, and a decline in the water flow from Mogan to Eğmir has been observed. For the elaboration of the present method, required conventional maps (at 1/25,000 scale) of topography (for slope analysis) and geology (for erodibility and permeability analysis) were transferred to computer media using AutoCAD R.14 software. The rectification of the transferred data was done using ERDAS Imagine 8.3. All data

  1. Dmt and opioid peptides: a potent alliance.

    PubMed

    Bryant, Sharon D; Jinsmaa, Yunden; Salvadori, Severo; Okada, Yoshio; Lazarus, Lawrence H

    2003-01-01

    The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.

  2. Viscum album Exerts Anti-Inflammatory Effect by Selectively Inhibiting Cytokine-Induced Expression of Cyclooxygenase-2

    PubMed Central

    Hegde, Pushpa; Maddur, Mohan S.; Friboulet, Alain; Bayry, Jagadeesh; Kaveri, Srini V.

    2011-01-01

    Viscum album (VA) preparations are extensively used as complementary therapy in cancer and are shown to exert anti-tumor activities which involve the cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their application in cancer therapy, VA preparations have also been successfully utilized in the treatment of several inflammatory pathologies. Owing to the intricate association of inflammation and cancer and in view of the fact that several anti-tumor phytotherapeutics also exert a potent anti-inflammatory effect, we hypothesized that VA exerts an anti-inflammatory effect that is responsible for its therapeutic benefit. Since, inflammatory cytokine-induced cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play a critical role in the pathogenesis of inflammatory diseases, we investigated the anti-inflammatory effect of VA on regulation of cyclo-oxygenase expression and PGE2 biosynthesis by using human lung adenocarcinoma cells (A549 cells) as a model. A549 cells were stimulated with IL-1β and treated with VA preparation (VA Qu Spez) for 18 hours. PGE2 was analysed in the culture supernatants by enzyme immunoassay. Expression of COX-2 and COX-1 proteins was analyzed by immunoblotting and the expression of COX-2 mRNA was assessed by semi-quantitative RT-PCR. We found that VA Qu Spez inhibit the secretion of IL-1β-induced PGE2 in a dose-dependent manner. Further, we also show that this inhibitory action was associated with a reduced expression of COX-2 without modulating the COX-1 expression. Together these results demonstrate a novel anti-inflammatory mechanism of action of VA preparations wherein VA exerts an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2. PMID:22028854

  3. Endoscopic Thermal Fasciotomy for Chronic Exertional Compartment Syndrome

    PubMed Central

    Voleti, Pramod B.; Lebrun, Drake G.; Roth, Cameron A.; Kelly, John D.

    2015-01-01

    Chronic exertional compartment syndrome is an activity-induced condition that occurs when intracompartmental pressures within an osteofascial envelope increase during exercise, leading to reversible ischemic symptoms such as pain, cramping, numbness, or weakness. Nonoperative treatment options for this condition have shown limited success and are often undesirable for the patient given the requirement for activity modification. Traditional surgical treatment options involving open or subcutaneous fasciotomies have more favorable results, but these techniques are associated with significant morbidity. Endoscopically assisted fasciotomy techniques afford the advantages of being minimally invasive, providing excellent visualization, and allowing accelerated rehabilitation. The purpose of this article is to describe a technique for performing endoscopically assisted fasciotomies for chronic exertional compartment syndrome of the lower leg using an entirely endoscopic thermal ablating device. The endoscopic thermal fasciotomy technique is associated with minimal morbidity, ensures excellent hemostasis, and affords an early return to sports. PMID:26900549

  4. Exertional dyspnea as a symptom of infrarenal aortic occlusive disease.

    PubMed

    Schott, Stacey L; Carreiro, Fernanda Porto; Harkness, James R; Malas, Mahmoud B; Sozio, Stephen M; Zakaria, Sammy

    2014-06-01

    Advanced atherosclerosis of the aorta can cause severe ischemia in the kidneys, refractory hypertension, and claudication. However, no previous reports have clearly associated infrarenal aortic stenosis with shortness of breath. A 77-year-old woman with hypertension and hyperlipidemia presented with exertional dyspnea. Despite extensive testing and observation, no apparent cause for this patient's dyspnea was found. Images revealed severe infrarenal aortic stenosis. After the patient underwent stenting of the aortic occlusion, she had immediate symptomatic improvement and complete resolution of her dyspnea within one month. Twelve months after vascular intervention, the patient remained asymptomatic. In view of the distinct and lasting elimination of dyspnea after angioplasty and stenting of a nearly occluded infrarenal aortic lesion, we hypothesize that infrarenal aortic stenosis might be a treatable cause of exertional dyspnea. Clinicians should consider infrarenal aortic stenosis as a possible cause of dyspnea. Treatment of the stenosis might relieve symptoms.

  5. Wall pressure exerted by hydrogenation of sodium aluminum hydride.

    SciTech Connect

    Perras, Yon E.; Dedrick, Daniel E.; Zimmerman, Mark D.

    2009-06-01

    Wall pressure exerted by the bulk expansion of a sodium aluminum hydride bed was measured as a function of hydrogen content. A custom apparatus was designed and loaded with sodium alanates at densities of 1.0, 1.1, and 1.16 g/cc. Four complete cycles were performed to identify variations in measured pressure. Results indicated poor correlation between exerted pressure and hydrogen capacity of the sodium alanate beds. Mechanical pressure due to the hydrogenation of sodium alanates does not influence full-scale system designs as it falls within common design factors of safety. Gas pressure gradients within the porous solid were identified and may limit reaction rates, especially for high aspect ratio beds.

  6. A Virtual Rat for Simulating Environmental and Exertional Heat Stress

    DTIC Science & Technology

    2014-10-02

    A virtual rat for simulating environmental and exertional heat stress Vineet Rakesh,1 X Jonathan D. Stallings,2 and Jaques Reifman1 1Department of...Health Research, Fort Detrick, Maryland Submitted 8 July 2014; accepted in final form 18 September 2014 Rakesh V, Stallings JD, Reifman J. A virtual rat ...different heat-stress conditions. To this end, we used our previously published virtual rat , which is capable of computing the spatiotemporal

  7. Failing phrenics: an obscure cause of exertional dyspnea

    PubMed Central

    Rafiq, Arsalan; Ijaz, Mohsin; Tariq, Hassan; Vakde, Trupti; Duncalf, Richard

    2016-01-01

    Abstract Introduction: Idiopathic phrenic nerve palsy is a rare cause of exertional dyspnea. We present a case of a patient presenting with worsening dyspnea of an unknown etiology found to be related to bilateral phrenic nerve palsy. Discussion: Forty-two-year-old man presented to our emergency department with exertional dyspnea, orthopnea, and a left lower lobe consolidation treated initially as bronchitis by his primary physician as an outpatient, then subsequently as pneumonia at another institution, with no improvement in symptomatology. After admission to our hospital, CT chest demonstrated only supradiaphragmatic atelectatic changes. Echocardiography was normal. Bronchoscopy was contemplated however the patient could not lie flat. A fluoroscopic sniff test demonstrated diaphragmatic dysfunction and pulmonary function tests revealed restrictive pulmonary disease with evidence of neuromuscular etiology. Nerve conduction studies confirmed bilateral phrenic neuropathy. He was referred to a specialized neuromuscular disease center where subsequent workup did not demonstrate any specific etiology. A sleep study confirmed sleep disordered breathing suggestive of diaphragmatic paralysis and he was discharged on bi-level positive pressure ventilation. Conclusion: This is a unique case of exertional dyspnea and orthopnea from diaphragmatic paresis caused by bilateral phrenic nerve palsy where the initial workup for pulmonary and cardiovascular etiologies was essentially unremarkable. Shortness of breath and orthopnea caused by phrenic neuropathy is a rare condition, yet has a variety of etiologies. Our case suggests a template to the diagnostic approach, management, and follow up of bilateral phrenic nerve palsy. PMID:27442657

  8. Exercise, physical activity, and exertion over the business cycle.

    PubMed

    Colman, Gregory; Dave, Dhaval

    2013-09-01

    Shifts in time and income constraints over economic expansions and contractions would be expected to affect individuals' behaviors. We explore the impact of the business cycle on individuals' exercise, time use, and total physical exertion, utilizing information on 112,000 individual records from the 2003-2010 American Time Use Surveys. In doing so, we test a key causal link that has been hypothesized in the relation between unemployment and health, but not heretofore assessed. Using more precise measures of exercise (and other activities) than previous studies, we find that as work-time decreases during a recession, recreational exercise, TV-watching, sleeping, childcare, and housework increase. This, however, does not compensate for the decrease in work-related exertion due to job-loss, and total physical exertion declines. These effects are strongest among low-educated men, which is validating given that employment in the Great Recession has declined most within manufacturing, mining, and construction. We also find evidence of intra-household spillover effects, wherein individuals respond to shifts in spousal employment conditional on their own labor supply. The decrease in total physical activity during recessions is especially problematic for vulnerable populations concentrated in boom-and-bust industries, and may have longer-term effects on obesity and related health outcomes.

  9. “Non-Toxic” Proteins of the Botulinum Toxin Complex Exert In-vivo Toxicity

    PubMed Central

    Miyashita, Shin-Ichiro; Sagane, Yoshimasa; Suzuki, Tomonori; Matsumoto, Takashi; Niwa, Koichi; Watanabe, Toshihiro

    2016-01-01

    The botulinum neurotoxin (BoNT) causes muscle paralysis and is the most potent toxin in nature. BoNT is associated with a complex of auxiliary “Non-Toxic” proteins, which constitute a large-sized toxin complex (L-TC). However, here we report that the “Non-Toxic” complex of serotype D botulinum L-TC, when administered to rats, exerts in-vivo toxicity on small-intestinal villi. Moreover, Serotype C and D of the “Non-Toxic” complex, but not BoNT, induced vacuole-formation in a rat intestinal epithelial cell line (IEC-6), resulting in cell death. Our results suggest that the vacuole was formed in a manner distinct from the mechanism by which Helicobacter pylori vacuolating toxin (VacA) and Vibrio cholerae haemolysin induce vacuolation. We therefore hypothesise that the serotype C and D botulinum toxin complex is a functional hybrid of the neurotoxin and vacuolating toxin (VT) which arose from horizontal gene transfer from an ancestral BoNT-producing bacterium to a hypothetical VT-producing bacterium. PMID:27507612

  10. The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action.

    PubMed

    Lee, Margaret S; Johansen, Lisa; Zhang, Yanzhen; Wilson, Amy; Keegan, Mitchell; Avery, William; Elliott, Peter; Borisy, Alexis A; Keith, Curtis T

    2007-12-01

    Combination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents.

  11. Plumbagin exerts an immunosuppressive effect on human T-cell acute lymphoblastic leukemia MOLT-4 cells.

    PubMed

    Bae, Kyoung Jun; Lee, Yura; Kim, Soon Ae; Kim, Jiyeon

    2016-04-22

    Of the hematological disorders typified by poor prognoses and survival rates, T-cell acute lymphoblastic leukemia (T-ALL) is one of the most commonly diagnosed. Despite the development of new therapeutic agents, the treatment options for this cancer remain limited. In this manuscript, we investigated the anti-proliferative effects of plumbagin, mediated by the activation of mitogen-activated protein kinase (MAPK) pathways, and inhibition of NF-κB signaling; the human T-ALL MOLT-4 cell line was used as our experimental system. Plumbagin is a natural, plant derived compound, which exerts an anti-proliferative activity against many types of human cancer. Our experiments confirm that plumbagin induces a caspase-dependent apoptosis of MOLT-4 cells, with no significant cytotoxicity seen for normal peripheral blood mononuclear cells (PBMCs). Plumbagin also inhibited LPS-induced phosphorylation of p65, and the transcription of NF-κB target genes. Our results now show that plumbagin is a potent inhibitor of the NF-κB signaling pathway, and suppressor of T-ALL cell proliferation.

  12. Conformation-dependent high-affinity potent ricin-neutralizing monoclonal antibodies.

    PubMed

    Hu, Wei-Gang; Yin, Junfei; Chau, Damon; Hu, Charles Chen; Lillico, Dustin; Yu, Justin; Negrych, Laurel M; Cherwonogrodzky, John W

    2013-01-01

    Ricin is a potential biothreat agent with no approved antidote available for ricin poisoning. The aim of this study was to develop potent antibody-based antiricin antidotes. Four strong ricin resistant hybridoma clones secreting antiricin monoclonal antibodies (mAbs) were developed. All four mAbs are bound to conformational epitopes of ricin toxin B (RTB) with high affinity (KD values from 2.55 to 36.27 nM). RTB not only triggers cellular uptake of ricin, but also facilitates transport of the ricin toxin A (RTA) from the endoplasmic reticulum to the cytosol, where RTA exerts its toxic activity. The four mAbs were found to have potent ricin-neutralizing capacities and synergistic effects among them as determined by an in vitro neutralization assay. In vivo protection assay demonstrated that all four mAbs had strong efficacy against ricin challenges. D9 was found to be exceptionally effective. Intraperitoneal (i.p.) administration of D9, at a dose of 5 μ g, 6 weeks before or 6 hours after an i.p. challenge with 5 × LD50 of ricin was able to protect or rescue 100% of the mice, indicating that mAb D9 is an excellent candidate to be developed as a potent antidote against ricin poisoning for both prophylactic and therapeutic purposes.

  13. Conformation-Dependent High-Affinity Potent Ricin-Neutralizing Monoclonal Antibodies

    PubMed Central

    Hu, Wei-Gang; Yin, Junfei; Chau, Damon; Hu, Charles Chen; Lillico, Dustin; Yu, Justin; Negrych, Laurel M.; Cherwonogrodzky, John W.

    2013-01-01

    Ricin is a potential biothreat agent with no approved antidote available for ricin poisoning. The aim of this study was to develop potent antibody-based antiricin antidotes. Four strong ricin resistant hybridoma clones secreting antiricin monoclonal antibodies (mAbs) were developed. All four mAbs are bound to conformational epitopes of ricin toxin B (RTB) with high affinity (KD values from 2.55 to 36.27 nM). RTB not only triggers cellular uptake of ricin, but also facilitates transport of the ricin toxin A (RTA) from the endoplasmic reticulum to the cytosol, where RTA exerts its toxic activity. The four mAbs were found to have potent ricin-neutralizing capacities and synergistic effects among them as determined by an in vitro neutralization assay. In vivo protection assay demonstrated that all four mAbs had strong efficacy against ricin challenges. D9 was found to be exceptionally effective. Intraperitoneal (i.p.) administration of D9, at a dose of 5 μg, 6 weeks before or 6 hours after an i.p. challenge with 5 × LD50 of ricin was able to protect or rescue 100% of the mice, indicating that mAb D9 is an excellent candidate to be developed as a potent antidote against ricin poisoning for both prophylactic and therapeutic purposes. PMID:23484120

  14. A virtual rat for simulating environmental and exertional heat stress.

    PubMed

    Rakesh, Vineet; Stallings, Jonathan D; Reifman, Jaques

    2014-12-01

    Severe cases of environmental or exertional heat stress can lead to varying degrees of organ dysfunction. To understand heat-injury progression and develop efficient management and mitigation strategies, it is critical to determine the thermal response in susceptible organs under different heat-stress conditions. To this end, we used our previously published virtual rat, which is capable of computing the spatiotemporal temperature distribution in the animal, and extended it to simulate various heat-stress scenarios, including 1) different environmental conditions, 2) exertional heat stress, 3) circadian rhythm effect on the thermal response, and 4) whole body cooling. Our predictions were consistent with published in vivo temperature measurements for all cases, validating our simulations. We observed a differential thermal response in the organs, with the liver experiencing the highest temperatures for all environmental and exertional heat-stress cases. For every 3°C rise in the external temperature from 40 to 46°C, core and organ temperatures increased by ∼0.8°C. Core temperatures increased by 2.6 and 4.1°C for increases in exercise intensity from rest to 75 and 100% of maximal O2 consumption, respectively. We also found differences as large as 0.8°C in organ temperatures for the same heat stress induced at different times during the day. Even after whole body cooling at a relatively low external temperature (1°C for 20 min), average organ temperatures were still elevated by 2.3 to 2.5°C compared with normothermia. These results can be used to optimize experimental protocol designs, reduce the amount of animal experimentation, and design and test improved heat-stress prevention and management strategies.

  15. Pressure garment design tool to monitor exerted pressures.

    PubMed

    Macintyre, Lisa; Ferguson, Rhona

    2013-09-01

    Pressure garments are used in the treatment of hypertrophic scarring following serious burns. The use of pressure garments is believed to hasten the maturation process, reduce pruritus associated with immature hypertrophic scars and prevent the formation of contractures over flexor joints. Pressure garments are normally made to measure for individual patients from elastic fabrics and are worn continuously for up to 2 years or until scar maturation. There are 2 methods of constructing pressure garments. The most common method, called the Reduction Factor method, involves reducing the patient's circumferential measurements by a certain percentage. The second method uses the Laplace Law to calculate the dimensions of pressure garments based on the circumferential measurements of the patient and the tension profile of the fabric. The Laplace Law method is complicated to utilise manually and no design tool is currently available to aid this process. This paper presents the development and suggested use of 2 new pressure garment design tools that will aid pressure garment design using the Reduction Factor and Laplace Law methods. Both tools calculate the pressure garment dimensions and the mean pressure that will be exerted around the body at each measurement point. Monitoring the pressures exerted by pressure garments and noting the clinical outcome would enable clinicians to build an understanding of the implications of particular pressures on scar outcome, maturation times and patient compliance rates. Once the optimum pressure for particular treatments is known, the Laplace Law method described in this paper can be used to deliver those average pressures to all patients. This paper also presents the results of a small scale audit of measurements taken for the fabrication of pressure garments in two UK hospitals. This audit highlights the wide range of pressures that are exerted using the Reduction Factor method and that manual pattern 'smoothing' can dramatically

  16. [Exertion syncope disclosing supravalvular mitral stenosis in an infant].

    PubMed

    Buyse, G; Kuchler, H; Crittin, J; Sekarski, N; Hurni, M; Cotting, J; Payot, M

    1993-05-01

    An infant with frequent upper airways infections presented syncopes during meals and weeping since the age of eleven months. Cardiac examination was always normal. At 14 months of age, an echocardiogram with colour Doppler demonstrated a severely stenotic isolated supramitral membrane with severe pulmonary hypertension. The membrane was immediately excised curing the malformation and suppressing definitively the syncopes, probably due to decreased cerebral blood flow during exertion. An echocardiogram should always be performed when syncopes remain unexplained in small children. It allows early diagnosis and treatment of congenital heart defects which do not have auscultatory findings especially those resulting in severe pulmonary venous obstruction.

  17. Vaccine strategies against Babesia bovis based on prime-boost immunizations in mice with modified vaccinia Ankara vector and recombinant proteins.

    PubMed

    Jaramillo Ortiz, José Manuel; Del Médico Zajac, María Paula; Zanetti, Flavia Adriana; Molinari, María Paula; Gravisaco, María José; Calamante, Gabriela; Wilkowsky, Silvina Elizabeth

    2014-08-06

    In this study, a recombinant modified vaccinia virus Ankara vector expressing a chimeric multi-antigen was obtained and evaluated as a candidate vaccine in homologous and heterologous prime-boost immunizations with a recombinant protein cocktail. The chimeric multi-antigen comprises immunodominant B and T cell regions of three Babesia bovis proteins. Humoral and cellular immune responses were evaluated in mice to compare the immunogenicity induced by different immunization schemes. The best vaccination scheme was achieved with a prime of protein cocktail and a boost with the recombinant virus. This scheme induced high level of specific IgG antibodies and secreted IFN and a high degree of activation of IFNγ(+) CD4(+) and CD8(+) specific T cells. This is the first report in which a novel vaccine candidate was constructed based on a rationally designed multi-antigen and evaluated in a prime-boost regime, optimizing the immune response necessary for protection against bovine babesiosis.

  18. Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses.

    PubMed

    Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W; Hewson, Roger

    2016-01-01

    Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge.

  19. Improvement of BCG protective efficacy with a novel chimpanzee adenovirus and a modified vaccinia Ankara virus both expressing Ag85A.

    PubMed

    Stylianou, E; Griffiths, K L; Poyntz, H C; Harrington-Kandt, R; Dicks, M D; Stockdale, L; Betts, G; McShane, H

    2015-11-27

    A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also expressing Ag85A (MVA85A), for its immunogenicity and protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge in mice. Naïve and BCG-primed mice were vaccinated or boosted with ChAdOx1.85A and MVA85A in different combinations. Although intranasally administered ChAdOx1.85A induced strong immune responses in the lungs, it failed to consistently protect against aerosol M.tb challenge. In contrast, ChAdOx1.85A followed by MVA85A administered either mucosally or systemically, induced strong immune responses and was able to improve the protective efficacy of BCG. This vaccination regime has consistently shown superior protection over BCG alone and should be evaluated further.

  20. Safety, Immunogenicity and Efficacy of Modified Vaccinia Ankara (MVA) Against Dryvax® Challenge in Vaccinia-Naïve and Vaccinia-Immune Individuals

    PubMed Central

    Parrino, Janie; McCurdy, Lewis H.; Larkin, Brenda D.; Gordon, Ingelise J.; Rucker, Steven E.; Enama, Mary E.; Koup, Richard A.; Roederer, Mario; Bailer, Robert T.; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S.

    2007-01-01

    Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax® in vaccinia-naïve and immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax® challenge at 3 months. Two or more doses of MVA prior to Dryvax® reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax® vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax® vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. PMID:17126963

  1. Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses

    PubMed Central

    Dowall, Stuart D.; Graham, Victoria A.; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W.; Hewson, Roger

    2016-01-01

    Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge. PMID:27272940

  2. Caffeine ingestion, affect and perceived exertion during prolonged cycling.

    PubMed

    Backhouse, Susan H; Biddle, Stuart J H; Bishop, Nicolette C; Williams, Clyde

    2011-08-01

    Caffeine's metabolic and performance effects have been widely reported. However, caffeine's effects on affective states during prolonged exercise are unknown. Therefore, this was examined in the present study. Following an overnight fast and in a randomised, double-blind, counterbalanced design, twelve endurance trained male cyclists performed 90 min of exercise at 70% VO(₂ max) 1h after ingesting 6 mg kg⁻¹ BM of caffeine (CAF) or placebo (PLA). Dimensions of affect and perceived exertion were assessed at regular intervals. During exercise, pleasure ratings were better maintained (F(₃,₃₈)=4.99, P < 0.05) in the CAF trial compared to the PLA trial with significantly higher ratings at 15, 30 and 75 min (all P < 0.05). Perceived exertion increased (F(₃,₃₈) = 19.86, P < 0.01) throughout exercise and values, overall, were significantly lower (F(₁,₁₁) = 9.26, P < 0.05) in the CAF trial compared to the PLA trial. Perceived arousal was elevated during exercise but did not differ between trials. Overall, the results suggest that a moderate dose of CAF ingested 1h prior to exercise maintains a more positive subjective experience during prolonged cycling. This observation may partially explain caffeine's ergogenic effects.

  3. National Athletic Trainers' Association Position Statement: Exertional Heat Illnesses

    PubMed Central

    Casa, Douglas J.; DeMartini, Julie K.; Bergeron, Michael F.; Csillan, Dave; Eichner, E. Randy; Lopez, Rebecca M.; Ferrara, Michael S.; Miller, Kevin C.; O'Connor, Francis; Sawka, Michael N.; Yeargin, Susan W.

    2015-01-01

    Objective  To present best-practice recommendations for the prevention, recognition, and treatment of exertional heat illnesses (EHIs) and to describe the relevant physiology of thermoregulation. Background  Certified athletic trainers recognize and treat athletes with EHIs, often in high-risk environments. Although the proper recognition and successful treatment strategies are well documented, EHIs continue to plague athletes, and exertional heat stroke remains one of the leading causes of sudden death during sport. The recommendations presented in this document provide athletic trainers and allied health providers with an integrated scientific and clinically applicable approach to the prevention, recognition, treatment of, and return-to-activity guidelines for EHIs. These recommendations are given so that proper recognition and treatment can be accomplished in order to maximize the safety and performance of athletes. Recommendations  Athletic trainers and other allied health care professionals should use these recommendations to establish onsite emergency action plans for their venues and athletes. The primary goal of athlete safety is addressed through the appropriate prevention strategies, proper recognition tactics, and effective treatment plans for EHIs. Athletic trainers and other allied health care professionals must be properly educated and prepared to respond in an expedient manner to alleviate symptoms and minimize the morbidity and mortality associated with these illnesses. PMID:26381473

  4. Designing pressure garments capable of exerting specific pressures on limbs.

    PubMed

    Macintyre, Lisa

    2007-08-01

    Pressure garments have been used prophylactically and to treat hypertrophic scars, resulting from serious burns, since the early 1970s. They are custom-made from elastic fabrics by commercial producers and hospital staff. However, no clear scientifically established method has ever been published for their design and manufacture. Previous work [2] identified the most commonly used fabrics and construction methods for the production of pressure garments by hospital staff in UK burn units. These methods were evaluated by measuring pressures delivered to both cylinder models and to human limbs using I-scan pressure sensors. A new calibration method was developed for the I-scan system to enable measurement of low interface pressures to an accuracy of +/-2.5 mmHg. The effects of cylinder/limb circumference and pressure garment design on the pressures exerted were established. These measurements confirm the limitations of current pressure garment construction methods used in UK hospitals. A new method for designing pressure garments that will exert specific known pressures is proposed and evaluated for human thighs. Evaluation of the proposed design method is ongoing for other body parts.

  5. Development of the color scale of perceived exertion: preliminary validation.

    PubMed

    Serafim, Thais H S; Tognato, Andrea C; Nakamura, Priscila M; Queiroga, Marcos R; Nakamura, Fábio Y; Pereira, Gleber; Kokubun, Eduardo

    2014-12-01

    This study developed a Color Scale of Perceived Exertion (RPE-color scale) and assessed its concurrent and construct validity in adult women. One hundred participants (18-77 years), who were habitual exercisers, associated colors with verbal anchors of the Borg RPE scale (RPE-Borg scale) for RPE-color scale development. For RPE-color scale validation, 12 Young (M = 21.7 yr., SD = 1.5) and 10 Older (M = 60.3 yr., SD = 3.5) adult women performed a maximal graded exercise test on a treadmill and reported perceived exertion in both RPE-color and RPE-Borg scales. In the Young group, the RPE-color scale was significantly associated with heart rate and oxygen consumption, having strong correlations with the RPE-Borg scale. In the Older group, the RPE-color scale was significantly associated with heart rate, having moderate to high correlations with the RPE-Borg scale. The RPE-color scale demonstrated concurrent and construct validity in the Young women, as well as construct validity in Older adults.

  6. Short communication: investigation of aflatoxin M1 levels in infant follow-on milks and infant formulas sold in the markets of Ankara, Turkey.

    PubMed

    Er, B; Demirhan, B; Yentür, G

    2014-01-01

    Aflatoxins are fungal toxins known to be carcinogenic and are classified as food contaminants. This study was performed to investigate aflatoxin (AF) M1 levels in baby foods sold in Ankara (Turkey) and to evaluate the obtained results according to the Turkish Food Codex (TFC). For this purpose, a total of 84 baby food samples (50 follow-on milks and 34 infant formulas) were obtained from different markets in Ankara and the presence of AFM1 in the samples was analyzed by ELISA. In 32 (38.1%) of 84 infant food samples, the presence of AFM1 was detected in concentrations ranging between 0.0055 and 0.0201 µg/kg. The mean level (± standard error) of AFM1 was found to be 0.0089 ± 0.0006 µg/kg in positive infant follow-on milks. Aflatoxin M1 was detected in only 1 infant formula sample (2.94%) at a concentration of 0.0061 µg/kg. The extrapolated levels of AFB1 contamination in feedstuffs were calculated based on levels of AFM1 in baby food samples. The data estimating AFB1 contamination in dairy cattle feedstuff indicate that contamination may range from 0.3410 to 1.2580 µg/kg, with the mean level (± standard error) being 0.5499 ± 0.0385 µg/kg, which is lower than the level set by the TFC and European Union regulations (5 µg/kg). According to the obtained results, the levels of AFM1 in analyzed samples were within the allowed limit (0.025 µg/kg) set in the TFC. Low levels of AFM1 in infant follow-on milks and infant formula samples obtained during the study do not pose a health risk to infants.

  7. Fatal ethyl and methyl alcohol-related poisoning in Ankara: A retrospective analysis of 10,720 cases between 2001 and 2011.

    PubMed

    Celik, Safa; Karapirli, Mustafa; Kandemir, Eyup; Ucar, Fatma; Kantarcı, Muhammed Nabi; Gurler, Mukaddes; Akyol, Omer

    2013-04-01

    Methyl and ethyl alcohol poisoning are still responsible for high morbidity and mortality rates. The purpose of this retrospective study was to examine ethyl and methyl alcohol poisoning related deaths in Ankara and surrounding cities between 2001 and 2011 and compare them with previous studied conducted in Turkey and other countries. For this purpose, 10,720 medico-legal autopsy cases performed in Ankara Branch of the Council of Forensic Medicine were reviewed in terms of alcohol poisonings. The deaths due to methanol and ethanol poisoning were 74 (0.69% of all medico-legal autopsies performed) and the distribution among them was 35 (47.3%) for methanol poisoning and 39 (52.7%) for ethanol poisoning. Overwhelming majority of the cases were male (n = 67, 90.5%). The mean age of the victims was 44.9 ± 10.9 years and ranging from 21 to 92 years. The age group of 35-49 years was the mostly affected. Most of the cases were seen in 2004 (n = 12, 16.2%). The levels of postmortem blood alcohol levels were available for all cases and the mean alcohol levels were 322.8 ± 155.5 mg/dL ranging from 74 to 602 mg/dL for methanol and 396.8 ± 87.1 mg/dL and ranging from 136 to 608 mg/dL for ethanol. Early diagnosis is essential for successful treatment in methanol and ethanol poisoning. Besides increased awareness, more sensitive/specific diagnostic tools, and the prompt approach to the poisoned individual should be implemented in the hospitals.

  8. Further characterization of a new recombinant group of Plum pox virus isolates, PPV-T, found in orchards in the Ankara province of Turkey.

    PubMed

    Serçe, Ciğdem Ulubaş; Candresse, Thierry; Svanella-Dumas, Laurence; Krizbai, Laszlo; Gazel, Mona; Cağlayan, Kadriye

    2009-06-01

    Sixteen Plum pox virus (PPV) isolates collected in the Ankara region of Turkey were analyzed using available serological and molecular typing assays. Surprisingly, despite the fact that all isolates except one, which was a mix infection, were typed as belonging to the PPV-M strain in four independent molecular assays, nine of them (60%) reacted with both PPV-M specific and PPV-D specific monoclonal antibodies. Partial 5' and 3' genomic sequence analysis on four isolates demonstrated that irrespective of their reactivity towards the PPV-D specific monoclonal antibody, they were all closely related to a recombinant PPV isolate from Turkey, Ab-Tk. All three isolates for which the relevant genomic sequence was obtained showed the same recombination event as Ab-Tk in the HC-Pro gene, around position 1566 of the genome. Complete genomic sequencing of Ab-Tk did not provide evidence for additional recombination events in its evolutionary history. Taken together, these results indicate that a group of closely related PPV isolates characterized by a unique recombination in the HC-Pro gene is prevalent under field conditions in the Ankara region of Turkey. Similar to the situation with the PPV-Rec strain, we propose that these isolates represent a novel strain of PPV, for which the name PPV-T (Turkey) is proposed. Given that PPV-T isolates cannot be identified by currently available typing techniques, it is possible that their presence has been overlooked in other situations. Further efforts should allow a precise description of their prevalence and of their geographical distribution in Turkey and, possibly, in other countries.

  9. Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer's Disease.

    PubMed

    Liu, Kai; Chojnacki, Jeremy E; Wade, Emily E; Saathoff, John M; Lesnefsky, Edward J; Chen, Qun; Zhang, Shijun

    2015-01-01

    Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.

  10. Optimum polygenic profile to resist exertional rhabdomyolysis during a marathon

    PubMed Central

    Valero, Marjorie; Salinero, Juan José; Lara, Beatriz; Gallo-Salazar, César; Areces, Francisco

    2017-01-01

    Purpose Exertional rhabdomyolysis can occur in individuals performing various types of exercise but it is unclear why some individuals develop this condition while others do not. Previous investigations have determined the role of several single nucleotide polymorphisms (SNPs) to explain inter-individual variability of serum creatine kinase (CK) concentrations after exertional muscle damage. However, there has been no research about the interrelationship among these SNPs. The purpose of this investigation was to analyze seven SNPs that are candidates for explaining individual variations of CK response after a marathon competition (ACE = 287bp Ins/Del, ACTN3 = p.R577X, CKMM = NcoI, IGF2 = C13790G, IL6 = 174G>C, MLCK = C37885A, TNFα = 308G>A). Methods Using Williams and Folland’s model, we determined the total genotype score from the accumulated combination of these seven SNPs for marathoners with a low CK response (n = 36; serum CK <400 U·L-1) vs. marathoners with a high CK response (n = 31; serum CK ≥400 U·L-1). Results At the end of the race, low CK responders had lower serum CK (290±65 vs. 733±405 U·L-1; P<0.01) and myoglobin concentrations (443±328 vs. 1009±971 ng·mL-1, P<0.01) than high CK responders. Although the groups were similar in age, anthropometric characteristics, running experience and training habits, total genotype score was higher in low CK responders than in high CK responders (5.2±1.4 vs. 4.4±1.7 point, P = 0.02). Conclusion Marathoners with a lower CK response after the race had a more favorable polygenic profile than runners with high serum CK concentrations. This might suggest a significant role of genetic polymorphisms in the levels of exertional muscle damage and rhabdomyolysis. Yet other SNPs, in addition to exercise training, might also play a role in the values of CK after damaging exercise. PMID:28257486

  11. Highly potent fibrinolytic serine protease from Streptomyces.

    PubMed

    Uesugi, Yoshiko; Usuki, Hirokazu; Iwabuchi, Masaki; Hatanaka, Tadashi

    2011-01-05

    We introduce a highly potent fibrinolytic serine protease from Streptomyces omiyaensis (SOT), which belongs to the trypsin family. The fibrinolytic activity of SOT was examined using in vitro assays and was compared with those of known fibrinolytic enzymes such as plasmin, tissue-type plasminogen activator (t-PA), urokinase, and nattokinase. Compared to other enzymes, SOT showed remarkably higher hydrolytic activity toward mimic peptides of fibrin and plasminogen. The fibrinolytic activity of SOT is about 18-fold higher than that of plasmin, and is comparable to that of t-PA by fibrin plate assays. Furthermore, SOT had some plasminogen activator-like activity. Results show that SOT and nattokinase have very different fibrinolytic and fibrinogenolytic modes, engendering significant synergetic effects of SOT and nattokinase on fibrinolysis. These results suggest that SOT presents important possibilities for application in the therapy of thrombosis.

  12. Potent antitrypanosomal triterpenoid saponins from Mussaenda luteola

    PubMed Central

    Mohamed, Shaymaa M.; Bachkeet, Enaam Y.; Bayoumi, Soad A.; Jain, Surendra; Cutler, Stephen J.; Tekwani, Babu L.; Ross, Samir A.

    2016-01-01

    Five new triterpenoid saponins, heinsiagenin A 3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)]-β-d-glucopyranoside (1), heinsiagenin A 3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→4)]-β-d-glucopyranoside (2), 2α-hydroxyheinsiagenin A 3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)]-β-d-glucopyranoside (3), 2α-hydroxyheinsiagenin A 3-O-[β-d-glucopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→4)]-β-d-glucopyranoside (4) and N-(2S, 3R, 4R-3-methyl-4-pentanolid-2-yl)-18-hydroxylanosta-8 (9), 22E, 24E-trien-27-amide-3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)]-[β-d-glucopyranosyl-(1→4)]-β-d-glucopyranoside (5) were isolated from the aerial parts of Mussaenda luteola Delile (Rubiaceae). Structural elucidation was based on the analysis of spectroscopic data (1D and 2D NMR) and HR-ESI-MS. Compound 1 showed potent antitrypanosomal activity with an IC50 value of 8.80 μM. Compounds 2–4 showed highly potent antitrypanosomal activity with IC50 values ranging between (2.57–2.84 μM) and IC90 values ranging between (3.36–4.35 μM), which are 5 fold greater than the positive control DFMO (IC50 and IC90 values of 13.06 and 28.99 μM, respectively). Compounds 1 and 2 showed moderate affinity to μ-opioid receptors with Ki values of 9.936 μM and 0.872 μM, respectively compared to a Ki value of 1.958 nM for the positive control, naloxone HCl. PMID:26524249

  13. Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor.

    PubMed

    Xie, Weijia; Tanabe, Genzoh; Matsuoka, Kanjyun; Amer, Mumen F A; Minematsu, Toshie; Wu, Xiaoming; Yoshikawa, Masayuki; Muraoka, Osamu

    2011-04-01

    Synthesis and evaluation of four diastereomers (9a, 9b, 9c and 9d) of kotalanol, a potent α-glucosidase inhibitor isolated from an Ayurvedic medicinal plant Salacia species, are described. Stereo-inversion at C-3' and C-4' of kotalanol (2) caused significant decrease of the inhibitory activities against maltase and sucrase, whereas inhibitory activity against isomaltase sustained, thus resulted in exerting selectivity against isomaltase.

  14. Exertional rhabdomyolysis and heat stroke: Beware of volatile anesthetic sedation

    PubMed Central

    Heytens, Karel; De Bleecker, Jan; Verbrugghe, Walter; Baets, Jonathan; Heytens, Luc

    2017-01-01

    In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units (ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension. PMID:28224104

  15. Reflections on the Institute of Medicine's systemic exertion intolerance disease.

    PubMed

    Jason, Leonard A; Sunnquist, Madison; Brown, Abigail; McManimen, Stephanie; Furst, Jacob

    2015-01-01

    The Institute of Medicine (IOM) in the United States has recently proposed that the term systemic exertion intolerance disease (SEID) replace chronic fatigue syndrome. In addition, the IOM proposed a new case definition for SEID, which includes substantial reductions or impairments in the ability to engage in pre‑illness activities, unrefreshing sleep, postexertional malaise, and either cognitive impairment or orthostatic intolerance. Unfortunately, these recommendations for a name change were not vetted with patient and professional audiences, and the new criteria were not evaluated with data sets of patients and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies have found that prevalence rates will dramatically increase with the new criteria, particularly due to the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria. The implications of these findings are discussed in the current review.

  16. Physiological responses and perceived exertion during cycling with superimposed electromyostimulation.

    PubMed

    Wahl, Patrick; Schaerk, Jonas; Achtzehn, Silvia; Kleinöder, Heinz; Bloch, Wilhelm; Mester, Joachim

    2012-09-01

    The goal of the study was to evaluate and to quantify the effects of local electromyostimulation (EMS) during cycling on the cardiorespiratory system, muscle metabolism, and perceived exertion compared with cycling with no EMS. Ten healthy men (age: 24.6 ± 3.2 years, V[Combining Dot Above]O2max: 54.1 ± 6.0 ml·min·kg) performed 3 incremental cycle ergometer step tests, 1 without and 2 with EMS (30 and 85 Hz) until volitional exhaustion. Lactate values and respiratory exchange ratio were significantly higher at intensities ≥75% peak power output (PPO) when EMS was applied. Bicarbonate concentration, base excess (BE), and Pco2 were significantly lower when EMS was applied compared with the control at intensities ≥75% PPO. Saliva cortisol levels increased because of the exercise but were unaffected by EMS. Furthermore, EMS showed greater effects on CK levels 24 hours postexercise than normal cycling did. Rating of perceived exertion was significantly higher at 100% PPO with EMS. No statistical differences were found for heart rate, pH, and Po2 between the tested cycling modes. The main findings of this study are greater metabolic changes (lactate, respiratory exchange ratio, BE, (Equation is included in full-text article.), Pco2) during cycling with EMS compared with normal cycling independent of frequency, mainly visible at higher work rates. Because metabolic alterations are important for the induction of cellular signaling cascades and adaptations, these results lead to the hypothesis that applied EMS stimulations during cycling exercise might be an enhancing stimulus for skeletal muscle metabolism and related adaptations. Thus, superimposed EMS application during cycling could be beneficial to aerobic performance enhancements in athletes and in patients who cannot perform high workloads. However, the higher demand on skeletal muscles involved must be considered.

  17. The use of subjective rating of exertion in Ergonomics.

    PubMed

    Capodaglio, P

    2002-01-01

    In Ergonomics, the use of psychophysical methods for subjectively evaluating work tasks and determining acceptable loads has become more common. Daily activities at the work site are studied not only with physiological methods but also with perceptual estimation and production methods. The psychophysical methods are of special interest in field studies of short-term work tasks for which valid physiological measurements are difficult to obtain. The perceived exertion, difficulty and fatigue that a person experiences in a certain work situation is an important sign of a real or objective load. Measurement of the physical load with physiological parameters is not sufficient since it does not take into consideration the particular difficulty of the performance or the capacity of the individual. It is often difficult from technical and biomechanical analyses to understand the seriousness of a difficulty that a person experiences. Physiological determinations give important information, but they may be insufficient due to the technical problems in obtaining relevant but simple measurements for short-term activities or activities involving special movement patterns. Perceptual estimations using Borg's scales give important information because the severity of a task's difficulty depends on the individual doing the work. Observation is the most simple and used means to assess job demands. Other evaluations integrating observation are the followings: indirect estimation of energy expenditure based on prediction equations or direct measurement of oxygen consumption; measurements of forces, angles and biomechanical parameters; measurements of physiological and neurophysiological parameters during tasks. It is recommended that determinations of performances of occupational activities assess rating of perceived exertion and integrate these measurements of intensity levels with those of activity's type, duration and frequency. A better estimate of the degree of physical activity

  18. Core-Scaffold-Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis.

    PubMed

    Leng, Hai-Jun; Peng, Fu; Zingales, Sarah; Huang, Wei; Wang, Biao; Zhao, Qian; Zhou, Rui; He, Gu; Peng, Cheng; Han, Bo

    2015-12-07

    The highly enantioselective preparation of pharmacologically interesting hexahydropyridazine derivatives based on a multicomponent cascade reaction is described. This one-pot approach utilizes an organocatalytic Michael reaction followed by intermolecular α-amination and intramolecular hemiaminalization to yield a chiral pyridazine backbone with contiguous stereogenic centers and multiple functional groups in good yield and with high stereoselectivity. Compounds synthesized by this method potently inhibited proliferation of MCF-7 breast cancer cells. Mechanistic studies suggest that compound 5 c exerts these anticancer effects by inducing apoptosis through extracellular signal related kinase (ERK)- and poly(adenosine diphosphate ribose) polymerase (PARP)-regulated pathways, as well as mitochondrial pathways.

  19. Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid.

    PubMed

    Punganuru, Surendra R; Mostofa, A G M; Madala, Hanumantha Rao; Basak, Debasish; Srivenugopal, Kalkunte S

    2016-06-15

    Ethacrynic acid (EA), a known inhibitor of the neoplastic marker glutathione S-transferase P1 and other GSTs, exerts a weak antiproliferative activity against human cancer cells. The clinical use of EA (Edecrin) as an anticancer drug is limited by its potent loop diuretic activity. In this study, we developed a non-diuretic 2-amino-2-deoxy-d-glucose conjugated EA (EAG) to target tumors cells via the highly expressed glucose transporter 1 (GLUT1). Cell survival assays revealed that EAG had little effect on normal cells, but was cytotoxic 3 to 4.5-fold greater than EA. Mechanistically, the EAG induced selective cell death in cancer cells by inhibiting GSTP1 and generating abundant reactive oxygen species. Furthermore, EAG induced p21(cip1) expression and a G2/M cell cycle block irrespective of the p53 gene status in tumor cells. These data encourage the development of new EA analogs.

  20. Simultaneous Multiple Control Force Exertion Capabilities of Males and Females versus Helicopter Control Force Design Limits,

    DTIC Science & Technology

    1987-09-01

    percent) than for collective inputs ( typically 20-35 percent). Substantial proportions of the subjects (approximately 50 percent of the males and more ...nearly 86 percent of the females performed one or more exertions below the design limit. The exertions of 28.6 percent of the females were below the pedal...design limit for more than one-half of the 16 exertions they performed; 75 percent of the exertions by 6 of the 63 females were below design-limit

  1. Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells

    PubMed Central

    Folgiero, V; Di Carlo, S E; Bon, G; Spugnini, E P; Di Benedetto, A; Germoni, S; Pia Gentileschi, M; Accardo, A; Milella, M; Morelli, G; Bossi, G; Mottolese, M; Falcioni, R

    2012-01-01

    The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity. PMID:23222510

  2. Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma.

    PubMed

    Perumal, Deepak; Kuo, Pei-Yu; Leshchenko, Violetta V; Jiang, Zewei; Divakar, Sai Krishna Athaluri; Cho, Hearn Jay; Chari, Ajai; Brody, Joshua; Reddy, M V Ramana; Zhang, Weijia; Reddy, E Premkumar; Jagannath, Sundar; Parekh, Samir

    2016-03-01

    Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma.

  3. Compounds isolated from the aerial part of Crataegus azarolus inhibit growth of B16F10 melanoma cells and exert a potent inhibition of the melanin synthesis.

    PubMed

    Mustapha, Nadia; Bzéouich, Imèn Mokdad; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

    2015-02-01

    Poor therapeutic results have been reported for treatment of malignant melanoma; therefore in this study, we have investigated inhibitory capacity of vitexin-2''-O-rhamnoside as well as the extract from which it was isolated, i.e. the ethyl acetate extract obtained from the leaves of Crataegus azarolus, on mouse melanoma (B16F10) proliferation. Cell viability was determined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, amounts of melanin and tyrosinase were measured spectrophotometrically at 475nm. Ethyl acetate extract and vitexin-2''-O-rhamnoside exhibited significant anti-proliferative activity against B16F10 melanoma cells after incubation for 48hours with IC50s of 50μg/mL and 20μM, respectively. Furthermore, these two compounds have the ability to reduce the melanin content by inhibiting the tyrosinase activity of B16F10 cells. Thus, further investigations are merited to ascertain their potential application in treating hyperpigmentation disorders.

  4. miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221.

    PubMed

    Kotani, Ai; Ha, Daon; Hsieh, James; Rao, Prakash K; Schotte, Diana; den Boer, Monique L; Armstrong, Scott A; Lodish, Harvey F

    2009-11-05

    MLL-AF4 acute lymphocytic leukemia (ALL) has a poor prognosis. MicroRNAs (miRNA) are small noncoding RNAs that posttranscriptionally regulate expression of target mRNAs. Our analysis of previously published data showed that expression of miR-128b and miR-221 is down-regulated in MLL-rearranged ALL relative to other types of ALL. Reexpression of these miRNAs cooperatively sensitizes 2 cultured lines of MLL-AF4 ALL cells to glucocorticoids. Target genes down-regulated by miR-128b include MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes; miR-221 down-regulates CDKN1B. These results demonstrate that down-regulation of miR-128b and miR-221 is implicated in glucocorticoid resistance and that restoration of their levels is a potentially promising therapeutic in MLL-AF4 ALL.

  5. Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.

    PubMed

    Muñoz-Castañeda, Juan R; Túnez, Isaac; Herencia, Carmen; Ranchal, Isidora; González, Raúl; Ramírez, Luz M; Arjona, Alvaro; Barcos, Montserrat; Espejo, Isabel; Cruz, Adolfo; Montilla, Pedro; Padillo, Francisco J; Muntané, Jordi

    2008-07-30

    Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.

  6. A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation.

    PubMed

    Nishiya, Y; Kosaka, N; Uchii, M; Sugimoto, S

    2002-01-01

    During their differentiation, osteoblasts sequentially express type I collagen, alkaline phosphatase (ALP), and osteocalcin, and then undergo mineral deposition. Among dihydropyridine-type calcium channel blockers, only benidipine stimulated ALP activity of osteoblastic cells derived from neonatal mouse calvaria. To identify the molecular target of benidipine and elucidate the mechanism of action of the drug in osteoblasts, the mouse osteoblastic cell line MC3T3-E1 was used. Benidipine prompted ALP activity and ALP transcription induced by ascorbic acid, and mineral deposition by ascorbic acid and b-glycerophosphate. Benidipine, however, did not change collagen accumulation. MC3T3-E1 cells expressed the L-type Ca channel a1C subunit throughout the differentiation process, and Ca influx by potassium ions and Bay K 8644, an agonist, was strongly attenuated by benidipine. Each one of three structurally different classes of Ca channel blockers, nifedipine, verapamil, and diltiazem stimulated ALP activity, although at much higher concentrations of ca. 100 nM than benidipine, 1 pM. These results suggest that benidipine directly exerts its effect on osteoblasts and promotes osteoblast differentiation after the step of collagen accumulation by blocking the L-type Ca channel. Since benidipine blocked Ca influx more potently than the three other Ca channel blockers, the unique and potent osteoblast differentiating ability of benidipine may be due to its high affinity for Ca channel together with its high membrane retaining ability, as has been previously reported.

  7. Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies.

    PubMed

    Migliore, Marco; Habrant, Damien; Sasso, Oscar; Albani, Clara; Bertozzi, Sine Mandrup; Armirotti, Andrea; Piomelli, Daniele; Scarpelli, Rita

    2016-02-15

    Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.

  8. [Investigation of norovirus infection incidence among 0-5 years old children with acute gastroenteritis admitted to two different hospitals in ankara, Turkey].

    PubMed

    Altay, Aylin; Bozdayı, Gülendam; Meral, Melda; Dallar Bilge, Yıldız; Dalgıç, Buket; Ozkan, Seçil; Ahmed, Kamruddin

    2013-01-01

    Norovirus causes severe gastroenteritis requiring hospitalization especially in children less than five years of age both in developed and developing countries. Therefore, we aimed to investigate the incidence of norovirus (NoV) in 0-5 years old children with acute gastroenteritis in two large hospitals in Ankara, Turkey. Stool samples were obtained from 1000 (413 female, 587 male) children between 0-5 years old with acute gastroenteritis who attended to the Department of Paediatrics, Ministry of Health Ankara Training and Education Hospital and affiliated hospital of Gazi University Faculty of Medicine between October 2004 and June 2011. Antigens of norovirus GI and GII genogroups in the stool specimens were detected by ELISA (RIDASCREEN® Norovirus (C1401) 3rd Generation, R-Biopharm, Germany). Norovirus GI and GII antigens were determined in a total of 141 (14.1%) samples, of them 62 (15%) were female and 79 (13.5%) were male, yielding no statistically significant difference (p> 0.05). The highest NoV positivity was detected in children between 12-23 months (17.1%), however there was no statistically significant difference between ELISA positivity and age (p> 0.05). NoV detection rate was highest in 2007 (18.4%) and in 2009 (18%), and the difference regarding ELISA positivity among the study years was not statistically significant (p> 0.05). The prevalences of norovirus infection in spring, summer, autumn and winter were 13.8%, 17.7%, 14.7% and 11.2%, respectively. Therefore no seasonal variation was found in the incidence of norovirus infection. However when the monthly prevalence was analyzed, a statistically significant difference was found (p< 0.05) between the rate of norovirus infection in july (24.2%) and december (4.1%). When evaluating the clinical symptoms, all of 141 patients (100%) had diarrhoea, while 72 (51.1%) had vomiting. Stool samples were also evaluated for the presence of parasitic and bacterial agents. Coinfection rate with parasites was

  9. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial.

    PubMed

    Overton, Edgar Turner; Stapleton, Jack; Frank, Ian; Hassler, Shawn; Goepfert, Paul A; Barker, David; Wagner, Eva; von Krempelhuber, Alfred; Virgin, Garth; Meyer, Thomas Peter; Müller, Jutta; Bädeker, Nicole; Grünert, Robert; Young, Philip; Rösch, Siegfried; Maclennan, Jane; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

    2015-04-01

    Background.  First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods.  An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results.  Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions.  Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.

  10. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial

    PubMed Central

    Overton, Edgar Turner; Stapleton, Jack; Frank, Ian; Hassler, Shawn; Goepfert, Paul A.; Barker, David; Wagner, Eva; von Krempelhuber, Alfred; Virgin, Garth; Meyer, Thomas Peter; Müller, Jutta; Bädeker, Nicole; Grünert, Robert; Young, Philip; Rösch, Siegfried; Maclennan, Jane; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

    2015-01-01

    Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results. Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions. Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations. PMID:26380340

  11. National Athletic Trainers' Association Position Statement: Exertional Heat Illnesses

    PubMed Central

    Binkley, Helen M.; Beckett, Joseph; Casa, Douglas J.; Kleiner, Douglas M.; Plummer, Paul E.

    2002-01-01

    Objective: To present recommendations for the prevention, recognition, and treatment of exertional heat illnesses and to describe the relevant physiology of thermoregulation. Background: Certified athletic trainers evaluate and treat heat-related injuries during athletic activity in “safe” and high-risk environments. While the recognition of heat illness has improved, the subtle signs and symptoms associated with heat illness are often overlooked, resulting in more serious problems for affected athletes. The recommendations presented here provide athletic trainers and allied health providers with an integrated scientific and practical approach to the prevention, recognition, and treatment of heat illnesses. These recommendations can be modified based on the environmental conditions of the site, the specific sport, and individual considerations to maximize safety and performance. Recommendations: Certified athletic trainers and other allied health providers should use these recommendations to establish on-site emergency plans for their venues and athletes. The primary goal of athlete safety is addressed through the prevention and recognition of heat-related illnesses and a well-developed plan to evaluate and treat affected athletes. Even with a heat-illness prevention plan that includes medical screening, acclimatization, conditioning, environmental monitoring, and suitable practice adjustments, heat illness can and does occur. Athletic trainers and other allied health providers must be prepared to respond in an expedient manner to alleviate symptoms and minimize morbidity and mortality. PMID:12937591

  12. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

    PubMed Central

    Zhang, Li; Wang, Handong

    2015-01-01

    Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma (PPARγ). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX. PMID:26184238

  13. Respiratory and leg muscles perceived exertion during exercise at altitude.

    PubMed

    Aliverti, A; Kayser, B; Lo Mauro, A; Quaranta, M; Pompilio, P; Dellacà, R L; Ora, J; Biasco, L; Cavalleri, L; Pomidori, L; Cogo, A; Pellegrino, R; Miserocchi, G

    2011-07-31

    We compared the rate of perceived exertion for respiratory (RPE,resp) and leg (RPE,legs) muscles, using a 10-point Borg scale, to their specific power outputs in 10 healthy male subjects during incremental cycle exercise at sea level (SL) and high altitude (HA, 4559 m). Respiratory power output was calculated from breath-by-breath esophageal pressure and chest wall volume changes. At HA ventilation was increased at any leg power output by ∼ 54%. However, for any given ventilation, breathing pattern was unchanged in terms of tidal volume, respiratory rate and operational volumes of the different chest wall compartments. RPE,resp scaled uniquely with total respiratory power output, irrespectively of SL or HA, while RPE,legs for any leg power output was exacerbated at HA. With increasing respective power outputs, the rate of change of RPE,resp exponentially decreased, while that of RPE,legs increased. We conclude that RPE,resp uniquely relates to respiratory power output, while RPE,legs varies depending on muscle metabolic conditions.

  14. Resveratrol exerts pharmacological preconditioning by activating PGC-1alpha.

    PubMed

    Tan, Lan; Yu, Jin-Tai; Guan, Hua-Shi

    2008-11-01

    Resveratrol (RSV), a polyphenol phytoalexin abundantly found in grape skins and in wines, is currently the focus of intense research as a pharmacological preconditioning agent in kidney, heart, and brain from ischemic injury. However, the exact molecular mechanism of RSV preconditioning remains obscure. The data from current studies indicate that pharmacological preconditioning with RSV were attributed to its role as intracellular antioxidant, anti-inflammatory agent, its ability to induce nitric oxide synthase (NOS) expression, its ability to induce angiogenesis, and its ability to increases sirtuin 1 (SIRT1) activity. Peroxisome proliferators-activated receptor (PPAR) gamma co-activator-1alpha (PGC-1alpha) is a member of a family of transcription coactivators that owns mitochondrial biogenesis, antioxidation, growth factor signaling regulation, and angiogenesis activities. And, almost all the signaling pathways activated by RVS involve in PGC-1alpha activity. Moreover, it has been proofed that RVS could mediate an increase PGC-1alpha activity. These significant conditions support the hypothesis that RSV exerts pharmacological preconditioning by activating PGC-1alpha. Attempts to confirm this hypothesis will provide new directions in the study of pharmaceutical preconditioning and the development of new treatment approaches for reducing the extent of ischemia/reperfusion injury.

  15. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

    PubMed Central

    Oláh, Attila; Tóth, Balázs I.; Borbíró, István; Sugawara, Koji; Szöllõsi, Attila G.; Czifra, Gabriella; Pál, Balázs; Ambrus, Lídia; Kloepper, Jennifer; Camera, Emanuela; Ludovici, Matteo; Picardo, Mauro; Voets, Thomas; Zouboulis, Christos C.; Paus, Ralf; Bíró, Tamás

    2014-01-01

    The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris. PMID:25061872

  16. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.

    PubMed

    Oláh, Attila; Tóth, Balázs I; Borbíró, István; Sugawara, Koji; Szöllõsi, Attila G; Czifra, Gabriella; Pál, Balázs; Ambrus, Lídia; Kloepper, Jennifer; Camera, Emanuela; Ludovici, Matteo; Picardo, Mauro; Voets, Thomas; Zouboulis, Christos C; Paus, Ralf; Bíró, Tamás

    2014-09-01

    The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.

  17. Matrix Metalloproteinase 9 Exerts Antiviral Activity against Respiratory Syncytial Virus

    PubMed Central

    Dabo, Abdoulaye J.; Cummins, Neville; Eden, Edward; Geraghty, Patrick

    2015-01-01

    Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of Mmp9 expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, Mmp9-/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in Mmp9-/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR. PMID:26284919

  18. [Characterization of Shigella strains isolated in ankara, Turkey by antimicrobial resistance models, plasmid profile analysis and pulsed-field gel electrophoresis].

    PubMed

    Saran, Begüm; Erdem, Birsel; Tekeli, Fazıl Alper; Sahin, Fikret; Aysev, Ahmet Derya

    2013-01-01

    Shigella is one of the most important causative agents of diarrhea especially in childhood. Since man is the main reservoir of Shigella and human to human transmission is possible, Shigella can easily spread in public and cause outbreaks. In this study, a total of 60 Shigella strains isolated in Ankara, Turkey by years 2001, 2008 and 2009 were investigated by their antimicrobial susceptibility profiles, plasmid profile analysis (PPA) and pulsed-field gel electrophoresis (PFGE). For epidemiological investigation, the results obtained by antibiotic resistance typing (ART) which was the phenotyping method, was compared to the results of the genotyping methods which were PPA and PFGE. Of the isolates 49 (81.6%) were S.sonnei, 10 (16.6%) were S.flexneri and one was (1.6%) S.dysenteriae. Antimicrobial susceptibilities were evaluated by disc diffusion method and the highest resistance rates were found against trimethoprim/sulfamethoxazole (91.6%), followed by tetracycline (68.3%) and ampicillin (26.6%). Resistance against ampicillin, chloramphenicol and amoxycillin/clavulanic acid were found higher in S.flexneri isolates than S.sonnei (p< 0.001). All isolates were found to be susceptible to ciprofloxacin, gentamicin and ceftazidime. S.sonnei demonstrated 12 and S.flexneri demonstrated 4 antibiotic resistance models. All isolates were carrying plasmids with varying sizes and varying numbers between 1 to 7. S.sonnei isolates demonstrated 27 and S.flexneri isolates demonstrated 8 plasmid profiles. S.sonnei isolates were clustered in 4 patterns and S.flexneri were clustered in 5 patterns by PFGE. This method demonstrated obvious clonal similarity among S.sonnei strains isolated in Ankara and discriminative power (DP) was calculated as 0.26. PPA and ART demonstrated higher DP among S.sonnei strains (0.97 and 0.75, respectively). In this study gain or loss of instable genetic mobile elements were thought to be responsible for higher discriminative powers of PPA and ART methods

  19. Environmental Conditions and the Occurrence of Exertional Heat Illnesses and Exertional Heat Stroke at the Falmouth Road Race

    PubMed Central

    DeMartini, Julie K.; Casa, Douglas J.; Belval, Luke N.; Crago, Arthur; Davis, Rob J.; Jardine, John J.; Stearns, Rebecca L.

    2014-01-01

    Context: The Falmouth Road Race is unique because of the environmental conditions and relatively short distance, which allow runners to maintain a high intensity for the duration of the event. Therefore, the occurrence of exertional heat illnesses (EHIs), especially exertional heat stroke (EHS), is 10 times higher than in other races. Objective: To summarize the occurrence and relationship of EHI and environmental conditions at the Falmouth Road Race. Design: Descriptive epidemiologic study. Setting: An 11.3-km (7-mile) road race in Falmouth, Massachusetts. Patients or Other Participants: Runners who sustained an EHI while participating in the Falmouth Road Race. Main Outcome Measure(s): We obtained 18 years of medical records and environmental conditions from the Falmouth Road Race and documented the incidence of EHI, specifically EHS, as related to ambient temperature (Tamb), relative humidity, and heat index (HI). Results: Average Tamb, relative humidity, and HI were 23.3 ± 2.5°C, 70 ± 16%, and 24 ± 3.5°C, respectively. Of the 393 total EHI cases observed, EHS accounted for 274 (70%). An average of 15.2 ± 13.0 EHS cases occurred each year; the incidence was 2.13 ± 1.62 cases per 1000 runners. Regression analysis revealed a relationship between the occurrence of both EHI and EHS and Tamb (R2 = 0.71, P = .001, and R2 = 0.65, P = .001, respectively) and HI (R2 = 0.76, P < .001, and R2 = 0.74, P < .001, respectively). Occurrences of EHS (24.2 ± 15.5 cases versus 9.3 ± 4.3 cases) and EHI (32.3 ± 16.3 versus 13.0 ± 4.9 cases) were higher when Tamb and HI were high compared with when Tamb and HI were low. Conclusions: Because of the environmental conditions and race duration, the Falmouth Road Race provides a unique setting for a high incidence of EHS. A clear relationship exists between environmental stress, especially as measured by Tamb and HI, and the occurrence of EHS or other EHI. Proper prevention and treatment strategies should be used during periods

  20. Sifuvirtide, a potent HIV fusion inhibitor peptide

    SciTech Connect

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang

    2009-05-08

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC{sub 50}), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC{sub 50}) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1{sub IIIB} were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  1. De Novo Design of Potent Antimicrobial Peptides

    PubMed Central

    Frecer, V.; Ho, B.; Ding, J. L.

    2004-01-01

    Lipopolysaccharide (LPS), shed by gram-negative bacteria during infection and antimicrobial therapy, may lead to lethal endotoxic shock syndrome. A rational design strategy based on the presumed mechanism of antibacterial effect was adopted to design cationic antimicrobial peptides capable of binding to LPS through tandemly repeated sequences of alternating cationic and nonpolar residues. The peptides were designed to achieve enhanced antimicrobial potency due to initial bacterial membrane binding with a reduced risk of endotoxic shock. The peptides designed displayed binding affinities to LPS and lipid A (LA) in the low micromolar range and by molecular modeling were predicted to form amphipathic β-hairpin-like structures when they bind to LPS or LA. They also exhibited strong effects against gram-negative bacteria, with MICs in the nanomolar range, and low cytotoxic and hemolytic activities at concentrations significantly exceeding their MICs. Quantitative structure-activity relationship (QSAR) analysis of peptide sequences and their antimicrobial, cytotoxic, and hemolytic activities revealed that site-directed substitutions of residues in the hydrophobic face of the amphipathic peptides with less lipophilic residues selectively decrease the hemolytic effect without significantly affecting the antimicrobial or cytotoxic activity. On the other hand, the antimicrobial effect can be enhanced by substitutions in the polar face with more polar residues, which increase the amphipathicity of the peptide. On the basis of the QSARs, new analogs that have strong antimicrobial effects but that lack hemolytic activity can be proposed. The findings highlight the importance of peptide amphipathicity and allow a rational method that can be used to dissociate the antimicrobial and hemolytic effects of cationic peptides, which have potent antimicrobial properties, to be proposed. PMID:15328096

  2. Carbapenems: a potent class of antibiotics.

    PubMed

    Nicolau, David P

    2008-01-01

    The purpose of this review is to assess the relative strengths and weaknesses of individual members of the carbapenem class of antibiotics. Clinical trials and review articles were identified from a Medline search (1979 - July 2006), in addition to, reference citations from identified publications, abstracts from the Interscience Conferences on Antimicrobial Agents and Chemotherapy and the 12th International Congress on Infectious Disease, and package inserts. Articles in English were reviewed, with emphasis on those containing efficacy or safety data. Carbapenems bind to critical penicillin-binding proteins, disrupting the growth and structural integrity of bacterial cell walls. They provide enhanced anaerobic and Gram-negative coverage as compared with other beta-lactams and their stability against extended-spectrum beta-lactamases (ESBLs) makes them an effective treatment option. The most common adverse effects are infusion-site complications and gastrointestinal distress. Ertapenem has limited efficacy against non-fermenting, Gram-negative bacteria, restricting its use to community-acquired infections. Imipenem is slightly more effective against Gram-positive organisms and meropenem slightly more effective against Gram-negative organisms. However, both have broad-spectrum activity, including non-fermenting, Gram-negative bacteria. Among non-fermenting, Gram-negatives, resistance to imipenem in particular is increasing. Doripenem is in late-stage clinical development and combines the broad-spectrum coverage of imipenem and meropenem, and more potent activity against Pseudomonas aeruginosa. Due to the increasing challenges represented by ESBLs and multi-drug resistant organisms, the carbapenems are assuming a greater role in the treatment of serious infections. Imipenem and meropenem are presently available and have been shown to be effective against nosocomial infections. Doripenem is an investigational carbapenem that has completed Phase III clinical trials and

  3. Effects of caffeine on session ratings of perceived exertion.

    PubMed

    Killen, L G; Green, J M; O'Neal, E K; McIntosh, J R; Hornsby, J; Coates, T E

    2013-03-01

    This study examined effects of caffeine on session ratings of perceived exertion (RPE) following 30 min constant-load cycling. Individuals (n = 15) of varying aerobic fitness completed a [Formula: see text] max trial and two 30 min cycling bouts (double-blind, counterbalanced) following ingestion of 6 mL/kg of caffeine or matched placebo. RPE overall, legs and breathing were estimated every 5 min and session RPE was estimated 30 min post-exercise using the OMNI pictorial scale. Session RPE for caffeine and placebo trails were compared using paired t test. Between-trial comparisons of HR, RPE overall, RPE legs and RPE breathing were analyzed using an independent 2 (trial) × 6 (time point) repeated measures analysis of variance (ANOVA) for each dependent variable. Caffeine resulted in a significantly lower session RPE (p < 0.05) for caffeine (6.1 ± 2.2) versus placebo (6.8 ± 2.1). Acute perceptual responses were significantly lower for caffeine for RPE overall (15, 20, 25, and 30 min), RPE breathing (15, 20, 25, and 30 min) and RPE legs (20 and 30 min). Survey responses post-exercise revealed greater feelings of nervousness, tremors, restlessness and stomach distress following caffeine versus placebo. Blunted acute RPE and survey responses suggest participants responded to caffeine ingestion. Caffeine decreased acute RPE during exercise which could partially account for lower session RPE responses. However, decreased session RPE could also reveal a latent analgesic affect of caffeine extending into recovery. Extending the understanding of session RPE could benefit coaches in avoiding overtraining when adjusting training programs.

  4. Perceived exertion responses to changing resistance training programming variables.

    PubMed

    Hiscock, Daniel J; Dawson, Brian; Peeling, Peter

    2015-06-01

    This study examined the influence of intensity (%1 repetition maximum [1RM]), tonnage (sets × repetitions × load), rate of fatigue (percentage decrement in repetitions from set to set), work rate (total tonnage per unit of time), rest interval (time between sets), time under load, and session duration on session rating of perceived exertion (sRPE: Borg's CR-10 scale). Here, participants performed a standardized lifting session of 5 exercises (bench press, leg press, lat pulldown, leg curl, and triceps pushdown) as either: (a) 3 sets × 8 repetitions × 3-minute recovery at 70% 1RM, (b) 3 sets × 14 repetitions × 3-minute recovery at 40% 1RM, (c) 3 sets × MNR (maximum number of repetitions) × 1-minute recovery at 70% 1RM, (d) 3 sets × MNR × 3-minute recovery at 70% 1RM, (e) 3 sets × MNR × 1-minute recovery at 40% 1RM, or (f) 3 sets × MNR × 3-minute recovery at 40% 1RM. The sRPE for session A (4 ± 1) was significantly higher than session B (2.5 ± 1), despite matched tonnage. Protocols involving MNR showed no significant difference in sRPE. Work rate was the only variable to significantly relate with sRPE (r = 0.45). Additionally, sRPE at 15-minute postexercise (5 ± 2) was not different to 30-minute postexercise (5 ± 2). In resistance training with matched tonnage and rest duration between sets, sRPE increases with intensity. In sets to volitional failure, sRPE is likely to be similar, regardless of intensity or rest duration between sets.

  5. Grip forces exerted against stationary held objects during gravity changes.

    PubMed

    Hermsdörfer, J; Marquardt, C; Philipp, J; Zierdt, A; Nowak, D; Glasauer, S; Mai, N

    1999-05-01

    In the present study, grip forces exerted against a stationary held object were recorded during parabolic flights. Such flight maneuvers induce changes of gravity with two periods of hypergravity, associated with a doubling of normal terrestrial gravity, and a 20 s period of microgravity. Accordingly, the object's weight changed from being twice as heavy as normally experienced and weightless. Grip-force recordings demonstrated that force control was seriously disturbed only during the first experience of hyper- and microgravity, with the grip forces being exceedingly high and yielding irregular fluctuations. Thereafter, however, grip force traces were smooth, the force level was scaled to the object's weight under normal and high-G conditions, and the grip force changed in parallel with the weight during the transitions between hyper- and microgravity. In addition, during weightlessness, when virtually no force was necessary to stabilize the object, a low force was established, which obviously represented a reasonable safety margin for preventing possible perturbations. Thus, all relevant aspects of grip-force control observed under normal gravity conditions were preserved during gravity changes induced by parabolic flights. Hence, grip-force control mechanisms were able to cope with hyper- and microgravity, either by incorporating relevant receptor signals, such as those originating from cutaneous mechanoreceptors, or by adequately including perceived gravity signals into control programs. However, the adaptation to the uncommon gravity conditions was not complete following the first experience; finer tuning of the control system to both hyper- and microgravity continued over the measurement interval, presumably with a longer observation period being necessary before a stable performance can be reached.

  6. Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

    PubMed Central

    Chiuppesi, Flavia; Wussow, Felix; Johnson, Erica; Bian, Chao; Zhuo, Meng; Rajakumar, Augustine; Barry, Peter A.; Britt, William J.; Chakraborty, Rana

    2015-01-01

    ABSTRACT Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells. IMPORTANCE As a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based

  7. Vaccination of horses with a recombinant modified vaccinia Ankara virus (MVA) expressing African horse sickness (AHS) virus major capsid protein VP2 provides complete clinical protection against challenge.

    PubMed

    Alberca, Berta; Bachanek-Bankowska, Katarzyna; Cabana, Marta; Calvo-Pinilla, Eva; Viaplana, Elisenda; Frost, Lorraine; Gubbins, Simon; Urniza, Alicia; Mertens, Peter; Castillo-Olivares, Javier

    2014-06-17

    African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant modified vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR -/-) against virulent AHSV challenge. This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection. These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field.

  8. [Isolation of coagulase-positive staphylococci from cheese and ice-cream samples sold in Ankara and some biochemical properties of the isolates].

    PubMed

    Baştepe, S; Köşker, O

    1981-01-01

    Coagulase-positive staphylococci were isolated from different kinds of cheese and ice-cream sold in Ankara and some biochemical properties of these isolates were determined. 55 cheese, 52 ice-cream (107 samples) were examined for the presence of coagulase-positive staphylococci. Baird Parker Medium was used and 26 samples constituting of 13 cheese and 13 ice-cream were found to be contaminated with coagulase-positive staphylococci and ratio of the contaminated samples to the total was calculated as 24.3%. Highest count was determined to be 176, 166/g in Izmir Tulum Cheese, whereas none of the other tulum cheese samples yielded this bacteria. In general, coagulase-positive staphylococci of cheese samples were higher than ice-cream samples. Among the ice-cream samples highest coagulase-positive staphylococci count was obtained in nutty ice-cream. From the 26 contaminated samples 164 coagulase-positive staphylococci were isolated. Results indicate that an important number of the coagulase forming isolates were also phosphatase positive, forming pigment and haemolysin, able to utilize mannitol. No relation could be observed between the coagulase formation and ability to produce lysin.

  9. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults

    PubMed Central

    Edwards, Nick J.; Roberts, Rachel; Mwacharo, Jedidah; Bowyer, Georgina; Bliss, Carly; Hodgson, Susanne H.; Njuguna, Patricia; Viebig, Nicola K.; Nicosia, Alfredo; Gitau, Evelyn; Douglas, Sandy; Illingworth, Joe; Marsh, Kevin; Lawrie, Alison; Imoukhuede, Egeruan B.; Ewer, Katie

    2015-01-01

    Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio,0.24; 95% CI, 0.08 to 0.75; P = 0.016). PMID:25947165

  10. The fatal poisoning pattern of Ankara (Turkey) and nearby cities from 2007 to June 2011: a retrospective study in forensic autopsies.

    PubMed

    Karaarslan, Bekir; Karapirli, Mustafa; Kandemir, Eyup; Kucuker, Hudaverdi; Gurler, Mukaddes; Ince, Cengiz Haluk; Akyol, Omer

    2013-11-01

    We aimed to obtain an outline of the nature and number of fatal poisonings which still appear to affect widely the population in Turkey. A total of 5921 forensic autopsies were performed between 2007 and 2011 in Ankara and nearby cities and 366 of them were fatal poisonings (219 male, 147 female). Most of the cases were between 41 and 60 years old (n = 84). Most of the fatalities were reported during winter months (48.1%). Carbon monoxide exposure was the most common reason (66.7%) within all the causes followed by medicine and narcotics (13.9%). Postmortem blood alcohol concentrations in ethyl and methyl alcohol poisonings were 385.1 ± 61.9 and 206.8 ± 138.9 mg/dL, respectively. The most common location of deaths was home (71.3%). Fatal poisonings have been a growing global problem because of some shortcomings about the socioeconomic conditions and increasing illicit drug abuse. The level of education, socioeconomic conditions, and legal approaches are very important for the prevention fatal poisonings.

  11. Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects

    PubMed Central

    Greenberg, Richard N.; Overton, Edgar Turner; Haas, David W.; Frank, Ian; Goldman, Mitchell; von Krempelhuber, Alfred; Virgin, Garth; Bädeker, Nicole; Vollmar, Jens; Chaplin, Paul

    2013-01-01

    Background. Human immunodeficiency virus (HIV)–infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. Methods. The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4+ T-cell counts, ≥350 cells/mm3) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects. Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola. Conclusions. MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile. Clinical Trials Registration. NCT00189904. PMID:23225902

  12. An intact signal peptide on dengue virus E protein enhances immunogenicity for CD8(+) T cells and antibody when expressed from modified vaccinia Ankara.

    PubMed

    Quinan, Bárbara R; Flesch, Inge E A; Pinho, Tânia M G; Coelho, Fabiana M; Tscharke, David C; da Fonseca, Flávio G

    2014-05-23

    Dengue is a global public health concern and this is aggravated by a lack of vaccines or antiviral therapies. Despite the well-known role of CD8(+) T cells in the immunopathogenesis of Dengue virus (DENV), only recent studies have highlighted the importance of this arm of the immune response in protection against the disease. Thus, the majority of DENV vaccine candidates are designed to achieve protective titers of neutralizing antibodies, with less regard for cellular responses. Here, we used a mouse model to investigate CD8(+) T cell and humoral responses to a set of potential DENV vaccines based on recombinant modified vaccinia virus Ankara (rMVA). To enable this study, we identified two CD8(+) T cell epitopes in the DENV-3 E protein in C57BL/6 mice. Using these we found that all the rMVA vaccines elicited DENV-specific CD8(+) T cells that were cytotoxic in vivo and polyfunctional in vitro. Moreover, vaccines expressing the E protein with an intact signal peptide sequence elicited more DENV-specific CD8(+) T cells than those expressing E proteins in the cytoplasm. Significantly, it was these same ER-targeted E protein vaccines that elicited antibody responses. Our results support the further development of rMVA vaccines expressing DENV E proteins and add to the tools available for dengue vaccine development.

  13. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults.

    PubMed

    Ogwang, Caroline; Kimani, Domtila; Edwards, Nick J; Roberts, Rachel; Mwacharo, Jedidah; Bowyer, Georgina; Bliss, Carly; Hodgson, Susanne H; Njuguna, Patricia; Viebig, Nicola K; Nicosia, Alfredo; Gitau, Evelyn; Douglas, Sandy; Illingworth, Joe; Marsh, Kevin; Lawrie, Alison; Imoukhuede, Egeruan B; Ewer, Katie; Urban, Britta C; S Hill, Adrian V; Bejon, Philip

    2015-05-06

    Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).

  14. Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast-derived HTR-8/SVneo cells.

    PubMed

    Cervellati, F; Pavan, B; Lunghi, L; Manni, E; Fabbri, E; Mascoli, C; Biondi, C; Patella, A; Vesce, F

    2011-01-01

    Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRβ, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.

  15. The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.

    PubMed

    Walker, A K; Rivera, P D; Wang, Q; Chuang, J-C; Tran, S; Osborne-Lawrence, S; Estill, S J; Starwalt, R; Huntington, P; Morlock, L; Naidoo, J; Williams, N S; Ready, J M; Eisch, A J; Pieper, A A; Zigman, J M

    2015-04-01

    Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

  16. Bamboo salt has in vitro anticancer activity in HCT-116 cells and exerts anti-metastatic effects in vivo.

    PubMed

    Zhao, Xin; Kim, So-Young; Park, Kun-Young

    2013-01-01

    Bamboo salt is a traditional food widely used in Korea. The in vitro anticancer effects of this salt were evaluated in HCT-116 human colon cancer cells using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. A 1% salt concentration of bamboo salt baked nine times (9×) inhibited the growth of HCT-116 cells by 53%, which was higher than salt baked three times (3×) or once (1×; 44% and 41%, respectively) and much higher than solar sea salt (Korean sea salt) and purified salt (22% and 18%, respectively). To elucidate the inhibitory mechanisms underlying the anticancer effect of the salt samples in cancer cells, expression of genes associated with apoptosis, inflammation, and metastasis was measured with reverse transcription-polymerase chain reaction and Western blotting. Bamboo salt (9×) significantly induced apoptosis in cancer cells (P<.05) by upregulating Bax, caspase-9, and caspase-3, and downregulating Bcl-2. The expression of genes associated with inflammation (NF-κB, iNOS, and COX-2) was significantly downregulated (P<.05) by 9× bamboo salt, demonstrating its anti-inflammatory properties. The 9× bamboo salt also exerted a greater anti-metastatic effect on cancer cells than the other salts as demonstrated by decreased mRNA expression of MMP genes and increased expression of tissue inhibitors of metalloproteinases, which was confirmed by the inhibition of tumor metastasis induced in colon 26-M3.1 cells in BALB/c mice. In contrast, purified and solar salts increased metastasis in the mice. Our results demonstrated that 9× bamboo salt had the most potent in vitro anticancer effect, induced apoptosis, had anti-inflammatory activities, and exerted in vivo anti-metastatic effects. Additionally, the anticancer, anti-inflammatory, and anti-metastatic effects of the 1× and 3× bamboo salts were stronger than those of the purified and solar salts.

  17. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

    PubMed Central

    Mastrangelo, Eloise; Pezzullo, Margherita; De Burghgraeve, Tine; Kaptein, Suzanne; Pastorino, Boris; Dallmeier, Kai; de Lamballerie, Xavier; Neyts, Johan; Hanson, Alicia M.; Frick, David N.; Bolognesi, Martino; Milani, Mario

    2012-01-01

    Objectives Infection with yellow fever virus (YFV), the prototypic mosquito-borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. Moreover, in recent years the Flavivirus genus has gained further attention due to re-emergence and increasing incidence of West Nile, dengue and Japanese encephalitis viruses. Potent and safe antivirals are urgently needed. Methods Starting from the crystal structure of the NS3 helicase from Kunjin virus (an Australian variant of West Nile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. In silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. Their activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. The effect on the in vitro replication of flaviviruses was then evaluated. Results Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC50 values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase. Conclusions The well-tolerated drug ivermectin may hold great potential for treatment of YFV infections. Furthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than YFV. PMID:22535622

  18. A novel curcumin analogue is a potent chemotherapy candidate for human hepatocellular carcinoma

    PubMed Central

    Zhao, Ji-An; Sang, Mei-Xiang; Geng, Cui-Zhi; Wang, Shi-Jie; Shan, Bao-En

    2016-01-01

    Curcumin (CUR) has been demonstrated to protect against carcinogenesis and to prevent tumor development in cancer; however, the clinical application of CUR is limited by its instability and poor metabolic properties. The present study offers an strategy for a novel CUR analogue, (1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one (GL63), to be used as a potential therapeutic agent for hepatocellular carcinoma (HCC) in vitro and in vivo. The current study demonstrated that GL63 exhibited more potent inhibition of proliferation of HCC cells than CUR. GL63 induced G0/G1 phase cell cycle arrest and apoptosis in SK-HEP-1 cells in a dose-dependent manner, and was more potent than CUR, according to the flow cytometry data. The present study demonstrated for the first time that the inhibition of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway by GL63 resulted in a protective effect against HCC cell growth. GL63 was more effective than CUR in regulating STAT3 downstream targets, which contributed to the suppression of cell proliferation and the induction of cell apoptosis. In addition, the effects of GL63 were tested in a model of N-nitrosodiethylamine (DEN)-induced HCC in Wistar rats. Although macroscopic and microscopic features suggested that both GL63 and CUR were effective in inhibiting DEN-induced hepatocarcinogenesis, GL63 exerted a stronger effect than CUR. Immunohistochemical analysis for proliferating cell nuclear antigen demonstrated significant differences among the DEN-bearing non-treated, DEN-bearing GL63-treated and DEN-bearing, CUR-treated groups (P=0.039). It was concluded that GL63 was a potent agent able to suppress the proliferation of HCC cells by inhibition of the JAK2/STAT3 signaling pathway, with more favorable pharmacological activity than CUR, and may be a more potent compound for the prevention of DEN-induced hepatocarcinogenesis in rats than CUR. PMID:27895800

  19. Azachalcones: a new class of potent polyphenol oxidase inhibitors.

    PubMed

    Radhakrishnan, Sini Karanayil; Shimmon, Ronald Gibrial; Conn, Costa; Baker, Anthony T

    2015-04-15

    A library of potent inhibitors of polyphenol oxidase and their structure activity relationships are described. Azachalcone derivatives were synthesized and tested for their tyrosinase inhibitory activity. Their inhibitory activities on mushroom tyrosinase using l-DOPA as a substrate were investigated. Two compounds that are the reduction congeners of the pyridinyl azachalcones strongly inhibited the enzyme activity and were more potent than the positive control kojic acid.

  20. Development of a potent and selective cell penetrant Legumain inhibitor.

    PubMed

    Ness, Kerry A; Eddie, Sharon L; Higgins, Catherine A; Templeman, Amy; D'Costa, Zenobia; Gaddale, Kishore K D; Bouzzaoui, Samira; Jordan, Linda; Janssen, Dominic; Harrison, Timothy; Burkamp, Frank; Young, Andrew; Burden, Roberta; Scott, Christopher J; Mullan, Paul B; Williams, Rich

    2015-12-01

    This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.

  1. Placenta Growth Factor-1 Exerts Time-Dependent Stabilization of Adherens Junctions Following VEGF-Induced Vascular Permeability

    PubMed Central

    Cai, Jun; Wu, Lin; Qi, Xiaoping; Shaw, Lynn; Li Calzi, Sergio; Caballero, Sergio; Jiang, Wen G.; Vinores, Stanley A.; Antonetti, David; Ahmed, Asif; Grant, Maria B.; Boulton, Michael E.

    2011-01-01

    Increased vascular permeability is an early event characteristic of tissue ischemia and angiogenesis. Although VEGF family members are potent promoters of endothelial permeability the role of placental growth factor (PlGF) is hotly debated. Here we investigated PlGF isoforms 1 and 2 and present in vitro and in vivo evidence that PlGF-1, but not PlGF-2, can inhibit VEGF-induced permeability but only during a critical window post-VEGF exposure. PlGF-1 promotes VE-cadherin expression via the trans-activating Sp1 and Sp3 interaction with the VE-cadherin promoter and subsequently stabilizes transendothelial junctions, but only after activation of endothelial cells by VEGF. PlGF-1 regulates vascular permeability associated with the rapid localization of VE-cadherin to the plasma membrane and dephosphorylation of tyrosine residues that precedes changes observed in claudin 5 tyrosine phosphorylation and membrane localization. The critical window during which PlGF-1 exerts its effect on VEGF-induced permeability highlights the importance of the translational significance of this work in that PLGF-1 likely serves as an endogenous anti-permeability factor whose effectiveness is limited to a precise time point following vascular injury. Clinical approaches that would pattern nature's approach would thus limit treatments to precise intervals following injury and bring attention to use of agents only during therapeutic windows. PMID:21464949

  2. Zoledronic acid exerts antitumor effects in NB4 acute promyelocytic leukemia cells by inducing apoptosis and S phase arrest.

    PubMed

    Liu, Shou-Sheng; Wang, Xiao-Pai; Li, Xiu-Bo; Liang, Jia-Yi; Liu, Ling-Ling; Lu, Ying; Zhong, Xue-Yun; Chen, Yun-Xian

    2014-10-01

    The aim of this study was to investigate the antitumor effect of zoledronic acid (ZOL) in the NB4 human acute promyelocytic leukemia (APL) cell line and explore the potential mechanism of action of this compound. NB4 cells were exposed to various concentrations (0-200μM) of ZOL. Cell viability was measured by MTS assay. The extent of cell apoptosis and distribution of cells in the different phases of the cell cycle were analyzed with flow cytometry. The expression of apoptosis- and cell cycle-related proteins was assayed by Western blot. The combined effect of ZOL and arsenic trioxide (ATO) on the proliferation of NB4 cells was also determined. The results of this study indicate that ZOL inhibits cell proliferation in a time- and dose-dependent fashion and also induces apoptosis and S phase arrest in a dose-dependent manner. The Western blot analysis confirmed the induction of apoptosis and S phase arrest, revealing that the pro-apoptosis proteins Bax, Puma and activated caspase-9 were upregulated and the anti-apoptosis proteins Bcl-2 and Bcl-xL were downregulated. ZOL at a concentration of 50μM synergized with 0.5μM ATO on the growth inhibition of NB4 cells. Taken together, our data indicate that ZOL exerts a potent antitumor effect on NB4 cells by inducing apoptosis and cell cycle arrest, and that ZOL can synergize with the traditional chemotherapy drug ATO.

  3. Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

    PubMed Central

    Kennelly, Helen; Mahon, Bernard P.; English, Karen

    2016-01-01

    Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emphysema the efficacy of human MSC therapy and optimal cell dose were investigated. Protective effects were examined in the lung through histological examination. Further in vivo experiments examined the reparative abilities of MSCs after tissue damage was established and the role played by soluble factors secreted by MSCs. The mechanism of MSC action was determined in using shRNA gene knockdown. Human MSC therapy and MSC conditioned media exerted significant cytoprotective effects when administered early at the onset of the disease. These protective effects were due to significant anti-inflammatory, anti-fibrotic and anti-apoptotic mechanisms, mediated in part through MSC production of hepatocyte growth factor (HGF). When MSC administration was delayed, significant protection of the lung architecture was observed but this was less extensive. MSC cell therapy was more effective than MSC conditioned medium in this emphysema model. PMID:27922052

  4. Dynamics of Perceived Exertion in Constant-Power Cycling: Time- and Workload-Dependent Thresholds

    ERIC Educational Resources Information Center

    Balagué, Natàlia; Hristovski, Robert; García, Sergi; Aguirre, Cecilia; Vázquez, Pablo; Razon, Selen; Tenenbaum, Gershon

    2015-01-01

    Purpose: The purpose of this study was to test the dynamics of perceived exertion shifts (PES) as a function of time and workload during constant-power cycling. Method: Fifty-two participants assigned to 4 groups performed a cycling task at 4 different constant workloads corresponding to their individual rates of perceived exertion (RPEs = 13, 15,…

  5. Fatigue Induced by Physical and Mental Exertion Increases Perception of Effort and Impairs Subsequent Endurance Performance

    PubMed Central

    Pageaux, Benjamin; Lepers, Romuald

    2016-01-01

    Endurance performance involves the prolonged maintenance of constant or self-regulated power/velocity or torque/force. While the impact of numerous determinants of endurance performance has been previously reviewed, the impact of fatigue on subsequent endurance performance still needs to be documented. This review aims to present the impact of fatigue induced by physical or mental exertion on subsequent endurance performance. For the purpose of this review, endurance performance refers to performance during whole-body or single-joint endurance exercise soliciting mainly the aerobic energy system. First, the impact of physical and mental exertion on force production capacity is presented, with specific emphasize on the fact that solely physical exertion and not mental exertion induces a decrease in force production capacity of the working muscles. Then, the negative impact of fatigue induced by physical exertion and mental exertion on subsequent endurance performance is highlighted based on experimental data. Perception of effort being identified as the variable altered by both prior physical exertion and mental exertion, future studies should investigate the underlying mechanisms increasing perception of effort overtime and in presence of fatigue during endurance exercise. Perception of effort should be considered not only as marker of exercise intensity, but also as a factor limiting endurance performance. Therefore, using a psychophysiological approach to explain the regulation of endurance performance would allow a better understanding of the interaction between physiological and psychological phenomena known to impact endurance performance. PMID:27965592

  6. Induction of HIV immunity in the genital tract after intranasal delivery of a MVA vector: enhanced immunogenicity after DNA prime-modified vaccinia virus Ankara boost immunization schedule.

    PubMed

    Gherardi, M Magdalena; Pérez-Jiménez, Eva; Nájera, José Luis; Esteban, Mariano

    2004-05-15

    Vaccines intended to prevent mucosal transmission of HIV should be able to induce multiple immune effectors in the host including Abs and cell-mediated immune responses at mucosal sites. The aim of this study was to characterize and to enhance the immunogenicity of a recombinant modified vaccinia virus Ankara (MVA) expressing HIV-1 Env IIIB Ag (MVAenv) inoculated in BALB/c mice by mucosal routes. Intravaginal inoculation of MVAenv was not immunogenic, whereas intranasally it induced a significant immune response to the HIV Ag. Intranasal codelivery of MVAenv plus cholera toxin (CT) significantly enhanced the cellular and humoral immune response against Env in the spleen and genitorectal draining lymph nodes, respectively. Heterologous DNAenv prime-MVAenv boost by intranasal immunization, together with CT, produced a cellular immune response in the spleen 10-fold superior to that in the absence of CT. A key finding of these studies was that both MVAenv/MVAenv and DNAenv/MVAenv schemes, plus CT, induced a specific mucosal CD8(+) T cell response in genital tissue and draining lymph nodes. In addition, both immunizations also generated systemic Abs, and more importantly, mucosal IgA and IgG Abs in vaginal washings. Specific secretion of beta-chemokines was also generated by both immunizations, with a stronger response in mice immunized by the DNA-CT/MVA-CT regimen. Our findings are of relevance in the area of vaccine development and support the optimization of protocols of immunization based on MVA as vaccine vectors to induce mucosal immune responses against HIV.

  7. Deletion of specific immune-modulatory genes from modified vaccinia virus Ankara-based HIV vaccines engenders improved immunogenicity in rhesus macaques.

    PubMed

    Garber, David A; O'Mara, Leigh A; Gangadhara, Sailaja; McQuoid, Monica; Zhang, Xiugen; Zheng, Rui; Gill, Kiran; Verma, Meena; Yu, Tianwei; Johnson, Brent; Li, Bing; Derdeyn, Cynthia A; Ibegbu, Chris; Altman, John D; Hunter, Eric; Feinberg, Mark B

    2012-12-01

    Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 10(8) PFU) or low-dose (1 × 10(7) PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates.

  8. The orthopoxvirus 68-kilodalton ankyrin-like protein is essential for DNA replication and complete gene expression of modified vaccinia virus Ankara in nonpermissive human and murine cells.

    PubMed

    Sperling, Karin M; Schwantes, Astrid; Staib, Caroline; Schnierle, Barbara S; Sutter, Gerd

    2009-06-01

    Modified vaccinia virus Ankara (MVA) is a highly attenuated and replication-deficient vaccinia virus (VACV) that is being evaluated as replacement smallpox vaccine and candidate viral vector. MVA lacks many genes associated with virulence and/or regulation of virus tropism. The 68-kDa ankyrin-like protein (68k-ank) is the only ankyrin repeat-containing protein that is encoded by the MVA genome and is highly conserved throughout the Orthopoxvirus genus. We showed previously that 68k-ank is composed of ankyrin repeats and an F-box-like domain and forms an SCF ubiquitin ligase complex together with the cellular proteins Skp1a and Cullin-1. We now report that 68k-ank (MVA open reading frame 186R) is an essential factor for completion of the MVA intracellular life cycle in nonpermissive human and murine cells. Infection of mouse NIH 3T3 and human HaCaT cells with MVA with a deletion of the 68k-ank gene (MVA-Delta68k-ank) was characterized by an extensive reduction of viral intermediate RNA and protein, as well as late transcripts and drastically impaired late protein synthesis. Furthermore, infections with MVA-Delta68k-ank failed to induce the host protein shutoff that is characteristic of VACV infections. Although we demonstrated that proteasome function in general is essential for the completion of the MVA molecular life cycle, we found that a mutant 68k-ank protein with a deletion of the F-box-like domain was able to fully complement the deficiency of MVA-Delta68k-ank to express all classes of viral genes. Thus, our data demonstrate that the 68k-ank protein contains another critical domain that may function independently of SCF ubiquitin ligase complex formation, suggesting multiple activities of this interesting regulatory protein.

  9. Environmental Harmony and Evaluation of Advertisement Billboards with Digital Photogrammetry Technique and GIS Capabilities: A Case Study in the City of Ankara.

    PubMed

    Aydın, Cevdetx C; Nisancı, Recep

    2008-05-19

    Geographical Information Systems (GIS) have been gaining a growing interest in Turkey. Many local governments and public agencies have been struggling to set up such systems to serve the needs and meet public requirements. Urban life shelters the advertisement reality which is presented at various places, on vehicles, shops etc. in daily life. It can be said that advertisement is a part of daily life in urban area, especially in city centers. In addition, one of the main sources of revenue for municipalities comes from advertising and notices. The advertising sector provides a great level of income today. Therefore advertising is individually very important for local governments and urban management. Although it is valuable for local governments, it is also very important for urban management to place these advertisement signs and billboards in an orderly fashion which is pleasing to the eye. Another point related to this subject is the systematic control mechanism which is necessary for collecting taxes regularly and updating. In this paper, first practical meaning of notice and advertisement subject, problem definition and objectives are described and then legal support and daily practice are revised. Current practice and problems are mentioned. Possibilities of measuring and obtaining necessary information by using digital images and transferring them to spatial databases are studied. By this study, a modern approach was developed for urban management and municipalities by using information technology which is an alternative to current application. Criteria which provide environmental harmony such as urban beauty, colour, compatibility and safety were also evaluated. It was finally concluded that measuring commercial signs and keeping environmental harmony under control for urban beauty can be provided by Digital Photogrammetry (DP) technique and GIS capabilities which were studied with pilot applications in the city center of Ankara.

  10. Immunity, safety and protection of an Adenovirus 5 prime--Modified Vaccinia virus Ankara boost subunit vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves.

    PubMed

    Bull, Tim J; Vrettou, Christina; Linedale, Richard; McGuinnes, Catherine; Strain, Sam; McNair, Jim; Gilbert, Sarah C; Hope, Jayne C

    2014-10-29

    Vaccination is the most cost effective control measure for Johne's disease caused by Mycobacterium avium subspecies paratuberculosis (MAP) but currently available whole cell killed formulations have limited efficacy and are incompatible with the diagnosis of bovine tuberculosis by tuberculin skin test. We have evaluated the utility of a viral delivery regimen of non-replicative human Adenovirus 5 and Modified Vaccinia virus Ankara recombinant for early entry MAP specific antigens (HAV) to show protection against challenge in a calf model and extensively screened for differential immunological markers associated with protection. We have shown that HAV vaccination was well tolerated, could be detected using a differentiation of infected and vaccinated animals (DIVA) test, showed no cross-reactivity with tuberculin and provided a degree of protection against challenge evidenced by a lack of faecal shedding in vaccinated animals that persisted throughout the 7 month infection period. Calves given HAV vaccination had significant priming and boosting of MAP derived antigen (PPD-J) specific CD4+, CD8+ IFN-γ producing T-cell populations and, upon challenge, developed early specific Th17 related immune responses, enhanced IFN-γ responses and retained a high MAP killing capacity in blood. During later phases post MAP challenge, PPD-J antigen specific IFN-γ and Th17 responses in HAV vaccinated animals corresponded with improvements in peripheral bacteraemia. By contrast a lack of IFN-γ, induction of FoxP3+ T cells and increased IL-1β and IL-10 secretion were indicative of progressive infection in Sham vaccinated animals. We conclude that HAV vaccination shows excellent promise as a new tool for improving control of MAP infection in cattle.

  11. Comparing adjuvanted H28 and modified vaccinia virus ankara expressingH28 in a mouse and a non-human primate tuberculosis model.

    PubMed

    Billeskov, Rolf; Christensen, Jan P; Aagaard, Claus; Andersen, Peter; Dietrich, Jes

    2013-01-01

    Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein "H28" (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-γ expressing T cells, the highest production of IFN-γ per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-α/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-α/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-γ. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-α/IL-2 double producing but not IFN-γ single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model.

  12. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo

    PubMed Central

    Ranganath, Sheila; Bhandari, Ashok; Avitahl-Curtis, Nicole; McMahon, Jaimee; Wachtel, Derek; Zhang, Jenny; Leitheiser, Christopher; Bernier, Sylvie G.; Liu, Guang; Tran, Tran T.; Celino, Herodion; Tobin, Jenny; Jung, Joon; Zhao, Hong; Glen, Katie E.; Graul, Chris; Griffin, Aliesha; Schairer, Wayne C.; Higgins, Carolyn; Reza, Tammi L.; Mowe, Eva; Rivers, Sam; Scott, Sonya; Monreal, Alex; Shea, Courtney; Bourne, Greg; Coons, Casey; Smith, Adaline; Tang, Kim; Mandyam, Ramya A.; Masferrer, Jaime; Liu, David; Patel, Dinesh V.; Fretzen, Angelika; Murphy, Craig A.; Milne, G. Todd; Smythe, Mark L.; Carlson, Kenneth E.

    2015-01-01

    Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman’s Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology. PMID:26555695

  13. Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.

    PubMed

    Rossi, Antonietta; Di Paola, Rosanna; Mazzon, Emanuela; Genovese, Tiziana; Caminiti, Rocco; Bramanti, Placido; Pergola, Carlo; Koeberle, Andreas; Werz, Oliver; Sautebin, Lidia; Cuzzocrea, Salvatore

    2009-04-01

    Myrtucommulone (MC), a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-alpha and interleukin-1beta) in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B(4), but not prostaglandin E(2), levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation.

  14. Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro.

    PubMed

    Kasperk, C H; Wakley, G K; Hierl, T; Ziegler, R

    1997-03-01

    Androgens stimulate bone formation and play an important role in the maintenance of bone mass. Clinical observations suggest that both gonadal and adrenal androgens contribute to the positive impact of androgenic steroids on bone metabolism. We investigated the mechanism of action of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated compound dehydroepiandrosterone sulfate (DHEAS) on human osteoblastic cells (HOCs) in vitro. The DHEA- and DHEAS-induced effects were analyzed in parallel with the actions elicited by the gonadal androgen dihydrotestosterone (DHT). There was no qualitative difference between the effects of gonadal and adrenal androgens on HOC metabolism in vitro. Both were stimulatory as regards cell proliferation and differentiated functions, but the gonadal androgen DHT was significantly more potent than DHEA. The actions of DHT and DHEA on HOC proliferation and alkaline phosphatase (ALP) production could be prevented by the androgen receptor antagonist hydroxyflutamide and inhibitory transforming growth factor beta antibodies (TGF-beta ab), respectively, but were not affected by the presence of the 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 5-alpha-reductase (5-AR) inhibitor 17 beta-N,N-diethylcarbamoyl-4-methyl- 4aza-5 alpha-androstan-3-one (4-MA). This indicates that DHT and DHEA (1) exert their mitogenic effects by androgen receptor-mediated mechanisms, (2) stimulate ALP production by increased TGF-beta expression, (3) that the action of DHT is not affected by the presence of 4-MA, and that (4) DHEA does not need to be metabolized by 3 beta HSD or 5-AR first to exert its effects on HOCs in vitro.

  15. Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses.

    PubMed

    Burton, Samantha L; Kilgore, Katie M; Smith, S Abigail; Reddy, Sharmila; Hunter, Eric; Robinson, Harriet L; Silvestri, Guido; Amara, Rama R; Derdeyn, Cynthia A

    2015-08-25

    Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742-1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

  16. The effects of running in an exerted state on lower extremity kinematics and joint timing.

    PubMed

    Dierks, Tracy A; Davis, Irene S; Hamill, Joseph

    2010-11-16

    Runners rarely run to the point of maximum fatigue or exhaustion. However, no studies have investigated how the level of exertion associated with a typical running session influences running mechanics. The purpose of this study was to investigate the effects that running in an exerted state had on the kinematics and joint timing within the lower extremity of uninjured, recreational runners. Twenty runners performed a prolonged treadmill run at a self-selected pace that best represented each runner's typical training run. The run ended based on heart rate or perceived exertion levels that represented a typical training run. Kinematics and joint timing between the foot, knee, and hip were analyzed at the beginning and end of the run. Increases were primarily observed at the end of the run for the peak angles, excursions, and peak velocities of eversion, tibial internal rotation, and knee internal rotation. No differences were observed for knee flexion, hip internal rotation, or any joint timing relationship. Based on these results, runners demonstrated subtle changes in kinematics in the exerted state, most notably for eversion. However, runners were able to maintain joint timing throughout the leg, which may have been a function of the knee. Thus, uninjured runners normally experience small alterations in kinematics when running with typical levels of exertion. It remains unknown how higher levels of exertion influence kinematics with joint timing and the association with running injuries, or how populations with running injuries respond to typical levels of exertion.

  17. Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion.

    PubMed

    Luethi, Matthias S; Friese, Malte; Binder, Julia; Boesiger, Peter; Luechinger, Roger; Rasch, Björn

    2016-10-01

    Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self-control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation.

  18. COPD Patients with Exertional Desaturation Are at a Higher Risk of Rapid Decline in Lung Function

    PubMed Central

    Kim, Changhwan; Park, Yong Bum; Park, So Young; Park, Sunghoon; Kim, Cheol-Hong; Park, Sang Myeon; Lee, Myung-Goo; Hyun, In-Gyu; Jung, Ki-Suck

    2014-01-01

    Purpose A recent study demonstrated that exertional desaturation is a predictor of rapid decline in lung function in patients with chronic obstructive pulmonary disease (COPD); however, the study was limited by its method used to detect exertional desaturation. The main purpose of this study was to explore whether exertional desaturation assessed using nadir oxygen saturation (SpO2) during the 6-minute walk test (6MWT) can predict rapid lung function decline in patients with COPD. Materials and Methods A retrospective analysis was performed on 57 patients with moderate to very severe COPD who underwent the 6MWT. Exertional desaturation was defined as a nadir SpO2 of <90% during the 6MWT. Rapid decline was defined as an annual rate of decline in forced expiratory volume in 1 second (FEV1) ≥50 mL. Patients were divided into rapid decliner (n=26) and non-rapid decliner (n=31) groups. Results A statistically significant difference in exertional desaturation was observed between rapid decliners and non-rapid decliners (17 vs. 8, p=0.003). No differences were found between the groups for age, smoking status, BODE index, and FEV1. Multivariate analysis showed that exertional desaturation was a significant independent predictor of rapid decline in patients with COPD (relative risk, 6.8; 95% CI, 1.8 to 25.4; p=0.004). Conclusion This study supports that exertional desaturation is a predictor of rapid lung function decline in male patients with COPD. PMID:24719141

  19. Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.

    PubMed

    Tang, Li; Zhao, Liying; Hong, Lingjuan; Yang, Fenyan; Sheng, Rong; Chen, Jianzhong; Shi, Ying; Zhou, Naimin; Hu, Yongzhou

    2013-10-01

    A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.

  20. Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo.

    PubMed

    Zhao, Yanxia; Yu, Dandan; Wu, Hongge; Liu, Hongli; Zhou, Hongxia; Gu, Runxia; Zhang, Ruiguang; Zhang, Sheng; Wu, Gang

    2014-02-01

    Suberoylanilide hydroxamic acid (SAHA), a potent pan-histone deacetylase (HDAC) inhibitor, has been clinically approved for the treatment of cutaneous T-cell lymphoma (CTCL). SAHA has also been shown to exert a variety of anticancer activities in many other types of tumors, however, few studies have been reported in large-cell lung carcinoma (LCC). Our study aimed to investigate the potential antitumor effects of SAHA on LCC cells. Here, we report that SAHA was able to inhibit the proliferation of the LCC cell line NCI-H460 in a dose- and time-dependent manner, induced cell apoptosis and G2/M cell cycle arrest, decreased AKT and ERK phosphorylation, inhibited the expression of pro-angiogenic factors (VEGF, HIF-1α) in vitro, and suppressed tumor progression in an NCI-H460 cell nude mouse xenograft model in vivo. These results indicate that SAHA can exert its strong antitumor effects in LCC patient.

  1. Synchrony and exertion during dance independently raise pain threshold and encourage social bonding

    PubMed Central

    Tarr, Bronwyn; Launay, Jacques; Cohen, Emma; Dunbar, Robin

    2015-01-01

    Group dancing is a ubiquitous human activity that involves exertive synchronized movement to music. It is hypothesized to play a role in social bonding, potentially via the release of endorphins, which are analgesic and reward-inducing, and have been implicated in primate social bonding. We used a 2 × 2 experimental design to examine effects of exertion and synchrony on bonding. Both demonstrated significant independent positive effects on pain threshold (a proxy for endorphin activation) and in-group bonding. This suggests that dance which involves both exertive and synchronized movement may be an effective group bonding activity. PMID:26510676

  2. Synchrony and exertion during dance independently raise pain threshold and encourage social bonding.

    PubMed

    Tarr, Bronwyn; Launay, Jacques; Cohen, Emma; Dunbar, Robin

    2015-10-01

    Group dancing is a ubiquitous human activity that involves exertive synchronized movement to music. It is hypothesized to play a role in social bonding, potentially via the release of endorphins, which are analgesic and reward-inducing, and have been implicated in primate social bonding. We used a 2 × 2 experimental design to examine effects of exertion and synchrony on bonding. Both demonstrated significant independent positive effects on pain threshold (a proxy for endorphin activation) and in-group bonding. This suggests that dance which involves both exertive and synchronized movement may be an effective group bonding activity.

  3. The Effects of Local Exertion and Anticipation on the Performance of a Discrete Skill.

    DTIC Science & Technology

    1986-01-01

    8217 AFIT/CI/NR 86- 81D . TITLE (and Subtitle) 5. TYPE OF REPORT & PERIOD COVERED The Effects of Local Exertion and Anticipation on the Performance of a...34I i. ’’ , ’."k’ ’* The Effects of Local Exertion and Anticipation on the Performance of a Discrete Skill by Bruce Jaeger Captain, USAF 1986 NTIS GRA...Carolina State University I I p -. ~~ h~~~A k. .IbJ .~ .2~ ~or The Effects of Local Exertion and Anticipation on the Performance of a Discrete Skill by

  4. 9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors.

    PubMed

    Rodrigues, Marili V N; Barbosa, Alexandre F; da Silva, Júlia F; dos Santos, Deborah A; Vanzolini, Kenia L; de Moraes, Marcela C; Corrêa, Arlene G; Cass, Quezia B

    2016-01-15

    A novel potent xanthine oxidase inhibitor, 3-nitrobenzoyl 9-deazaguanine (LSPN451), was selected from a series of 10 synthetic derivatives. The enzymatic assays were carried out using an on-flow bidimensional liquid chromatography (2D LC) system, which allowed the screening¸ the measurement of the kinetic inhibition constant and the characterization of the inhibition mode. This compound showed a non-competitive inhibition mechanism with more affinity for the enzyme-substrate complex than for the free enzyme, and inhibition constant of 55.1±9.80 nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein.

  5. Design, synthesis and biological evaluation of potent FAAH inhibitors.

    PubMed

    Tuo, Wei; Leleu-Chavain, Natascha; Barczyk, Amélie; Renault, Nicolas; Lemaire, Lucas; Chavatte, Philippe; Millet, Régis

    2016-06-01

    A new series of 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and evaluated for their biological activity. Different pharmacomodulations have been explored and the lipophilicity of these compounds was assessed. Investigation of the in vitro biological activity led to the identification of 5 compounds as potent FAAH inhibitors, their good FAAH inhibition capacity is probably correlated with their suitable lipophilicity. Specifically, compound 25 showed similar inhibition potency against FAAH in comparison with URB597, one of the most potent FAAH inhibitor known to date.

  6. Novel indole sulfides as potent HIV-1 NNRTIs.

    PubMed

    Brigg, Siobhan; Pribut, Nicole; Basson, Adriaan E; Avgenikos, Moscos; Venter, Reinhardt; Blackie, Margaret A; van Otterlo, Willem A L; Pelly, Stephen C

    2016-03-15

    In a previous communication we described a series of indole based NNRTIs which were potent inhibitors of HIV replication, both for the wild type and K103N strains of the virus. However, the methyl ether functionality on these compounds, which was crucial for potency, was susceptible to acid promoted indole assisted SN1 substitution. This particular problem did not bode well for an orally bioavailable drug. Here we describe bioisosteric replacement of this problematic functional group, leading to a series of compounds which are potent inhibitors of HIV replication, and are acid stable.

  7. Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome.

    PubMed

    Mrówka, Piotr; Głodkowska, Eliza; Młynarczuk-Biały, Izabela; Biały, Lukasz; Kuckelkorn, Ulrike; Nowis, Dominika; Makowski, Marcin; Legat, Magdalena; Gołab, Jakub

    2008-01-01

    Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-gamma agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.

  8. AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects

    PubMed Central

    Papp, Diána; Kovács, Tibor; Billes, Viktor; Varga, Máté; Tarnóci, Anna; Hackler, László; Puskás, László G; Liliom, Hanna; Tárnok, Krisztián; Schlett, Katalin; Borsy, Adrienn; Pádár, Zsolt; Kovács, Attila L; Hegedűs, Krisztina; Juhász, Gábor; Komlós, Marcell; Erdős, Attila; Gulyás, Balázs; Vellai, Tibor

    2016-01-01

    abstract Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases. PMID:26312549

  9. Na⁺-K⁺-ATPase, a potent neuroprotective modulator against Alzheimer disease.

    PubMed

    Zhang, Li-Nan; Sun, Yong-Jun; Pan, Shuo; Li, Jun-Xia; Qu, Yin-E; Li, Yao; Wang, Yong-Li; Gao, Zi-Bin

    2013-02-01

    Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na⁺-K⁺-ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in-depth understanding of Na⁺-K⁺-ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD. 1. The deficiency in Na⁺, K⁺-ATPase α1, α2 and α3 isoform genes induced learning and memory deficits, and α isoform was evidently changed in AD, revealing that Na⁺, K⁺-ATPase α isoform genes may play an important role in AD. 2. Some factors, such as β-amyloid, cholinergic and oxidative stress, can modulate learning and memory in AD through the mondulation of Na⁺-K⁺-ATPase activity. 3. Some substances, such as Zn, s-Ethyl cysteine, s-propyl cysteine, citicoline, rivastigmine, Vit E, memantine, tea polyphenol, curcumin, caffeine, Alpinia galanga (L.) fractions, and Bacopa monnieri could play a role in improving memory performance and exert protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.

  10. Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms

    PubMed Central

    Shi, Xiao-Jing; Yu, Bin; Wang, Jun-Wei; Qi, Ping-Ping; Tang, Kai; Huang, Xin; Liu, Hong-Min

    2016-01-01

    Cancer cells always have increased ROS levels, thus making them more vulnerable to persistent endogenous oxidative stress. The biochemical difference between cancer and normal cells could be exploited to achieve selective cancer cell killing by exogenous ROS-producing agents. Herein we described a structurally novel steroidal spirooxindole by241 and its anticancer efficacy. By241 exhibited potent inhibition against human cancer cells and less toxic to normal cells. By241 concentration-dependently induced apoptosis of MGC-803 and EC9706 cells, accompanied with the mitochondrial dysfunction and increased ROS levels. NAC can completely restore the decreased cell viability of MGC-803 cells caused by by241, suggesting ROS-mediated mechanisms. The expression levels of proteins involved in the mitochondrion-related pathways were detected, showing increased expression of proapoptotic proteins and decreased expression of anti-apoptotic proteins, and activation of caspases-9/-3, but without activating caspase-8 expression. Pretreatment with Z-VAD-FMK partially rescued by241-induced apoptosis of MGC-803 cells. Additionally, by241 inhibited mTOR, activated p53 and its downstream proteins, cleaved MDM2 and PI3K/AKT as well as NF-κB signaling pathway. In vivo experiments showed that by241 did not have significant acute oral toxicity and exerted good anticancer efficacy against MGC-803 bearing mice models. Therefore, by241 may serve as a lead for further development for cancer therapy. PMID:27527552

  11. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.

    PubMed

    Freeman, Michael M; Seaman, Michael S; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D; Chen, Bing

    2010-12-08

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  12. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody

    PubMed Central

    Freeman, Michael M.; Seaman, Michael S.; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D.; Chen, Bing

    2010-01-01

    Summary Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry. PMID:21134642

  13. Alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons.

    PubMed

    Osakada, Fumitaka; Hashino, Asami; Kume, Toshiaki; Katsuki, Hiroshi; Kaneko, Shuji; Akaike, Akinori

    2004-11-01

    Oxidative stress and apoptosis play pivotal roles in the pathogenesis of neurodegenerative diseases. We investigated the effects of vitamin E analogs on oxidative stress and apoptosis using primary neuronal cultures of rat striatum. A tocotrienol-rich fraction of edible oil derived from palm oil (Tocomin 50%), which contains alpha-tocopherol, and alpha-, gamma- and delta-tocotrienols, significantly inhibited hydrogen peroxide (H2O2)-induced neuronal death. Each of the tocotrienols, purified from Tocomin 50% by high-performance liquid chromatography, significantly attenuated H2O2-induced neurotoxicity, whereas alpha-tocopherol did not. alpha-, gamma- and delta-Tocotrienols also provided significant protection against the cytotoxicity of a superoxide donor, paraquat, and nitric oxide donors, S-nitrosocysteine and 3-morpholinosydnonimine. Moreover, tocotrienols blocked oxidative stress-mediated cell death with apoptotic DNA fragmentation caused by an inhibitor of glutathione synthesis, L-buthionine-[S,R]-sulfoximine. In addition, alpha-tocotrienol, but not gamma- or delta-tocotrienol, prevented oxidative stress-independent apoptotic cell death, DNA cleavage and nuclear morphological changes induced by a non-specific protein kinase inhibitor, staurosporine. These findings suggest that alpha-tocotrienol can exert anti-apoptotic neuroprotective action independently of its antioxidant property. Among the vitamin E analogs examined, alpha-tocotrienol exhibited the most potent neuroprotective actions in rat striatal cultures.

  14. AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects.

    PubMed

    Papp, Diána; Kovács, Tibor; Billes, Viktor; Varga, Máté; Tarnóci, Anna; Hackler, László; Puskás, László G; Liliom, Hanna; Tárnok, Krisztián; Schlett, Katalin; Borsy, Adrienn; Pádár, Zsolt; Kovács, Attila L; Hegedűs, Krisztina; Juhász, Gábor; Komlós, Marcell; Erdős, Attila; Gulyás, Balázs; Vellai, Tibor

    2016-01-01

    Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.

  15. Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase.

    PubMed

    Lee, Yu-Ting; Cui, Chang-Jun; Chow, Eve W L; Pue, Nason; Lonhienne, Thierry; Wang, Jian-Guo; Fraser, James A; Guddat, Luke W

    2013-01-10

    The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans , attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed, and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate (10c), which has a K(i) value of 3.8 nM for C. albicans AHAS and an MIC₉₀ of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity toward C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell.

  16. Chiari-associated exertional, cough, and sneeze headache responsive to medical therapy.

    PubMed

    Buzzi, M Gabriella; Formisano, Rita; Colonnese, Claudio; Pierelli, Francesco

    2003-04-01

    Benign exertional headache is coded as a separate entity within the International Headache Society's classification system, but the pathophysiological mechanisms underlying this clinical headache subtype are unknown and possibly are similar to those generating migraine. Coexistence of migraine and benign exertional headache in the same patient is not unusual, and antimigraine pharmacologic treatments are often effective in both headache types. Regardless, optimal management mandates that the clinician exclude any intracranial or systemic disease that could mimic "primary" exertional headache. The same holds for primary headaches induced by coughing or sneezing; congenital malformations or neoplasms, particularly within the posterior fossa, are not rare in these patients. The neurologic examination may not be sufficiently sensitive to detect the offending lesion. We describe a patient with migraine without aura and exertional secondary headache due to Chiari malformation type I whose headaches responded to treatment with propranolol and indomethacin.

  17. Petrological Features of The Post-Collisional Volcanics on the Izmir-Ankara-Erzincan Suture Zone at Around Almus and Yıldızeli Regions, NE Turkey.

    NASA Astrophysics Data System (ADS)

    Göçmengil, G.; Karacik, Z.; Genç, Ş. C.

    2014-12-01

    Following the closure of the northern Neo-Tethyan ocean, post-collisional magmatism developed both on the Izmir-Ankara-Erzincan suture zone (IAESZ) and the northern (Pontides) and southern (Kırşehir block) continents. Cenozoic volcanics (particularly Middle to Upper Eocene) from the Almus and Yıldızeli regions (NE, Turkey) have poorly known and exposed along the northern and southern part of the IAESZ respectively. In this presentation; we present geological, geochemical and isotopic data of these volcanic rocks to characterize the petrological evolution and petrogenesis on the different tectonic blocks. Almus region, have a composite basement of Mesozoic metamorphic and ophiolitic rocks. Volcanic and sedimentary units of the Middle Eocene covering the basement units have a stratigraphic sequence of: a basal conglomerate; fossiliferous sandstone/shale; epiclastic rocks; auto-brecciated lavas with basalt/basaltic andesite lava flows. All these units are cut by trachyte stocks. Besides, basement of Yıldızeli region consisting of Cretaceous Kırşehir block metamorphics with IAESZ melangé and flysch units. Volcanic and sedimentary units covers the basement are trachyte-trachyandesite lavas; fossiliferous limestone; basalt/basaltic andesite lava flows; pyroclastic units with dacitic lavas. Basalt/basaltic andesites from Almus region are sub-alkaline/mildly alkaline and display middle to high-K character. REE data display relative enrichments in LILE (Sr, K, Rb, Ba, Th) together with negative anomalies of Nb, Ta and P. Trachyte stocks are shoshonitic and display LILE enrichment together with negative patters of Nb, Ta, P and Eu. Besides, trachyte-trachyandesite and basalt/basaltic andesite from Yıldızeli region are sub-alkaline/mildly alkaline with middle-K to shoshonitic character. REE patterns show enrichments in LILE and depletion of Nb, Ta, P and Ti for both rock suites. The 87Sr/86Sr and 143Nd/144Nd ratios of volcanic rocks from both regions, range from 0

  18. [An imported Chikungunya fever case from New Delhi, India to Ankara, Turkey: the first imported case of Turkey and review of the literature].

    PubMed

    Yağcı Çağlayık, Dilek; Uyar, Yavuz; Korukluoğlu, Gülay; Ertek, Mustafa; Unal, Serhat

    2012-01-01

    Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that causes an acute febrile illness, chikungunya fever. CHIKV virus is geographically distributed in Africa, India, and South-East Asia. Chikungunya fever outbreaks have been reported from India since 2006. The incubation period is 3-7 days, and the disease is characterized by sudden onset of high fever and severe arthralgia. Other symptoms can be rash, headache, fatigue, nausea-vomiting, and myalgias. Here, we report the first Chikungunya case imported from India, New-Delhi to Ankara, Turkey. In December 2010, a 55-year-old female Turkish government employee living in urban area of New Delhi for the last 3 years had sudden onset fever up to 38.4°C for 2 days. Itching rash and arthralgia also developed. Symptomatic treatment was given to patient in New Delhi. She returned to Turkey and was admitted to Hacettepe University Medical Faculty, Department of Internal Medicine, Infectious Diseases Unit, since arthralgia has continued on the 26th day of her complaints. Hepatomegaly and tenosynovitis were detected in her physical examination. Serum sample sent to Refik Saydam National Public Health Agency, Virology Reference and Research Laboratory, yielded negative results for specific IgM and IgG antibodies against Hantavirus and Dengue virus types 1-4; however, the results were positive for CHIKV specific IgM and IgG antibodies by commercial immunofluorescence method (Euroimmun, Germany). CHIKV RNA which was searched by in-house real-time RT-PCR was negative. The second serum sample obtained three weeks later also found positive for CHIKV specific IgM and IgG antibodies. This was the first laboratory confirmed imported Chikungunya case in Turkey. There are predictions regarding the presence of Aedes species mosquitos that can transmit this virus in Turkey. This case report will be an alarming signal for the clinicians in our country to consider Chikungunya fever in the differential diagnosis of patients

  19. Descriptive Features of Mesothelioma Cases Diagnosed in a Special Hospital in Ankara and Assessment of Domestic Environmental Exposure to Asbestosis and Erionite: Preliminary Results

    NASA Astrophysics Data System (ADS)

    Demirkaya, E.; Özden, A.; Aydogdu, K.; Polat, A.; Findik, G.; Agackiran, Y.; Ozaydin, S.; Ozturk, M.; Acikel, C.

    2013-05-01

    Background: Unlike Western countries where asbestosis and erionite exposure is industrial, domestic exposure of these chriystals is common in central and eastern Turkey where they are used as a constrcution material for houses. This life-long exposure to these materials has been showed to be causing endemies of mesothelioma at younger ages in central Turkey. In this study it was aimed to assess the descriptive features of malignant mesothelioma cases and evaluate the domestic exposure of asbestosis and erionite. Method: Data were obtained through retrospective reviewing of the patient files of a pulmonary disease hospital in Ankara. Demographical features such as age, gender, the place of birth, migration and living, age of diagnosis and some clinical features were evaluated. Results: A total of 44 files of patients diagnosed with malignant mesothelioma were screened. The female to male ratio was 19/25. Of the patients 43 (97 %) were born in asbestosis-rich and only one (3 %)was born in erionite-rich region. All of the patients had resided in asbestosis-rich regions where they were born and the places where some of the patients moved were known to be rich for asbestosis as well. The age of diagnosis was between 32 and 78 years and the median age of diagnosis was 54,5 years. Family history of malignancy was negative in 39 patients (88.6%) and was positive in 5 patients (11.4%). History for smoking was 40.9%. The 81.1 % of the patients applied with the complaint of dispnea; 48.8 % with cough and 45.5 % with chest pain. Median time period between the date of disease onset and diagnosis was 91 days. The most rapid diagnosis was made as early as 28 days. Pleural fluid was seen in 95.5 % while pleural thickening was seen in 29,5 % of the patients. Respiratory funcitons were found to be deteriorated in 86.4 %. The histological types of epitheloid and mixt mesothelioma were seen with the percentages of 69 % and 31 % respectively. Conclusion: This was a descriptive study

  20. Innate Immune Sensing of Modified Vaccinia Virus Ankara (MVA) Is Mediated by TLR2-TLR6, MDA-5 and the NALP3 Inflammasome

    PubMed Central

    Delaloye, Julie; Roger, Thierry; Steiner-Tardivel, Quynh-Giao; Le Roy, Didier; Knaup Reymond, Marlies; Akira, Shizuo; Petrilli, Virginie; Gomez, Carmen E.; Perdiguero, Beatriz; Tschopp, Jürg; Pantaleo, Giuseppe; Esteban, Mariano; Calandra, Thierry

    2009-01-01

    Modified vaccinia virus Ankara (MVA) is an attenuated double-stranded DNA poxvirus currently developed as a vaccine vector against HIV/AIDS. Profiling of the innate immune responses induced by MVA is essential for the design of vaccine vectors and for anticipating potential adverse interactions between naturally acquired and vaccine-induced immune responses. Here we report on innate immune sensing of MVA and cytokine responses in human THP-1 cells, primary human macrophages and mouse bone marrow-derived macrophages (BMDMs). The innate immune responses elicited by MVA in human macrophages were characterized by a robust chemokine production and a fairly weak pro-inflammatory cytokine response. Analyses of the cytokine production profile of macrophages isolated from knockout mice deficient in Toll-like receptors (TLRs) or in the adapter molecules MyD88 and TRIF revealed a critical role for TLR2, TLR6 and MyD88 in the production of IFNβ-independent chemokines. MVA induced a marked up-regulation of the expression of RIG-I like receptors (RLR) and the IPS-1 adapter (also known as Cardif, MAVS or VISA). Reduced expression of RIG-I, MDA-5 and IPS-1 by shRNAs indicated that sensing of MVA by RLR and production of IFNβ and IFNβ-dependent chemokines was controlled by the MDA-5 and IPS-1 pathway in the macrophage. Crosstalk between TLR2-MyD88 and the NALP3 inflammasome was essential for expression and processing of IL-1β. Transcription of the Il1b gene was markedly impaired in TLR2−/− and MyD88−/− BMDM, whereas mature and secreted IL-1β was massively reduced in NALP3−/− BMDMs or in human THP-1 macrophages with reduced expression of NALP3, ASC or caspase-1 by shRNAs. Innate immune sensing of MVA and production of chemokines, IFNβ and IL-1β by macrophages is mediated by the TLR2-TLR6-MyD88, MDA-5-IPS-1 and NALP3 inflammasome pathways. Delineation of the host response induced by MVA is critical for improving our understanding of poxvirus antiviral escape

  1. The use of certified seeds of improved wheat varieties in farms and the contributions of certified seed usage to enterprise economies: the case of Ankara province in Turkey.

    PubMed

    Tanrivermiş, Harun; Akdoğan, Ilyas

    2007-12-15

    In this research, the use of certificated seeds of improved wheat varieties in farms of Ankara, which have an important share in wheat production of Turkey and the contributions of the certified seeds usage to enterprise economy have been evaluated by using data collected from farms via a questionnaire. The low level of use of certificated wheat seed in farms is associated with many factors, such as price of the seed (cost), yield gains and suitability of the varieties for the farming aims of producers. Average productivity is 49.5% and average net profit is 39.7% higher in the production of wheat with certificated seeds of improved varieties in farms in comparison to farming with traditional varieties. Average productivity in wheat production with uncertified seeds of improved varieties is 24.9% and net profit per unit area is 24.3% higher than wheat production with traditional varieties. The net economic benefit of wheat production using certificated seeds of improved varieties and that of wheat farming with uncertified seeds has been estimated at $ 102.40 and $ 62.70 ha(-1), respectively. Some $ 6.4 benefit is generated in return for $ 1 of expense in wheat farming with certificated seeds of improved varieties instead of traditional varieties. In the absence of state subsidies for certificated seeds the use of uncertified seeds seems to be advantageous for producers. While the amount of subsidy per hectare will be a minimum of $ 101 for certificated seeds per hectare of planting area (as technological improvement), the support will be encouraging for usage of certified seeds. Many variables, such as farm size, use of certified seeds, topography of land, production system, education level and frequency of visiting the agriculture organizations of the producers influence the level of gross profit per unit area in wheat farming. Low level of use of certificated seed in farms decreases the economic benefit of new varieties which are developed as a result of long

  2. The carboxy-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity.

    PubMed Central

    Di Fiore, P P; Segatto, O; Lonardo, F; Fazioli, F; Pierce, J H; Aaronson, S A

    1990-01-01

    The erbB-2 gene product, gp185erbB-2, displays a potent transforming effect when overexpressed in NIH 3T3 cells. In addition, it possesses constitutively high levels of tyrosine kinase activity in the absence of exogenously added ligand. In this study, we demonstrate that its carboxy-terminal domain exerts an enhancing effect on erbB-2 kinase and transforming activities. A premature termination mutant of the erbB-2 protein, lacking the entire carboxy-terminal domain (erbB-2 delta 1050), showed a 40-fold reduction in transforming ability and a lowered in vivo kinase activity for intracellular substrates. When the carboxy-terminal domain of erbB-2 was substituted for its analogous region in the epidermal growth factor receptor (EGFR) (EGFR/erbB-2COOH chimera), it conferred erbB-2-like properties to the EGFR, including transforming ability in the absence of epidermal growth factor, elevated constitutive autokinase activity in vivo and in vitro, and constitutive ability to phosphorylate phospholipase C-gamma. Conversely, a chimeric erbB-2 molecule bearing an EGFR carboxy-terminal domain (erbB-2/EGFRCOOH chimera) showed reduced transforming and kinase activity with respect to the wild-type erbB-2 and was only slightly more efficient than the erbB-2 delta 1050 mutant. Thus, we conclude that the carboxy-terminal domains of erbB-2 and EGFR exert different regulatory effects on receptor kinase function and biological activity. The up regulation of gp185erbB-2 enzymatic activity exerted by its carboxy-terminal domain can explain, at least in part, its constitutive level of kinase activity. Images PMID:2188097

  3. A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

    PubMed Central

    Sulaiman, Azad A.; Zolnierczyk, Katarzyna; Japa, Ornampai; Owen, Jonathan P.; Maddison, Ben C.; Hodgkinson, Jane E.; Gough, Kevin C.

    2016-01-01

    The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allowing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF) superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL)-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory receptor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is dependent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs) in their evasion of antibody-dependent cell cytotoxicity (ADCC) by reducing the NO response of macrophages—again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for dampened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow for a reduced

  4. The Influence of a Bout of Exertion on Novice Barefoot Running Dynamics.

    PubMed

    Hashish, Rami; Samarawickrame, Sachithra D; Baker, Lucinda; Salem, George J

    2016-06-01

    Barefoot, forefoot strike (FFS) running has recently risen in popularity. Relative to shod, rear-foot strike (RFS) running, employing a FFS is associated with heightened triceps surae muscle activation and ankle mechanical demand. Novice to this pattern, it is plausible that habitually shod RFS runners exhibit fatigue to the triceps surae when acutely transitioning to barefoot running, thereby limiting their ability to attenuate impact. Therefore, the purpose was to determine how habitually shod RFS runners respond to an exertion bout of barefoot running, operationally defined as a barefoot run 20% of mean daily running distance. Twenty-one RFS runners performed novice barefoot running, before and after exertion. Ankle peak torque, triceps surae EMG median frequency, foot-strike patterns, joint energy absorption, and loading rates were evaluated. Of the 21 runners, 6 maintained a RFS, 10 adopted a mid-foot strike (MFS), and 5 adopted a FFS during novice barefoot running. In-response to exertion, MFS and FFS runners demonstrated reductions in peak torque, median frequency, and ankle energy absorption, and an increase in loading rate. RFS runners demonstrated reductions in peak torque and loading rate. These results indicate that a short bout of running may elicit fatigue to novice barefoot runners, limiting their ability to attenuate impact. Key pointsIn response to exertion, novice barefoot runners demonstrate fatigue to their soleus.In response to exertion, novice barefoot runners demonstrate a reduction in ankle energy absorptionIn response to exertion, novice barefoot runners demonstrate an increase in loading rate.

  5. The Influence of a Bout of Exertion on Novice Barefoot Running Dynamics

    PubMed Central

    Hashish, Rami; Samarawickrame, Sachithra D.; Baker, Lucinda; Salem, George J.

    2016-01-01

    Barefoot, forefoot strike (FFS) running has recently risen in popularity. Relative to shod, rear-foot strike (RFS) running, employing a FFS is associated with heightened triceps surae muscle activation and ankle mechanical demand. Novice to this pattern, it is plausible that habitually shod RFS runners exhibit fatigue to the triceps surae when acutely transitioning to barefoot running, thereby limiting their ability to attenuate impact. Therefore, the purpose was to determine how habitually shod RFS runners respond to an exertion bout of barefoot running, operationally defined as a barefoot run 20% of mean daily running distance. Twenty-one RFS runners performed novice barefoot running, before and after exertion. Ankle peak torque, triceps surae EMG median frequency, foot-strike patterns, joint energy absorption, and loading rates were evaluated. Of the 21 runners, 6 maintained a RFS, 10 adopted a mid-foot strike (MFS), and 5 adopted a FFS during novice barefoot running. In-response to exertion, MFS and FFS runners demonstrated reductions in peak torque, median frequency, and ankle energy absorption, and an increase in loading rate. RFS runners demonstrated reductions in peak torque and loading rate. These results indicate that a short bout of running may elicit fatigue to novice barefoot runners, limiting their ability to attenuate impact. Key points In response to exertion, novice barefoot runners demonstrate fatigue to their soleus. In response to exertion, novice barefoot runners demonstrate a reduction in ankle energy absorption In response to exertion, novice barefoot runners demonstrate an increase in loading rate PMID:27274672

  6. Assessment of decision-making performance and in-game physical exertion of Australian football umpires.

    PubMed

    Larkin, Paul; O'Brien, Brendan; Mesagno, Christopher; Berry, Jason; Harvey, Jack; Spittle, Michael

    2014-01-01

    The aim of this study is to investigate the effects of in-game physical exertion on decision-making performance of Australian football umpires. Fifteen Australian football umpires (Mage = 36, s = 13.5 years; Mgames umpired = 235.2, s = 151.3) volunteered to participate in the study. During five competitive Australian football pre-season games, measures of in-game physical exertion (blood lactate levels, global positioning system [GPS]) and decision-making performance (video-based test) were obtained. There were no significant correlations between physical exertion in a particular quarter and decision-making performance in either the same quarter or any other quarter. Video-based decision-making performance was effected by time in game χ(2)(3) = 24.24, P = 0.001, with Quarter 4 performance significantly better than both Quarter 2 and Quarter 3. In-game physical exertion (blood lactate) significantly decreased over the course of the game χ(2)(3) = 11.58, P = 0.009. Results indicate no definable link between in-game physical exertion and decision-making performance. It is, however, presumed that decision-making performance may be affected by the time or context of the game. Future research is warranted to explore the relationship between physical exertion and decision-making performance to potentially inform Australian football umpire training programmes that replicate in-game physical and decision-making demands.

  7. Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases.

    PubMed

    Pascual, J; Iglesias, F; Oterino, A; Vázquez-Barquero, A; Berciano, J

    1996-06-01

    We analyzed our experience with cough, exertional, and vascular sexual headaches, evaluated the interrelationships among them, and examined the possible symptomatic cases. Seventy-two patients consulted us because of headaches precipitated by coughing (n = 30), physical exercise (n = 28), or sexual excitement (n = 14). Thirty (42%) were symptomatic. The 17 cases of symptomatic cough headache were secondary to Chiari type I malformation, while the majority of cases of symptomatic exertional headaches and the only case of symptomatic sexual headache were secondary to subarachnoid hemorrhage. Although the precipitant was the same, benign and symptomatic headaches differed in several clinical aspects, such as age at onset, associated clinical manifestations, or response to pharmacologic treatment. Although sharing some properties, such as male predominance, benign cough headache and benign exertional headache are clinically separate conditions. Benign cough headache began significantly later, 43 years on average, than benign exertional headache. By contrast, our findings suggest that there is a close relationship between benign exertional headache and benign vascular sexual headache. We conclude that benign and symptomatic cough headaches are different from both benign and symptomatic exertional and sexual headaches.

  8. Quadriceps activation and perceived exertion during a high intensity, steady state contraction to failure.

    PubMed

    Pincivero, D M; Gear, W S

    2000-04-01

    The ability to sustain a high-intensity, steady-state muscle contraction may have differential effects on neuromuscular activation and perceived exertion. The purpose of this study was to examine changes in neuromuscular activation and perceived exertion at a near-maximal steady-state contraction of the quadriceps in healthy men. Seventeen healthy, college-aged male volunteers were studied during isometric contractions equivalent to 80% of the maximum voluntary contraction (MVC). Perceived exertion was measured with a modified category-ratio scale (CR-10). The CR-10 scale was anchored with one high anchor at 100% MVC and one low anchor at 10% MVC. Subjects then performed an 80% MVC for as long as they could sustain it. Subjects were asked to rate the feelings in their quadriceps every 5 s during the contraction. The results demonstrated significant increases in neuromuscular activation of the vastus medialis and vastus lateralis muscles (P < 0.05) during the 80% MVC, but there were no significant muscle by time interactions. The results also demonstrated a significant increase (P < 0.05) in perceived exertion during the 80% MVC. Neuromuscular activation of both muscles, and perceived exertion, were found to increase in linear (P < 0.05) and quadratic (P < 0.05) trends. Alterations in motor unit discharge properties or impairments in muscle fiber membrane excitability may account for nonlinear increases in vastii muscle activation and perceived exertion.

  9. Extensive screening for herbal extracts with potent antioxidant properties.

    PubMed

    Niwano, Yoshimi; Saito, Keita; Yoshizaki, Fumihiko; Kohno, Masahiro; Ozawa, Toshihiko

    2011-01-01

    This paper summarizes our research for herbal extracts with potent antioxidant activity obtained from a large scale screening based on superoxide radical (O(2) (•-)) scavenging activity followed by characterization of antioxidant properties. Firstly, scavenging activity against O(2) (•-) was extensively screened from ethanol extracts of approximately 1000 kinds of herbs by applying an electron spin resonance (ESR)-spin trapping method, and we chose four edible herbal extracts with prominently potent ability to scavenge O(2) (•-). They are the extracts from Punica granatum (Peel), Syzygium aromaticum (Bud), Mangifera indica (Kernel), and Phyllanthus emblica (Fruit). These extracts were further examined to determine if they also scavenge hydroxyl radical ((•)OH), by applying the ESR spin-trapping method, and if they have heat resistance as a desirable characteristic feature. Experiments with the Fenton reaction and photolysis of H(2)O(2) induced by UV irradiation demonstrated that all four extracts have potent ability to directly scavenge (•)OH. Furthermore, the scavenging activities against O(2) (•-) and (•)OH of the extracts of P. granatum (peel), M. indica (kernel) and P. emblica (fruit) proved to be heat-resistant.The results of the review might give useful information when choosing a potent antioxidant as a foodstuff. For instance, the four herbal extracts chosen from extensive screening possess desirable antioxidant properties. In particular, the extracts of the aforementioned three herbs are expected to be suitable for food processing in which thermal devices are used, because of their heat resistance.

  10. Benzoxazinones as potent positive allosteric AMPA receptor modulators: part I.

    PubMed

    Mueller, Rudolf; Li, Yong-Xin; Hampson, Aidan; Zhong, Sheng; Harris, Clayton; Marrs, Christopher; Rachwal, Stanislaw; Ulas, Jolanta; Nielsson, Lena; Rogers, Gary

    2011-07-01

    AMPA receptors (AMPARs) are an increasingly important therapeutic target in the CNS. Aniracetam, the first identified potentiator of AMPARs, led to the rigid and more potent CX614. This lead molecule was optimized in order to increase affinity towards the AMPA receptor. The substitution of the dioxine with a benzoxazinone ring system increased the activity and allowed further investigation of the sidechain SAR.

  11. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors

    SciTech Connect

    Iserloh, U.; Wu, Y.; Cumming, J.N.; Pan, J.; Wang, L.Y.; Stamford, A.W.; Kennedy, M.E.; Kuvelkar, R.; Chen, X.; Parker, E.M.; Strickland, C.; Voigt, J.

    2008-08-18

    Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date. The discovery and development of novel BACE-1 inhibitors incorporating a cyclic amine scaffold is described.

  12. DIMETHYLARSINE AND TRIMETHYLARSINE ARE POTENT GENOTOXINS IN VITRO.

    EPA Science Inventory

    Dimethylarsine and Trimethylarsine are potent genotoxins in vitro
    Andrewes, P; Kitchin, KT; and Wallace, KA

    Abstract
    The mechanism of arsenic carcinogenesis is unclear. A complicating factor receiving increasing attention is that arsenic is biomethylated to form vari...

  13. Diethylamide of thujic acid: a potent repellent of Aedes aegypti.

    PubMed

    Hach, V; McDonald, E C

    1971-10-08

    A series of novel, representatively substituted amides of thujic acid were prepared and screened for insect repellent and attractant potential. In repel-lency tests the N,N-diethylamide was the most potent compound, surpassing the activity of the standard repellents dimethyl phthalate and fencholic acid. In contrast, the N-monoethylamide displayed attractant activity.

  14. Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci.

    PubMed

    Mohammad, Haroon; Younis, Waleed; Chen, Lu; Peters, Christine E; Pogliano, Joe; Pogliano, Kit; Cooper, Bruce; Zhang, Jianan; Mayhoub, Abdelrahman; Oldfield, Eric; Cushman, Mark; Seleem, Mohamed N

    2017-03-23

    The emergence of antibiotic-resistant bacterial species, such as vancomycin-resistant enterococci (VRE), necessitates the development of new antimicrobials. Here, we investigate the spectrum of antibacterial activity of three phenylthiazole-substituted aminoguanidines. These compounds possess potent activity against VRE, inhibiting growth of clinical isolates at concentrations as low as 0.5 μg/mL. The compounds exerted a rapid bactericidal effect, targeting cell wall synthesis. Transposon mutagenesis suggested three possible targets: YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)), and YubD. Both UPPP as well as undecaprenyl diphosphate synthase were inhibited by compound 1. YubA and YubD are annotated as transporters and may also be targets because 1 collapsed the proton motive force in membrane vesicles. Using Caenorhabditis elegans, we demonstrate that two compounds (1, 3, at 20 μg/mL) retain potent activity in vivo, significantly reducing the burden of VRE in infected worms. Taken altogether, the results indicate that compounds 1 and 3 warrant further investigation as novel antibacterial agents against drug-resistant enterococci.

  15. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.

    PubMed

    Guo, Dan-yang; Li, De-wen; Ning, Meng-meng; Dang, Xiang-yu; Zhang, Li-na; Zeng, Li-min; Hu, You-hong; Leng, Ying

    2015-10-30

    G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes.

  16. 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects.

    PubMed

    El Sayed, S M; El-Magd, R M Abou; Shishido, Y; Chung, S P; Diem, T H; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

    2012-02-01

    Oxidative stress-energy depletion therapy using oxidative stress induced by D-amino acid oxidase (DAO) and energy depletion induced by 3-bromopyruvate (3BP) was reported recently (El Sayed et al., Cancer Gene Ther., 19, 1-18, 2012). Even in the presence of oxygen, cancer cells oxidize glucose preferentially to produce lactate (Warburg effect) which seems vital for cancer microenvironment and progression. 3BP is a closely related structure to lactate and pyruvate and may antagonize their effects as a novel mechanism of its action. Pyruvate exerted a potent H(2)O(2) scavenging effect to exogenous H(2)O(2), while lactate had no scavenging effect. 3BP induced H(2)O(2) production. Pyruvate protected against H(2)O(2)-induced C6 glioma cell death, 3BP-induced C6 glioma cell death but not against DAO/D-serine-induced cell death, while lactate had no protecting effect. Lactate and pyruvate protected against 3BP-induced C6 glioma cell death and energy depletion which were overcome with higher doses of 3BP. Lactate and pyruvate enhanced migratory power of C6 glioma which was blocked by 3BP. Pyruvate and lactate did not protect against C6 glioma cell death induced by other glycolytic inhibitors e.g. citrate (inhibitor of phosphofructokinase) and sodium fluoride (inhibitor of enolase). Serial doses of 3BP were synergistic with citrate in decreasing viability of C6 glioma cells and spheroids. Glycolysis subjected to double inhibition using 3BP with citrate depleted ATP, clonogenic power and migratory power of C6 glioma cells. 3BP induced a caspase-dependent cell death in C6 glioma. 3BP was powerful in decreasing viability of human glioblastoma multiforme cells (U373MG) and C6 glioma in a dose- and time-dependent manner.

  17. Selenoprotein T Exerts an Essential Oxidoreductase Activity That Protects Dopaminergic Neurons in Mouse Models of Parkinson's Disease

    PubMed Central

    Boukhzar, Loubna; Hamieh, Abdallah; Cartier, Dorthe; Tanguy, Yannick; Alsharif, Ifat; Castex, Matthieu; Arabo, Arnaud; Hajji, Sana El; Bonnet, Jean-Jacques; Errami, Mohammed; Falluel-Morel, Anthony; Chagraoui, Abdeslam; Lihrmann, Isabelle

    2016-01-01

    Abstract Aims: Oxidative stress is central to the pathogenesis of Parkinson's disease (PD), but the mechanisms involved in the control of this stress in dopaminergic cells are not fully understood. There is increasing evidence that selenoproteins play a central role in the control of redox homeostasis and cell defense, but the precise contribution of members of this family of proteins during the course of neurodegenerative diseases is still elusive. Results: We demonstrated first that selenoprotein T (SelT) whose gene disruption is lethal during embryogenesis, exerts a potent oxidoreductase activity. In the SH-SY5Y cell model of dopaminergic neurons, both silencing and overexpression of SelT affected oxidative stress and cell survival. Treatment with PD-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone triggered SelT expression in the nigrostriatal pathway of wild-type mice, but provoked rapid and severe parkinsonian-like motor defects in conditional brain SelT-deficient mice. This motor impairment was associated with marked oxidative stress and neurodegeneration and decreased tyrosine hydroxylase activity and dopamine levels in the nigrostriatal system. Finally, in PD patients, we report that SelT is tremendously increased in the caudate putamen tissue. Innovation: These results reveal the activity of a novel selenoprotein enzyme that protects dopaminergic neurons against oxidative stress and prevents early and severe movement impairment in animal models of PD. Conclusions: Our findings indicate that selenoproteins such as SelT play a crucial role in the protection of dopaminergic neurons against oxidative stress and cell death, providing insight into the molecular underpinnings of this stress in PD. Antioxid. Redox Signal. 24, 557–574. PMID:26866473

  18. Elderly deaths in Ankara, Turkey.

    PubMed

    Akar, Taner; Karapirli, Mustafa; Akcan, Ramazan; Demirel, Birol; Akduman, Barış; Dursun, Ahmet Zahit; Sari, Serhat; Özkök, Alper

    2014-01-01

    According to World Health Organization, the life expectancy at birth is increasing. An increase in life expectancy might result in increased morbidity and mortality in elderly. The increase in the elderly population also leads to an increase in medico-legal problems, as well. Autopsy is of high importance for determination of cause of death in clinical and forensic cases. The purpose of this study was to find out general characteristics elderly deaths by examining forensic autopsy records. Out of 7033 forensic autopsies performed between years of 2007 and 2011, 1324 were elderly deaths and were included in the scope of the study. The records of public prosecutor office, crime scene investigation and autopsy findings were examined. The majority of victims (70.6%) were male, while 29.4% were female, with a male to female ratio of 2.4/1. Victims' ages ranged between 65 and 96 years, and the mean age was 74.8 years. A great number of presented elderly deaths were due to unnatural causes, followed by natural deaths cases. Out of unnatural deaths, 63.2% were related to accidents, 23.7% were suicides, and remaining 13.1% were homicides. More than half (56.6%) of all suicidal deaths were due to hanging. Of natural deaths, the majority (82.7%) were due to cardiovascular system disease. In the presented series the cause of death was determined in 90.9% of all elderly deaths, which validates the need for a forensic autopsy. Data obtained through autopsy procedures is of high importance for death statistics.

  19. F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential.

    PubMed

    Koek, W; Patoiseau, J F; Assié, M B; Cosi, C; Kleven, M S; Dupont-Passelaigue, E; Carilla-Durand, E; Palmier, C; Valentin, J P; John, G; Pauwels, P J; Tarayre, J P; Colpaert, F C

    1998-10-01

    F 11440 (4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H, 4H-1,2,4-triazin-3,5-dione) was the outcome of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT1A binding sites (pKi, 8.33) was higher than that of buspirone (pKi, 7.50), and somewhat lower than that of flesinoxan (pKi, 8.91). In vivo, F 11440 was 4- to 20-fold more potent than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively). F 11440 did not have detectable antidopaminergic activity (unlike buspirone, which inhibited all of the directly observable behavioral effects of methylphenidate in rats), showed no evidence of antihistaminergic activity (unlike flesinoxan, which protected against the effects of a histamine aerosol in guinea pigs), and had a 70-fold separation between its 5-HT1A agonist and alpha-1 adrenergic antagonist properties (measured as the ability to inhibit the methoxamineinduced increase in blood pressure in rats), unlike flesinoxan, which showed a <3-fold separation. In HeLa cells expressing human 5-HT1A receptors, F 11440 decreased the forskolin-induced increase in AMP, and, based on its maximal effect, was found to have an intrinsic activity of 1.0 relative to that of 5-HT, which was significantly higher than that of buspirone (0.49), ipsapirone (0.46) and flesinoxan (0.93). Consistent with the aforementioned hypothesis, F 11440 produced anxiolytic- and antidepressant-like effects in animal models (i.e., increased punished responding in a pigeon conflict procedure and decreased immobility in a rat forced swimming test, respectively) that were more

  20. Exertional responses to sprint interval training: a comparison of 30-sec. and 60-sec. conditions.

    PubMed

    Kilpatrick, Marcus W; Greeley, Samuel J

    2014-06-01

    The purpose of this study was to assess the effect of sprint interval training on rating of perceived exertion. 20 healthy participants (11 men, 9 women; M age = 23 yr.) completed a maximal cycle ergometer test and two high-intensity interval training cycling sessions. Each session utilized the same work-to-rest ratio (1:1), work intensity (90% max), recovery intensity (10% work intensity), and session duration (16 min.). Trials differed on duration of the interval segment, with a 30-sec. trial and a 60-sec. trial. Sessions required the same amount of total work over the duration of the trial. Rating of perceived exertion assessed before, during, and after exercise were higher for the 60-sec. trial than the 30-sec. trial despite no difference in total work. High intensity interval training trials utilizing the same total external work but differing in interval length produced different ratings of perceived exertion. Perceived exertion is significantly higher for sessions of exercise that utilize longer work intervals. These findings suggest that shorter intervals may produce more favorable exertional responses that could positively affect future behavior.

  1. Vaticaffinol, a resveratrol tetramer, exerts more preferable immunosuppressive activity than its precursor in vitro and in vivo through multiple aspects against activated T lymphocytes

    SciTech Connect

    Feng, Li-Li; Wu, Xue-Feng; Liu, Hai-Liang; Guo, Wen-Jie; Luo, Qiong; Tao, Fei-Fei; Ge, Hui-Ming; Shen, Yan; Tan, Ren-Xiang; Xu, Qiang Sun, Yang

    2013-03-01

    In the present study, we aimed to investigate the immunosuppressive activity of vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, on T lymphocytes both in vitro and in vivo, and further explored its potential molecular mechanism. Resveratrol had a wide spectrum of healthy beneficial effects with multiple targets. Interestingly, its tetramer, vaticaffinol, exerted more intensive immunosuppressive activity than resveratrol. Vaticaffinol significantly inhibited T cells proliferation activated by concanavalin A (Con A) or anti-CD3 plus anti-CD28 in a dose- and time-dependent manner. It also induced Con A-activated T cells undergoing apoptosis through mitochondrial pathway. Moreover, this compound prevented cells from entering S phase and G2/M phase during T cells activation. In addition, vaticaffinol inhibited ERK and AKT signaling pathways in Con A-activated T cells. Furthermore, vaticaffinol significantly ameliorated ear swelling in a mouse model of picryl chloride-induced ear contact dermatitis in vivo. In most of the aforementioned experiments, however, resveratrol had only slight effects on the inhibition of T lymphocytes compared with vaticaffinol. Taken together, our findings suggest that vaticaffinol exerts more preferable immunosuppressive activity than its precursor resveratrol both in vitro and in vivo by affecting multiple targets against activated T cells. - Graphical abstract: Vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, exerts more intensive immunosuppressive activity than its precursor resveratrol does in vitro and in vivo. Its mechanism may involve multiple effects against activated T cells: regulation of signalings involved in cell proliferation, G0/G1 arrest of T cells, as well as an apoptosis induction in activated effector T cells. Highlights: ► Vaticaffinol, a resveratrol tetramer, exerts more potent activity than its precursor. ► It inhibited T cells proliferation and prevented them from entering

  2. UNC1062, a new and potent Mer inhibitor.

    PubMed

    Liu, Jing; Zhang, Weihe; Stashko, Michael A; Deryckere, Deborah; Cummings, Christopher T; Hunter, Debra; Yang, Chao; Jayakody, Chatura N; Cheng, Nancy; Simpson, Catherine; Norris-Drouin, Jacqueline; Sather, Susan; Kireev, Dmitri; Janzen, William P; Earp, H Shelton; Graham, Douglas K; Frye, Stephen V; Wang, Xiaodong

    2013-07-01

    Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

  3. UNC1062, a new and potent Mer inhibitor

    PubMed Central

    Liu, Jing; Zhang, Weihe; Stashko, Michael A; DeRyckere, Deborah; Cummings, Christopher T.; Hunter, Debra; Yang, Chao; Jayakody, Chatura N.; Cheng, Nancy; Simpson, Catherine; Norris-Drouin, Jacqueline; Sather, Susan; Kireev, Dmitri; Janzen, William P.; Earp, H Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, Xiaodong

    2013-01-01

    Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development. PMID:23693152

  4. Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.

    PubMed

    McDonnell, Mark E; Bian, Haiyan; Wrobel, Jay; Smith, Garry R; Liang, Shuguang; Ma, Haiching; Reitz, Allen B

    2014-02-15

    We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

  5. Highly Potent Triazole-Based Tubulin Polymerization Inhibitors

    PubMed Central

    Zhang, Qiang; Peng, Youyi; Wang, Xin I.; Keenan, Susan M.; Arora, Sonia; Welsh, William J.

    2009-01-01

    We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents. PMID:17249649

  6. Discovery of potent, selective chymase inhibitors via fragment linking strategies.

    PubMed

    Taylor, Steven J; Padyana, Anil K; Abeywardane, Asitha; Liang, Shuang; Hao, Ming-Hong; De Lombaert, Stéphane; Proudfoot, John; Farmer, Bennett S; Li, Xiang; Collins, Brandon; Martin, Leslie; Albaugh, Daniel R; Hill-Drzewi, Melissa; Pullen, Steven S; Takahashi, Hidenori

    2013-06-13

    Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.

  7. Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases

    NASA Astrophysics Data System (ADS)

    Morisseau, Christophe; Goodrow, Marvin H.; Dowdy, Deanna; Zheng, Jiang; Greene, Jessica F.; Sanborn, James R.; Hammock, Bruce D.

    1999-08-01

    The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tightbinding inhibitors with nanomolar Ki values interacted stoichiometrically with the homogenous recombinant murine and human sEHs. These inhibitors enhance cytotoxicity of trans-stilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome. These potent inhibitors may be valuable tools for testing hypotheses of involvement of diol and epoxide lipids in chemical mediation in vitro or in vivo systems.

  8. Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

    PubMed

    Brasca, Maria Gabriella; Nesi, Marcella; Avanzi, Nilla; Ballinari, Dario; Bandiera, Tiziano; Bertrand, Jay; Bindi, Simona; Canevari, Giulia; Carenzi, Davide; Casero, Daniele; Ceriani, Lucio; Ciomei, Marina; Cirla, Alessandra; Colombo, Maristella; Cribioli, Sabrina; Cristiani, Cinzia; Della Vedova, Franco; Fachin, Gabriele; Fasolini, Marina; Felder, Eduard R; Galvani, Arturo; Isacchi, Antonella; Mirizzi, Danilo; Motto, Ilaria; Panzeri, Achille; Pesenti, Enrico; Vianello, Paola; Gnocchi, Paola; Donati, Daniele

    2014-09-01

    We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

  9. Extensive screening for herbal extracts with potent antioxidant properties

    PubMed Central

    Niwano, Yoshimi; Saito, Keita; Yoshizaki, Fumihiko; Kohno, Masahiro; Ozawa, Toshihiko

    2011-01-01

    This paper summarizes our research for herbal extracts with potent antioxidant activity obtained from a large scale screening based on superoxide radical (O2•−) scavenging activity followed by characterization of antioxidant properties. Firstly, scavenging activity against O2•− was extensively screened from ethanol extracts of approximately 1000 kinds of herbs by applying an electron spin resonance (ESR)-spin trapping method, and we chose four edible herbal extracts with prominently potent ability to scavenge O2•−. They are the extracts from Punica granatum (Peel), Syzygium aromaticum (Bud), Mangifera indica (Kernel), and Phyllanthus emblica (Fruit). These extracts were further examined to determine if they also scavenge hydroxyl radical (•OH), by applying the ESR spin-trapping method, and if they have heat resistance as a desirable characteristic feature. Experiments with the Fenton reaction and photolysis of H2O2 induced by UV irradiation demonstrated that all four extracts have potent ability to directly scavenge •OH. Furthermore, the scavenging activities against O2•− and •OH of the extracts of P. granatum (peel), M. indica (kernel) and P. emblica (fruit) proved to be heat-resistant. The results of the review might give useful information when choosing a potent antioxidant as a foodstuff. For instance, the four herbal extracts chosen from extensive screening possess desirable antioxidant properties. In particular, the extracts of the aforementioned three herbs are expected to be suitable for food processing in which thermal devices are used, because of their heat resistance. PMID:21297917

  10. Diversity Against Adversity: How Adaptive Immune System Evolves Potent Antibodies

    NASA Astrophysics Data System (ADS)

    Heo, Muyoung; Zeldovich, Konstantin B.; Shakhnovich, Eugene I.

    2011-07-01

    Adaptive immunity is an amazing mechanism, whereby new protein functions—affinity of antibodies (Immunoglobulins) to new antigens—evolve through mutation and selection in a matter of a few days. Despite numerous experimental studies, the fundamental physical principles underlying immune response are still poorly understood. In considerable departure from past approaches, here, we propose a microscopic multiscale model of adaptive immune response, which consists of three essential players: The host cells, viruses, and B-cells in Germinal Centers (GC). Each moiety carries a genome, which encodes proteins whose stability and interactions are determined from their sequences using laws of Statistical Mechanics, providing an exact relationship between genomic sequences and strength of interactions between pathogens and antibodies and antibodies and host proteins (autoimmunity). We find that evolution of potent antibodies (the process known as Affinity Maturation (AM)) is a delicate balancing act, which has to reconcile the conflicting requirements of protein stability, lack of autoimmunity, and high affinity of antibodies to incoming antigens. This becomes possible only when antibody producing B cells elevate their mutation rates (process known as Somatic Hypermutation (SHM)) to fall into a certain range—not too low to find potency increasing mutations but not too high to destroy stable Immunoglobulins and/or already achieved affinity. Potent antibodies develop through clonal expansion of initial B cells expressing marginally potent antibodies followed by their subsequent affinity maturation through mutation and selection. As a result, in each GC the population of mature potent Immunoglobulins is monoclonal being ancestors of a single cell from initial (germline) pool. We developed a simple analytical theory, which provides further rationale to our findings. The model and theory reveal the molecular factors that determine the efficiency of affinity maturation

  11. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2010-07-01

    or 9), although these compounds still showed anti-DHT effects (lanes 2 vs. 6, 8, or 10). Figure 4 . The effects of DHEA derivatives on PSA...2009 - 30 JUN 2010 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens 5a. CONTRACT NUMBER with Marginal Agonist...words) We hypothesized that dehydroepiandrosterone ( DHEA ) metabolites or their synthetic derivatives are able to bind to the androgen receptor with

  12. Inappropriate use of potent topical glucocorticoids in infants.

    PubMed

    Ozon, Alev; Cetinkaya, Semra; Alikasifoglu, Ayfer; Gonc, E Nazli; Sen, Yaşar; Kandemir, Nurgün

    2007-02-01

    Topical therapy with glucocorticoids (GCs) is used commonly in chronic dermatoses. Side effects are less common compared to systemic use; however, newer potent preparations may have serious side effects. A potential danger is their inappropriate use. Three infants who developed iatrogenic Cushing's syndrome and prolonged adrenal suppression in the course of GC therapy for simple diaper dermatitis are described. One patient also developed steatohepatitis which is uncommon with local GCs.

  13. Ways of increasing muscular activity by means of isometric muscular exertion

    NASA Technical Reports Server (NTRS)

    Kovalik, A. V.

    1980-01-01

    The effect of isometric muscular exertion on the human body was investigated by having subjects perform basic movements in a sitting position in the conventional manner with additional muscle tension at 50% maximum force and at maximum force. The pulse, arterial pressure, skin temperature, respiratory rate, minute respiratory volume and electrical activity of the muscles involved were all measured. Performance of the exercises with maximum muscular exertion for 20 sec and without movement resulted in the greatest shifts in these indices; in the conventional manner substantial changes did not occur; and with isometric muscular exertion with 50% maximum force with and without movement, optimal functional shifts resulted. The latter is recommended for use in industrial exercises for the prevention of hypodynamia. Ten exercises are suggested.

  14. Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.

    PubMed

    Keung, W M; Vallee, B L

    1993-02-15

    Human mitochondrial aldehyde dehydrogenase (ALDH-I) is potently, reversibly, and selectively inhibited by an isoflavone isolated from Radix puerariae and identified as daidzin, the 7-glucoside of 4',7-dihydroxyisoflavone. Kinetic analysis with formaldehyde as substrate reveals that daidzin inhibits ALDH-I competitively with respect to formaldehyde with a Ki of 40 nM, and uncompetitively with respect to the coenzyme NAD+. The human cytosolic aldehyde dehydrogenase isozyme (ALDH-II) is nearly 3 orders of magnitude less sensitive to daidzin inhibition. Daidzin does not inhibit human class I, II, or III alcohol dehydrogenases, nor does it have any significant effect on biological systems that are known to be affected by other isoflavones. Among more than 40 structurally related compounds surveyed, 12 inhibit ALDH-I, but only prunetin and 5-hydroxydaidzin (genistin) combine high selectivity and potency, although they are 7- to 15-fold less potent than daidzin. Structure-function relationships have established a basis for the design and synthesis of additional ALDH inhibitors that could both be yet more potent and specific.

  15. Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.

    PubMed

    Chebib, Mary; Hinton, Tina; Schmid, Katrina L; Brinkworth, Darren; Qian, Haohua; Matos, Susana; Kim, Hye-Lim; Abdel-Halim, Heba; Kumar, Rohan J; Johnston, Graham A R; Hanrahan, Jane R

    2009-02-01

    This study reports pharmacological and physiological effects of cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid (cis- and trans-3-ACPBPA). These compounds are conformationally restricted analogs of the orally active GABA(B/C) receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis-[IC(50)(rho1) = 5.06 microM and IC(50)(rho2) = 11.08 microM; n = 4] and trans-3-ACPMPA [IC(50)(rho1) = 72.58 microM and IC(50)(rho2) = 189.7 microM; n = 4] seem competitive at GABA(C) receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABA(A) and GABA(B) receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABA(C) than GABA(A) or GABA(B) receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABA(C) receptor (IC(50) = 47 +/- 4.5 microM; n = 6). When applied to the eye as intravitreal injections, cis- and trans-3-ACPBPA prevented experimental myopia development and inhibited the associated vitreous chamber elongation, in a dose-dependent manner in the chick model. Doses only 10 times greater than required to inhibit recombinant GABA(C) receptors caused the antimyopia effects. Using intraperitoneal administration, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared with vehicle there was a significant reduction in time for rats to find the platform in the Morris water maze task (p < 0.05; n = 10). As the physiological effects of cis- and trans-3-ACPBPA are similar to those reported for CGP36742, the memory and refractive effects of CGP36742 may be due in part to its GABA(C) activity.

  16. Potent Anticancer Effects of Bioactive Mushroom Extracts (Phellinus linteus) on a Variety of Human Cancer Cells

    PubMed Central

    Konno, Sensuke; Chu, Kevin; Feuer, Nicholas; Phillips, John; Choudhury, Muhammad

    2015-01-01

    Background Although several therapeutic options are currently available for patients with various cancers, the outcomes are often disappointing and a more effective modality needs to be promptly established. We have been exploring an alternative approach using natural agents and two bioactive mushroom extracts isolated from Phellinus linteus (PL), namely PL-ES and PL-I-ES, were of our interest. As anticancer effects of similar extracts have been reported in several cancers, we investigated whether PL-ES and PL-I-ES might have such anticancer activities on a variety of human cancer cells in vitro. Methods Ten different types of human cancer cell lines, including three metastatic prostate, bladder, kidney, lung, breast, stomach, liver, and brain cancer cells, were employed and tested with PL-ES or PL-I-ES. Cell growth/viability, exertion of oxidative stress, and induction of apoptosis were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay, lipid peroxidation (LPO) assay, and specific enzymatic assay, respectively. Results PL-ES (100 µg/mL) exhibited potent anticancer activity, resulting in a significant (40-80%) growth reduction in all 10 cancer cells at 72 hours. PL-I-ES (100 µg/mL) was effective on only four cancer cells but its higher concentration at 250 µg/mL led to a significant (25-90%) growth reduction in seven cancer cells. LPO assays indicated that such a significant growth reduction by PL-ES (100 µg/mL) or PL-I-ES (100 or 250 µg/mL) could result from cell death due to a cytotoxic effect of oxidative stress (through free radicals). Moreover, enzymatic assays for caspase-3 (Csp-3) and caspase-9 (Csp-9), the pro-apoptotic regulators, showed that both enzymes were significantly activated by PL-ES or PL-I-ES, indicating that cell death due to oxidative stress was more likely associated with apoptosis. Conclusions The present study shows that both PL-ES and PL-I-ES indeed have anticancer effects on a variety of cancer

  17. Novel phospholipase A2 inhibitors from python serum are potent peptide antibiotics.

    PubMed

    Samy, Ramar Perumal; Thwin, Maung Maung; Stiles, Brad G; Satyanarayana-Jois, Seetharama; Chinnathambi, Arunachalam; Zayed, M E; Alharbi, Sulaiman Ali; Siveen, Kodappully Sivaraman; Sikka, Sakshi; Kumar, Alan Prem; Sethi, Gautam; Lim, Lina Hsiu Kim

    2015-04-01

    Antimicrobial peptides (AMPs) play a vital role in defense against resistant bacteria. In this study, eight different AMPs synthesized from Python reticulatus serum protein were tested for bactericidal activity against various Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Burkholderia pseudomallei (KHW and TES strains), and Proteus vulgaris) using a disc-diffusion method (20 μg/disc). Among the tested peptides, phospholipase A2 inhibitory peptide (PIP)-18[59-76], β-Asp65-PIP[59-67], D-Ala66-PNT.II, and D60,65E-PIP[59-67] displayed the most potent bactericidal activity against all tested pathogens in a dose-dependent manner (100-6.8 μg/ml), with a remarkable activity noted against S. aureus at 6.8 μg/ml dose within 6 h of incubation. Determination of minimum inhibitory concentrations (MICs) by a micro-broth dilution method at 100-3.125 μg/ml revealed that PIP-18[59-76], β-Asp65-PIP[59-67] and D-Ala66-PNT.II peptides exerted a potent inhibitory effect against S. aureus and B. pseudomallei (KHW) (MICs 3.125 μg/ml), while a much less inhibitory potency (MICs 12.5 μg/ml) was noted for β-Asp65-PIP[59-67] and D-Ala66-PNT.II peptides against B. pseudomallei (TES). Higher doses of peptides had no effect on the other two strains (i.e., Klebsiella pneumoniae and Streptococcus pneumoniae). Overall, PIP-18[59-76] possessed higher antimicrobial activity than that of chloramphenicol (CHL), ceftazidime (CF) and streptomycin (ST) (30 μg/disc). When the two most active peptides, PIP-18[59-76] and β-Asp65-PIP[59-67], were applied topically at a 150 mg/kg dose for testing wound healing activity in a mouse model of S. aureus infection, the former accelerates faster wound healing than the latter peptide at 14 days post-treatment. The western blot data suggest that the topical application of peptides (PIP-18[59-67] and β-Asp65-PIP[59-67]) modulates NF-kB mediated wound repair in mice with relatively little haemolytic (100-1.56 μg/ml) and cytotoxic (1000

  18. Chronic exertional compartment syndrome in a collegiate soccer player: a case report and literature review.

    PubMed

    Farr, Derek; Selesnick, Harlan

    2008-07-01

    Chronic exertional compartment syndrome is a relatively rare condition among running athletes. In those who engage in repetitive activity, it can cause severe, debilitating leg pain. The diagnosis can be made with a thorough workup that includes history and physical examination, radiologic studies (x-rays, magnetic resonance imaging, bone scan), and compartment pressure monitoring. Most patients do not respond well to nonoperative intervention. Fasciotomy provides satisfactory relief of symptoms and helps patients return to their sports. We present the case of a high-level collegiate soccer player with chronic exertional compartment syndrome.

  19. Induction of Both Local Immune Response in Mice and Protection in a Rabbit Model by Intranasal Immunization with Modified Vaccinia Ankara Virus Expressing a Secreted Form of Bovine Herpesvirus 1 Glycoprotein D.

    PubMed

    Del Medico Zajac, María Paula; Zanetti, Flavia Adriana; Esusy, María Soledad; Federico, Carlos Rodolfo; Zabal, Osvaldo; Valera, Alejandro Rafael; Calamante, Gabriela

    In this study, we evaluated the immunogenicity and efficacy of mucosal delivery of a recombinant modified vaccinia Ankara virus (MVA) expressing the secreted version of bovine herpesvirus type 1 (BoHV-1) glycoprotein D (MVA-gDs) without addition of adjuvant in two animal models. First, we demonstrated the capability of MVA-gDs of inducing both local and systemic anti-gD humoral immune response after intranasal immunization of mice. Then, we confirmed that two doses of MVA-gDs administered intranasally to rabbits induced systemic anti-gD antibodies and conferred protection against BoHV-1 challenge. Our results show the potential of using MVA as a vector for the rational design of veterinary vaccines capable of inducing specific and protective immune responses both at local and systemic level.

  20. Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist

    PubMed Central

    2009-01-01

    This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.

  1. Catechins and procyanidins of Ginkgo biloba show potent activities towards the inhibition of β-amyloid peptide aggregation and destabilization of preformed fibrils.

    PubMed

    Xie, Haiyan; Wang, Jing-Rong; Yau, Lee-Fong; Liu, Yong; Liu, Liang; Han, Quan-Bin; Zhao, Zhongzhen; Jiang, Zhi-Hong

    2014-04-22

    Catechins and procyanidins, together with flavonoid glycosides and terpene trilactones, are three important categories of components in the standard extract of Ginkgo biloba leaves (EGb761). In this research, catechins and proanthocyanidins were found to exist in both the extract of Ginkgo leaves and Ginkgo products. By comparing with reference compounds, six of them were identified as (+)-catechin, (-)-epicatechin, (-)-gallocatechin, (-)-epigallocatechin and procyanidins B1 and B3. The activities of these polyphenols in the inhibition of Aβ42 aggregation and the destabilization of preformed fibrils were evaluated using biochemical assays, which showed that all six of the polyphenols, as well as a fraction of the extract of Ginkgo biloba leaves (EGb) containing catechins and procyanidins, exerted potent inhibitory activities towards Aβ42 aggregation and could also destabilize the performed fibrils. Catechins and procyanidins can therefore be regarded as the potent active constituents of EGb761 in terms of their inhibition of Aβ42 aggregation and destabilization of the fibrils. Although quantitative mass spectroscopic analysis revealed that the catechins and procyanidins are only present in low concentrations in EGb761, these components should be studied in greater detail because of their potent inhibitory effects towards Aβ42 aggregation and their ability to destabilize preformed fibrils, especially during the quality control of Ginkgo leaves and the manufacture of Ginkgo products.

  2. Promoting Best Practices regarding Exertional Heat Stroke: A Perspective from the Team Physician

    ERIC Educational Resources Information Center

    Mazerolle, Stephanie M.; Pagnotta, Kelly D.; McDowell, Lindsey; Casa, Douglas J.; Armstrong, Lawrence

    2012-01-01

    Context: Knowing the team physician's perspective regarding the use of evidence-based practice (EBP) for treatment of exertional heat stroke (EHS) may help increase the number of athletic trainers (ATs) implementing best practices and avoiding the use of improper assessment tools and treatment methods. Objective: To ascertain team physicians'…

  3. Usefulness of a Perceived Exertion Scale for Monitoring Exercise Intensity in Adults with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Stanish, Heidi I.; Aucoin, Michael

    2007-01-01

    In order to gain physical fitness and health, exercise must be performed at a sufficient level of intensity. Exercise intensity can be monitored with rated perceived exertion (RPE) scales to promote safe and effective programming. The usefulness of the Children's OMNI Scale as a subjective measure of intensity for adults with intellectual…

  4. Endurance time, muscular activity and the hand/arm tremor for different exertion forces of holding.

    PubMed

    Lee, Tzu-Hsien

    2016-01-01

    This study aimed to examine the effects of exertion force on endurance time, muscular activity and hand/arm tremor during holding. Fifteen healthy young males were recruited as participants. The independent variable was exertion force (20%, 40%, 60% and 80% maximum holding capacity). The dependent variables were endurance time, muscular activity and hand/arm tremor. The results showed that endurance time decreased with exertion force while muscular activity and hand/arm tremor increased with exertion force. Hand/arm tremor increased with holding time. Endurance time of 40%, 60% and 80% maximum holding capacity was approximately 22.7%, 12.0% and 5.6% of that of 20% maximum holding capacity, respectively. The rms (root mean square) acceleration of hand/arm tremor of the final phase of holding was 2.27-, 1.33-, 1.20- and 1.73-fold of that of the initial phase of holding for 20%, 40%, 60% and 80% maximum holding capacity, respectively.

  5. A comparison of the impacts of continuous and interval cycle exercise on perceived exertion.

    PubMed

    Kilpatrick, Marcus W; Greeley, Samuel J; Ferron, John M

    2016-01-01

    Ratings of perceived exertion (RPE) were developed to assess exertion during exercise testing. However, assessments of RPE prior to and after exercise have become common and potentially important in understanding exercise behaviour. The purpose of this project was to compare RPE taken before, during and after interval and continuous exercise sessions. Twenty-four participants (12 men, 12 women, body mass index = 24, VO2peak = 41 mL · kg · min(-1)) completed a maximal cycle ergometer test used to prescribe experimental trials: (1) moderate continuous (MC), (2) vigorous continuous (VC), (3) vigorous interval and (4) severe interval. All trials were 20 minutes in length and all intervals utilised 60-second segments and a 1:1 work-to-rest ratio. Predicted exertion was highest in the continuous vigorous trial (p < .05). Exertion increased from beginning to end in all trials (p < .05). Session RPE values were highest for the continuous vigorous trial (p < .05). Findings suggest that interval protocols produce perceptions of effort that are lower than VC exercise but similar to MC exercise. These results help describe the perceptions of effort associated with continuous and interval exercise and suggest that interval exercise can be performed with lower perceived work, which may encourage increased participation.

  6. Implicit theories about willpower predict the activation of a rest goal following self-control exertion.

    PubMed

    Job, Veronika; Bernecker, Katharina; Miketta, Stefanie; Friese, Malte

    2015-10-01

    Past research indicates that peoples' implicit theories about the nature of willpower moderate the ego-depletion effect. Only people who believe or were led to believe that willpower is a limited resource (limited-resource theory) showed lower self-control performance after an initial demanding task. As of yet, the underlying processes explaining this moderating effect by theories about willpower remain unknown. Here, we propose that the exertion of self-control activates the goal to preserve and replenish mental resources (rest goal) in people with a limited-resource theory. Five studies tested this hypothesis. In Study 1, individual differences in implicit theories about willpower predicted increased accessibility of a rest goal after self-control exertion. Furthermore, measured (Study 2) and manipulated (Study 3) willpower theories predicted an increased preference for rest-conducive objects. Finally, Studies 4 and 5 provide evidence that theories about willpower predict actual resting behavior: In Study 4, participants who held a limited-resource theory took a longer break following self-control exertion than participants with a nonlimited-resource theory. Longer resting time predicted decreased rest goal accessibility afterward. In Study 5, participants with an induced limited-resource theory sat longer on chairs in an ostensible product-testing task when they had engaged in a task requiring self-control beforehand. This research provides consistent support for a motivational shift toward rest after self-control exertion in people holding a limited-resource theory about willpower.

  7. Hydrocortisone Infusion Exerts Dose- and Sex-Dependent Effects on Attention to Emotional Stimuli

    ERIC Educational Resources Information Center

    Breitberg, Alaina; Drevets, Wayne C.; Wood, Suzanne E.; Mah, Linda; Schulkin, Jay; Sahakian, Barbara J.; Erickson, Kristine

    2013-01-01

    Glucocorticoid administration has been shown to exert complex effects on cognitive and emotional processing. In the current study we investigated the effects of glucocorticoid administration on attention towards emotional words, using an Affective Go/No-go task on which healthy humans have shown an attentional bias towards positive as compared to…

  8. Effect of Carbohydrate Ingestion on Ratings of Perceived Exertion during a Marathon.

    ERIC Educational Resources Information Center

    Utter, Alan C.; Kang, Jie; Robertson, Robert J.; Nieman, David C.; Chaloupka, Edward C.; Suminski, Richard R.; Piccinni, Cristiana R.

    2002-01-01

    Investigated the effects of carbohydrate substrate availability on ratings of perceived exertion (RPE) and hormonal regulation during a competitive marathon. Data on marathon runners randomly assigned to receive carbohydrate or placebo indicated that those who ingested carbohydrate rather than placebo beverages were able to run at a higher…

  9. Risk factors predicting exertional heat illness in male Marine Corps recruits.

    PubMed

    Gardner, J W; Kark, J A; Karnei, K; Sanborn, J S; Gastaldo, E; Burr, P; Wenger, C B

    1996-08-01

    A matched population-based case-control study was conducted on exertional heat illness (EHI) in male Marine Corps recruits in basic training at Parris Island, SC. Physical fitness and anthropometric measurements were obtained for 391 of 528 cases of EHI identified in this population during 1988-1992, and 1467 of 1725 controls matched to cases by initial training platoon. The risk for developing EHI increased with increase in body mass index (BMI = weight.height-2) as measured on arrival and with increase in time to complete a 1.5-mile run conducted during the first week. Recruits at highest risk for developing exertional heat illness had a BMI of 22 or more kg.m-2 and a 1.5-mile run-time for 12 of more minutes. These recruits had an eightfold higher risk for developing exertional heat illness during basic training when compared with those with BMI less than 22 kg.m-2 and 1.5-mile run-time under 10 min (P < 10(-6). Only one-fifth (18%) of male recruits met these criteria for high risk, but they accounted for nearly half (47%) of the exertional heat illness cases occurring during the 12-wk basic training course.

  10. Saving the Seneca Outdoor Recreation Program: A Case Study in Exerting Political Influence.

    ERIC Educational Resources Information Center

    Magee, Clare

    1998-01-01

    This case study demonstrates the process of exerting political influence in faculty's systematic efforts to save the outdoor recreation program at Seneca College (Ontario). A chart and explanatory list present a seven-stage plan for influencing political decision-making. (SAS)

  11. Observational assessment of forceful exertion and the perceived force demands of daily activities.

    PubMed

    Marshall, Matthew M; Armstrong, Thomas J

    2004-12-01

    The primary objective of this study was to assess the accuracy and precision with which analysts observe and estimate the force produced as subjects performed exertions on a work simulator. Eight analysts observed 32 subjects and estimated force as a percent of subjects' maximum voluntary contraction (% MVC). Analysts exhibited bias toward the mean, as high force exertions (> 67% MVC) were underestimated (mean: 11.6% MVC) and low force exertions (<34% MVC) were overestimated (mean: 6.7% MVC). Average error for medium force exertions (34-67% MVC) was not statistically different from zero (2.1% MVC). For all force levels, precision of the estimate was very poor (standard deviation range: 16.2-20.7% MVC). Experience of the analyst in performing ergonomic analysis did not affect accuracy. A secondary objective of the study was to conduct a survey in which subjects identified activities of daily living they perceived as equivalent to controlled force levels. A total of 59 different activities ranging from minimal force required to near maximum were listed by at least 5% of the participants. This list may be used to assist health care practitioners and patients convey the force demands required of occupational tasks as well as for evaluating the diminished strength of the patient.

  12. Reliability of Heart Rate Responses at Given Ratings of Perceived Exertion in Cycling and Walking

    ERIC Educational Resources Information Center

    Katsanos, Christos S.; Moffatt, Robert J.

    2005-01-01

    Eleven healthy men (M age = 27 years, SD = 4) completed three cycling and three walking trials in an alternating order. During each trial, participants were allowed, within 3 min, to adjust the work rate to correspond to given rating of perceived exertion (RPE) values according to the following order: RPE 11, 13, and 15. For cycling as well as…

  13. Humans and Monkeys Exert Metacognitive Control Based on Learning Difficulty in a Perceptual Categorization Task

    ERIC Educational Resources Information Center

    Redford, Joshua S.

    2010-01-01

    Recently, Redford (2010) found that monkeys seemed to exert metacognitive control in a category-learning paradigm. Specifically, they selected more trials to view as the difficulty of the category-learning task increased. However, category-learning difficulty was determined by manipulating the family resemblance across the to-be-learned exemplars.…

  14. Professional Preparation regarding the Recognition and Treatment of Exertional Heat Stroke: The Student Perspective

    ERIC Educational Resources Information Center

    Mazerolle, Stephanie M.; Pagnotta, Kelly D.; Casa, Douglas J.; Armstrong, Lawrence; Maresh, Carl

    2011-01-01

    Context: Current evidence suggests rectal temperature(T[subscript re] and cold-water immersion (CWI) are the most effective means to diagnose and treat exertional heat stroke (EHS), respectively. Educators, clinicians, and students should be apprised of this evidence to guide their practice. Objective: Investigate what athletic training students…

  15. Cardio-Respiratory and Perceived Exertion Responses to Different Cranking Rates during Maximal Arm Ergometry.

    ERIC Educational Resources Information Center

    Israel, Richard G.; And Others

    This study compared cardio-respiratory and perceived exertion responses for four cranking rates (50, 60, 70 and 80 rpm) during a continuous maximal arm ergometry protocol in order to determine the most efficient cranking rate for maximal testing. Fifteen male volunteers from 18-30 years of age performed a continuous arm ergometry stress test in…

  16. Tannic acid, a potent inhibitor of epidermal growth factor receptor tyrosine kinase.

    PubMed

    Yang, Er Bin; Wei, Liu; Zhang, Kai; Chen, Yu Zong; Chen, Wei Ning

    2006-03-01

    Increasing evidence supports the hypothesis that tannic acid, a plant polyphenol, exerts anticarcinogenic activity in chemically induced cancers. In the present study, tannic acid was found to strongly inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFr) in vitro (IC50 = 323 nM). In contrast, the inhibition by tannic acid of p60(c-src) tyrosine kinase (IC50 = 14 microM) and insulin receptor tyrosine kinase (IC50 = 5 microM) was much weaker. The inhibition of EGFr tyrosine kinase by tannic acid was competitive with respect to ATP and non-competitive with respect to peptide substrate. In cultured cells, growth factor-induced tyrosine phosphorylation of growth factor receptors, including EGFr, platelet-derived growth factor receptor, and basic fibroblast growth factor receptor, was inhibited by tannic acid. No inhibition of insulin-induced tyrosine phosphorylation of insulin receptor and insulin-receptor substrate-1 was observed. EGF-stimulated growth of HepG2 cells was inhibited in the presence of tannic acid. The inhibition of serine/threonine-specific protein kinases, including cAMP-dependent protein kinase, protein kinase C and mitogen-activated protein kinase, by tannic acid was only detected at relatively high concentration, IC50 being 3, 325 and 142 microM respectively. The molecular modeling study suggested that tannic acid could be docked into the ATP binding pockets of either EGFr or insulin receptor. These results demonstrate that tannic acid is an in vitro potent inhibitor of EGFr tyrosine kinase.

  17. Effect of Complement on HIV-2 Plasma Antiviral Activity Is Intratype Specific and Potent

    PubMed Central

    Özkaya Şahin, Gülşen; Holmgren, Birgitta; Sheik-Khalil, Enas; da Silva, Zacarias; Nielsen, Jens; Nowroozalizadeh, Salma; Månsson, Fredrik; Norrgren, Hans; Aaby, Peter; Fenyö, Eva Maria

    2013-01-01

    Human immunodeficiency virus type 2 (HIV-2)-infected individuals develop immunodeficiency with a considerable delay and transmit the virus at rates lower than HIV-1-infected persons. Conceivably, comparative studies on the immune responsiveness of HIV-1- and HIV-2-infected hosts may help to explain the differences in pathogenesis and transmission between the two types of infection. Previous studies have shown that the neutralizing antibody response is more potent and broader in HIV-2 than in HIV-1 infection. In the present study, we have examined further the function of the humoral immune response and studied the effect of complement on the antiviral activity of plasma from singly HIV-1- or HIV-2-infected individuals, as well as HIV-1/HIV-2 dually infected individuals. The neutralization and antibody-dependent complement-mediated inactivation of HIV-1 and HIV-2 isolates were tested in a plaque reduction assay using U87.CD4.CCR5 cells. The results showed that the addition of complement increased intratype antiviral activities of both HIV-1 and HIV-2 plasma samples, although the complement effect was more pronounced with HIV-2 than HIV-1 plasma. Using an area-under-the-curve (AUC)-based readout, multivariate statistical analysis confirmed that the type of HIV infection was independently associated with the magnitude of the complement effect. The analyses carried out with purified IgG indicated that the complement effect was largely exerted through the classical complement pathway involving IgG in both HIV-1 and HIV-2 infections. In summary, these findings suggest that antibody binding to HIV-2 structures facilitates the efficient use of complement and thereby may be one factor contributing to a strong antiviral activity present in HIV-2 infection. PMID:23077299

  18. Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylococcus aureus.

    PubMed

    Haeili, Mehri; Moore, Casey; Davis, Christopher J C; Cochran, James B; Shah, Santosh; Shrestha, Tej B; Zhang, Yaofang; Bossmann, Stefan H; Benjamin, William H; Kutsch, Olaf; Wolschendorf, Frank

    2014-07-01

    Macrophages take advantage of the antibacterial properties of copper ions in the killing of bacterial intruders. However, despite the importance of copper for innate immune functions, coordinated efforts to exploit copper ions for therapeutic interventions against bacterial infections are not yet in place. Here we report a novel high-throughput screening platform specifically developed for the discovery and characterization of compounds with copper-dependent antibacterial properties toward methicillin-resistant Staphylococcus aureus (MRSA). We detail how one of the identified compounds, glyoxal-bis(N4-methylthiosemicarbazone) (GTSM), exerts its potent strictly copper-dependent antibacterial properties on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species- and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface.

  19. The effect of passive heating and face cooling on perceived exertion during exercise in the heat.

    PubMed

    Armada-da-Silva, P A S; Woods, J; Jones, D A

    2004-05-01

    Increased body temperature is thought to be an important component of the higher perception of exertion that is a feature of fatigue during exercise in the heat but a causal relationship has yet to be demonstrated. We have investigated the effect of passive heating on the perception of exertion during a standard bout of exercise and also assessed the effect of cooling the head on compensating for the increased body temperature on the feelings of exertion. Ten male subjects performed a 14-min cycling exercise [average power approximately 63% of maximum power output ( W(max))] at an ambient temperature of 35 degrees C at resting rectal temperature [mean (SD): 37.49 (0.27) degrees C; control (CON) trial] on one occasion, and after sitting in a sauna to raise rectal temperature [mean (SD): 38.95(0.13) degrees C; sauna (SAU) trial]. During the exercise, subjects reported their ratings of overall perceived exertion (RPE), perceived exertion of the legs (RPE(legs)) and thermal comfort (TC). A blood sample was collected by the end of the exercise for determination of plasma glucose, lactate and prolactin and haematocrit. RPE values were significantly elevated after passive heating [mean (SE): 14.5 (0.7) units in CON and 17.2 (0.5) units in SAU, at the end of exercise; P<0.001] as were the RPE(legs) ( P<0.01), while ratings of TC were similar in CON and SAU trials. Passive heating increased blood glucose ( P<0.05) but had no effect on lactate at the end of the exercise. Plasma prolactin was markedly elevated as a result of the sauna exposure [mean (SE): 1598 (152) versus 225 (31) mU l(-1) in SAU and CON trials, respectively; P<0.001]. Six of the subjects repeated the two trials but with the face cooled during exercise (trials CON(FAN) and SAU(FAN)) that was achieved by combining face fanning and spraying the face with a mist of cooled water. Face cooling decreased RPE values after sauna to a point that no differences between the two conditions existed. RPE(legs) scores and

  20. Exertion and body discomfort perceived symptoms associated with carpentry tasks: an on-site evaluation.

    PubMed

    Dimov, M; Bhattacharya, A; Lemasters, G; Atterbury, M; Greathouse, L; Ollila-Glenn, N

    2000-01-01

    The purpose of this study was to determine how carpenters subjectively perceived the exertion level and body discomfort associated with their daily tasks. Two psychophysical instruments were utilized. The Borg Whole Body Physical Exertion Instrument, a measure of overall physical demand, and the Body Segment instrument (modified Bishop-Corlett Scale), a measure of body discomfort, were given to 73 carpenters at the end of a shift. Carpentry specialties evaluated included ceiling, drywall, formwork, finishing work, pile driving, fixtures, welding, and scaffolding. The mean Borg's exertion score for the subjects combining all specialties was 14.4 (+/-2.51 standard deviation), a score between "somewhat hard" and "hard." The perception of whole body physical exertion appeared to be a consequence of the specific task. There was no significant correlation between whole body physical exertion perception and age or the number of years as a carpenter. The findings from the body discomfort scale for the total group indicated that the three primary discomfort frequencies by body segment were mid-to-lower back (65.8%), knees (45.2%), and the neck (28.8%). The next highest discomfort rating by body segment (back, knee, right wrist, right leg/foot, and right shoulder) for those subjects in the top three job specialties represented (drywall, ceiling, and formwork; n = 38) resulted in significantly higher ratings for back (60.5%) than right leg/foot (34.2%) and right shoulder (31.6%). All other body segment ratings were not significantly different from one another using Tukey's studentized range test.

  1. Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing.

    PubMed

    Li, Mian; Xu, Changqing; Yao, Wenguo; Mahan, Clare M; Kang, Han K; Sandbrink, Friedhelm; Zhai, Ping; Karasik, Pamela A

    2014-01-07

    To determine if objective evidence of autonomic dysfunction exists from a group of Gulf War veterans with self-reported post-exertional fatigue, we evaluated 16 Gulf War ill veterans and 12 Gulf War controls. Participants of the ill group had self- reported, unexplained chronic post-exertional fatigue and the illness symptoms had persisted for years until the current clinical study. The controls had no self-reported post-exertional fatigue either at the time of initial survey nor at the time of the current study. We intended to identify clinical autonomic disorders using autonomic and neurophysiologic testing in the clinical context. We compared the autonomic measures between the 2 groups on cardiovascular function at both baseline and head-up tilt, and sudomotor function. We identified 1 participant with orthostatic hypotension, 1 posture orthostatic tachycardia syndrome, 2 distal small fiber neuropathy, and 1 length dependent distal neuropathy affecting both large and small fiber in the ill group; whereas none of above definable diagnoses was noted in the controls. The ill group had a significantly higher baseline heart rate compared to controls. Compound autonomic scoring scale showed a significant higher score (95% CI of mean: 1.72-2.67) among ill group compared to controls (0.58-1.59). We conclude that objective autonomic testing is necessary for the evaluation of self-reported, unexplained post-exertional fatigue among some Gulf War veterans with multi-symptom illnesses. Our observation that ill veterans with self-reported post-exertional fatigue had objective autonomic measures that were worse than controls warrants validation in a larger clinical series.

  2. Design of potent substrate-analogue inhibitors of canine renin

    NASA Technical Reports Server (NTRS)

    Hui, K. Y.; Siragy, H. M.; Haber, E.

    1992-01-01

    Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.

  3. Vaginal concentrations of lactic acid potently inactivate HIV

    PubMed Central

    Aldunate, Muriel; Tyssen, David; Johnson, Adam; Zakir, Tasnim; Sonza, Secondo; Moench, Thomas; Cone, Richard; Tachedjian, Gilda

    2013-01-01

    Objectives When Lactobacillus spp. dominate the vaginal microbiota of women of reproductive age they acidify the vagina to pH <4.0 by producing ∼1% lactic acid in a nearly racemic mixture of d- and l-isomers. We determined the HIV virucidal activity of racemic lactic acid, and its d- and l-isomers, compared with acetic acid and acidity alone (by the addition of HCl). Methods HIV-1 and HIV-2 were transiently treated with acids in the absence or presence of human genital secretions at 37°C for different time intervals, then immediately neutralized and residual infectivity determined in the TZM-bl reporter cell line. Results l-lactic acid at 0.3% (w/w) was 17-fold more potent than d-lactic acid in inactivating HIVBa-L. Complete inactivation of different HIV-1 subtypes and HIV-2 was achieved with ≥0.4% (w/w) l-lactic acid. At a typical vaginal pH of 3.8, l-lactic acid at 1% (w/w) more potently and rapidly inactivated HIVBa-L and HIV-1 transmitter/founder strains compared with 1% (w/w) acetic acid and with acidity alone, all adjusted to pH 3.8. A final concentration of 1% (w/w) l-lactic acid maximally inactivated HIVBa-L in the presence of cervicovaginal secretions and seminal plasma. The anti-HIV activity of l-lactic acid was pH dependent, being abrogated at neutral pH, indicating that its virucidal activity is mediated by protonated lactic acid and not the lactate anion. Conclusions l-lactic acid at physiological concentrations demonstrates potent HIV virucidal activity distinct from acidity alone and greater than acetic acid, suggesting a protective role in the sexual transmission of HIV. PMID:23657804

  4. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    SciTech Connect

    Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  5. New potent calcimimetics: II. Discovery of benzothiazole trisubstituted ureas.

    PubMed

    Deprez, Pierre; Temal, Taoues; Jary, Hélène; Auberval, Marielle; Lively, Sarah; Guédin, Denis; Vevert, Jean-Paul

    2013-04-15

    Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50=20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.

  6. Organometallic osmium arene complexes with potent cancer cell cytotoxicity.

    PubMed

    Fu, Ying; Habtemariam, Abraha; Pizarro, Ana M; van Rijt, Sabine H; Healey, David J; Cooper, Patricia A; Shnyder, Steven D; Clarkson, Guy J; Sadler, Peter J

    2010-11-25

    Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms.

  7. Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR

    SciTech Connect

    Mitchell, Charlotte J.; Ballantine, Stuart P.; Coe, Diane M.; Cook, Caroline M.; Delves, Christopher J.; Dowle, Mike D.; Edlin, Chris D.; Hamblin, J. Nicole; Holman, Stuart; Johnson, Martin R.; Jones, Paul S.; Keeling, Sue E.; Kranz, Michael; Lindvall, Mika; Lucas, Fiona S.; Neu, Margarete; Solanke, Yemisi E.; Somers, Don O.; Trivedi, Naimisha A.; Wiseman, Joanne O.

    2012-05-03

    Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-{alpha} production from isolated human peripheral blood mononuclear cells.

  8. Discovery of Potent Dual PPARα Agonists/CB1 Ligands.

    PubMed

    Pérez-Fernández, Ruth; Fresno, Nieves; Macías-González, Manuel; Elguero, José; Decara, Juan; Girón, Rocío; Rodríguez-Álvarez, Ana; Martín, María Isabel; Rodríguez de Fonseca, Fernando; Goya, Pilar

    2011-11-10

    This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpectedly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.

  9. Design and synthesis of a potent histone deacetylase inhibitor.

    PubMed

    Liu, Tao; Kapustin, Galina; Etzkorn, Felicia A

    2007-05-03

    Histone deacetylase (HDAC) inhibitors have potential for cancer therapy. An HDAC inhibitor based on a cyclic peptide mimic of known structure, linked by an aliphatic chain to a hydroxamic acid, was designed and synthesized. The chimeric compound showed potent competitive inhibition of nuclear HDACs, with an IC50 value of 46 nM and a Ki value of 13.7 nM. The designed inhibitor showed 4-fold selectivity for HDAC1 (57 nM) over HDAC8 (231 nM).

  10. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2014-07-01

    Summary 3. DATES COVERED 1 JUL 2013 - 30 JUN 2014 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens with... 4 Conclusion…………………………………………………………………………… 5 References……………………………………………………………………………. 6 Appendices...metabolite from dehydroepiandrosterone ( DHEA ) and a precursor of testosterone, has an intrinsic androgenic activity which was not completely antagonized by

  11. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2013-07-01

    DATES COVERED 01 July 2012 – 30 June 2013 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist...Page Introduction…………………………………………………………….………..….. 1 Body………………………………………………………………………………….. 1- 4 Key Research...In addition, we previously found that androstenediol (Adiol), a physiological metabolite from dehydroepiandrosterone ( DHEA ) and a precursor of

  12. A potent alpha-glucosidase inhibitor from Myristica cinnamomea King.

    PubMed

    Sivasothy, Yasodha; Loo, Kong Yong; Leong, Kok Hoong; Litaudon, Marc; Awang, Khalijah

    2016-02-01

    A dimeric acylphenol and a potent α-glucosidase inhibitor, giganteone D (IC50 5.05μM), was isolated and characterized from the bark of Myristica cinnamomea King. The bark also yielded an acylphenol with an unprecedented skeleton for which the name cinnamomeone A (IC50 358.80μM) was proposed. Their structures were established by means of NMR and MS spectrometric analyses. The Lineweaver-Burk plot of giganteone D indicated that it was a mixed-type inhibitor. This is the first report on the α-glucosidase inhibiting potential of acylphenols.

  13. Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis▿

    PubMed Central

    Mallevaey, Thierry; Fontaine, Josette; Breuilh, Laetitia; Paget, Christophe; Castro-Keller, Alexandre; Vendeville, Catherine; Capron, Monique; Leite-de-Moraes, Maria; Trottein, François; Faveeuw, Christelle

    2007-01-01

    CD1d-restricted natural killer T (NKT) cells represent a heterogeneous population of innate memory immune cells expressing both NK and T-cell markers distributed into two major subsets, i.e., invariant NKT (iNKT) cells, which express exclusively an invariant T-cell receptor (TCR) α chain (Vα14Jα18 in mice), and non-iNKT cells, which express more diverse TCRs. NKT cells quickly produce Th1- and/or Th2-type cytokines following stimulation with glycolipid antigen (Ag) and, through this property, play potent immunoregulatory roles in autoimmune diseases, cancer, and infection. No study has addressed the role of NKT cells in metazoan parasite infections so far. We show that during murine schistosomiasis, the apparent frequency of both iNKT cells and non-iNKT cells decreased in the spleen as early as 3 weeks postinfection (p.i.) and that both populations expressed a greater amount of the activation marker CD69 at 6 weeks p.i., suggesting an activated phenotype. Two different NKT-cell-deficient mouse models, namely, TCR Jα18−/− (exclusively deficient in iNKT cells) and CD1d−/− (deficient in both iNKT and non-iNKT cells) mice, were used to explore the implication of these subsets in infection. We show that whereas both iNKT and non-iNKT cells do not have a major impact on the immune response during the early phase (1 and 4 weeks) of infection, they exert important, although opposite, effects on the immune response during the acute phase of the disease (7 and 12 weeks), after schistosome egg production. Indeed, iNKT cells contribute to Th1 cell differentiation whereas non-iNKT cells might be mostly implicated in Th2 cell differentiation in response to parasite Ag. Our findings suggest, for the first time, that helminths activate both iNKT and non-iNKT cells in vivo, enabling them to differentially influence the Th1/Th2 balance of the immune response. PMID:17353286

  14. A Monoclonal Antibody Directed against a Candida albicans Cell Wall Mannoprotein Exerts Three Anti-C. albicans Activities

    PubMed Central

    Moragues, María D.; Omaetxebarria, Miren J.; Elguezabal, Natalia; Sevilla, María J.; Conti, Stefania; Polonelli, Luciano; Pontón, José

    2003-01-01

    Antibodies are believed to play a role in the protection against Candida albicans infections by a number of mechanisms, including the inhibition of adhesion or germ tube formation, opsonization, neutralization of virulence-related enzymes, and direct candidacidal activity. Although some of these biological activities have been demonstrated individually in monoclonal antibodies (MAbs), it is not clear if all these anti-C. albicans activities can be displayed by a single antibody. In this report, we characterized a monoclonal antibody raised against the main target of salivary secretory immunoglobulin A in the cell wall of C. albicans, which exerts three anti-C. albicans activities: (i) inhibition of adherence to HEp-2 cells, (ii) inhibition of germination, and (iii) direct candidacidal activity. MAb C7 reacted with a proteinic epitope from a mannoprotein with a molecular mass of >200 kDa predominantly expressed on the C. albicans germ tube cell wall surface as well as with a number of antigens from Candida lusitaniae, Cryptococcus neoformans, Aspergillus fumigatus, and Scedosporium prolificans. MAb C7 caused a 31.1% inhibition in the adhesion of C. albicans to HEp-2 monolayers and a 55.3% inhibition in the adhesion of C. albicans to buccal epithelial cells, produced a 38.5% decrease in the filamentation of C. albicans, and exhibited a potent fungicidal effect against C. albicans, C. lusitaniae, Cryptococcus neoformans, A. fumigatus, and S. prolificans, showing reductions in fungal growth ranging from 34.2 to 88.7%. The fungicidal activity showed by MAb C7 seems to be related to that reported by antibodies mimicking the activity of a killer toxin produced by the yeast Pichia anomala, since one of these MAbs also reacted with the C. albicans mannoprotein with a molecular mass of >200 kDa. Results presented in this study support the concept of a family of microbicidal antibodies that could be useful in the treatment of a wide range of microbial infections when used

  15. Identification and Quantitation of Potent Odorants in Spearmint Oils.

    PubMed

    Kelley, Lauren E; Cadwallader, Keith R

    2017-01-17

    Potent odorants in Native spearmint, Scotch spearmint, and Macho mint oils were determined by the combined use of gas chromatography-olfactometry (GCO), gas chromatography-mass spectrometry (GC-MS), and aroma extract dilution analysis (AEDA). Of the 85 odorants detected, (R)-(-)-carvone was the most potent odorant in all three spearmint oils. Additional predominant odorants in all spearmint oils included eugenol, ethyl (S)-(+)-2-methylbutanoate, (E)-β-damascenone, and (3E,5Z)-1,3,5-undecatriene. Forty-six compounds were quantitated using various methods, including 19 by gas chromatography with flame ionization detection (GC-FID), 20 by stable isotope dilution analysis (SIDA), and 14 by GCO dilution analysis. Concentrations were used to calculate the odor activity values (OAVs) for predominant odorants in the oils. Among the compounds quantitated, those with the highest OAVs were (R)-(-)-carvone, 1,8-cineole, (E,Z)-2,6-nonadienal, (E)-β-damascenone, and (3E,5Z)-1,3,5-undecatriene.

  16. Acridone alkaloids as potent inhibitors of cathepsin V.

    PubMed

    Severino, Richele P; Guido, Rafael V C; Marques, Emerson F; Brömme, Dieter; da Silva, M Fátima das G F; Fernandes, João B; Andricopulo, Adriano D; Vieira, Paulo C

    2011-02-15

    Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 μM). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i)=1.2 μM; 6, K(i)=1.0 μM; 7, K(i)=0.2 μM; and 11, K(i)=1.7 μM). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM.

  17. Potent inhibition of tau fibrillization with a multivalent ligand

    SciTech Connect

    Honson, Nicolette S.; Jensen, Jordan R.; Darby, Michael V.; Kuret, Jeff

    2007-11-09

    Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at {approx}80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.

  18. Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

    PubMed Central

    Sidhu, Preetpal Singh; Liang, Aiye; Mehta, Akul Y.; Abdel Aziz, May H.; Zhou, Qibing; Desai, Umesh R.

    2011-01-01

    Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, eleven exhibited reasonable inhibition of human α-thrombin at pH 7.4. Structure activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A t-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 μM under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin. PMID:21714536

  19. Cancer immunotherapy using a potent immunodominant CTL epitope.

    PubMed

    Song, Liwen; Yang, Ming-Chieh; Knoff, Jayne; Sun, Zu-Yue; Wu, T-C; Hung, Chien-Fu

    2014-10-21

    Immunotherapy has emerged as a promising approach that can be used in conjunction with conventional chemotherapy and radiotherapy to further improve the survival rate of patients with advanced cancer. We have recently shown in previous studies that chemotherapy and radiation therapy can alter the tumor microenvironment and allow intratumoral vaccination to prime the adaptive immune system leading to the generation of antigen-specific cell-mediated immune responses. Here, we investigated whether intratumoral injection of a foreign immunodominant peptide (GP33) and the adjuvant CpG into tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and GP33 was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and GP33 also enhanced the generation of GP33-specific and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci, a process found to be mediated by the Fas-FasL apoptosis pathway. The treatment regimen presented here represents a universal approach to cancer control.

  20. Physiological Importance of Hydrogen Sulfide: Emerging Potent Neuroprotector and Neuromodulator

    PubMed Central

    Chung, Hyung-Joo

    2016-01-01

    Hydrogen sulfide (H2S) is an emerging neuromodulator that is considered to be a gasotransmitter similar to nitrogen oxide (NO) and carbon monoxide (CO). H2S exerts universal cytoprotective effects and acts as a defense mechanism in organisms ranging from bacteria to mammals. It is produced by the enzymes cystathionine β-synthase (CBS), cystathionine ϒ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (MST), and D-amino acid oxidase (DAO), which are also involved in tissue-specific biochemical pathways for H2S production in the human body. H2S exerts a wide range of pathological and physiological functions in the human body, from endocrine system and cellular longevity to hepatic protection and kidney function. Previous studies have shown that H2S plays important roles in peripheral nerve regeneration and degeneration and has significant value during Schwann cell dedifferentiation and proliferation but it is also associated with axonal degradation and the remyelination of Schwann cells. To date, physiological and toxic levels of H2S in the human body remain unclear and most of the mechanisms of action underlying the effects of H2S have yet to be fully elucidated. The primary purpose of this review was to provide an overview of the role of H2S in the human body and to describe its beneficial effects. PMID:27413423

  1. Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.

    PubMed

    Sainas, Stefano; Pippione, Agnese C; Giorgis, Marta; Lupino, Elisa; Goyal, Parveen; Ramondetti, Cristina; Buccinnà, Barbara; Piccinini, Marco; Braga, Rodolpho C; Andrade, Carolina H; Andersson, Mikael; Moritzer, Ann-Christin; Friemann, Rosmarie; Mensa, Stefano; Al-Kadaraghi, Salam; Boschi, Donatella; Lolli, Marco L

    2017-03-31

    A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.

  2. Differentiated perceptions of exertion: part I. mode of integration of regional signals.

    PubMed

    Robertson, R J; Gillespie, R L; McCarthy, J; Rose, K D

    1979-12-01

    The mode of sensory integration of differentiated perceptions of exertion from the legs and chest was determined during sub-maximal cycle ergometer exercise. 50 male subjects performed three separate cycle ergometer tests. Power output was held constant at 840 kpm/min., while pedalling rate was randomly set at 40, 60, or 80 rpm. The over-all rating of perceived exertion was significantly lower than the rating for the legs and higher than that for the chest at each pedalling rate. Local signals from the legs dominated the sensory process. Central signals were less pronounced. The mean of the ratings for the legs and chest was slightly but significantly higher than the over-all rating at each pedalling rate. Therefore, the integration process at the superordinate level of sensory processing appeared as a weighted average of the involved regional signals.

  3. Interaction of some limbic structures which exert inhibitory effect on corticosterone secretion.

    PubMed

    Suárez, M; Perassi, N I

    1990-12-01

    The interaction between limbic structures which exert inhibitory influence on corticosterone secretion was investigated in the rat. The following experiments were performed: 1) electrical stimulation at mammillary medial nucleus (MMN) in rats with lesioned anterodrosal thalami nucleus (ADTN) or intermediate tegmental area; 2) electrical stimulation at ADTN in rats with lesioned retrosplenial cortex (RC). Bilateral stimulation at MMN in ADTN or RC-lesioned rats produces an increase in plasma corticosterone concentration. In animals with lesioned RC, values of plasma corticosterone after stimulation at ADTN were higher than before stimulation. Taking into consideration that electrical stimulation of MMN or ADTN in intact rats produces a decrease in plasma corticosterone concentration, these studies demonstrate that MMN and ADTN exert inhibitory influence on corticoadrenal activity only when their projection areas remain intact.

  4. Biomechanical analysis for handle stability during maximum push and pull exertions.

    PubMed

    Seo, Na Jin; Armstrong, Thomas J

    2009-12-01

    This study investigated the effect of handle stability on maximum push/pull force. It was hypothesised that people apply force in directions deviated from the pure push/pull direction to generate a moment that assists producing greater push/pull force when the handle position is fixed (stable) compared to when it is not fixed (unstable). Eight healthy subjects performed maximum push and pull exertions on a stable and an unstable handle in a seated posture, while maximum push/pull force, vertical force and lateral force were recorded. For the unstable handle, vertical and lateral forces were not different from zero during push and pull. For the stable handle, subjects intuitively applied significant downward force during push and significant upward force during pull exertions. As predicted from biomechanical analysis, this downward and upward force was found to be significantly associated with increased push and pull force, respectively, for the stable handle compared to the unstable handle.

  5. A field test comparison of hiking stick use on heartrate and rating of perceived exertion.

    PubMed

    Jacobson, B H; Wright, T

    1998-10-01

    The purpose of this study was to compare heartrate carrying a load and rating of perceived exertion with and without hiking sticks while ascending and descending a slope. 11 novice, moderately fit volunteers, ages 18 to 21 years (M = 19.3 yr.) completed two alternate 50-meter, uphill and downhill hikes on a 40 degrees slope during randomly ordered trials with and without fitted hiking sticks and backpacks (15 kg). Paired t test comparisons for 4 trials indicated that mean heartrate was significantly lower only following the first ascent by those using hiking sticks than those without sticks. Rating of perceived exertion also was significantly lower (p < .05) for those using hiking sticks. Perhaps heartrate may be lower at the onset of climbing using hiking sticks, but as the duration the hike is extended, heartrates become comparable, presumably due to the transfer of energy utilization from the legs to the upper body.

  6. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy

    SciTech Connect

    Nesto, R.W.; Phillips, R.T.; Kett, K.G.; Hill, T.; Perper, E.; Young, E.; Leland, O.S. Jr.

    1988-02-01

    Patients with diabetes mellitus and coronary artery disease are thought to have painless myocardial ischemia more often than patients without diabetes. We studied 50 consecutive patients with diabetes and 50 consecutive patients without diabetes, all with ischemia, on exercise thallium scintigraphy to show the reliability of angina as a marker for exertional ischemia. The two groups had similar clinical characteristics, treadmill test results, and extent of infarction and ischemia, but only 7 patients with diabetes compared with 17 patients without diabetes had angina during exertional ischemia. In diabetic patients the extent of retinopathy, nephropathy, or peripheral neuropathy was similar in patients with and without angina. Angina is an unreliable index of myocardial ischemia in diabetic patients with coronary artery disease. Given the increased cardiac morbidity and mortality in such patients, periodic objective assessments of the extent of ischemia are warranted.

  7. Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

    PubMed

    Lundin, Anna; Dijkman, Ronald; Bergström, Tomas; Kann, Nina; Adamiak, Beata; Hannoun, Charles; Kindler, Eveline; Jónsdóttir, Hulda R; Muth, Doreen; Kint, Joeri; Forlenza, Maria; Müller, Marcel A; Drosten, Christian; Thiel, Volker; Trybala, Edward

    2014-05-01

    Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

  8. Effect of Stimulant Medication Use by Children with ADHD on Heart Rate and Perceived Exertion

    ERIC Educational Resources Information Center

    Mahon, Anthony D.; Woodruff, Megan E.; Horn, Mary P.; Marjerrison, Andrea D.; Cole, Andrew S.

    2012-01-01

    The effect of stimulant medication use by children with attention deficit/hyperactivity disorder (ADHD) on the rating of perceived exertion (RPE)--heart rate (HR) relationship was examined. Children with ADHD (n = 20; 11.3 [plus or minus] 1.8 yrs) and children without ADHD (n = 25; 11.2 [plus or minus] 2.1 yrs) were studied. Children with ADHD…

  9. Determination of muscle mitochondrial respiratory capacity in Standardbred racehorses as an aid to predicting exertional rhabdomyolysis.

    PubMed

    Houben, Rosa; Leleu, Claire; Fraipont, Audrey; Serteyn, Didier; Votion, Dominique-M

    2015-09-01

    This prospective cohort study evaluated the potential of high-resolution respirometry applied to permeabilized muscle fibers for fitness evaluation in French Standardbred racehorses. Fitness evaluation by means of respirometric parameters did not correlate with racing performance registered over the following racing season. However, altered mitochondrial energy metabolism was associated with higher risk of developing exertional rhabdomyolysis, a common cause of exercise intolerance in racehorses. These data represent a first step towards establishing reference values for muscle OXPHOS capacity in this breed.

  10. The Effect of Rocktape on Rating of Perceived Exertion and Cycling Efficiency.

    PubMed

    Miller, Michael G; Michael, Timothy J; Nicholson, Karrie S; Petro, Rebecca V; Hanson, Nicholas J; Prater, Daryl R

    2015-09-01

    The purpose of this study was to investigate the effects of Rocktape (RT), a type of kinesiology tape, on perceived exertion and cycling efficiency. Eighteen recreational cyclists volunteered as subjects for this study. Four experimental conditions were used: (a) 60% VO2peak with RT, (b) 60% VO2peak without RT, (c) 80% VO2peak with RT, and (d) 80% VO2peak without RT. The Borg rating of perceived exertion (RPE) scale was used to evaluate subjective exertion during the cycling bouts. Overall RPE and leg, arm, and chest RPEs were obtained (RPE-O, RPE-L, RPE-A, and RPE-C, respectively). Gross cycling efficiency was determined by calculating the ratio of the amount of work performed to the energy expended. Repeated-measures analysis of variance was used to investigate the differences between the 2 intensities and 2 tape conditions. There were main effects of intensity (p < 0.001) and tape (p = 0.02) found for the RPE-O, with RPE-C showing similar results for intensity (p < 0.001) and tape (p = 0.02). Similar findings were present for the RPE-C, and main effects of intensity (p < 0.001) and tape (p = 0.02) were discovered. A significant main effect of intensity was found for efficiency (p = 0.03), with the 80% intensity condition showing a greater level of efficiency than the 60% intensity condition. However, the use of RT did not increase gross efficiency (p = 0.61). The main finding in this study was that subjects reported a lower level of exertion overall and at the chest, which may lead to increases in overall performance of these athletes. The use of RT before athletic events should not be discouraged.

  11. What Does It Take to Synergistically Combine Sub-Potent Natural Products into Drug-Level Potent Combinations?

    PubMed Central

    Qin, Chu; Tan, Kai Leng; Zhang, Cun Long; Tan, Chun Yan; Chen, Yu Zong; Jiang, Yu Yang

    2012-01-01

    There have been renewed interests in natural products as drug discovery sources. In particular, natural product combinations have been extensively studied, clinically tested, and widely used in traditional, folk and alternative medicines. But opinions about their therapeutic efficacies vary from placebo to synergistic effects. The important questions are whether synergistic effects can sufficiently elevate therapeutic potencies to drug levels, and by what mechanisms and at what odds such combinations can be assembled. We studied these questions by analyzing literature-reported cell-based potencies of 190 approved anticancer and antimicrobial drugs, 1378 anticancer and antimicrobial natural products, 99 natural product extracts, 124 synergistic natural product combinations, and 122 molecular interaction profiles of the 19 natural product combinations with collective potency enhanced to drug level or by >10-fold. Most of the evaluated natural products and combinations are sub-potent to drugs. Sub-potent natural products can be assembled into combinations of drug level potency at low probabilities by distinguished multi-target modes modulating primary targets, their regulators and effectors, and intracellular bioavailability of the active natural products. PMID:23209627

  12. Effects of physical exertion on trans-tibial prosthesis users' ability to accommodate alignment perturbations

    PubMed Central

    Fiedler, Goeran; Slavens, Brooke A; O'Connor, Kristian M; Smith, Roger O; Hafner, Brian J

    2015-01-01

    Background It has long been reported that a range of prosthesis alignments is acceptable in trans-tibial prosthetics. This range was shown to be smaller when walking on uneven surfaces. It has also been argued that findings on gait with prostheses that were obtained under laboratory conditions are limited in their applicability to real-life environments. Objectives This study investigated the hypothesis that efforts to compensate for suboptimal alignments by active users of trans-tibial prostheses become less effective when levels of physical exertion increase. Study design A 2 × 2 repeated-measures analysis of variance was conducted to compare the effects of physical exertion and subtle alignment perturbations on gait with trans-tibial prostheses. Methods The gait of eight subjects with trans-tibial amputation was analyzed when walking with two different prosthesis alignments and two different physical exertion levels. The main and interaction effects were statistically evaluated. Results Bilateral step length symmetry and measures of step variability within the same leg were found to be affected by the intervention. There was no significant effect on index variables that combined kinematic or kinetic measures. Conclusion Findings showed that persons with trans-tibial prostheses responded heterogeneously to the interventions. For most variables, the research hypothesis could not be confirmed. PMID:25138114

  13. Caffeine and theanine exert opposite effects on attention under emotional arousal.

    PubMed

    Giles, Grace E; Mahoney, Caroline R; Brunyé, Tad T; Taylor, Holly A; Kanarek, Robin B

    2017-01-01

    Tea is perceived as more relaxing than coffee, even though both contain caffeine. L-theanine in tea may account for the difference. Consumed together, caffeine and theanine exert similar cognitive effects to that of caffeine alone, but exert opposite effects on arousal, in that caffeine accentuates and theanine mitigates physiological and felt stress responses. We evaluated whether caffeine and theanine influenced cognition under emotional arousal. Using a double-blind, repeated-measures design, 36 participants received 4 treatments (200 mg caffeine + 0 mg theanine, 0 mg caffeine + 200 mg theanine, 200 mg caffeine + 200 mg theanine, 0 mg caffeine + 0 mg theanine) on separate days. Emotional arousal was induced by highly arousing negative film clips and pictures. Mood, salivary cortisol, and visual attention were evaluated. Caffeine accentuated global processing of visual attention on the hierarchical shape task (p < 0.05), theanine accentuated local processing (p < 0.05), and the combination did not differ from placebo. Caffeine reduced flanker conflict difference scores on the Attention Network Test (p < 0.05), theanine increased difference scores (p < 0.05), and the combination did not differ from placebo. Thus, under emotional arousal, caffeine and theanine exert opposite effects on certain attentional processes, but when consumed together, they counteract the effects of each other.

  14. A Study of Exertional Headache’s Prevalence and Characteristics Among Conscripts

    PubMed Central

    Tofangchiha, Shahnaz; Rabiee, Behnam; Mehrabi, Farzad

    2016-01-01

    Background Headache is one of the most common complaints in today's society. Patterns and prevalence of headache, especially headaches associated with physical activity (Exertional Headache) in the population of conscripts in our country is unknown. Objectives In this cross sectional study we tried to answer these questions to some extent. Patients and Methods Using a Persian questionnaire based on international headache society criteria of headache types (ICHD-II) and a sample size of 300, filled by two trained medical doctors, we gathered our data and analyzed it with an acceptable P value of < 0.05 and a confidence interval of 95%. Results Headache prevalence among our conscript participants was 78.7%. The prevalence of exertional headache was 12.7%. EH sufferers’ mean age was 22.16 (SD: 2.60) years. EH was found more often bilaterally and almost equally pulsating or compressive. The main location of pain was frontotemporal region. The most common aggravating and alleviating factors of EH were hot environment and discontinuation of exercise respectively. Conclusions Our team provided a reasonable database of exertional headache and its characteristics in conscripts’ population which could be used in further investigations to improve their general health and function. PMID:27826395

  15. Defining the Focus of Attention: Effects of Attention on Perceived Exertion and Fatigue

    PubMed Central

    Lohse, Keith R.; Sherwood, David E.

    2011-01-01

    This manuscript presents two experiments designed to explore the effects of attention on perceived exertion and time to failure in a fatiguing athletic task. There were two major motivating factors for these experiments. First, there are few studies evaluating attentional focus effects in endurance tasks and, second, there is a lack of integration between studies of attentional focus as external/internal (e.g., Wulf, 2007a) compared to associative/dissociative (e.g., Stevinson and Biddle, 1998). In Experiment 1, we used a fatiguing wall-sit posture (essentially a complex, isometric task) to compare two different types of external attention with an internal focus on the position of the legs. An external focus (regardless of type) increased the time taken to failure and reduced perceived exertion. In Experiment 2, we manipulated subjects’ expectancy of fatigue to test the interaction of attention and expectancy (both top-down factors) in this highly fatiguing task. Previous theories of attention during endurance tasks have suggested that as fatigue/pain increase, bottom-up factors begin to dominate subjects’ attention. While this may be true, Experiment 2 showed that even in a highly fatiguing task, attentional strategies, and expectancies affected the time to failure and perceived exertion. PMID:22102843

  16. Effects of the Visual Exercise Environments on Cognitive Directed Attention, Energy Expenditure and Perceived Exertion

    PubMed Central

    Rogerson, Mike; Barton, Jo

    2015-01-01

    Green exercise research often reports psychological health outcomes without rigorously controlling exercise. This study examines effects of visual exercise environments on directed attention, perceived exertion and time to exhaustion, whilst measuring and controlling the exercise component. Participants completed three experimental conditions in a randomized counterbalanced order. Conditions varied by video content viewed (nature; built; control) during two consistently-ordered exercise bouts (Exercise 1: 60% VO2peakInt for 15-mins; Exercise 2: 85% VO2peakInt to voluntary exhaustion). In each condition, participants completed modified Backwards Digit Span tests (a measure of directed attention) pre- and post-Exercise 1. Energy expenditure, respiratory exchange ratio and perceived exertion were measured during both exercise bouts. Time to exhaustion in Exercise 2 was also recorded. There was a significant time by condition interaction for Backwards Digit Span scores (F2,22 = 6.267, p = 0.007). Scores significantly improved in the nature condition (p < 0.001) but did not in the built or control conditions. There were no significant differences between conditions for either perceived exertion or physiological measures during either Exercise 1 or Exercise 2, or for time to exhaustion in Exercise 2. This was the first study to demonstrate effects of controlled exercise conducted in different visual environments on post-exercise directed attention. Via psychological mechanisms alone, visual nature facilitates attention restoration during moderate-intensity exercise. PMID:26133125

  17. Effects of the Visual Exercise Environments on Cognitive Directed Attention, Energy Expenditure and Perceived Exertion.

    PubMed

    Rogerson, Mike; Barton, Jo

    2015-06-30

    Green exercise research often reports psychological health outcomes without rigorously controlling exercise. This study examines effects of visual exercise environments on directed attention, perceived exertion and time to exhaustion, whilst measuring and controlling the exercise component. Participants completed three experimental conditions in a randomized counterbalanced order. Conditions varied by video content viewed (nature; built; control) during two consistently-ordered exercise bouts (Exercise 1: 60% VO2peakInt for 15-mins; Exercise 2: 85% VO2peakInt to voluntary exhaustion). In each condition, participants completed modified Backwards Digit Span tests (a measure of directed attention) pre- and post-Exercise 1. Energy expenditure, respiratory exchange ratio and perceived exertion were measured during both exercise bouts. Time to exhaustion in Exercise 2 was also recorded. There was a significant time by condition interaction for Backwards Digit Span scores (F2,22 = 6.267, p = 0.007). Scores significantly improved in the nature condition (p < 0.001) but did not in the built or control conditions. There were no significant differences between conditions for either perceived exertion or physiological measures during either Exercise 1 or Exercise 2, or for time to exhaustion in Exercise 2. This was the first study to demonstrate effects of controlled exercise conducted in different visual environments on post-exercise directed attention. Via psychological mechanisms alone, visual nature facilitates attention restoration during moderate-intensity exercise.

  18. Self-reported exertion levels on time/activity diaries: application to exposure assessment

    SciTech Connect

    Schwab, M.; Terblanche, A.P.; Spengler, J.D. )

    1991-07-01

    Recent developments in air pollution analysis have focused on methods for collecting data on contaminant levels in the locations actually frequented by people, especially personal monitoring. While there is still much to understand about human exposures, the next advancements will be in the area of dose assessment. This paper discusses the results of a study designed to provide data for linking exposure to dose. Specifically, we used time/activity diaries to collect information on the exertion levels associated with the reported activities. As part of a community health study, 91 children between the ages of 9 and 11 kept diaries over a two-week summer-time period (July 1989) and during a two-week school-time period (September 1989). The diary was also administered for two days to 42 teenagers between the ages of 15 and 17. This paper describes our concerns about interpreting self-reported exertion levels, particularly with respect to the disparity between participant and researcher perception and coding. We then present the distribution of exertion levels associated with children's activities, highlighting seasonal, day-of-week, and age-group differences.

  19. Consistency and variation in phenotypic selection exerted by a community of seed predators.

    PubMed

    Benkman, Craig W; Smith, Julie W; Maier, Monika; Hansen, Leif; Talluto, Matt V

    2013-01-01

    Phenotypic selection that is sustained over time underlies both anagenesis and cladogenesis, but the conditions that lead to such selection and what causes variation in selection are not well known. We measured the selection exerted by three species of predispersal seed predators of lodgepole pine (Pinus contorta latifolia) in the South Hills, Idaho, and found that net selection on different cone and seed traits exerted by red crossbills (Loxia curvirostra) and cone borer moths (Eucosma recissoriana) over 10 years of seed crops was similar to that measured in another mountain range. We also found that the strength of selection increased as seed predation increased, which provides a mechanism for the correlation between the escalation of seed defenses and the density of seed predators. Red crossbills consume the most seeds and selection they exert accounts for much of the selection experienced by lodgepole pine, providing additional support for a coevolutionary arms race between crossbills and lodgepole pine in the South Hills. The third seed predator, hairy woodpeckers (Picoides villosus), consumed less than one-sixth as many seeds as crossbills. Across the northern Rocky Mountains, woodpecker abundance and therefore selective impact appears limited by the elevated seed defenses of lodgepole pine.

  20. Novel Gallate Triphenylphosphonium Derivatives with Potent Antichagasic Activity

    PubMed Central

    Cortes, Leonel A.; Castro, Lorena; Pesce, Bárbara; Maya, Juan D.; Ferreira, Jorge; Castro-Castillo, Vicente; Parra, Eduardo; Jara, José A.; López-Muñoz, Rodrigo

    2015-01-01

    Chagas disease is one of the most neglected tropical diseases in the world, affecting nearly 15 million people, primarily in Latin America. Only two drugs are used for the treatment of this disease, nifurtimox and benznidazole. These drugs have limited efficacy and frequently induce adverse effects, limiting their usefulness. Consequently, new drugs must be found. In this study, we demonstrated the in vitro trypanocidal effects of a series of four gallic acid derivatives characterized by a gallate group linked to a triphenylphosphonium (TPP+) moiety (a delocalized cation) via a hydrocarbon chain of 8, 10, 11, or 12 atoms (TPP+-C8, TPP+-C10, TPP+-C11, and TPP+-C12, respectively). We analyzed parasite viability in isolated parasites (by MTT reduction and flow cytometry) and infected mammalian cells using T. cruzi Y strain trypomastigotes. Among the four derivatives, TPP+-C10 and TPP+-C12 were the most potent in both models, with EC50 values (in isolated parasites) of 1.0 ± 0.6 and 1.0 ± 0.7 μM, respectively, and were significantly more potent than nifurtimox (EC50 = 4.1 ± 0.6 μM). At 1 μM, TPP+-C10 and TPP+-C12 induced markers of cell death, such as phosphatidylserine exposure and propidium iodide permeabilization. In addition, at 1 μM, TPP+-C10 and TPP+-C12 significantly decreased the number of intracellular amastigotes (TPP+-C10: 24.3%, TPP+-C12: 19.0% of control measurements, as measured by DAPI staining) and the parasite’s DNA load (C10: 10%, C12: 13% of control measurements, as measured by qPCR). Based on the previous mode of action described for these compounds in cancer cells, we explored their mitochondrial effects in isolated trypomastigotes. TPP+-C10 and TPP+-C12 were the most potent compounds, significantly altering mitochondrial membrane potential at 1 μM (measured by JC-1 fluorescence) and inducing mitochondrial transition pore opening at 5 μM. Taken together, these results indicate that the TPP+-C10 and TPP+-C12 derivatives of gallic acid are

  1. Novel Gallate Triphenylphosphonium Derivatives with Potent Antichagasic Activity.

    PubMed

    Cortes, Leonel A; Castro, Lorena; Pesce, Bárbara; Maya, Juan D; Ferreira, Jorge; Castro-Castillo, Vicente; Parra, Eduardo; Jara, José A; López-Muñoz, Rodrigo

    2015-01-01

    disease is one of the most neglected tropical diseases in the world, affecting nearly 15 million people, primarily in Latin America. Only two drugs are used for the treatment of this disease, nifurtimox and benznidazole. These drugs have limited efficacy and frequently induce adverse effects, limiting their usefulness. Consequently, new drugs must be found. In this study, we demonstrated the in vitro trypanocidal effects of a series of four gallic acid derivatives characterized by a gallate group linked to a triphenylphosphonium (TPP(+)) moiety (a delocalized cation) via a hydrocarbon chain of 8, 10, 11, or 12 atoms (TPP(+)-C8, TPP(+)-C10, TPP(+)-C11, and TPP(+)-C12, respectively). We analyzed parasite viability in isolated parasites (by MTT reduction and flow cytometry) and infected mammalian cells using T. cruzi Y strain trypomastigotes. Among the four derivatives, TPP(+)-C10 and TPP(+)-C12 were the most potent in both models, with EC50 values (in isolated parasites) of 1.0 ± 0.6 and 1.0 ± 0.7 μM, respectively, and were significantly more potent than nifurtimox (EC50 = 4.1 ± 0.6 μM). At 1 μM, TPP(+)-C10 and TPP(+)-C12 induced markers of cell death, such as phosphatidylserine exposure and propidium iodide permeabilization. In addition, at 1 μM, TPP(+)-C10 and TPP(+)-C12 significantly decreased the number of intracellular amastigotes (TPP(+)-C10: 24.3%, TPP(+)-C12: 19.0% of control measurements, as measured by DAPI staining) and the parasite's DNA load (C10: 10%, C12: 13% of control measurements, as measured by qPCR). Based on the previous mode of action described for these compounds in cancer cells, we explored their mitochondrial effects in isolated trypomastigotes. TPP(+)-C10 and TPP(+)-C12 were the most potent compounds, significantly altering mitochondrial membrane potential at 1 μM (measured by JC-1 fluorescence) and inducing mitochondrial transition pore opening at 5 μM. Taken together, these results indicate that the TPP(+)-C10 and TPP(+)-C12

  2. A wogonin-rich-fraction of Scutellaria baicalensis root extract exerts chondroprotective effects by suppressing IL-1β-induced activation of AP-1 in human OA chondrocytes

    PubMed Central

    Khan, Nazir M.; Haseeb, Abdul; Ansari, Mohammad Y.; Haqqi, Tariq M.

    2017-01-01

    Osteoarthritis (OA) is a common joint disorder with varying degrees of inflammation and sustained oxidative stress. The root extract of Scutellaria baicalensis (SBE) has been used for the treatment of inflammatory and other diseases. Here, we performed activity-guided HPLC-fractionation of SBE, identified the active ingredient(s) and investigated its chondroprotective potential. We found that the Wogonin containing fraction-4 (F4) was the most potent fraction based on its ability to inhibit ROS production and the suppression of catabolic markers including IL-6, COX-2, iNOS, MMP-3, MMP-9, MMP-13 and ADAMTS-4 in IL-1β-treated OA chondrocytes. OA chondrocytes treated with F4 in the presence of IL-1β showed significantly enhanced expression of anabolic genes ACAN and COL2A1. In an in vitro model of cartilage degradation treatment with F4 inhibited s-GAG release from IL-1β-treated human cartilage explants. The inhibitory effect of F4 was not mediated through the inhibition of MAPKs and NF-κB activation but was mediated through the suppression of c-Fos/AP-1 activity at transcriptional and post transcriptional levels in OA chondrocytes. Purified Wogonin mimicked the effects of F4 in IL-1β-stimulated OA chondrocytes. Our data demonstrates that a Wogonin-rich fraction of SBE exert chondroprotective effects through the suppression of c-Fos/AP-1 expression and activity in OA chondrocytes under pathological conditions. PMID:28256567

  3. Catecholamines released from the adrenal medulla exert a compensatory, protective effect at beta 2-adrenoceptors against Paf-induced death in mice.

    PubMed

    Criscuoli, M; Subissi, A

    1988-01-01

    1. The effects of a number of drugs and experimental conditions, which inhibit or stimulate adrenergic function, were evaluated on platelet-activating factor (Paf)-induced death in conscious mice. 2. Adrenalectomy markedly potentiated Paf toxicity, while guanethidine and reserpine did not. However, reserpine, which produced a virtually complete depletion of catecholamines (CA) in cardiac tissue, was not able to reduce adrenal CA by more than 58%. Drugs which release noradrenaline from the adrenergic nerve terminals, such as tyramine and amphetamine, did not protect mice from Paf toxicity, while drugs or conditions which favour the release of CA from the adrenal medulla, such as urethane and cold-induced stress, did. 3. beta 2- and beta 1 + beta 2-adrenoceptor antagonists (ICI 118551, propranolol and nadolol), but not beta 1-antagonists (atenolol, practolol, metoprolol and CGP 20712 A), potentiated Paf toxicity at low doses; beta 2- and beta 1 + beta 2-agonists (salbutamol, fenoterol and isoprenaline), but not beta 1-agonists (prenalterol and tazolol) were potent inhibitors of Paf toxicity. alpha 1- and alpha 2-adrenoceptor agonists and antagonists did not exert significant effects. Propranolol did not appear to enhance the hypotensive action of Paf in pentobarbitone-anaesthetized mice. 4. It is concluded that manipulation of the release of CA from the adrenal medulla, but not from adrenergic nerves, has profound effects on Paf toxicity in mice. A number of considerations support the hypothesis that bronchoconstriction is a major determinant of Paf-induced death in mice.

  4. Interleukin 12 exerts a differential effect on the maturation of neonatal and adult human CD45R0- CD4 T cells.

    PubMed Central

    Shu, U; Demeure, C E; Byun, D G; Podlaski, F; Stern, A S; Delespesse, G

    1994-01-01

    It is now recognized that IL-12 plays a predominant role in protective immunity against intracellular pathogens by promoting the development of T helper type 1 (Th1) responses. We here report the unexpected observations that IL-12 exerts differential effects on the maturation of "native" human CD4 T cells isolated from umbilical cord blood or from the blood of healthy adults. After priming in the presence of IL-12, naive cells of adult donors, defined as CD45R0- CD4+ T cells, acquire a Th1 phenotype whereas neonatal cells develop into effector cells producing high levels of IL-4 in addition to IFN-gamma. This effect of IL-12 on neonatal T cells is direct inasmuch as it is observed on highly purified CD4 T cells, however, it is not inhibited by CD8 T cells and natural killer cells. Unstimulated neonatal T cells which have been preincubated with IL-12 before the priming behave like adult T cells and acquire a Th1 phenotype after stimulation in the presence of IL-12. Given that IL-4 is a potent antagonist of Th1 responses, the finding that IL-12 promotes the maturation of neonatal T cells into IL-4 producers may explain the increased susceptibility of neonates to intracellular pathogens and should be taken into account for the development of vaccines to be used in the perinatal period. Images PMID:7929809

  5. Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens

    PubMed Central

    Lin, Leo; Nonejuie, Poochit; Munguia, Jason; Hollands, Andrew; Olson, Joshua; Dam, Quang; Kumaraswamy, Monika; Rivera, Heriberto; Corriden, Ross; Rohde, Manfred; Hensler, Mary E.; Burkart, Michael D.; Pogliano, Joe; Sakoulas, George; Nizet, Victor

    2015-01-01

    Antibiotic resistance poses an increasingly grave threat to the public health. Of pressing concern, rapid spread of carbapenem-resistance among multidrug-resistant (MDR) Gram-negative rods (GNR) is associated with few treatment options and high mortality rates. Current antibiotic susceptibility testing guiding patient management is performed in a standardized manner, identifying minimum inhibitory concentrations (MIC) in bacteriologic media, but ignoring host immune factors. Lacking activity in standard MIC testing, azithromycin (AZM), the most commonly prescribed antibiotic in the U.S., is never recommended for MDR GNR infection. Here we report a potent bactericidal action of AZM against MDR carbapenem-resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. This pharmaceutical activity is associated with enhanced AZM cell penetration in eukaryotic tissue culture media and striking multi-log-fold synergies with host cathelicidin antimicrobial peptide LL-37 or the last line antibiotic colistin. Finally, AZM monotherapy exerts clear therapeutic effects in murine models of MDR GNR infection. Our results suggest that AZM, currently ignored as a treatment option, could benefit patients with MDR GNR infections, especially in combination with colistin. PMID:26288841

  6. Present-day chaotic formations around the Japanese trenches: Comparison to the on land examples from the Shimanto and Miura-Boso, and from the Franciscan, Mineoka and Ankara

    NASA Astrophysics Data System (ADS)

    Ogawa, Yujiro; Kawamura, Kiichiro; Tsunogae, Toshiaki; Mori, Ryota; Chiba, Tae; Sasaki, Tomoyuki

    2010-05-01

    Four different types of chaotic formations were recognized by the submersible observation around the Japanese trenches, including the Nankai and Sagami troughs, Boso triple junction, Japan trench, and Izu-Bonin arc, and each type is summarized and discussed in view of comparison to the on land examples, such as from the Franciscan, Shimanto and Miura-Boso belts in the circum Pacifc margins, and the Ankara. The submarine geologies are present actual examples to give us a critical key to understanding the formation processes and emplacement mechanisms for the so-called mélange bodies, either sedimentary, tectonic or diapiric. Some are made of alternated beds of sandstone and mudstone that show broken or block-in-matrix fashion, in most cases in muddy matrix. These are commonly developed on the trench landward slope toe of the Nankai and Sagami troughs and Boso triple junction area as well as the Japan trench slope. One type is from the landward slope, but another type is from the oceanward slopes. The former type is in places calcareous cemented, probably caused by hydraulic fracturing by high pore pressure along the thrust fault and oxidized methane-made carbonate precipitation. They are seen on the feet of the thrust-dominated slope and to be compared to the so-called sedimentary mélanges due to the gravitational sliding, which occur because of tectonically induced steep slopes. Most of such thrusts are related to large subduction type earthquakes, and await for further critical consideration on to the relation to the asperity problem. Some of large scale gravitational collapses may be related to the seamount or ridge subduction to the trench, both in case of accretionary and non-accretionary type margins, the former is for the examples from the Nankai and Sagami troughs and the Boso triple junction, latter for the Japan trench. In all cases on land and under the sea in the trench landward slope, some calcareous breccias are associated with methane

  7. Potent social synchronization can override photic entrainment of circadian rhythms

    PubMed Central

    Fuchikawa, Taro; Eban-Rothschild, Ada; Nagari, Moshe; Shemesh, Yair; Bloch, Guy

    2016-01-01

    Circadian rhythms in behaviour and physiology are important for animal health and survival. Studies with individually isolated animals in the laboratory have consistently emphasized the dominant role of light for the entrainment of circadian rhythms to relevant environmental cycles. Although in nature interactions with conspecifics are functionally significant, social signals are typically not considered important time-givers for the animal circadian clock. Our results challenge this view. By studying honeybees in an ecologically relevant context and using a massive data set, we demonstrate that social entrainment can be potent, may act without direct contact with other individuals and does not rely on gating the exposure to light. We show for the first time that social time cues stably entrain the clock, even in animals experiencing conflicting photic and social environmental cycles. These findings add to the growing appreciation for the importance of studying circadian rhythms in ecologically relevant contexts. PMID:27210069

  8. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

  9. Cocaethylene is more potent than cocaine in mediating lethality.

    PubMed

    Hearn, W L; Rose, S; Wagner, J; Ciarleglio, A; Mash, D C

    1991-06-01

    Cocaethylene is a pharmacologically active cocaine metabolite that is formed in the presence of ethanol by the activity of liver enzymes. The pharmacology of cocaethylene has not been extensively investigated and its acute toxicity is unknown. The acute toxicity of cocaethylene was compared to cocaine in Swiss-Webster mice. The LD50 of cocaethylene was 60.7 mg/kg and 63.8 mg/kg in female and male mice, respectively. In comparison, the LD50 of cocaine was 93.0 mg/kg in both female and male mice. These studies demonstrate that the cocaine-alcohol metabolite, cocathylene, is more potent in mediating lethality than the parent drug.

  10. New Conjugates of Quinoxaline as Potent Antitubercular and Antibacterial Agents

    PubMed Central

    Kuppusamy, Rajendran; Killi, Sunil Kumar; Reddy, Y. Padmanabha

    2016-01-01

    Considering quinoxaline as a privileged structure for the design of potent intercalating agents, some new sugar conjugates of quinoxaline were synthesized and characterized by IR, 1HNMR, 13C NMR, and mass spectral data. In vitro testing for antitubercular and antimicrobial activities was performed against Mycobacterium tuberculosis H37Rv and some pathogenic bacteria. Results revealed that conjugate containing ribose moiety demonstrated the most promising activity against Mycobacteria and bacteria with minimum inhibitory concentrations (MIC) of 0.65 and 2.07 μM, respectively. Other conjugates from xylose, glucose, and mannose were moderately active whilst disaccharides conjugates were found to be less active. In silico docking analysis of prototype compound revealed that ATP site of DNA gyrase B subunit could be a possible site for inhibitory action of these synthesized compounds. PMID:27051530

  11. Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors.

    PubMed

    Wurtz, Nicholas R; Parkhurst, Brandon L; Jiang, Wen; DeLucca, Indawati; Zhang, Xiaojun; Ladziata, Vladimir; Cheney, Daniel L; Bozarth, Jeffrey R; Rendina, Alan R; Wei, Anzhi; Luettgen, Joseph M; Wu, Yiming; Wong, Pancras C; Seiffert, Dietmar A; Wexler, Ruth R; Priestley, E Scott

    2016-12-08

    Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

  12. Nanosulfur: A Potent Fungicide Against Food Pathogen, Aspergillus niger

    NASA Astrophysics Data System (ADS)

    Choudhury, Samrat Roy; Nair, Kishore K.; Kumar, Rajesh; Gogoi, Robin; Srivastava, Chitra; Gopal, Madhuban; Subhramanyam, B. S.; devakumar, C.; Goswami, Arunava

    2010-10-01

    Elemental sulfur (S0), man's oldest eco-friendly fungicide for curing fungal infections in plants and animals, is registered in India as a non-systemic and contact fungicide. However due to its high volume requirement, Indian agrochemical industry and farmers could not effectively use this product till date. We hypothesize that intelligent nanoscience applications might increase the visibility of nanosulfur in Indian agriculture as a potent and eco-safe fungicide. Sulfur nanoparticles (NPs) were synthesized bottom-up via a liquid synthesis method with average particle size in the range of 50-80 nm and the shapes of the NPs were spherical. A comparative study of elemental and nano-sulfur produced has been tested against facultative fungal food pathogen, Aspergillus niger. Results showed that nanosulfur is more efficacious than its elemental form.

  13. Isolation of more potent oncolytic paramyxovirus by bioselection.

    PubMed

    Beier, R; Hermiston, T; Mumberg, D

    2013-01-01

    Newcastle disease virus (NDV) is an oncolytic paramyxovirus with a nonsegmented single-stranded RNA genome. In this report, a recombinant oncolytic NDV was passaged in human tumor xenografts and reisolated and characterized after two rounds of bioselection. Several isolates could be recovered that differed from the parental virus with respect to virus spread in tumor cells and the ability to form syncytia in human tumor cells. Three isolates were identified that demonstrated superior oncolytic potency compared with the parental virus as measured by increased oncolytic potency in confluent tumor cell monolayers, in tumor cell spheroids and in a mouse xenograft tumor model. The surface proteins F and HN were sequence analyzed and characterized for fusogenicity. The present study demonstrates that in vivo NDV bioselection can enable the isolation of novel, oncolytic NDV and thus represents a powerful methodology for the development of highly potent oncolytic viruses.

  14. Nanosulfur: A Potent Fungicide Against Food Pathogen, Aspergillus niger

    SciTech Connect

    Choudhury, Samrat Roy; Goswami, Arunava; Nair, Kishore K.; Kumar, Rajesh; Gopal, Madhuban; Devakumar, C.; Gogoi, Robin; Srivastava, Chitra; Subhramanyam, B. S.

    2010-10-04

    Elemental sulfur (S{sup 0}), man's oldest eco-friendly fungicide for curing fungal infections in plants and animals, is registered in India as a non-systemic and contact fungicide. However due to its high volume requirement, Indian agrochemical industry and farmers could not effectively use this product till date. We hypothesize that intelligent nanoscience applications might increase the visibility of nanosulfur in Indian agriculture as a potent and eco-safe fungicide. Sulfur nanoparticles (NPs) were synthesized bottom-up via a liquid synthesis method with average particle size in the range of 50-80 nm and the shapes of the NPs were spherical. A comparative study of elemental and nano-sulfur produced has been tested against facultative fungal food pathogen, Aspergillus niger. Results showed that nanosulfur is more efficacious than its elemental form.

  15. IRAS galaxies versus POTENT mass - Density fields, biasing, and Omega

    NASA Technical Reports Server (NTRS)

    Dekel, Avishai; Bertschinger, Edmund; Yahil, Amos; Strauss, Michael A.; Davis, Marc; Huchra, John P.

    1993-01-01

    A comparison of the galaxy density field extracted from a complete redshift survey of IRAS galaxies brighter than 1.936 Jy with the mass-density field reconstructed by the POTENT procedure from the observed peculiar velocities of 493 objects is presented. A strong correlation is found between the galaxy and mass-density fields; both feature the Great Attractor, part of the Perseus-Pisces supercluster, and the large void between them. Monte Carlo noise simulations show that the data are consistent with the hypotheses that the smoothed fluctuations of galaxy and mass densities at each point are proportional to each other with the 'biasing' factor of IRAS galaxies, b(I), and that the peculiar velocity field is related to the mass-density field as expected according to the gravitational instability theory. Under these hypotheses, the two density fields can be related by specifying b(I) and the cosmological density parameter, Omega.

  16. Design of potent fluoro-substituted chalcones as antimicrobial agents.

    PubMed

    Burmaoglu, Serdar; Algul, Oztekin; Gobek, Arzu; Aktas Anil, Derya; Ulger, Mahmut; Erturk, Busra Gul; Kaplan, Engin; Dogen, Aylin; Aslan, Gönül

    2017-12-01

    Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9-15, and 20-23) using a structure-activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC50 values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12-14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.

  17. Quantitative trait loci mapping of the stigma exertion rate and spikelet number per panicle in rice (Oryza sativa L.).

    PubMed

    Rahman, M H; Yu, P; Zhang, Y X; Sun, L P; Wu, W X; Shen, X H; Zhan, X D; Chen, D B; Cao, L Y; Cheng, S H

    2016-10-17

    The stigma exertion rate is a polygenic inherited trait that is important for increased seed yield in hybrid rice breeding. To identify quantitative trait loci (QTL) associated with high stigma exertion rate, we conducted QTL mapping using 134 recombinant inbred lines derived from XieqingzaoB and Zhonghui9308, which have high and low stigma exertion rates, respectively. A total of eight QTLs (qSES6, qSSE11, qDSE1a, qDSE1b, qDSE10, qDSE11, qTSE1, and qTSE11) for single stigma exertion, double stigma exertion, and total stigma exertion were detected. The locations of qSSE11 and qTSE11 have not been previously reported, and the qDSE11 allele from parent XQZB exhibited a positive additive effect. In addition, three QTLs (qSNP1, qSNP3a, and qSNP3b), for spikelet number per panicle were identified. Of note, one QTL (qSNP1) was detected in two different environments (Hainan and Zhejiang). To evaluate the advantage of exerted stigma for cross-pollination, single, dual, and total stigma exertion should be considered separately for future genetic improvement in the production of rice hybrid seeds. In addition, this study provides information for fine mapping, gene cloning, and marker assisted selection, with emphasis on the latter.

  18. Potent anti-seizure effects of D-leucine.

    PubMed

    Hartman, Adam L; Santos, Polan; O'Riordan, Kenneth J; Stafstrom, Carl E; Hardwick, J Marie

    2015-10-01

    There are no effective treatments for millions of patients with intractable epilepsy. High-fat ketogenic diets may provide significant clinical benefit but are challenging to implement. Low carbohydrate levels appear to be essential for the ketogenic diet to work, but the active ingredients in dietary interventions remain elusive, and a role for ketogenesis has been challenged. A potential antiseizure role of dietary protein or of individual amino acids in the ketogenic diet is understudied. We investigated the two exclusively ketogenic amino acids, L-leucine and L-lysine, and found that only L-leucine potently protects mice when administered prior to the onset of seizures induced by kainic acid injection, but not by inducing ketosis. Unexpectedly, the D-enantiomer of leucine, which is found in trace amounts in the brain, worked as well or better than L-leucine against both kainic acid and 6Hz electroshock-induced seizures. However, unlike L-leucine, D-leucine potently terminated seizures even after the onset of seizure activity. Furthermore, D-leucine, but not L-leucine, reduced long-term potentiation but had no effect on basal synaptic transmission in vitro. In a screen of candidate neuronal receptors, D-leucine failed to compete for binding by cognate ligands, potentially suggesting a novel target. Even at low doses, D-leucine suppressed ongoing seizures at least as effectively as diazepam but without sedative effects. These studies raise the possibility that D-leucine may represent a new class of anti-seizure agents, and that D-leucine may have a previously unknown function in eukaryotes.

  19. Are genotoxic carcinogens more potent than nongenotoxic carcinogens?

    PubMed Central

    Parodi, S; Malacarne, D; Romano, P; Taningher, M

    1991-01-01

    In this report we have raised the question whether genotoxic carcinogens are more potent than nongenotoxic carcinogens when studied in long-term carcinogenicity assays in rodents. To build a large database of compounds for which both carcinogenicity and genotoxicity had been investigated, we have used a database produced by Gold and co-workers for carcinogenic potency data (975 chemicals) and a database produced by Würgler for genotoxicity data (2834 chemicals). Considering compounds positive or negative in at least three short-term tests and in at least 75% of available tests, we could define 67 genotoxic carcinogens and 46 nongenotoxic carcinogens. Carcinogenic potency of genotoxic carcinogens was about 50 times higher than carcinogenic potency of nongenotoxic carcinogens. Our results are different from the results of Tennant et al.; their database (24 genotoxic carcinogens and 12 nongenotoxic carcinogens compatible with our definition) seems to suggest that there is practically no difference in potency between genotoxic and nongenotoxic carcinogens. The two databases have only four compounds in common and are also different in terms of number of elements for different chemical classes. Nitrosocompounds, nitrogen mustards, hydrazine derivatives, and polycyclic aromatic hydrocarbons are not represented in the database of Tennant. The overall impression from our analysis is that the usefulness of short-term tests of genotoxicity could be significantly better than what has been suggested by the previous work of Tennant et al. because these tests tend to detect, at least for many important chemical classes, the most potent carcinogens. This consideration may not be valid for certain classes of chemicals. PMID:1821372

  20. The generation of torque in the horizontal plane at the foot-base during laterally directed manual exertions.

    PubMed Central

    Wilkinson, A T; Grieve, D W

    1996-01-01

    Two experiments were carried out to investigate the mechanisms by which both translational forces and a turning moment in the horizontal plane at the foot-base are transmitted by the lower limb during laterally directed manual exertions. The first used a force plate to measure forces and moments exerted by the feet separately or together in order to investigate the contribution of each foot to the moment. The second examined the role of flexors and extensors of the hip, knee and ankle in the transmission of torque. The results suggest that approximately half of the moment is generated by each foot exerting a translational force at a distance from, and in the opposite direction to, the other. The other half is by each foot exerting an individual torque upon the floor. It is suggested that biomechanical models of asymmetric exertion should take these mechanisms into account. Images Fig. 1 Fig. 4 PMID:8771404

  1. Photocatalytic Cellulosic Electrospun Fibers for the Degradation of Potent Cyanobacteria Toxin Microcystin-LR

    DTIC Science & Technology

    2012-01-01

    Photocatalytic cellulosic electrospun fibers for the degradation of potent cyanobacteria toxin microcystin-LR† Nicholas M. Bedford,ab Miguel Pelaez,c...photocatalytic decomposition of the potent cyanobacteria toxin microcystin-LR (MC-LR). Electrospun fibers of cellulose acetate were converted to succinylated...00-2012 4. TITLE AND SUBTITLE Photocatalytic cellulosic electrospun fibers for the degradation of potent cyanobacteria toxin microcystin-LR 5a

  2. Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation.

    PubMed

    Knerr, Patrick J; Oman, Trent J; Garcia De Gonzalo, Chantal V; Lupoli, Tania J; Walker, Suzanne; van der Donk, Wilfred A

    2012-11-16

    Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode-of-action of other lantibiotics.

  3. Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeling.

    PubMed

    Li, Tiezheng; Tong, Xin; Yang, Qiang; Giddens, John P; Wang, Lai-Xi

    2016-08-05

    Glycosylation can exert a profound impact on the structures and biological functions of antibodies. Glycosylation remodeling using the endoglycosidase-catalyzed deglycosylation and transglycosylation approach is emerging as a promising platform to produce homogeneous glycoforms of antibodies, but the broad application of this method will require the availability of highly efficient glycosynthase mutants. We describe in this paper a systematic site-directed mutagenesis of an endoglycosidase from Streptococcus pyogenes of serotype M49 (Endo-S2) and the evaluation of the resulting mutants for their hydrolysis and transglycosylation activities. We found that mutations at the Asp-184 residue gave mutants that demonstrated significantly different properties, some possessed potent transglycosylation activity with diminished hydrolysis activity but others did not, which would be otherwise difficult to predict without the comparative study. In contrast to the previously reported Endo-S mutants that are limited to action on complex type N-glycans, the Endo-S2 glycosynthases described here, including D184M and D184Q, were found to have remarkably relaxed substrate specificity and were capable of transferring three major types (complex, high-mannose, and hybrid type) of N-glycans for antibody glycosylation remodeling. In addition, the Endo-S2 glycosynthase mutants were found to be much more active in general than the Endo-S mutants for transglycosylation. The usefulness of these Endo-S2 glycosynthase mutants was exemplified by an efficient glycosylation remodeling of two therapeutic monoclonal antibodies, rituximab and trastuzumab (Herceptin).

  4. Mammea E/BB, an isoprenylated dihydroxycoumarin protonophore that potently uncouples mitochondrial electron transport, disrupts hypoxic signaling in tumor cells.

    PubMed

    Du, Lin; Mahdi, Fakhri; Jekabsons, Mika B; Nagle, Dale G; Zhou, Yu-Dong

    2010-11-29

    The mammea-type coumarin mammea E/BB (1) was found to inhibit both hypoxia-induced and iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in human breast tumor T47D cells with IC(50) values of 0.96 and 0.89 μM, respectively. Compound 1 suppressed the hypoxic induction of secreted VEGF protein (T47D cells) and inhibited cell viability/proliferation in four human tumor cell lines. Compound 1 (at 5 and 20 μM) inhibited human breast tumor MDA-MB-231 cell migration. While the mechanisms that underlie their biological activities have remained unknown, prenylated mammea coumarins have been shown to be cytotoxic to human tumor cells, suppress tumor growth in animal models, and display a wide variety of antimicrobial effects. Mechanistic studies revealed that 1 appears to exert an assemblage of cellular effects by functioning as an anionic protonophore that potently uncouples mitochondrial electron transport and disrupts mitochondrial signaling in human tumor cell lines.

  5. Mammea E/BB, An Isoprenylated Dihydroxycoumarin Protonophore that Potently Uncouples Mitochondrial Electron Transport Disrupts Hypoxic Signaling in Tumor Cells

    PubMed Central

    Du, Lin; Mahdi, Fakhri; Jekabsons, Mika B.; Nagle, Dale G.; Zhou, Yu-Dong

    2010-01-01

    The mammea-type coumarin mammea E/BB (1) was found to inhibit both hypoxia-induced and iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in human breast tumor T47D cells with IC50 values of 0.96 and 0.89 µM, respectively. Compound 1 suppressed the hypoxic induction of secreted VEGF protein (T47D cells) and inhibited cell viability/proliferation in four human tumor cell lines. Compound 1 (at 5 and 20 µM) inhibited human breast tumor MDA-MB-231 cell migration. While the mechanisms that underlay their biological activities have remained unknown, prenylated mammea coumarins have been shown to be cytotoxic to human tumor cells, suppress tumor growth in animal models, and display a wide variety of antimicrobial effects. Mechanistic studies revealed that 1 appears to exert an assemblage of cellular effects by functioning as an anionic protonophore that potently uncouples mitochondrial electron transport and disrupts mitochondrial signaling in human tumor cell lines. PMID:20929261

  6. Core Muscle Activity, Exercise Preference, and Perceived Exertion during Core Exercise with Elastic Resistance versus Machine.

    PubMed

    Vinstrup, Jonas; Sundstrup, Emil; Brandt, Mikkel; Jakobsen, Markus D; Calatayud, Joaquin; Andersen, Lars L

    2015-01-01

    Objectives. To investigate core muscle activity, exercise preferences, and perceived exertion during two selected core exercises performed with elastic resistance versus a conventional training machine. Methods. 17 untrained men aged 26-67 years participated in surface electromyography (EMG) measurements of five core muscles during torso-twists performed from left to right with elastic resistance and in the machine, respectively. The order of the exercises was randomized and each exercise consisted of 3 repetitions performed at a 10 RM load. EMG amplitude was normalized (nEMG) to maximum voluntary isometric contraction (MVC). Results. A higher right erector spinae activity in the elastic exercise compared with the machine exercise (50% [95% CI 36-64] versus 32% [95% CI 18-46] nEMG) was found. By contrast, the machine exercise, compared with the elastic exercise, showed higher left external oblique activity (77% [95% CI 64-90] versus 54% [95% CI 40-67] nEMG). For the rectus abdominis, right external oblique, and left erector spinae muscles there were no significant differences. Furthermore, 76% preferred the torso-twist with elastic resistance over the machine exercise. Perceived exertion (Borg CR10) was not significantly different between machine (5.8 [95% CI 4.88-6.72]) and elastic exercise (5.7 [95% CI 4.81-6.59]). Conclusion. Torso-twists using elastic resistance showed higher activity of the erector spinae, whereas torso-twist in the machine resulted in higher activity of the external oblique. For the remaining core muscles the two training modalities induced similar muscular activation. In spite of similar perceived exertion the majority of the participants preferred the exercise using elastic resistance.

  7. The effect of galactose ingestion on affect and perceived exertion in recreationally active females.

    PubMed

    Duckworth, Lauren C; Backhouse, Susan H; Stevenson, Emma J

    2013-12-01

    The beneficial effects of acute carbohydrate (CHO) supplementation on exercise performance have been well described. Also reported is the attenuation of perceived exertion and enhancement of affect during prolonged exercise following CHO ingestion. However, no studies to date have assessed the impact of the type of CHO ingested on affective responses during moderate intensity exercise, lasting 60 min or less. Therefore, the aim of the present study was to investigate the effects of consuming a galactose (GAL) CHO drink versus a glucose (GLU) CHO or placebo (PLA) drink before and during exercise on affect and perceived exertion. Nine recreationally active females undertook three trials, each consisting of running for 60 min at 65% VO2max followed immediately by a 90 min rest period. Prior to (300 ml) and at every 15 min during exercise (150 ml), participants consumed either a GLU or GAL drink each containing 45 g of CHO, or an artificially-sweetened PLA drink. Ratings of pleasure-displeasure and perceived activation were measured throughout exercise and the rest period and measures of perceived exertion were measured during exercise. Plasma glucose and serum insulin were significantly greater throughout exercise and rest following the GLU trial compared with the GAL and PLA trials (P<0.05). Measures of perceived activation and pleasure-displeasure were not enhanced nor RPE reduced as a result of ingestion of a CHO solution. In conclusion, the GAL beverage elicited a more favourable metabolic profile in the exercising females but this did not translate into an enhanced affective profile. Indeed, CHO ingestion had no noticeable effect on the assessed psychological indices during 60 min of moderate-intensity exercise in females. It is suggested that the maintenance of a positive affective profile may be explained more by the level of hydration as opposed to fuel availability. Therefore, those seeking to use beverages containing CHO to enhance their exercise experience

  8. Core Muscle Activity, Exercise Preference, and Perceived Exertion during Core Exercise with Elastic Resistance versus Machine

    PubMed Central

    Vinstrup, Jonas; Sundstrup, Emil; Brandt, Mikkel; Jakobsen, Markus D.; Calatayud, Joaquin; Andersen, Lars L.

    2015-01-01

    Objectives. To investigate core muscle activity, exercise preferences, and perceived exertion during two selected core exercises performed with elastic resistance versus a conventional training machine. Methods. 17 untrained men aged 26–67 years participated in surface electromyography (EMG) measurements of five core muscles during torso-twists performed from left to right with elastic resistance and in the machine, respectively. The order of the exercises was randomized and each exercise consisted of 3 repetitions performed at a 10 RM load. EMG amplitude was normalized (nEMG) to maximum voluntary isometric contraction (MVC). Results. A higher right erector spinae activity in the elastic exercise compared with the machine exercise (50% [95% CI 36–64] versus 32% [95% CI 18–46] nEMG) was found. By contrast, the machine exercise, compared with the elastic exercise, showed higher left external oblique activity (77% [95% CI 64–90] versus 54% [95% CI 40–67] nEMG). For the rectus abdominis, right external oblique, and left erector spinae muscles there were no significant differences. Furthermore, 76% preferred the torso-twist with elastic resistance over the machine exercise. Perceived exertion (Borg CR10) was not significantly different between machine (5.8 [95% CI 4.88–6.72]) and elastic exercise (5.7 [95% CI 4.81–6.59]). Conclusion. Torso-twists using elastic resistance showed higher activity of the erector spinae, whereas torso-twist in the machine resulted in higher activity of the external oblique. For the remaining core muscles the two training modalities induced similar muscular activation. In spite of similar perceived exertion the majority of the participants preferred the exercise using elastic resistance. PMID:26557405

  9. American College of Sports Medicine position stand. Exertional heat illness during training and competition.

    PubMed

    Armstrong, Lawrence E; Casa, Douglas J; Millard-Stafford, Mindy; Moran, Daniel S; Pyne, Scott W; Roberts, William O

    2007-03-01

    Exertional heat illness can affect athletes during high-intensity or long-duration exercise and result in withdrawal from activity or collapse during or soon after activity. These maladies include exercise associated muscle cramping, heat exhaustion, or exertional heatstroke. While certain individuals are more prone to collapse from exhaustion in the heat (i.e., not acclimatized, using certain medications, dehydrated, or recently ill), exertional heatstroke (EHS) can affect seemingly healthy athletes even when the environment is relatively cool. EHS is defined as a rectal temperature greater than 40 degrees C accompanied by symptoms or signs of organ system failure, most frequently central nervous system dysfunction. Early recognition and rapid cooling can reduce both the morbidity and mortality associated with EHS. The clinical changes associated with EHS can be subtle and easy to miss if coaches, medical personnel, and athletes do not maintain a high level of awareness and monitor at-risk athletes closely. Fatigue and exhaustion during exercise occur more rapidly as heat stress increases and are the most common causes of withdrawal from activity in hot conditions. When athletes collapse from exhaustion in hot conditions, the term heat exhaustion is often applied. In some cases, rectal temperature is the only discernable difference between severe heat exhaustion and EHS in on-site evaluations. Heat exhaustion will generally resolve with symptomatic care and oral fluid support. Exercise associated muscle cramping can occur with exhaustive work in any temperature range, but appears to be more prevalent in hot and humid conditions. Muscle cramping usually responds to rest and replacement of fluid and salt (sodium). Prevention strategies are essential to reducing the incidence of EHS, heat exhaustion, and exercise associated muscle cramping.

  10. Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability.

    PubMed

    Tong, Yunsong; Lin, Nan-Horng; Wang, Le; Hasvold, Lisa; Wang, Weibo; Leonard, Nicholas; Li, Tongmei; Li, Qun; Cohen, Jerry; Gu, Wen-Zhen; Zhang, Haiying; Stoll, Vincent; Bauch, Joy; Marsh, Kennan; Rosenberg, Saul H; Sham, Hing L

    2003-05-05

    A pyridyl moiety was introduced into a previously developed series of farnesyltransferase inhibitors containing imidazole and cyanophenyl (such as 4), resulting in potent inhibitors with improved pharmacokinetics.

  11. Application of the Repetitions in Reserve-Based Rating of Perceived Exertion Scale for Resistance Training

    PubMed Central

    Cronin, John; Storey, Adam; Zourdos, Michael C.

    2016-01-01

    ABSTRACT RATINGS OF PERCEIVED EXERTION ARE A VALID METHOD OF ESTIMATING THE INTENSITY OF A RESISTANCE TRAINING EXERCISE OR SESSION. SCORES ARE GIVEN AFTER COMPLETION OF AN EXERCISE OR TRAINING SESSION FOR THE PURPOSES OF ATHLETE MONITORING. HOWEVER, A NEWLY DEVELOPED SCALE BASED ON HOW MANY REPETITIONS ARE REMAINING AT THE COMPLETION OF A SET MAY BE A MORE PRECISE TOOL. THIS APPROACH ADJUSTS LOADS AUTOMATICALLY TO MATCH ATHLETE CAPABILITIES ON A SET-TO-SET BASIS AND MAY MORE ACCURATELY GAUGE INTENSITY AT NEAR-LIMIT LOADS. THIS ARTICLE OUTLINES HOW TO INCORPORATE THIS NOVEL SCALE INTO A TRAINING PLAN. PMID:27531969

  12. US space flight experience. Physical exertion and metabolic demand of extravehicular activity: Past, present, and future

    NASA Technical Reports Server (NTRS)

    Moore, Thomas P.

    1989-01-01

    A review of physical exertion and metabolic demands of extravehicular activity (EVA) on U.S. astronauts is given. Information is given on EVA during Gemini, Apollo and Skylab missions. It is noted that nominal EVA's should not be overstressful from a cardiovascular standpoint; that manual-intensive EVA's such as are planned for the construction phase of the Space Station can and will be demanding from a muscular standpoint, primarily for the upper extremities; that off-nominal unplanned EVA's can be physically demanding both from an endurance and from a muscular standpoint; and that crewmembers should be physically prepared and capable of performing these EVA's at any time during the mission.

  13. [Unusual triggering circumstance of benign acute cerebral angiopathy; link with exertion cephalalgia?].

    PubMed

    Iglesias, S; Baron, J C

    1994-01-01

    Immediately following a scream of fear, a sixty-year old woman complained of severe bilateral headache which relapsed several times over the following month during exercise. There was no history of sympathomimetic drug intake. The work-up was normal save for minimal subarachnoid bleeding and the angiogram showed a disseminated "sausage-string" appearance over all cerebral arterial territories, without aneurysm. The unusual triggering event in this case and the subsequent recurrence of headache in relation to exercise lead us to discuss possible links between the clinical entity of "Isolated benign cerebral angiopathy" and exertional headache.

  14. Effectiveness of cold water immersion for treating exertional heat stress when immediate response is not possible.

    PubMed

    Flouris, A D; Friesen, B J; Carlson, M J; Casa, D J; Kenny, G P

    2015-06-01

    Immediate treatment with cold water immersion (CWI) is the gold standard for exertional heatstroke. In the field, however, treatment is often delayed due to delayed paramedic response and/or inaccurate diagnosis. We examined the effect of treatment (reduction of rectal temperature to 37.5 °C) delays of 5, 20, and 40 min on core cooling rates in eight exertionally heat-stressed (40.0 °C rectal temperature) individuals. We found that rectal temperature was elevated above baseline (P < 0.05) at the end of all delay periods (5 min: 40.08 ± 0.32; 20 min: 39.92 ± 0.40; 40 min: 39.57 ± 0.29 °C). Mean arterial pressure was reduced (P < 0.05) below baseline (92 ± 1.8 mm Hg) after all delay periods (5 min: 75 ± 2.6; 20 min: 74 ± 1.7; 40 min: 70 ± 2.1 mm Hg; P > 0.05). Rectal core cooling rates were similar among conditions (5 min: 0.20 ± 0.01; 20 min: 0.17 ± 0.02; 40 min: 0.17 ± 0.01 °C/min; P > 0.05). The rectal temperature afterdrop following CWI was similar across conditions (5 min: 35.95; 20 min: 35.61; 40 min: 35.87 °C; P > 0.05). We conclude that the effectiveness of 2 °C CWI as a treatment for exertional heat stress remains high even when applied with a delay of 40 min. Therefore, our results support that CWI is the most appropriate treatment for exertional heatstroke as it is capable of quickly reversing hyperthermia even when treatment is commenced with a significant delay.

  15. Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis

    PubMed Central

    VALBERG, S. J.; McKENZIE, E. C.; EYRICH, L. V.; SHIVERS, J.; BARNES, N. E.; FINNO, C. J.

    2016-01-01

    Summary Reasons for performing study Although exertional rhabdomyolysis (ER) is common in Arabian horses, there are no dedicated studies describing histopathological characteristics of muscle from Arabian horses with ER. Objectives To prospectively identify distinctive histopathological features of muscle from Arabian endurance horses with a history of ER (pro-ER) and to retrospectively determine their prevalence in archived samples from Arabian horses with exertional myopathies (retro-ER). Study design Prospective and retrospective histopathological description. Methods Middle gluteal muscle biopsies obtained from Arabian controls (n = 14), pro-ER (n = 13) as well as archived retro-ER (n = 25) muscle samples previously classified with type 2 polysaccharide storage myopathy (15/25), recurrent exertional rhabdomyolysis (7/25) and no pathology (3/25) were scored for histopathology and immunohistochemical staining of cytoskeletal proteins. Glutaraldehyde-fixed samples (2 pro-ER, one control) were processed for electron microscopy. Pro-ER and retro-ER groups were compared with controls using Mann–Whitney U and Fisher's exact tests. Results Centrally located myonuclei in mature myofibres were found in significantly more (P<0.05) pro-ER (12/13) and retro-ER (21/25) horses than controls (4/14). Degenerating myofibres were not evident in any biopsies. Retro-ER horses had amylase-resistant polysaccharide (6/25, P<0.05) and higher scores for cytoplasmic glycogen, rimmed vacuoles and rod-like bodies. A few control horses (3/14) and significantly (P<0.05) more pro-ER (12/13) and retro-ER (18/25) horses had disrupted myofibrillar alignment and large desmin and αβ-crystallin positive cytoplasmic aggregates. Prominent Z-disc degeneration and focal myofibrillar disruption with regional accumulation of β-glycogen particles were identified on electron microscopy of the 2 pro-ER samples. Conclusions In a subset of Arabian horses with intermittent episodes of exertional

  16. The endoplasmic reticulum exerts control over organelle streaming during cell expansion.

    PubMed

    Stefano, Giovanni; Renna, Luciana; Brandizzi, Federica

    2014-03-01

    Cytoplasmic streaming is crucial for cell homeostasis and expansion but the precise driving forces are largely unknown. In plants, partial loss of cytoplasmic streaming due to chemical and genetic ablation of myosins supports the existence of yet-unknown motors for organelle movement. Here we tested a role of the endoplasmic reticulum (ER) as propelling force for cytoplasmic streaming during cell expansion. Through quantitative live-cell analyses in wild-type Arabidopsis thaliana cells and mutants with compromised ER structure and streaming, we demonstrate that cytoplasmic streaming undergoes profound changes during cell expansion and that it depends on motor forces co-exerted by the ER and the cytoskeleton.

  17. Late Jurassic-Early Cretaceous radiolarian age constraints from the sedimentary cover of the Amasia ophiolite (NW Armenia), at the junction between the Izmir-Ankara-Erzinçan and Sevan-Hakari suture zones

    NASA Astrophysics Data System (ADS)

    Danelian, T.; Asatryan, G.; Galoyan, Gh.; Sahakyan, L.; Stepanyan, J.

    2016-01-01

    The Amasia ophiolite, situated at the northernmost corner of Armenia, is part of the Sevan-Hakari suture zone which links with the Izmir-Ankara-Erzinçan suture zone in northern Turkey. Three new radiolarian assemblages have been extracted from siliceous sedimentary rocks that accumulated on the Amasia ophiolite in an oceanic setting. Two of these assemblages were extracted from red-brownish bedded cherts overlying basaltic lavas; one of these is likely to be middle Oxfordian to early Kimmeridgian in age, while the second correlates with the Berriasian. Similar time-equivalent lava-chert sequences have been dated recently using radiolarians from the Stepanavan, Vedi and Sevan ophiolite units, where they are considered to relate to submarine volcanic activity in the back-arc marginal basin in which the Armenian ophiolites were formed. The third radiolarian assemblage, of late Barremian age, was extracted from a more than 15-m-thick volcaniclastic-chert sequence. The related volcanic activity is likely to have been subaerial and probably relates to the formation of an oceanic volcanic plateau; no Cretaceous subaerial volcanism has been previously recorded in the Lesser Caucasus area.

  18. A single immunization with modified vaccinia virus Ankara-based influenza virus H7 vaccine affords protection in the influenza A(H7N9) pneumonia ferret model.

    PubMed

    Kreijtz, Joost H C M; Wiersma, Lidewij C M; De Gruyter, Heidi L M; Vogelzang-van Trierum, Stella E; van Amerongen, Geert; Stittelaar, Koert J; Fouchier, Ron A M; Osterhaus, Albert D M E; Sutter, Gerd; Rimmelzwaan, Guus F

    2015-03-01

    Since the first reports in early 2013, >440 human cases of infection with avian influenza A(H7N9) have been reported including 122 fatalities. After the isolation of the first A(H7N9) viruses, the nucleotide sequences became publically available. Based on the coding sequence of the influenza virus A/Shanghai/2/2013 hemagglutinin gene, a codon-optimized gene was synthesized and cloned into a recombinant modified vaccinia virus Ankara (MVA). This MVA-H7-Sh2 viral vector was used to immunize ferrets and proved to be immunogenic, even after a single immunization. Subsequently, ferrets were challenged with influenza virus A/Anhui/1/2013 via the intratracheal route. Unprotected animals that were mock vaccinated or received empty vector developed interstitial pneumonia characterized by a marked alveolitis, accompanied by loss of appetite, weight loss, and heavy breathing. In contrast, animals vaccinated with MVA-H7-Sh2 were protected from severe disease.

  19. DNA and modified vaccinia virus Ankara vaccines encoding multiple cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) are safe but weakly immunogenic in HIV-1-uninfected, vaccinia virus-naive adults.

    PubMed

    Gorse, Geoffrey J; Newman, Mark J; deCamp, Allan; Hay, Christine Mhorag; De Rosa, Stephen C; Noonan, Elizabeth; Livingston, Brian D; Fuchs, Jonathan D; Kalams, Spyros A; Cassis-Ghavami, Farah L

    2012-05-01

    We evaluated a DNA plasmid-vectored vaccine and a recombinant modified vaccinia virus Ankara vaccine (MVA-mBN32), each encoding cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) in a randomized, double-blinded, placebo-controlled trial in 36 HIV-1-uninfected adults using a heterologous prime-boost schedule. HIV-1-specific cellular immune responses, measured as interleukin-2 and/or gamma interferon production, were induced in 1 (4%) of 28 subjects after the first MVA-mBN32 immunization and in 3 (12%) of 25 subjects after the second MVA-mBN32 immunization. Among these responders, polyfunctional T-cell responses, including the production of tumor necrosis factor alpha and perforin, were detected. Vaccinia virus-specific antibodies were induced to the MVA vector in 27 (93%) of 29 and 26 (93%) of 28 subjects after the first and second immunizations with MVA-mBN32. These peptide-based vaccines were safe but were ineffective at inducing HIV-1-specific immune responses and induced much weaker responses than MVA vaccines expressing the entire open reading frames of HIV-1 proteins.

  20. Vaccination of mice with a modified Vaccinia Ankara (MVA) virus expressing the African horse sickness virus (AHSV) capsid protein VP2 induces virus neutralising antibodies that confer protection against AHSV upon passive immunisation.

    PubMed

    Calvo-Pinilla, Eva; de la Poza, Francisco; Gubbins, Simon; Mertens, Peter Paul Clement; Ortego, Javier; Castillo-Olivares, Javier

    2014-02-13

    In previous studies we showed that a recombinant Modified Vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR-/-) against challenge. We continued these studies and determined, in the IFNAR-/- mouse model, whether the antibody responses induced by MVA-VP2 vaccination play a key role in protection against AHSV. Thus, groups of mice were vaccinated with wild type MVA (MVA-wt) or MVA-VP2 and the antisera from these mice were used in a passive immunisation experiment. Donor antisera from (a) MVA-wt; (b) MVA-VP2 vaccinated; or (c) MVA-VP2 vaccinated and AHSV infected mice, were transferred to AHSV non-immune recipient mice. The recipients were challenged with virulent AHSV together with MVA-VP2 vaccinated and MVA-wt vaccinated control animals and the levels of protection against AHSV-4 were compared between all these groups. The results showed that following AHSV challenge, mice that were passively immunised with MVA-VP2 vaccinated antisera were highly protected against AHSV disease and had lower levels of viraemia than recipients of MVA-wt antisera. Our study indicates that MVA-VP2 vaccination induces a highly protective humoral immune response against AHSV.

  1. Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine.

    PubMed

    Gillis, Peter A; Hernandez-Alvarado, Nelmary; Gnanandarajah, Josephine S; Wussow, Felix; Diamond, Don J; Schleiss, Mark R

    2014-06-30

    The guinea pig (Cavia porcellus) provides a useful animal model for studying the pathogenesis of many infectious diseases, and for preclinical evaluation of vaccines. However, guinea pig models are limited by the lack of immunological reagents required for characterization and quantification of antigen-specific T cell responses. To address this deficiency, an enzyme-linked immunospot (ELISPOT) assay for guinea pig interferon (IFN)-γ was developed to measure antigen/epitope-specific T cell responses to guinea pig cytomegalovirus (GPCMV) vaccines. Using splenocytes harvested from animals vaccinated with a modified vaccinia virus Ankara (MVA) vector encoding the GPCMV GP83 (homolog of human CMV pp65 [gpUL83]) protein, we were able to enumerate and map antigen-specific responses, both in vaccinated as well as GPCMV-infected animals, using a panel of GP83-specific peptides. Several potential immunodominant GP83-specific peptides were identified, including one epitope, LGIVHFFDN, that was noted in all guinea pigs that had a detectable CD8+ response to GP83. Development of a guinea pig IFN-γ ELISPOT should be useful in characterization of additional T cell-specific responses to GPCMV, as well as other pathogens. This information in turn can help focus future experimental evaluation of immunization strategies, both for GPCMV as well as for other vaccine-preventable illnesses studied in the guinea pig model.

  2. Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine

    PubMed Central

    Gillis, Peter A.; Hernandez-Alvarado, Nelmary; Gnanandarajah, Josephine S.; Wussow, Felix; Diamond, Don J.; Schleiss, Mark R.

    2014-01-01

    The guinea pig (Cavia porcellus) provides a useful animal model for studying the pathogenesis of many infectious diseases, and for preclinical evaluation of vaccines. However, guinea pig models are limited by the lack of immunological reagents required for characterization and quantification of antigen-specific T cell responses. To address this deficiency, an enzyme-linked immunospot (ELISPOT) assay for guinea pig interferon (IFN)-γ was developed to measure antigen/epitope-specific T cell responses to guinea pig cytomegalovirus (GPCMV) vaccines. Using splenocytes harvested from animals vaccinated with a modified vaccinia virus Ankara (MVA) vector encoding the GPCMV GP83 (homolog of human CMV pp65 [gpUL83]) protein, we were able to enumerate and map antigen-specific responses, both in vaccinated as well as GPCMV-infected animals, using a panel of GP83-specific peptides. Several potential immunodominant GP83-specific peptides were identified, including one epitope, LGIVHFFDN, that was noted in all guinea pigs that had a detectable CD8+ response to GP83. Development of a guinea pig IFN-γ ELISPOT should be useful in characterization of additional T cell-specific responses to GPCMV, as well as other pathogens. This information in turn can help focus future experimental evaluation of immunization strategies, both for GPCMV as well as for other vaccine-preventable illnesses studied in the guinea pig model. PMID:24856783

  3. Design and simulation of 3½-cell superconducting gun cavity and beam dynamics studies of the SASE-FEL System at the Institute of Accelerator Technologies at Ankara University

    NASA Astrophysics Data System (ADS)

    Yildiz, H. Duran; Cakir, R.; Porsuk, D.

    2015-06-01

    Design and simulation of a superconducting gun cavity with 3½ cells have been studied in order to give the first push to the electron beam for the linear accelerating system at The Institute of Accelerator Technologies at Ankara University. Electrons are accelerated through the gun cavity with the help of the Radiofrequency power suppliers from cryogenic systems. Accelerating gradient should be as high as possible to accelerate electron beam inside the cavity. In this study, electron beam reaches to 9.17 MeV energy at the end of the gun cavity with the accelerating gradient; Ec=19.21 MV/m. 1.3 GHz gun cavity consists of three TESLA-like shaped cells while the special designed gun-cell includes a cathode plug. Optimized important beam parameters inside the gun cavity, average beam current 3 mA, transverse emittance 2.5 mm mrad, repetition rate 30 MHz and other parameters are obtained for the SASE-FEL System. The Superfish/Poisson program is used to design each cell of the superconducting cavity. Superconducting gun cavity and Radiofrequency properties are studied by utilizing 2D Superfish/Poisson, 3D Computer Simulation Technology Microwave Studio, and 3D Computer Simulation Technology Particle Studio. Superfish/Poisson is also used to optimize the geometry of the cavity cells to get the highest accelerating gradient. The behavior of the particles along the beamline is included in this study. ASTRA Code is used to track the particles.

  4. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

    PubMed

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D

    2005-11-01

    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  5. Hemin as a generic and potent protein misfolding inhibitor

    SciTech Connect

    Liu, Yanqin; Carver, John A.; Ho, Lam H.; Elias, Abigail K.; Musgrave, Ian F.; Pukala, Tara L.

    2014-11-14

    Highlights: • Hemin prevents Aβ42, α-synuclein and RCM-κ-casein forming amyloid fibrils. • Hemin inhibits the β-sheet structure formation of Aβ42. • Hemin reduces the cell toxicity caused by fibrillar Aβ42. • Hemin dissociates partially formed Aβ42 fibrils. • Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin. - Abstract: Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer’s disease, Parkinson’s disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases.

  6. Potent Anti-Trypanosoma cruzi Activities of Oxidosqualene Cyclase Inhibitors

    PubMed Central

    Buckner, Frederick S.; Griffin, John H.; Wilson, Aaron J.; Van Voorhis, Wesley C.

    2001-01-01

    Trypanosoma cruzi is the protozoan agent that causes Chagas' disease, a major health problem in Latin America. Better drugs are needed to treat infected individuals. The sterol biosynthesis pathway is a potentially excellent target for drug therapy against T. cruzi. In this study, we investigated the antitrypanosomal activities of a series of compounds designed to inhibit a key enzyme in sterol biosynthesis, oxidosqualene cyclase. This enzyme converts 2,3-oxidosqualene to the tetracyclic product, lanosterol. The lead compound, N-(4E,8E)-5,9, 13-trimethyl-4,8, 12-tetradecatrien-1-ylpyridinium, is an electron-poor aromatic mimic of a monocyclized transition state or high-energy intermediate formed from oxidosqualene. This compound and 27 related compounds were tested against mammalian-stage T. cruzi, and 12 inhibited growth by 50% at concentrations below 25 nM. The lead compound was shown to cause an accumulation of oxidosqualene and decreased production of lanosterol and ergosterol, consistent with specific inhibition of the oxidosqualene cyclase. The data demonstrate potent anti-T. cruzi activity associated with inhibition of oxidosqualene cyclase. PMID:11257036

  7. Carvacrol as a potent natural acaricide against Dermanyssus gallinae.

    PubMed

    Tabari, Mohaddeseh Abouhosseini; Youssefi, Mohammad Reza; Barimani, Alireza; Araghi, Atefeh

    2015-10-01

    Resistance to conventional synthetic pesticides has been widely reported in Dermanyssus gallinae in poultry production systems. Introducing novel acaricides to poultry industry today is more urgent than ever. Research in this field recently focused on plants and plant-derived compounds as acaricides. In the present study, acaricidal activity of three plant bioactive components, carvacrol, thymol, and farnesol, was assessed against D. gallinae and compared with synthetic pesticide permethrin. Mode of acaricidal action was determined by contact toxicity and fumigant toxicity bioassays. Except farnesol which did not cause any mortality, carvacrol and thymol were found to be toxic to D. gallinae with LD50 values of 1 and 3.15 μg/cm(3), respectively. Permethrin gave the LD50 value of 31.95 μg/cm(3) which was less efficient than carvacrol and thymol. In fumigant toxicity bioassay, mortality rate in carvacrol- and thymol-treated groups in closed method was significantly higher than the open one. On the other hand, permethrin exhibited poor fumigant toxicity as there was no statistically significant difference between mortality rate in open and closed methods. These findings revealed that mechanism of acaricidal activity of carvacrol and thymol but not permethrin was mainly due to fumigant action. Results of the present study suggested that carvacrol and thymol, especially carvacrol, can be developed as a novel potent bioacaricide against D. gallinae.

  8. Potent Kinetic Stabilizers that Prevent Transthyretin-mediated Cardiomyocyte Proteotoxicity

    PubMed Central

    Alhamadsheh, Mamoun M.; Connelly, Stephen; Cho, Ahryon; Reixach, Natàlia; Powers, Evan T.; Pan, Dorothy W.; Wilson, Ian A.; Kelly, Jeffery W.; Graef, Isabella A.

    2011-01-01

    The V122I mutation that alters the stability of transthyretin (TTR) affects 3–4% of African Americans and leads to amyloidogenesis and development of cardiomyopathy. In addition, 10–15% of individuals over the age of 65 develop senile systemic amyloidosis (SSA) and cardiac TTR deposits due to wild-type TTR amyloidogenesis. As no approved therapies for TTR amyloid cardiomyopathy are available, the development of drugs that prevent amyloid-mediated cardiotoxicity is desired. To this aim, we developed a fluorescence polarization-based HTS screen, which identified several new chemical scaffolds targeting TTR. These novel compounds were potent kinetic stabilizers of TTR and prevented tetramer dissociation, unfolding and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. Our study also showed that these compounds effectively inhibited the proteotoxicity of V122I-TTR towards human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is one of the best known inhibitors of TTR aggregation, and may be promising leads for the treatment and/or prevention of TTR-mediated cardiomyopathy. PMID:21865539

  9. 2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors

    PubMed Central

    Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

    2015-01-01

    Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure–activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson’s disease. PMID:26203229

  10. Acetone Extract from Rhodomyrtus tomentosa: A Potent Natural Antioxidant

    PubMed Central

    Lavanya, Goodla; Voravuthikunchai, Supayang Piyawan; Towatana, Nongporn Hutadilok

    2012-01-01

    Rhodomyrtus tomentosa (Myrtaceae) has been employed in traditional Thai medicine to treat colic diarrhoea, dysentery, abscesses, haemorrhage, and gynaecopathy. In addition, it has been used to formulate skin-whitening, anti-aging and skin beautifying agents. Ethnomedical activities of this plant may be due its antioxidant property. Hence, the aim of this study was to evaluate both in vitro and in vivo antioxidant activities of R. tomentosa leaf extract. In vitro antioxidant activity of the extract was assessed by lipid peroxidation inhibition capacity, ferric reducing antioxidant power, and metal chelating activity. R. tomentosa extract demonstrated its free radical scavenging effects in concentration dependent manner. In vivo antioxidant activity of the extract was conducted in Swiss Albino mice. Levels of thio-barbituric acid reactive substances (TBARS), glutathione (GSH), and the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in blood, liver, and kidney were analyzed using microtitre plate photometer. Administration of CCl4 caused significant increase in TBARS and decrease in GSH, SOD, CAT and GPx levels. In contrast, R. tomentosa extract (0.8 g/kg) effectively prevented these alterations and maintained the antioxidant status. The results suggest that R. tomentosa extract can serve as a potent antioxidant. PMID:23125869

  11. Acetone Extract from Rhodomyrtus tomentosa: A Potent Natural Antioxidant.

    PubMed

    Lavanya, Goodla; Voravuthikunchai, Supayang Piyawan; Towatana, Nongporn Hutadilok

    2012-01-01

    Rhodomyrtus tomentosa (Myrtaceae) has been employed in traditional Thai medicine to treat colic diarrhoea, dysentery, abscesses, haemorrhage, and gynaecopathy. In addition, it has been used to formulate skin-whitening, anti-aging and skin beautifying agents. Ethnomedical activities of this plant may be due its antioxidant property. Hence, the aim of this study was to evaluate both in vitro and in vivo antioxidant activities of R. tomentosa leaf extract. In vitro antioxidant activity of the extract was assessed by lipid peroxidation inhibition capacity, ferric reducing antioxidant power, and metal chelating activity. R. tomentosa extract demonstrated its free radical scavenging effects in concentration dependent manner. In vivo antioxidant activity of the extract was conducted in Swiss Albino mice. Levels of thio-barbituric acid reactive substances (TBARS), glutathione (GSH), and the activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in blood, liver, and kidney were analyzed using microtitre plate photometer. Administration of CCl(4) caused significant increase in TBARS and decrease in GSH, SOD, CAT and GPx levels. In contrast, R. tomentosa extract (0.8 g/kg) effectively prevented these alterations and maintained the antioxidant status. The results suggest that R. tomentosa extract can serve as a potent antioxidant.

  12. A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis

    PubMed Central

    Kachadourian, Remy; Day, Brian J.; Pugazhenti, Subbiah; Franklin, Christopher C.; Genoux-Bastide, Estelle; Mahaffey, Gregory; Gauthier, Charlotte; Di Pietro, Attilio; Boumendjel, Ahcène

    2014-01-01

    Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2′,5′-dihydroxychalcone (2′,5′-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure–activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4′,6′-dimethoxy-2′-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements. PMID:22239485

  13. Potent triazolothione inhibitor of heat-shock protein-90.

    PubMed

    Feldman, Richard I; Mintzer, Bob; Zhu, Daguang; Wu, James M; Biroc, Sandra L; Yuan, Shendong; Emayan, Kumar; Chang, Zheng; Chen, Deborah; Arnaiz, Damian O; Bryant, Judi; Ge, Xue Snow; Whitlow, Marc; Adler, Marc; Polokoff, Mark A; Li, Wei-Wei; Ferrer, Mike; Sato, Takashi; Gu, Jian-Ming; Shen, Jun; Tseng, Jih-Lie; Dinter, Harald; Buckman, Brad

    2009-07-01

    Heat-shock protein-90 is an attractive target for anticancer drugs, as heat-shock protein-90 blockers such as the ansamycin 17-(allylamino)-17-demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17-(allylamino)-17-demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template-related drawbacks. In this paper, we describe a new, potent non-ansamycin small-molecule inhibitor of heat-shock protein-90, BX-2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX-2819 to the ADP/ATP-binding pocket of heat-shock protein-90. The compound blocked expression of heat-shock protein-90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17-(allylamino)-17-demethoxygeldanamycin. In a panel of four cancer cell lines, BX-2819 blocked growth with an average IC(50) value of 32 nM (range of 7-72 nM). Efficacy studies demonstrated that treatment with BX-2819 significantly inhibited the growth of NCI-N87 and HT-29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat-shock protein-90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX-2819 and related analogs for the treatment of cancer.

  14. Potent neutralizing monoclonal antibodies against Ebola virus infection

    PubMed Central

    Zhang, Qi; Gui, Miao; Niu, Xuefeng; He, Shihua; Wang, Ruoke; Feng, Yupeng; Kroeker, Andrea; Zuo, Yanan; Wang, Hua; Wang, Ying; Li, Jiade; Li, Chufang; Shi, Yi; Shi, Xuanling; Gao, George F.; Xiang, Ye; Qiu, Xiangguo; Chen, Ling; Zhang, Linqi

    2016-01-01

    Ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. Here we show isolation of three (Q206, Q314 and Q411) neutralizing monoclonal antibodies (mAbs) against the surface glycoprotein (GP) of Ebola virus identified in West Africa in 2014 through sequential immunization of Chinese rhesus macaques and antigen-specific single B cell sorting. These mAbs demonstrated potent neutralizing activities against both pseudo and live Ebola virus independent of complement. Biochemical, single particle EM, and mutagenesis analysis suggested Q206 and Q411 recognized novel epitopes in the head while Q314 targeted the glycan cap in the GP1 subunit. Q206 and Q411 appeared to influence GP binding to its receptor NPC1. Treatment with these mAbs provided partial but significant protection against disease in a mouse model of Ebola virus infection. These novel mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola virus infection. PMID:27181584

  15. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

    PubMed Central

    Haj, Christeene G.; Sumariwalla, Percy F.; Hanuš, Lumír; Kogan, Natalya M.; Yektin, Zhana; Feldmann, Mark

    2015-01-01

    Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ9-tetrahydrocannabinol (Δ9-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC–like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC–like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases. PMID:26272937

  16. Plants from Brazilian Cerrado with Potent Tyrosinase Inhibitory Activity

    PubMed Central

    Souza, Paula Monteiro; Elias, Silvia Taveira; Simeoni, Luiz Alberto; de Paula, José Elias; Gomes, Sueli Maria; Guerra, Eliete Neves Silva; Fonseca, Yris Maria; Silva, Elton Clementino; Silveira, Dâmaris; Magalhães, Pérola Oliveira

    2012-01-01

    The increased amount of melanin leads to skin disorders such as age spots, freckles, melasma and malignant melanoma. Tyrosinase is known to be the key enzyme in melanin production. Plants and their extracts are inexpensive and rich resources of active compounds that can be utilized to inhibit tyrosinase as well as can be used for the treatment of dermatological disorders associated with melanin hyperpigmentation. Using in vitro tyrosinase inhibitory activity assay, extracts from 13 plant species from Brazilian Cerrado were evaluated. The results showed that Pouteria torta and Eugenia dysenterica extracts presented potent in vitro tyrosinase inhibition compared to positive control kojic acid. Ethanol extract of Eugenia dysenterica leaves showed significant (p<0.05) tyrosinase inhibitory activity exhibiting the IC50 value of 11.88 µg/mL, compared to kojic acid (IC50 value of 13.14 µg/mL). Pouteria torta aqueous extract leaves also showed significant inhibitory activity with IC50 value of 30.01 µg/mL. These results indicate that Pouteria torta and Eugenia dysenterica extracts and their isolated constituents are promising agents for skin-whitening or antimelanogenesis formulations. PMID:23173036

  17. Neutralization mechanism of a highly potent antibody against Zika virus

    PubMed Central

    Zhang, Shuijun; Kostyuchenko, Victor A.; Ng, Thiam-Seng; Lim, Xin-Ni; Ooi, Justin S. G.; Lambert, Sebastian; Tan, Ter Yong; Widman, Douglas G.; Shi, Jian; Baric, Ralph S.; Lok, Shee-Mei

    2016-01-01

    The rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies for ZIKV cross-neutralization activity showed antibody C10 as one of the most potent. To investigate the ability of the antibody to block fusion, we determined the cryoEM structures of the C10-ZIKV complex at pH levels mimicking the extracellular (pH8.0), early (pH6.5) and late endosomal (pH5.0) environments. The 4.0 Å resolution pH8.0 complex structure shows that the antibody binds to E proteins residues at the intra-dimer interface, and the virus quaternary structure-dependent inter-dimer and inter-raft interfaces. At pH6.5, antibody C10 locks all virus surface E proteins, and at pH5.0, it locks the E protein raft structure, suggesting that it prevents the structural rearrangement of the E proteins during the fusion event—a vital step for infection. This suggests antibody C10 could be a good therapeutic candidate. PMID:27882950

  18. Highly potent silver-organoalkoxysilane antimicrobial porous nanomembrane

    NASA Astrophysics Data System (ADS)

    Umar, Sirajo; Liu, Yuanfeng; Wu, Yiguang; Li, Guangtao; Ding, Jiabo; Xiong, Runsong; Chen, Jinchun

    2013-04-01

    We used a simple electrospinning technique to fabricate a highly potent silver-organoalkoxysilane antimicrobial composite from AgNO3-polyvinylpyrrolidone (PVP)/3-aminopropyltrimethoxysilane (APTMS)/tetraethoxysilane (TEOS) solution. Spectroscopic and microscopic analyses of the composite showed that the fibers contain an organoalkoxysilane `skeleton,' 0.18 molecules/nm2 surface amino groups, and highly dispersed and uniformly distributed silver nanoparticles (5 nm in size). Incorporation of organoalkoxysilanes is highly beneficial to the antimicrobial mat as (1) amino groups of APTMS are adhesive and biocidal to microorganisms, (2) polycondensation of APTMS and TEOS increases the membrane's surface area by forming silicon bonds that stabilize fibers and form a composite mat with membranous structure and high porosity, and (3) the organoalkoxysilanes are also instrumental to the synthesis of the very small-sized and highly dispersed silver metal particles in the fiber mat. Antimicrobial property of the composite was evaluated by disk diffusion, minimum inhibition concentration (MIC), kinetic, and extended use assays on bacteria (Escherichia coli, Bacillus anthracis, Staphylococcus aureus, and Brucella suis), a fungus (Aspergillus niger), and the Newcastle disease virus. The membrane shows quick and sustained broad-spectrum antimicrobial activity. Only 0.3 mg of fibers is required to achieve MIC against all the test organisms. Bacteria are inhibited within 30 min of contact, and the fibers can be used repeatedly. The composite is silver efficient and environment friendly, and its membranous structure is suitable for many practical applications as in air filters, antimicrobial linen, coatings, bioadhesives, and biofilms.

  19. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

    Budragchaa, Davaanyam; Bai, Shiming; Kanamoto, Taisei; Nakashima, Hideki; Han, Shuqin; Yoshida, Takashi

    2015-10-05

    Ring-opening polymerization of a new 1,6-anhydro disaccharide monomer, 1, 6-anhydro-2, 3-di-O-benzyl-4-O-(2', 3', 4', 6'-tetra-O-benzyl-α-d-galactopyranosyl)-α-d-mannopyranose, was carried out using PF5 as a catalyst under high vacuum at -60°C to give galactose branched mannopyranan (synthetic galactomannan), 4-O-α-d-galactopyranosyl-(1→6)-α-d-mannopyranan, after debenzylation with Na in liquid NH3. The ring-opening copolymerization with 1, 6-anhydro-tri-O-benzyl-α-d-mannopyranose in various feeds was also performed to give synthetic galactomannans with various proportions of galactose branches. After sulfation, sulfated synthetic galactomannans were found to have anti-HIV activity and cytotoxicity as high and low as those of standard curdlan and dextran sulfates, respectively, which are potent anti-HIV sulfated polysaccharides with low cytotoxicity. The anti-HIV mechanism of sulfated synthetic galactomannans used by poly-l-lysine as a model peptide of the HIV surface protein was estimated by using SPR, DSL, and zeta potential measurements, revealing the electrostatic interaction between negatively charged sulfate groups and positively charged amino groups.

  20. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid.

    PubMed

    Haj, Christeene G; Sumariwalla, Percy F; Hanuš, Lumír; Kogan, Natalya M; Yektin, Zhana; Mechoulam, Raphael; Feldmann, Mark; Gallily, Ruth

    2015-10-01

    Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ(9)-tetrahydrocannabinol (Δ(9)-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ(9)-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ(9)-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ(9)-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

  1. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2012-07-01

    July 2011 - 30 June 2012 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity 5a...Introduction…………………………………………………………….………..….. 1 Body………………………………………………………………………………….. 1 Key Research Accomplishments………………………………………….…….. 4 ...Reportable Outcomes……………………………………………………………… 4 Conclusion…………………………………………………………………………… 8 References……………………………………………………………………………. 9

  2. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters.

    PubMed

    Ren, Huiwen; Wang, Yanhua; Xing, Yongning; Ran, Jianhua; Liu, Ming; Lei, Tianluo; Zhou, Hong; Li, Runtao; Sands, Jeff M; Yang, Baoxue

    2014-12-15

    Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 μM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na(+), K(+), or Cl(-) levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics.

  3. Hydrogen sulfide as a potent cardiovascular protective agent.

    PubMed

    Yu, Xiao-Hua; Cui, Li-Bao; Wu, Kai; Zheng, Xi-Long; Cayabyab, Francisco S; Chen, Zhi-Wei; Tang, Chao-Ke

    2014-11-01

    Hydrogen sulfide (H2S) is a well-known toxic gas with the characteristic smell of rotten eggs. It is synthesized endogenously in mammals from the sulfur-containing amino acid l-cysteine by the action of several distinct enzymes: cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT). In particular, CSE is considered to be the major H2S-producing enzyme in the cardiovascular system. As the third gasotransmitter next to nitric oxide (NO) and carbon monoxide (CO), H2S plays an important role in the regulation of vasodilation, angiogenesis, inflammation, oxidative stress and apoptosis. Growing evidence has demonstrated that this gas exerts a significant protective effect against the progression of cardiovascular diseases by a number of mechanisms such as vasorelaxation, inhibition of cardiovascular remodeling and resistance to form foam cells. The aim of this review is to provide an overview of the physiological functions of H2S and its protection against several major cardiovascular diseases, and to explore its potential health and therapeutic benefits. A better understanding will help develop novel H2S-based therapeutic interventions for these diseases.

  4. Raw and thermally treated cement asbestos exerts different cytotoxicity effects on A549 cells in vitro.

    PubMed

    Pugnaloni, Armanda; Lucarini, Guendalina; Rubini, Corrado; Smorlesi, Arianna; Tomasetti, Marco; Strafella, Elisabetta; Armeni, Tatiana; Gualtieri, Alessandro F

    2015-01-01

    Raw cement asbestos (RCA) undergoes a complete solid state transformation when heated at high temperatures. The secondary raw material produced, high temperatures-cement asbestos (HT-CA) is composed of newly-formed crystals in place of the asbestos fibers present in RCA. Our previous study showed that HT-CA exerts lower cytotoxic cell damage compared to RCA. Nevertheless further investigations are needed to deepen our understanding of pathogenic pathways involving oxidative and nitrative damage. Our aim is to deepen the understanding of the biological effects on A549 cells of these materials regarding DNA damage related proteins (p53, its isoform p73 and TRAIL) and nitric oxide (NO) production during inducible nitric oxide synthase (iNOS)-mediated inflammation. Increments of p53/p73 expression, iNOS positive cells and NO concentrations were found with RCA, compared to HT-CA and controls mainly at 48 h. Interestingly, ferrous iron causing reactive oxygen species (ROS)-mediated DNA damage was found in RCA as a contaminant. HT-CA thermal treatment induces a global recrystallization with iron in a crystal form poorly released in media. HT-CA slightly interferes with genome expression and exerts lower inflammatory potential compared to RCA on biological systems. It could represent a safe approach for storing or recycling asbestos and an environmentally friendly alternative to asbestos waste.

  5. Forces exerted during exercises by patients with adolescent idiopathic scoliosis wearing fiberglass braces

    PubMed Central

    Romano, Michele; Carabalona, Roberta; Petrilli, Silvia; Sibilla, Paolo; Negrini, Stefano

    2006-01-01

    Objective To quantify and compare the forces exerted by scoliosis patients in fiberglass braces during exercises usually prescribed in departments where casts are made. The exercises are intended to increase corrective forces, activate muscles, stimulate ventilation and help the patient psychologically. Setting Outpatient care. Patients 17 consecutive adolescent patients wearing fiberglass brace for idiopathic scoliosis. Interventions Exercises (kyphotization, rotation, "escape from the pad") in different positions (sitting, supine, on all fours). Main outcome measure Pressure detected by the F-Socket System between the rib hump and the pad of the brace. Results In static and dynamic conditions, the position adopted did not alter the total pressure exerted by the brace, although the part of the sensor stimulated did vary. Kyphotization and rotation exercises produced a significant increase of pressure (+ 58.9% and +29.8%, respectively); however, the "escape from the pad" exercise, despite its name, did not produce any significant variation of pressure. Conclusion Exercises in the brace allow adjunctive forces to be applied on soft tissues and through them, presumably on the spine. Different exercises can be chosen to obtain different actions. Physical exercises and sporting activities are useful in mechanical terms, although other important actions should not be overlooked. PMID:16859544

  6. Mechanical and Magnetic Resonance Imaging Changes Following Eccentric or Concentric Exertions

    PubMed Central

    Sesto, Mary E.; Chourasia, Amrish O.; Block, Walter F.; Radwin, Robert G.

    2008-01-01

    Background Prior work has shown that changes in mechanical parameters and magnetic resonance imaging (MRI) parameters occur following submaximal eccentric activity but it is unclear whether similar changes occur following submaximal concentric activity. This study compared mechanical response parameters and MRI relaxation parameters following submaximal concentric or eccentric exertions. Methods This single site, randomized study investigated in-vivo changes in human upper limb dynamic mechanical properties following exposure to short term repetitive submaximal eccentric or concentric exertions. Eighteen subjects were assigned to either an eccentric or concentric group and exercised for 30 minutes at 50% of isometric forearm maximum voluntary contraction. Changes in strength, symptom intensity, MRI T2 relaxation measurements, which are indicative of edema, and dynamic mechanical parameters (stiffness, effective mass, and damping) were ascertained prior to exercise, one hour after, and 24 hours later. Findings Strength decreased following exercise (P < 0.01), however only the eccentric exercise group exhibited a reduction in mechanical stiffness (55%, P <0.01) and damping (31%, P < 0.05), and an increase (17%, P < 0.05) in MRI T2 relaxation time. Interpretations The changes in mechanical parameters and MRI findings following repetitive submaximal eccentric activity could negatively impact the ability of the arm to react to rapid forceful loading during repetitive industrial work activities and may result in increased strain on the upper limb. Similar changes were not observed following concentric exercise. PMID:18485551

  7. Activity Exerted by a Testosterone Derivative on Myocardial Injury Using an Ischemia/Reperfusion Model

    PubMed Central

    Lauro, Figueroa-Valverde; Francisco, Díaz-Cedillo; Elodia, García-Cervera; Eduardo, Pool-Gómez; Maria, López-Ramos; Marcela, Rosas-Nexticapa; Lenin, Hau-Heredia; Betty, Sarabia-Alcocer; Monica, Velázquez-Sarabia Betty

    2014-01-01

    Some reports indicate that several steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the activity exerted by the testosterone derivatives on cardiac injury caused by ischemia/reperfusion (I/R). Analyzing these data, in this study, a new testosterone derivative was synthetized with the objective of evaluating its effect on myocardial injury using an ischemia/reperfusion model. In addition, perfusion pressure and coronary resistance were evaluated in isolated rat hearts using the Langendorff technique. Additionally, molecular mechanism involved in the activity exerted by the testosterone derivative on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in the absence or presence of the following compounds: flutamide, prazosin, metoprolol, nifedipine, indomethacin, and PINANE TXA2. The results showed that the testosterone derivative significantly increases (P = 0.05) the perfusion pressure and coronary resistance in isolated heart. Other data indicate that the testosterone derivative increases left ventricular pressure in a dose-dependent manner (0.001–100 nM); however, this phenomenon was significantly inhibited (P = 0.06) by indomethacin and PINANE-TXA2  (P = 0.05) at a dose of 1 nM. In conclusion, these data suggest that testosterone derivative induces changes in the left ventricular pressure levels through thromboxane receptor activation. PMID:24839599

  8. Fruit extract of the medicinal plant Crataegus oxyacantha exerts genotoxic and mutagenic effects in cultured cells.

    PubMed

    de Quadros, Ana Paula Oliveira; Mazzeo, Dania Elisa Christofoletti; Marin-Morales, Maria Aparecida; Perazzo, Fábio Ferreira; Rosa, Paulo Cesar Pires; Maistro, Edson Luis

    2017-02-17

    Crataegus oxyacantha, a plant of the Rosaceae family also known "English hawthorn, haw, maybush, or whitethorn," has long been used for medicinal purposes such as digestive disorders, hyperlipidemia, dyspnea, inducing diuresis, and preventing kidney stones. However, the predominant use of this plant has been to treat cardiovascular disorders. Due to a lack of studies on the genotoxicity of C. oxyacantha, this investigation was undertaken to determine whether its fruit extract exerts cytotoxic, genotoxic, or clastogenic/aneugenic effects in leukocytes and HepG2 (liver hepatocellular carcinoma) cultured human cells, or mutagenic effects in TA100 and TA98 strains of Salmonella typhimurium bacterium. Genotoxicity analysis showed that the extract produced no marked genotoxic effects at concentrations of 2.5 or 5 µg/ml in either cell type; however, at concentrations of 10 µg/ml or higher significant DNA damage was detected. The micronucleus test also demonstrated that concentrations of 10 µg/ml or higher produced clastogenic/aneugenic responses. In the Ames test, the extract induced mutagenic effects in TA98 strain of S. typhimurium with metabolic activation at all tested concentrations (2.5 to 500 µg/ml). Data indicate that, under certain experimental conditions, the fruit extract of C. oxyacantha exerts genotoxic and clastogenic/aneugenic effects in cultured human cells, and with metabolism mutagenicity occurs in bacteria cells.

  9. Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system.

    PubMed

    Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

    2015-03-12

    Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain.

  10. Inner dialogue and its relationship to perceived exertion during different running intensities.

    PubMed

    Aitchison, Callum; Turner, Louise A; Ansley, Les; Thompson, Kevin G; Micklewright, Dominic; St Clair Gibson, Alan

    2013-08-01

    This study examined the effect of low- and high-intensity running on cognitive thoughts (an individual's "inner dialogue") and its relationship to ratings of perceived exertion (RPE). Cognitive thoughts and RPE of eight runners were collected during a 40-min. treadmill run at either a low (50% peak running speed) or a high (70% peak running speed) exercise intensity. Runners were asked to place their thoughts into one of 10 themed categories, which incorporated a broad association/dissociation classification (Schomer, 1986, 1987). At a low intensity and RPE (6-10), runners reported more dissociative thoughts, while at a high intensity and RPE (16-20) they reported more associative thoughts. Further, although the runners may report a particular RPE, the inner dialogue and description of perceived exertion and fatigue may be markedly different. These findings suggest that an athlete's "internal dialogue" is intensity dependent, and may relate to the more urgent need to self-monitor physical changes and sensations during high-intensity running.

  11. EXERTIONAL COMPARTMENT SYNDROME: REVIEW OF THE LITERATURE AND PROPOSED REHABILITATION GUIDELINES FOLLOWING SURGICAL RELEASE

    PubMed Central

    2011-01-01

    Background: There is little published information regarding postoperative management of patients with Chronic Exertional Compartment Syndrome (CECS). Reports of recurrence of symptoms following surgical decompression exist, and are not uncommon depending on the specific technique used. Recurrence suggests that more time and effort may need to be spent on implementing strategic post-operative rehabilitation management in order to avoid repeat surgical intervention or prolonged symptoms. Objective: To summarize relevant literature regarding CECS and propose scientifically-based guidelines for rehab following compartment release with the rationale based on tissue healing, muscle loading, and scar tissue formation and consideration of all tissues contained in the involved compartment. Literature review: A literature search was performed in PubMed, SPORTDiscus, CINAHL, PEDRO, and Google Scholar using the phrase: “chronic exertional compartment syndrome.” Results: No specific rehabilitation guidelines following surgical compartment release for lower extremity CECS were found in the literature search performed for this clinical commentary. Discussion: The development of the proposed post-operative guidelines may allow for improved long-term outcomes following anterior compartment release. Summary: Adequate description of long-term follow-up of outcomes following compartment release for CECS is lacking in current literature. The proposed guidelines for rehab following compartment release include consideration of tissue healing, muscle loading, scar tissue formation, and consideration of soft tissues contained in the involved compartment. Utilization of the proposed guidelines may allow for future research to be performed in order to assess outcomes following surgical intervention for CECS. PMID:21713230

  12. Validation of a personalized curved muscle model of the lumbar spine during complex dynamic exertions.

    PubMed

    Hwang, Jaejin; Knapik, Gregory G; Dufour, Jonathan S; Best, Thomas M; Khan, Safdar N; Mendel, Ehud; Marras, William S

    2017-01-09

    Previous curved muscle models have typically examined their robustness only under simple, single-plane static exertions. In addition, the empirical validation of curved muscle models through an entire lumbar spine has not been fully realized. The objective of this study was to empirically validate a personalized biologically-assisted curved muscle model during complex dynamic exertions. Twelve subjects performed a variety of complex lifting tasks as a function of load weight, load origin, and load height. Both a personalized curved muscle model as well as a straight-line muscle model were used to evaluate the model's fidelity and prediction of three-dimensional spine tissue loads under different lifting conditions. The curved muscle model showed better model performance and different spinal loading patterns through an entire lumbar spine compared to the straight-line muscle model. The curved muscle model generally showed good fidelity regardless of lifting condition. The majority of the 600 lifting tasks resulted in a coefficient of determination (R(2)) greater than 0.8 with an average of 0.83, and the average absolute error less than 15% between measured and predicted dynamic spinal moments. As expected, increased load and asymmetry were generally found to significantly increase spinal loads, demonstrating the ability of the model to differentiate between experimental conditions. A curved muscle model would be useful to estimate precise spine tissue loads under realistic circumstances. This precise assessment tool could aid in understanding biomechanical causal pathways for low back pain.

  13. Influence of music on ratings of perceived exertion during 20 minutes of moderate intensity exercise.

    PubMed

    Potteiger, J A; Schroeder, J M; Goff, K L

    2000-12-01

    The effects of different types of music on ratings of perceived exertion (RPE) during 20 min. of moderate intensity exercise were examined. 27 physically active subjects (age 18-30 yr.) performed a graded exercise test on a cycle ergometer to establish peak aerobic power (VO2peak). Four 20-min. exercise sessions were performed at a power output equal to 70% of VO2peak in a soundproof visually sterile room. The sessions were randomly assigned from the conditions of fast upbeat music, classical music, self-selected music, and no music. Heart rate, peripheral RPE, central RPE, and overall RPE were measured every 5 min. during exercise. No significant differences were found in heart rate among the four conditions indicating similar exercise intensity during each condition. Each type of music resulted in a reduced peripheral, central, and overall RPE when compared with the no-music condition. The data indicate that different types of music can act as an effective passive distractor during exercise and are associated with lower ratings of perceived exertion.

  14. Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting RAGE Signaling in Diabetic Atherosclerosis

    PubMed Central

    Chung, Jihwa; An, Shung Hyun; Kang, Sang Won; Kwon, Kihwan

    2016-01-01

    A naturally occurring bile acid, ursodeoxycholic acid (UDCA), is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, the detailed action mechanisms of UDCA in atherosclerosis are not fully understood. In this study, we demonstrated whether UDCA exerts anti-atherogenic activity in diabetic atherosclerosis by targeting ER stress and “receptor for advanced glycation endproduct” (RAGE) signaling. UDCA markedly reduced ER stress, RAGE expression, and pro-inflammatory responses [including NF-κB activation and reactive oxygen species (ROS) production] induced in endothelial cells (ECs) by high glucose (HG). In particular, UDCA inhibited HG-induced ROS production by increasing the Nrf2 level. In macrophages, UDCA also blocked HG-induced RAGE and pro-inflammatory cytokine expression and inhibited foam cell formation via upregulation of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. In the diabetic mouse model, UDCA inhibited atheromatous plaque formation by decreasing ER stress, and the levels of RAGE and adhesion molecules. In conclusion, UDCA exerts an anti-atherogenic activity in diabetic atherosclerosis by targeting both ER stress and RAGE signaling. Our work implicates UDCA as a potential therapeutic agent for prevention or treatment of diabetic atherosclerosis. PMID:26807573

  15. Absence of exertional hyperthermia in a 17-year-old boy with severe burns.

    PubMed

    McEntire, Serina J; Lee, Jong O; Herndon, David N; Suman, Oscar E

    2009-01-01

    An important safety concern when exercising burned patients is the potential for an excessive increase in core body temperature (hyperthermia=body core temperature>39 degrees C) during exercise. We examined the thermoregulatory response to exercise in the heat (31 degrees C, relative humidity 40%) in a 17-year-old boy with a 99% TBSA burn. A 30-minute exercise test was performed at an intensity of 75% of his peak aerobic capacity. Intestinal temperature was assessed via telemetry with an ingestible capsule. Intestinal temperature was measured before, during, and postexercise. The patient completed 12 minutes of the 30-minute exercise test. Starting core temperature was 36.98 degrees C and increased 0.69 degrees C during exercise. After exercise, intestinal temperature continued to increase, but no hyperthermia was noted. It has been reported that burned children can safely exercise at room temperature; however, the response in the heat is unknown. This patient did not develop exertional hyperthermia, which we propose is due to his low-fitness level and heat intolerance. However, the potential for hyperthermia would be increased if he was forced to maintain a high relative workload in the heat. We propose that severely burned individuals should be able to safely participate in physical activities. However, the decision to stop exercising should be accepted to avoid development of exertional hyperthermia.

  16. Adenovirus with p16 gene exerts antitumor effect on laryngeal carcinoma Hep2 cells.

    PubMed

    Yang, Zhengang; Hu, Jingxia; Li, Dajun; Pan, Xinliang

    2016-08-01

    Laryngeal cancer is an uncommon form of cancer. The tumor suppressor P16, known to be mutated or deleted in various types of human tumor, including laryngeal carcinoma, is involved in the formation and development of laryngeal carcinoma. It has been previously reported that the inactivation or loss of P16 is associated with the acquisition of malignant characteristics. The current study hypothesized that restoring wild‑type P16 activity into P16‑null malignant Hep2 cells may exert an antitumor effect. A recombinant adenovirus carrying the P16 gene (Ad‑P16) was used to infect and express high levels of P16 protein in P16‑null Hep2 cells. Cell proliferation and invasion assays and polymerase chain reaction were performed to evaluate the effects of the P16 gene on cell proliferation and the antitumor effect on Hep2 cells. The results demonstrated that the Hep2 cells infected with Ad‑P16 exhibited significantly reduced cell proliferation, invasion and tumor volume compared with untreated or control adenovirus cells. Furthermore, the expression of laryngeal carcinoma‑associated genes, EGFR, survivin and cyclin D1, were measured in Ad‑P16‑infected cells and were significantly reduced compared with control groups. The results of the current study demonstrate that restoring wild‑type P16 activity into P16-null Hep2 cells exerts an antitumor effect.

  17. Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting RAGE Signaling in Diabetic Atherosclerosis.

    PubMed

    Chung, Jihwa; An, Shung Hyun; Kang, Sang Won; Kwon, Kihwan

    2016-01-01

    A naturally occurring bile acid, ursodeoxycholic acid (UDCA), is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, the detailed action mechanisms of UDCA in atherosclerosis are not fully understood. In this study, we demonstrated whether UDCA exerts anti-atherogenic activity in diabetic atherosclerosis by targeting ER stress and "receptor for advanced glycation endproduct" (RAGE) signaling. UDCA markedly reduced ER stress, RAGE expression, and pro-inflammatory responses [including NF-κB activation and reactive oxygen species (ROS) production] induced in endothelial cells (ECs) by high glucose (HG). In particular, UDCA inhibited HG-induced ROS production by increasing the Nrf2 level. In macrophages, UDCA also blocked HG-induced RAGE and pro-inflammatory cytokine expression and inhibited foam cell formation via upregulation of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. In the diabetic mouse model, UDCA inhibited atheromatous plaque formation by decreasing ER stress, and the levels of RAGE and adhesion molecules. In conclusion, UDCA exerts an anti-atherogenic activity in diabetic atherosclerosis by targeting both ER stress and RAGE signaling. Our work implicates UDCA as a potential therapeutic agent for prevention or treatment of diabetic atherosclerosis.

  18. Influence of fatigue, stress, muscle soreness and sleep on perceived exertion during submaximal effort.

    PubMed

    Haddad, Monoem; Chaouachi, Anis; Wong, Del P; Castagna, Carlo; Hambli, Mourad; Hue, Olivier; Chamari, Karim

    2013-07-02

    The aim of this study was to assess the effects of the Hooper's Index variations (i.e., self-ratings of fatigue, stress, delayed onset muscle soreness (DOMS), and sleep) on rating of perceived exertion during a 10 min submaximal exercise training session (RPE-10 min) and then check the stability and the internal consistency of RPE-10 min. Seventeen junior soccer players took part in this study. The individual Hooper's indices taken before each training session were correlated with RPE-10 min during a constant intensity and duration effort (10 min) using Pearson product moment correlation. Intraclass correlation (ICC) was used to assess the internal consistency of the RPE-10 min. All individual correlations between RPE-10 min and quality of sleep and quantity of fatigue, stress, and DOMS were non-significant (p>0.05). No significant correlations were resulted between RPE-10 min and Hooper's Index in all athletes. The ICC of RPE-10 min was 0.77 thus demonstrating internal consistency. The results of the present study demonstrated the objectivity and utility of RPE as a psychological tool for monitoring training during traditional soccer training. Therefore, the results of the present study suggest that fatigue, stress, DOMS and sleep are not major contributors of perceived exertion during traditional soccer training without excessive training loads. It seems that psychobiological factors other than fatigue, stress, DOMS and sleep may have mediated the 10 min exercise perceptual intensity.

  19. Activity exerted by a testosterone derivative on myocardial injury using an ischemia/reperfusion model.

    PubMed

    Lauro, Figueroa-Valverde; Francisco, Díaz-Cedillo; Elodia, García-Cervera; Eduardo, Pool-Gómez; Maria, López-Ramos; Marcela, Rosas-Nexticapa; Lenin, Hau-Heredia; Betty, Sarabia-Alcocer; Monica, Velázquez-Sarabia Betty

    2014-01-01

    Some reports indicate that several steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the activity exerted by the testosterone derivatives on cardiac injury caused by ischemia/reperfusion (I/R). Analyzing these data, in this study, a new testosterone derivative was synthetized with the objective of evaluating its effect on myocardial injury using an ischemia/reperfusion model. In addition, perfusion pressure and coronary resistance were evaluated in isolated rat hearts using the Langendorff technique. Additionally, molecular mechanism involved in the activity exerted by the testosterone derivative on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in the absence or presence of the following compounds: flutamide, prazosin, metoprolol, nifedipine, indomethacin, and PINANE TXA2. The results showed that the testosterone derivative significantly increases (P = 0.05) the perfusion pressure and coronary resistance in isolated heart. Other data indicate that the testosterone derivative increases left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited (P = 0.06) by indomethacin and PINANE-TXA2  (P = 0.05) at a dose of 1 nM. In conclusion, these data suggest that testosterone derivative induces changes in the left ventricular pressure levels through thromboxane receptor activation.

  20. Update: Exertional hyponatremia, active component, U.S. Armed Forces, 1999-2013.

    PubMed

    2014-03-01

    From 1999 through 2013, there were 1,406 incident diagnoses of exertional hyponatremia among active component members of the U.S. Armed Forces. Annual incidence rates rose sharply from 2008 to 2010 but decreased by 59 percent from 2010 to 2013. In 2013, there were fewer incident cases (n=73) than in any of the previous 9 years. The recent decrease in overall rates reflects sharply declining rates in the Marine Corps and slight decreases in the other Services. Relative to their respective counterparts, crude incidence rates of exertional hyponatremia for the entire 15-year surveillance period were higher among females, those in the youngest age group, Marines, recruit trainees, and "other" military occupations. Service members (particularly recruit trainees) and their supervisors must be vigilant for early signs of heat-related illnesses and must be knowledgeable of the dangers of excessive water consumption and the prescribed limits for water intake during prolonged physical activity (e.g., field training exercises, personal fitness training, recreational activities) in hot, humid weather.

  1. Oleoylethanolamide exerts anti-inflammatory effects on LPS-induced THP-1 cells by enhancing PPARα signaling and inhibiting the NF-κB and ERK1/2/AP-1/STAT3 pathways

    PubMed Central

    Yang, Lichao; Guo, Han; Li, Ying; Meng, Xianglan; Yan, Lu; Dan Zhang; Wu, Sangang; Zhou, Hao; Peng, Lu; Xie, Qiang; Jin, Xin

    2016-01-01

    The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases. PMID:27721381

  2. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways

    PubMed Central

    del Río, Carmen; Navarrete, Carmen; Collado, Juan A.; Bellido, M. Luz; Gómez-Cañas, María; Pazos, M. Ruth; Fernández-Ruiz, Javier; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A.; Cantarero, Irene; Muñoz, Eduardo

    2016-01-01

    Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ–mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases. PMID:26887982

  3. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

    PubMed

    del Río, Carmen; Navarrete, Carmen; Collado, Juan A; Bellido, M Luz; Gómez-Cañas, María; Pazos, M Ruth; Fernández-Ruiz, Javier; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Cantarero, Irene; Muñoz, Eduardo

    2016-02-18

    Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.

  4. Concurrent validity and interobserver reliability of the EPInfant pediatric perceived exertion rating scale among healthy Chilean children.

    PubMed

    Rodríguez-Núñez, Iván; Manterola, Carlos

    2016-08-01

    The objective of this study was to determine the validity and reliability of the EPInfant pediatric perceived exertion rating scale among Chilean children. Children aged 8-12 years old were selected; their heart rate, perceived exertion and workload were recorded during two consecutive Chester tests performed with a one week interval. Pearson's r coefficient and the intraclass correlation coefficient were estimated. Thirty-one children (17 boys) were included in the study. A strong correlation was observed between perceived exertion and reference criteria, in addition to a high intraclass correlation coefficient. The average difference between the perceived exertion in each test was 1.4 (95% CI: -1.4 to 4.1) and 0.2 (95% CI: -1.8 to 2.2) for boys and girls, respectively. The EPInfant scale showed an acceptable criterion validity and interobserver reliability among children during an incremental step test.

  5. Maximal dynamic grip force and wrist torque: the effects of gender, exertion direction, angular velocity, and wrist angle.

    PubMed

    Morse, Jonathan L; Jung, Myung-Chul; Bashford, Gregory R; Hallbeck, M Susan

    2006-11-01

    The objective of this study was to examine the effects of gender, exertion direction, angular velocity and wrist angle on simultaneous grip force and wrist torque under the isokinetic condition. The study used 20 participants (10 males and 10 females) and included 6 angular velocities (15, 30, 45, 60, 75, and 90 degrees /s) and 2 wrist exertion directions (flexion and extension) over the wrist range of motion of 70 degrees flexion to 60 degrees extension in 5 degrees increments. Similar to other studies, males and flexion exertion produced larger forces than females and extension exertion, respectively. However, the largest forces were generated at near extreme flexion of the wrist and the dependent variable of angular velocity was not practically significant. These results can contribute to the evaluation of cumulative trauma syndromes, but there is a need for more research on the dynamic measures of the hand and wrist complex and for standard development for dynamic force measurement.

  6. Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle.

    PubMed

    Murata, Kazuya; Nakao, Kikuyo; Hirata, Noriko; Namba, Kensuke; Nomi, Takao; Kitamura, Yoshihisa; Moriyama, Kenzo; Shintani, Takahiro; Iinuma, Munekazu; Matsuda, Hideaki

    2009-07-01

    The screening of Piperaceous plants for xanthine oxidase inhibitory activity revealed that the extract of the leaves of Piper betle possesses potent activity. Activity-guided purification led us to obtain hydroxychavicol as an active principle. Hydroxychavicol is a more potent xanthine oxidase inhibitor than allopurinol, which is clinically used for the treatment of hyperuricemia.

  7. Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry.

    PubMed

    Cagide, F; Silva, T; Reis, J; Gaspar, A; Borges, F; Gomes, L R; Low, J N

    2015-02-18

    The discovery of potent and selective monoamine oxidase-B inhibitors for the management of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is still a challenging endeavor. Herein, we report the discovery of two new classes of potent and selective MAO-B inhibitors based on chromane-2,4-dione and chromone-3-carboxamide scaffolds.

  8. Optimization of 5-pyridazin-3-one phenoxypropylamines as potent, selective histamine H₃ receptor antagonists with potent cognition enhancing activity.

    PubMed

    Tao, Ming; Aimone, Lisa D; Huang, Zeqi; Mathiasen, Joanne; Raddatz, Rita; Lyons, Jacquelyn; Hudkins, Robert L

    2012-01-12

    Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

  9. Highly potent silver-organoalkoxysilane antimicrobial porous nanomembrane

    PubMed Central

    2013-01-01

    We used a simple electrospinning technique to fabricate a highly potent silver-organoalkoxysilane antimicrobial composite from AgNO3-polyvinylpyrrolidone (PVP)/3-aminopropyltrimethoxysilane (APTMS)/tetraethoxysilane (TEOS) solution. Spectroscopic and microscopic analyses of the composite showed that the fibers contain an organoalkoxysilane ‘skeleton,’ 0.18 molecules/nm2 surface amino groups, and highly dispersed and uniformly distributed silver nanoparticles (5 nm in size). Incorporation of organoalkoxysilanes is highly beneficial to the antimicrobial mat as (1) amino groups of APTMS are adhesive and biocidal to microorganisms, (2) polycondensation of APTMS and TEOS increases the membrane’s surface area by forming silicon bonds that stabilize fibers and form a composite mat with membranous structure and high porosity, and (3) the organoalkoxysilanes are also instrumental to the synthesis of the very small-sized and highly dispersed silver metal particles in the fiber mat. Antimicrobial property of the composite was evaluated by disk diffusion, minimum inhibition concentration (MIC), kinetic, and extended use assays on bacteria (Escherichia coli, Bacillus anthracis, Staphylococcus aureus, and Brucella suis), a fungus (Aspergillus niger), and the Newcastle disease virus. The membrane shows quick and sustained broad-spectrum antimicrobial activity. Only 0.3 mg of fibers is required to achieve MIC against all the test organisms. Bacteria are inhibited within 30 min of contact, and the fibers can be used repeatedly. The composite is silver efficient and environment friendly, and its membranous structure is suitable for many practical applications as in air filters, antimicrobial linen, coatings, bioadhesives, and biofilms. PMID:23574791

  10. 5% CO2 is a potent, fast acting inhalation anticonvulsant

    PubMed Central

    Tolner, Else A.; Hochman, Daryl W.; Hassinen, Pekka; Otáhal, Jakub; Gaily, Eija; Haglund, Michael M.; Kubová, Hana; Schuchmann, Sebastian; Vanhatalo, Sampsa; Kaila, Kai

    2010-01-01

    Purpose CO2 has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO2 can be used to suppress seizures in epilepsy patients. The effect of CO2 on cortical epileptic activity accompanying behavioral seizures was studied in rats and a non-human primate and based on these data, preliminary tests were carried out in humans. Methods In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor cortex stimulation. 5% CO2 was applied for 5 minutes, 3 minutes before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor cortex. Seven patients with drug-resistant partial epilepsy were examined with video-EEG and received 5% CO2 in medical carbogen shortly after electrographic seizure onset. Results In rats, 5% CO2 strongly suppressed cortical afterdischarges, by ca. 75%, while responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pCO2 from 37 to 44-45 mmHg (corresponding to inhalation of 5% CO2 or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by ca. 25%. In a pilot trial carried out in 7 patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO2 was started after seizure generalization. Conclusions 5% CO2 has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO2 can be used for acute treatment to suppress seizures in epilepsy patients. PMID:20887367

  11. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    PubMed

    Raveh, Avi; Delekta, Phillip C; Dobry, Craig J; Peng, Weiping; Schultz, Pamela J; Blakely, Pennelope K; Tai, Andrew W; Matainaho, Teatulohi; Irani, David N; Sherman, David H; Miller, David J

    2013-01-01

    Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the

  12. Imipenem: a potent inducer of multidrug resistance in Acinetobacter baumannii.

    PubMed

    Kuo, Han-Yueh; Chang, Kai-Chih; Kuo, Jai-Wei; Yueh, Hui-Wen; Liou, Ming-Li

    2012-01-01

    This study investigated the progression of multidrug resistance upon exposure to imipenem in Acinetobacter baumannii. Eighteen A. baumannii strains, including two reference strains (ATCC 19606 and ATCC 17978), four clinical strains (AB56, AB242, AB273 and AB279) and 12 antibiotic-selected mutant strains, were used in this study. Imipenem-selected mutants were generated from imipenem-susceptible strains (ATCC 19606, ATCC 17978 and AB242) by multistep selection resistance. Amikacin-, ciprofloxacin-, colistin-, meropenem- and ceftazidime-selected mutants were also generated from the two reference strains and were used for comparison. Antibiotic susceptibilities in the absence and presence of the efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 1-(1-naphthylmethyl)-piperazine (NMP) were examined in the three imipenem-selected mutants and the three clinical multidrug-resistant (MDR) isolates. Expression profiles of the antimicrobial resistance genes in the imipenem-selected mutants and their parental strains were also determined. The results showed that imipenem was more likely, compared with the other antibiotics, to induce a MDR phenotype in the two reference strains. Differences in OXA-51-like carbapenemase, efflux pumps or/and AmpC β-lactamase expression were observed in the three imipenem-selected mutants. Moreover, a reduction in imipenem or amikacin resistance was observed when the imipenem-selected mutants and clinical isolates were exposed to NMP and CCCP. This study concluded that imipenem might be a potent inducer of multidrug resistance in A. baumannii strains. OXA-51-like carbapenemase combined with other resistance mechanisms may contribute to the development of multidrug resistance in A. baumannii. Monitoring the use of carbapenems is required to reduce the spread of MDR A. baumannii in hospitals.

  13. Phenolic amides are potent inhibitors of De Novo nucleotide biosynthesis

    DOE PAGES

    Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; ...

    2015-06-12

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposuremore » leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. Furthermore, the results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals.« less

  14. Monochloramine potently inhibits arachidonic acid metabolism in rat platelets.

    PubMed

    Fujimoto, Yohko; Ikeda, Mai; Sakuma, Satoru

    2006-05-26

    In the present study, the effects of hypochlorous acid (HOCl), monochloramine (NH(2)Cl), glutamine-chloramine (Glu-Cl) and taurine-chloramine (Tau-Cl) on the formation of 12-lipoxygenase (LOX) metabolite, 12-HETE, and cyclooxygenase (COX) metabolites, TXB(2), and 12-HHT, from exogenous arachidonic acid (AA) in rat platelets were examined. Rat platelets (4x10(8)/ml) were preincubated with drugs for 5min at 37 degrees C prior to the incubation with AA (40microM) for 2min at 37 degrees C. HOCl (50-250microM) showed an inhibition on the formation of LOX metabolite (12-HETE, 5-67% inhibition) and COX metabolites (TXB(2), 33-73% inhibition; 12-HHT, 27-74% inhibition). Although Tau-Cl and Glu-Cl up to 100microM were without effect on the formation of 12-HETE, TXB(2) and 12-HTT, NH(2)Cl showed a strong inhibition on the formation of all three metabolites (10-100microM NH(2)Cl, 12-HETE, 21-92% inhibition; TXB(2), 58-94% inhibition; 12-HHT, 36-92% inhibition). Methionine reversed a reduction of formation of LOX and COX metabolites induced by NH(2)Cl, and taurine restoring that induced by both NH(2)Cl and HOCl. These results suggest that NH(2)Cl is a more potent inhibitor of COX and LOX pathways in platelets than HOCl, and taurine and methionine can be modulators of NH(2)Cl-induced alterations in the COX and LOX pathways in vivo.

  15. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

    PubMed Central

    Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; Stevenson, David M.

    2015-01-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransf