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Sample records for human granulocyte-colony stimulating

  1. Anti-apoptotic effects of recombinant human granulocyte colony-stimulating factor in focal cerebral ischemic rats

    Institute of Scientific and Technical Information of China (English)

    Xia Yuan; Shiming Zhang; Wanli Dong; Qi Fang

    2011-01-01

    The neuroprotective effects of granulocyte colony-stimulating factor in cerebral ischemia/reperfusion injury are currently contentious. The present study examined the effects of subcutaneous injection of recombinant human granulocyte colony-stimulating factor (50 μg/kg) over 5 days in a model of cerebral ischemia/reperfusion with intraluminal filament occlusion in rats. The results indicated that recombinant human granulocyte colony-stimulating factor reduced brain infarct volume following cerebral ischemia/reperfusion injury in rats, down-regulated the expression of caspase-3 mRNA (a key protease for apoptosis in the cerebral ischemia zone), lowered the rate of neuronal apoptosis in the cerebral ischemia zone, and notably ameliorated neurological function. These results indicate that recombinant human granulocyte colony-stimulating factor has anti-apoptotic effects on neurons following focal cerebral ischemia/reperfusion injury, and exerts neuroprotective effects.

  2. Human granulocyte colony stimulating factor (hG-CSF: cloning, overexpression, purification and characterization

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    Vanz Ana LS

    2008-04-01

    Full Text Available Abstract Background Biopharmaceutical drugs are mainly recombinant proteins produced by biotechnological tools. The patents of many biopharmaceuticals have expired, and biosimilars are thus currently being developed. Human granulocyte colony stimulating factor (hG-CSF is a hematopoietic cytokine that acts on cells of the neutrophil lineage causing proliferation and differentiation of committed precursor cells and activation of mature neutrophils. Recombinant hG-CSF has been produced in genetically engineered Escherichia coli (Filgrastim and successfully used to treat cancer patients suffering from chemotherapy-induced neutropenia. Filgrastim is a 175 amino acid protein, containing an extra N-terminal methionine, which is needed for expression in E. coli. Here we describe a simple and low-cost process that is amenable to scaling-up for the production and purification of homogeneous and active recombinant hG-CSF expressed in E. coli cells. Results Here we describe cloning of the human granulocyte colony-stimulating factor coding DNA sequence, protein expression in E. coli BL21(DE3 host cells in the absence of isopropyl-β-D-thiogalactopyranoside (IPTG induction, efficient isolation and solubilization of inclusion bodies by a multi-step washing procedure, and a purification protocol using a single cationic exchange column. Characterization of homogeneous rhG-CSF by size exclusion and reverse phase chromatography showed similar yields to the standard. The immunoassay and N-terminal sequencing confirmed the identity of rhG-CSF. The biological activity assay, in vivo, showed an equivalent biological effect (109.4% to the standard reference rhG-CSF. The homogeneous rhG-CSF protein yield was 3.2 mg of bioactive protein per liter of cell culture. Conclusion The recombinant protein expression in the absence of IPTG induction is advantageous since cost is reduced, and the protein purification protocol using a single chromatographic step should reduce cost

  3. Refolding of recombinant human granulocyte colony stimulating factor: effect of cysteine/cystine redox system.

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    Tiwari, Krishnanand; Shebannavar, Sunil; Kattavarapu, Krishna; Pokalwar, Santosh; Mishra, Maheshwari K; Chauhan, Ugam Kumari

    2012-08-01

    Granulocyte colony-stimulating factor (G-CSF) is a multifunctional cytokine which is widely used for treating neutropenia in humans. Evaluation of alternative to expensive components of redox buffer (reduced and oxidized glutathione) is an important step in reducing the cost of production of human biotherapeutic proteins. In the present study, refolding of recombinant human G-CSF expressed as inclusion bodies (IBs) in E. coli was optimized using cysteine and cystine redox agents. The refolding to correct native form of G-CSF was assessed by reverse phase high performance liquid chromatography (RP-HPLC). The optimized concentrations of cysteine and cystine for correct refolding of G-CSF were found to be 2 mM and 1 mM, respectively. The correctly refolded G-CSF was detected as early as 4 h of incubation in renaturation buffer containing optimized concentrations of cysteine (2 mM) and cystine (1 mM) redox agents. Refolding of G-CSF in optimized redox system increased with increase in shuffling time. Overall, the results suggested the use of cysteine/cystine redox pair could be an alternative to the costlier redox pairs for successful refolding of G-CSF and possibly other human biotherapeutic proteins of importance.

  4. Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

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    Hollenstein, U; Homoncik, M; Stohlawetz, P J; Marsik, C; Sieder, A; Eichler, H G; Jilma, B

    2000-07-01

    During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

  5. Enhanced and Secretory Expression of Human Granulocyte Colony Stimulating Factor by Bacillus subtilis SCK6

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    Shaista Bashir

    2015-01-01

    Full Text Available This study describes a simplified approach for enhanced expression and secretion of a pharmaceutically important human cytokine, that is, granulocyte colony stimulating factor (GCSF, in the culture supernatant of Bacillus subtilis SCK6 cells. Codon optimized GCSF and pNWPH vector containing SpymwC signal sequence were amplified by prolonged overlap extension PCR to generate multimeric plasmid DNA, which was used directly to transform B. subtilis SCK6 supercompetent cells. Expression of GCSF was monitored in the culture supernatant for 120 hours. The highest expression, which corresponded to 17% of the total secretory protein, was observed at 72 hours of growth. Following ammonium sulphate precipitation, GCSF was purified to near homogeneity by fast protein liquid chromatography on a QFF anion exchange column. Circular dichroism spectroscopic analysis showed that the secondary structure contents of the purified GCSF are similar to the commercially available GCSF. Biological activity, as revealed by the regeneration of neutrophils in mice treated with ifosfamine, was also similar to the commercial preparation of GCSF. This, to our knowledge, is the first study that reports secretory expression of human GCSF in B. subtilis SCK6 with final recovery of up to 96 mg/L of the culture supernatant, without involvement of any chemical inducer.

  6. Chronic Toxicity of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

    Institute of Scientific and Technical Information of China (English)

    Fei Xia; Qing-yu Zhang; Yong-ping Jiang

    2011-01-01

    Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship. Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group): four groups were treated with rhG-CSFa at 500, 100,10, 1 μg/kg, respectively, and one group was treated with vehicle only to serve as the control. The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks. During the course of the chronic toxicity study, the physical status, body weight, and food consumption were monitored. Half of the rats in each group (n= 10) were sacrificed after the last rhG-CSFa administration, and the other half were sacrificed at five weeks after the last rhG-CSFa administration. Urinalyses, blood biochemistry, hematological analysis, histopathological examination, and immunological tests were performed for each of the rats. Results The hematological analyses revealed that the mean white blood cells count, neutrophils count, and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher, and these were related with the biological activity of rhG-CSFa. Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg, a dosage of 200 folds higher than the normal clinical dosage), but these abnormalities were recovered within S-week recovery period. No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.

  7. A New Protocol for Solubilization, Refolding and Purification of Recombinant Human Granulocyte Colony-stimulating Factor in Inclusion Bodies

    Institute of Scientific and Technical Information of China (English)

    Jia Hua LIU; Chao Zhan WANG; Xin Du GENG

    2006-01-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) in inclusion bodies was solubilized by 8 mol/L urea solution and subsequently precipitated by acetone to improve its purity. After that, the precipitates were solubilized by sodium hydroxide solution containing 2 mol/L urea. Then the solubilized rhG-CSF was passed through a size exclusion chromatography for refolding and extensive purification, and further purified by a weak anion exchange chromatography. The purity and mass recovery of refolded rhG-CSF were 96.5% and 75.6%, respectively. The bioactivity was 8.4×107 IU/mg.

  8. Tumor necrosis factor downregulates granulocyte-colony-stimulating factor receptor expression on human acute myeloid leukemia cells and granulocytes.

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    Elbaz, O; Budel, L M; Hoogerbrugge, H; Touw, I P; Delwel, R.; Mahmoud, L A; Löwenberg, B. (Bernward)

    1991-01-01

    Tumor necrosis factor (TNF) inhibits granulocyte-colony-stimulating factor (G-CSF)-induced human acute myeloid leukemia (AML) growth in vitro. Incubation of blasts from three patients with AML in serum-free medium with TNF (10(3) U/ml), and subsequent binding studies using 125I-G-CSF reveal that TNF downregulates the numbers of G-CSF receptors by approximately 70%. G-CSF receptor numbers on purified blood granulocytes are also downmodulated by TNF. Downregulation of G-CSF receptor expression ...

  9. Refolding with Simultaneous Purification of Recombinant Human Granulocyte Colony-stimulating Factor from Escherichia coli Using Strong Anion Exchange Chromatography

    Institute of Scientific and Technical Information of China (English)

    Chao Zhan WANG; Jiang Feng LIU; Xin Du GENG

    2005-01-01

    The urea denatured recombinant human granulocyte colony-stimulating factor (rhGCSF) which was expressed in Escheriachia coli (E. coli) was refolded with simultaneous purification by strong anion exchange chromatography (SAX) in the presence of low concentration of urea. The effect of urea concentration on this refolding process was investigated. The obtained refolded rhG-CSF has a high specific activity of 2.3×108 U/mg, demonstrating that the proteins were completely refolded during the chromatographic process. With only one step by SAX in 40 min, purity and mass recovery of the refolded and purified rhG-CSF were 97% and43%, respectively.

  10. Methimazole-induced aplastic anemia in third exposure: successful treatment with recombinant human granulocyte colony-stimulating factor.

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    Mezquita, P; Luna, V; Muñoz-Torres, M; Torres-Vela, E; Lopez-Rodriguez, F; Callejas, J L; Escobar-Jimenez, F

    1998-09-01

    The major adverse reactions of antithyroid drugs are hematologic; aplastic anemia (AA) is one of the rarest and most severe complications. Use of recombinant human hemopoietic colony-stimulating factor was reported to be of benefit in patients who developed agranulocytosis, although there is still some doubt regarding the efficacy in AA. We present a case of a 58-year-old female patient with Graves' disease who developed AA in the third exposure to methimazole (MMI). The withdrawal of MMI and early treatment with 5 microg/kg per day recombinant human granulocyte colony-stimulating factor (G-CSF) for 9 days, allowed a favorable recovery of peripheral blood cell count. We conclude that the use of hemopoietic colony stimulating factors might be a suitable means to achieve the correction of severe thionamide-induced hematologic adverse reactions.

  11. Weekly CODE chemotherapy with recombinant human granulocyte colony-stimulating factor for relapsed or refractory small cell lung cancer.

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    Sato, K; Tsuchiya, S; Minato, K; Sunaga, N; Ishihara, S I; Makimoto, T; Naruse, I; Hoshino, H; Watanabe, S; Saitoh, R; Mori, M

    2000-01-01

    We used cisplatin, vincristine, doxorubicin, and etoposide (CODE) plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) weekly for salvage chemotherapy in relapsed or refractory small cell lung cancer (SCLC). We reviewed the medical charts of patients between January 1993 and December 1996 at the National Nishi-Gunma Hospital. Twenty patients were treated with salvage chemotherapy. The overall response rate was 55.0%. The median survival time of extensive disease patients from the start of CODE therapy was 23 weeks and the 1-year survival rate was 21.0%. Toxicities were severe, especially in myelosuppression. CODE could be selected as a salvage therapy for chemotherapy- relapsed SCLC cases.

  12. Efficient mobilization of haematopoietic progenitors after a single injection of pegylated recombinant human granulocyte colony-stimulating factor in mouse strains with distinct marrow-cell pool sizes

    NARCIS (Netherlands)

    de Haan, G; Ausema, A; Wilkens, M; Molineux, G; Dontje, B

    We have compared the efficacy of a single injection of SD/01, a newly engineered, pegylated form of recombinant human granulocyte colony stimulating factor (rhG-CSF), with a single injection of glycosylated rhG-CSF (Filgrastim). SD/01 was administered to regular and recombinant inbred strains of

  13. LONG-TERM RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR (RHG-CSF) TREATMENT SEVERELY DEPRESSES MURINE MARROW ERYTHROPOIESIS WITHOUT CAUSING AN ANEMIA

    NARCIS (Netherlands)

    DEHAAN, G; LOEFFLER, M; NIJHOF, W

    1992-01-01

    We hereby report profound effects of long-term granulocyte colony-stimulating factor (G-CSF) administration on murine erythropoiesis. Recombinant human (rh)G-CSF (150-mu-g/kg body weight/day) was administered over 24 days to female C57B1 mice. Marrow erythroid colony-forming units (CFU-E) and erythr

  14. Paclitaxel, ifosfamide and cisplatin with granulocyte colony-stimulating factor or recombinant human interleukin 3 and granulocyte colony-stimulating factor in ovarian cancer : A feasibility study

    NARCIS (Netherlands)

    Veldhuis, GJ; Willemse, PHB; Beijnen, JH; Piersma, H; vanderGraaf, WTA; deVries, EGE; Boonstra, J.

    1997-01-01

    The tolerability and efficacy of four courses of paclitaxel and ifosfamide plus cisplatin every 3 weeks was evaluated in patients with residual or refractory ovarian cancer. Additionally, supportive haematological effects of recombinant human interleukin 3 (rhIL-3) and recombinant human granulocyte

  15. Preferential response of acute myeloid leukemias with translocation involving chromosome 17 to human recombinant granulocyte colony-stimulating factor.

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    Pébusque, M J; Lafage, M; Lopez, M; Mannoni, P

    1988-07-01

    Induction of proliferation and differentiation in response to the addition of recombinant human granulocyte colony-stimulating factor (G-CSF) was studied by both suspension and semisolid cultures in a series of acute myeloid leukemias (AML). Induction of proliferation by G-CSF alone was observed in six of 27 cases of AML. All acute promyelocytic leukemias with the specific chromosomal translocation t(15;17) and one case of myelomonocytic leukemia with balanced chromosomal translocation involving chromosome 17 at band q12q21 were induced to proliferate strongly by the G-CSF. However, contrary to the long-term proliferative effect observed with granulocyte/macrophage colony-stimulating factor (GM-CSF), G-CSF activity can be characterized by its capability to initiate and promote the growth of responding AML cells but not to sustain long-term proliferation. Finally, no terminal differentiation was found, as assessed by morphology, cytochemistry, and cell surface marker analysis. These results indicate that G-CSF may be sufficient to provide a specific signal for induction of a transient proliferation in AML without induction of terminal differentiation. The cells with the highest response are clonal leukemia cells, all bearing a translocation involving the chromosome region 17q12q21 in which the G-CSF gene has been recently located.

  16. Simplified large-scale refolding, purification, and characterization of recombinant human granulocyte-colony stimulating factor in Escherichia coli.

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    Chang Kyu Kim

    Full Text Available Granulocyte-colony stimulating factor (G-CSF is a pleiotropic cytokine that stimulates the development of committed hematopoietic progenitor cells and enhances the functional activity of mature cells. Here, we report a simplified method for fed-batch culture as well as the purification of recombinant human (rh G-CSF. The new system for rhG-CSF purification was performed using not only temperature shift strategy without isopropyl-l-thio-β-d-galactoside (IPTG induction but also the purification method by a single step of prep-HPLC after the pH precipitation of the refolded samples. Through these processes, the final cell density and overall yield of homogenous rhG-CSF were obtained 42.8 g as dry cell weights, 1.75 g as purified active proteins, from 1 L culture broth, respectively. The purity of rhG-CSF was finally 99% since the isoforms of rhG-CSF could be separated through the prep-HPLC step. The result of biological activity indicated that purified rhG-CSF has a similar profile to the World Health Organization (WHO 2(nd International Standard for G-CSF. Taken together, our results demonstrate that the simple purification through a single step of prep-HPLC may be valuable for the industrial-scale production of biologically active proteins.

  17. Simplified in vitro refolding and purification of recombinant human granulocyte colony stimulating factor using protein folding cation exchange chromatography.

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    Vemula, Sandeep; Dedaniya, Akshay; Thunuguntla, Rahul; Mallu, Maheswara Reddy; Parupudi, Pavani; Ronda, Srinivasa Reddy

    2015-01-30

    Protein folding-strong cation exchange chromatography (PF-SCX) has been employed for efficient refolding with simultaneous purification of recombinant human granulocyte colony stimulating factor (rhG-CSF). To acquire a soluble form of renatured and purified rhG-CSF, various chromatographic conditions, including the mobile phase composition and pH was evaluated. Additionally, the effects of additives such as urea, amino acids, polyols, sugars, oxidizing agents and their amalgamations were also investigated. Under the optimal conditions, rhG-CSF was efficaciously solubilized, refolded and simultaneously purified by SCX in a single step. The experimental results using ribose (2.0M) and arginine (0.6M) combination were found to be satisfactory with mass yield, purity and specific activity of 71%, ≥99% and 2.6×10(8)IU/mg respectively. Through this investigation, we concluded that the SCX refolding method was more efficient than conventional methods which has immense potential for the large-scale production of purified rhG-CSF.

  18. Peripheral blood morphologic changes after high-dose antineoplastic chemotherapy and recombinant human granulocyte colony-stimulating factor administration.

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    Kerrigan, D P; Castillo, A; Foucar, K; Townsend, K; Neidhart, J

    1989-09-01

    The peripheral blood morphologic findings in 17 patients with cancer who had received high-dose cytotoxic chemotherapy followed by recombinant human-granulocyte colony-stimulating factor (rh-GCSF) were reviewed and compared with a control group of patients who received only high-dose chemotherapy. Both groups showed dysmyelopoiesis (abnormal granulation and nuclear lobulation) in the granulocytic series during the period of bone marrow recovery that followed the cytotoxic chemotherapy. Most of these morphologic abnormalities were more prominent in the rh-GCSF-treated group. Monocytic cells in both groups showed prominent vacuolation and immature nuclei. The percentages and absolute numbers of large granular lymphocytes were increased in the rh-GCSF group compared with the control group. No quantitative or qualitative abnormalities of eosinophilic or basophilic granulocytes were detected in either group. Both groups showed nonspecific red blood cell abnormalities, and large platelets were present in half of the control group smears. This report provides the first detailed peripheral blood morphologic description in patients treated with rh-GCSF and high-dose chemotherapy.

  19. Myeloid Engraftment in Humanized Mice: Impact of Granulocyte-Colony Stimulating Factor Treatment and Transgenic Mouse Strain.

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    Coughlan, Alice M; Harmon, Cathal; Whelan, Sarah; O'Brien, Eóin C; O'Reilly, Vincent P; Crotty, Paul; Kelly, Pamela; Ryan, Michelle; Hickey, Fionnuala B; O'Farrelly, Cliona; Little, Mark A

    2016-04-01

    Poor myeloid engraftment remains a barrier to experimental use of humanized mice. Focusing primarily on peripheral blood cells, we compared the engraftment profile of NOD-scid-IL2Rγc(-/-) (NSG) mice with that of NSG mice transgenic for human membrane stem cell factor (hu-mSCF mice), NSG mice transgenic for human interleukin (IL)-3, granulocyte-macrophage-colony stimulating factor (GM-CSF), and stem cell factor (SGM3 mice). hu-mSCF and SGM3 mice showed enhanced engraftment of human leukocytes compared to NSG mice, and this was reflected in the number of human neutrophils and monocytes present in these strains. Importantly, discrete classical, intermediate, and nonclassical monocyte populations were identifiable in the blood of NSG and hu-mSCF mice, while the nonclassical population was absent in the blood of SGM3 mice. Granulocyte-colony stimulating factor (GCSF) treatment increased the number of blood monocytes in NSG and hu-mSCF mice, and neutrophils in NSG and SGM3 mice; however, this effect appeared to be at least partially dependent on the stem cell donor used to engraft the mice. Furthermore, GCSF treatment resulted in a preferential expansion of nonclassical monocytes in both NSG and hu-mSCF mice. Human tubulointerstitial CD11c(+) cells were present in the kidneys of hu-mSCF mice, while monocytes and neutrophils were identified in the liver of all strains. Bone marrow-derived macrophages prepared from NSG mice were most effective at phagocytosing polystyrene beads. In conclusion, hu-mSCF mice provide the best environment for the generation of human myeloid cells, with GCSF treatment further enhancing peripheral blood human monocyte cell numbers in this strain.

  20. Granulocyte colony-stimulating factor and leukemogenesis

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    Lorena Lobo de Figueiredo

    2004-01-01

    Full Text Available THE granulocyte colony-stimulating factor (G-CSF plays an important role in normal granulopoiesis. Its functions are mediated by specific receptors on the surface of responsive cells and, upon ligand binding, several cytoplasmic tyrosine kinases are activated. The cytoplasmic region proximal to the membrane of the G-CSF receptor (G-CSF-R transduces proliferative and survival signals, whereas the distal carboxy-terminal region transduces maturation signals and suppresses the receptor's proliferative signals. Mutations in the G-CSF-R gene resulting in truncation of the carboxy-terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia (AML. In addition, the AML1-ETO fusion protein, expressed in leukemic cells harboring the t(8;21, disrupt the physiological function of transcription factors such as C/EBPα and C/EBPε, which in turn deregulate G-CSF-R expression. The resulting high levels of G-CSF-R and G-CSF-dependent cell proliferation may be associated with pathogenesis of AML with t(8;21. Moreover, in vitro and in vivo studies demonstrated that G-CSF may act as a co-stimulus augmenting the response of PML-RARα acute promyelocytic leukemia cells to all-trans-retinoic acid treatment. Finally, in the PLZF-RARα acute promyelocytic leukemia transgenic model, G-CSF deficiency suppressed leukemia development. Altogether, these data suggest that the G-CSF signaling pathway may play a role in leukemogenesis.

  1. Expression and purification of recombinant human granulocyte colony-stimulating factor in fed-batch culture of Escherichia coli.

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    Kim, Chang-Kyu; Choi, Jun-Ha; Lee, Seung-Bae; Lee, Sang-Mahn; Oh, Jae-Wook

    2014-03-01

    Granulocyte colony-stimulating factor (G-CSF) is a cytokine that has multiple roles in hematopoietic cells such as the regulation of proliferation and differentiation. Here, we describe fed-batch culture, refolding, and purification of rhG-CSF. The suitability of urea or sarcosine for solubilizing inclusion bodies (IBs) was tested. It was observed that urea is more efficient for solubilizing and refolding IBs than sarcosine is. The purity of rhG-CSF and the removal percentage of the rhG-CSF isoforms during purification were increased by pH 5.5 precipitation. The purity and the yield of purified rhG-CSF were 99% and 0.5 g of protein per liter culture broth, respectively. Our protocols of recombinant protein purification using ion exchange chromatography and semipreparative high performance liquid chromatography of pH-precipitated refolded solution may be informative to the industrial scale production of biopharmaceuticals.

  2. Granulocyte colony stimulating factor in neutropenic patients with infective endocarditis

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    Borgbjerg, B. M.; Hovgaard, D.; Laursen, J. B.; Aldershvile, J.

    1998-01-01

    A well known complication in the treatment of infectious endocarditis is development of neutropenia caused by treatment with antibiotics in high concentrations over long periods. Neutropenia often necessitates discontinuation of antibiotic treatment. Three patients with infectious endocarditis who developed neutropenia are reported. The patients were treated with granulocyte colony stimulating factor (G-CSF), a haematopoietic growth factor that stimulates neutrophils. G-CSF induced an immediate increase in white blood cell count, primarily neutrophils. G-CSF may be effective in ameliorating neutropenia in patients who receive antibiotics for treatment of infectious endocarditis.

 Keywords: granulocyte colony stimulating factor;  neutropenia;  endocarditis PMID:9505928

  3. Clinical efficacy and safety of Zarzio® (EP2006, a biosimilar recombinant human granulocyte colony-stimulating factor

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    Tharmarajah S

    2014-03-01

    Full Text Available Soba Tharmarajah,1,2 Abdulaziz Mohammed,3,4 Alaa Bagalagel,3,4 Karen MacDonald,2 Ivo Abraham2,3,5 1College of Pharmacy, University of Arizona, Tucson, AZ, USA; 2Matrix45, Tucson, AZ, USA; 3Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ, USA; 4College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 5Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA Abstract: This second review of biosimilar granulocyte colony-stimulating factors approved by the European Medicines Agency evaluates the evidence on the clinical efficacy and safety of prophylaxis of (febrile neutropenia with Zarzio® in chemotherapy-treated cancer patients relative to the originator product filgrastim (Neupogen®. Source documents include: publicly available documents of the European Medicines Agency; a published article reviewing the (preapproval clinical development of EP2006 (Zarzio®; and published (postapproval single-center experience reports on prophylaxis with Zarzio®, including two reports in the cancer setting and one in the setting of autologous peripheral blood stem cell mobilization. Also included is: a pooled analysis of these and other postapproval studies in the cancer setting that includes (interim data from the two single cancer center reports; one additional single-center experience study; one completed study; and one ongoing multicenter postapproval study. Based on the available therapeutic equivalence and safety data, the clinical and safety outcomes of Zarzio® are likely to be similar to those of Neupogen®. Thus, Zarzio® and Neupogen® may be assumed interchangeable. Keywords: biosimilars, biosimilar pharmaceuticals, efficacy, safety, granulocyte colony stimulating factor, recombinant proteins

  4. Clinical efficacy and safety of Tevagrastim® (XM02, a biosimilar recombinant human granulocyte colony-stimulating factor

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    Bagalagel A

    2013-08-01

    Full Text Available Alaa Bagalagel,1,2 Abdulaziz Mohammed,1,2 Karen MacDonald,3 Ivo Abraham1,3–5 1Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ, USA; 2College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 3Matrix45, Tucson, AZ, USA; 4Department of Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA; 5Department of Family and Community Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA Abstract: Since the expiration of the patent for filgrastim in Europe in 2006, the European Medicines Agency has approved three biosimilar granulocyte colony-stimulating factors, while the US Food and Drug Administration has approved one of these agents. Using the European Medicines Agency’s and the Food and Drug Administration’s regulatory reports and scientific publications, we review the evidence about the clinical efficacy and safety of XM02 (Tevagrastim® relative to the originator product filgrastim (Neupogen®. Clinical efficacy is assessed in terms of equivalence of XM02 and Neupogen®, while safety is evaluated in terms of immunogenicity, bone pain, splenomegaly, allergic reactions, acute respiratory distress syndrome, and mortality. Three Phase III studies in breast cancer patients treated with docetaxel/doxorubicin chemotherapy, lung cancer patients receiving platinum-based chemotherapy, and non-Hodgkin’s lymphoma receiving chemotherapy are reviewed. Also included is a postapproval, single-center experience study on peripheral blood stem mobilization. Based on the available therapeutic equivalence and safety data, the clinical and safety outcomes of XM02 are likely to be similar to those of Neupogen®. XM02 and Neupogen® can be considered interchangeable in the approved indications. Patients previously on Neupogen® and converted to XM02 can be expected to show similar efficacy and safety outcomes. Keywords: biosimilars, biosimilar pharmaceuticals, efficacy, safety

  5. Effect of a structurally modified human granulocyte colony stimulating factor, G-CSFa, on leukopenia in mice and monkeys

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    Qiu Yuchang

    2011-06-01

    Full Text Available Abstract Background Granulocyte colony stimulating factor (G-CSF regulates survival, proliferation, and differentiation of neutrophilic granulocyte precursors, Recombinant G-CSF has been used for the treatment of congenital and therapy-induced neutropenia and stem cell mobilization. Due to its intrinsic instability, recombinant G-CSF needs to be excessively and/or frequently administered to patients in order to maintain a plasma concentration high enough to achieve therapeutic effects. Therefore, there is a need for the development of G-CSF derivatives that are more stable and active in vivo. Methods Using site-direct mutagenesis and recombinant DNA technology, a structurally modified derivative of human G-CSF termed G-CSFa was obtained. G-CSFa contains alanine 17 (instead of cysteine 17 as in wild-type G-CSF as well as four additional amino acids including methionine, arginine, glycine, and serine at the amino-terminus. Purified recombinant G-CSFa was tested for its in vitro activity using cell-based assays and in vivo activity using both murine and primate animal models. Results In vitro studies demonstrated that G-CSFa, expressed in and purified from E. coli, induced a much higher proliferation rate than that of wild-type G-CSF at the same concentrations. In vivo studies showed that G-CSFa significantly increased the number of peripheral blood leukocytes in cesium-137 irradiated mice or monkeys with neutropenia after administration of clyclophosphamide. In addition, G-CSFa increased neutrophil counts to a higher level in monkeys with a concomitant slower declining rate than that of G-CSF, indicating a longer half-life of G-CSFa. Bone marrow smear analysis also confirmed that G-CSFa was more potent than G-CSF in the induction of granulopoiesis in bone marrows of myelo-suppressed monkeys. Conclusion G-CSFa, a structurally modified form of G-CSF, is more potent in stimulating proliferation and differentiation of myeloid cells of the granulocytic

  6. Granulocyte colony-stimulating factor and reproductive medicine: A review

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    Marcelo Borges Cavalcante

    2015-03-01

    Full Text Available Background: Recently, the use of granulocyte colony-stimulating factor (G-CSF has been proposed to improve pregnancy outcomes in reproductive medicine. Objective: A systematic review of the current use of G-CSF in patients who have difficulty conceiving and maintaining pregnancy was performed. Materials and Methods: Two electronic databases (PubMed/ Medline and Scopus were searched. Study selection, data extraction and quality assessment were performed in duplicate. The subject codes used were granulocyte colony-stimulating factor, G-CSF, recurrent miscarriage, IVF failure, and endometrium. Results: The search of electronic databases resulted in 215 citations (PubMed/ Medline: 139 and Scopus: 76, of which 38 were present in both databases. Of the remaining 177 publications, seven studies were included in the present review. Conclusion: Treatment with G-CSF is a novel proposal for immune therapy in patients with recurrent miscarriage and implantation failure following cycles of IVF. However, a larger number of well-designed studies are required for this treatment to be established.

  7. High pH solubilization and chromatography-based renaturation and purification of recombinant human granulocyte colony-stimulating factor from inclusion bodies.

    Science.gov (United States)

    Li, Ming; Fan, Hua; Liu, Jiahua; Wang, Minhong; Wang, Lili; Wang, Chaozhan

    2012-03-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a very efficient therapeutic protein drug which has been widely used in human clinics to treat cancer patients suffering from chemotherapy-induced neutropenia. In this study, rhG-CSF was solubilized from inclusion bodies by using a high-pH solution containing low concentration of urea. It was found that solubilization of the rhG-CSF inclusion bodies greatly depended on the buffer pH employed; alkalic pH significantly favored the solubilization. In addition, when small amount of urea was added to the solution at high pH, the solubilization was further enhanced. After solubilization, the rhG-CSF was renatured with simultaneous purification by using weak anion exchange, strong anion exchange, and hydrophobic interaction chromatography, separately. The results indicated that the rhG-CSF solubilized by the high-pH solution containing low concentration of urea had much higher mass recovery than the one solubilized by 8 M urea when using anyone of the three refolding methods employed in this work. In the case of weak anion exchange chromatography, the high pH solubilized rhG-CSF could get a mass recovery of 73%. The strategy of combining solubilization of inclusion bodies at high pH with refolding of protein using liquid chromatography may become a routine method for protein production from inclusion bodies.

  8. Expression of granulocyte colony stimulating factor (GCSF in Hansenula polymorpha

    Directory of Open Access Journals (Sweden)

    Yeganeh Talebkhan

    2016-03-01

    Full Text Available Background and Objectives: During past decades Hansenula polymorpha has attracted global attention for the expression of recombinant proteins due to its high growth rate, minimal nutritional porequirements and use of methanol as a low cost inducer.Materials and Methods: The corresponding nucleotide sequences for the expression of heterologous genes in Hansenula poylmorpha were extracted and assembled in an E. coli vector. The constructed expression cassette included formate dehy- drogenase promoter (pFMD, a secretory signal sequence, a multiple cloning site (MCS and methanol oxidase (MOX ter- minator. Zeocin resistance gene fragment and complete cDNA encoding granulocyte colony stimulating factor (GCSF were cloned downstream of the expression cassette in-frame with signal sequence. Restriction mapping and sequence analysis confirmed the correct cloning procedures. Final vector was transformed into Hansenula and recombinant host was induced for the expression of GCSF protein by adding methanol. SDS-PAGE and immuno-blotting were performed to confirm the identity of r-GCSF.Results: The expression cassette containing gcsf gene (615bp and zeocin resistance marker (sh-ble, 1200bp was prepared and successfully transformed into competent Hansenula polymorpha cells via electroporation. Zeocin resistant colonies were selected and GCSF expression was induced in recombinant Hansenula transformants using 0.5% methanol and an approx- imately 19kDa protein was observed on SDS-PAGE. Western blot analysis using serum isolated from GCSF-treated rabbit confirmed the identity of the protein.Conclusions: Molecular studies confirmed the designed expression cassette containing gcsf gene along with pFMD and sig- nal sequence. The expressed 19kDa protein also confirmed the ability of designed vector in expressing heterologous genes in Hansenula cells. Keywords: Hansenula polymorpha, expression cassette, GCSF

  9. Soluble prokaryotic overexpression and purification of bioactive human granulocyte colony-stimulating factor by maltose binding protein and protein disulfide isomerase.

    Directory of Open Access Journals (Sweden)

    Bich Hang Do

    Full Text Available Human granulocyte colony-stimulating factor (hGCSF, a neutrophil-promoting cytokine, is an effective therapeutic agent for neutropenia patients who have undergone several cancer treatments. Efficient production of hGCSF using E. coli is challenging because the hormone tends to aggregate and forms inclusion bodies. This study examined the ability of seven different N-terminal fusion tags to increase expression of soluble hGCSF in E. coli. Four tag proteins, namely maltose-binding protein (MBP, N-utilization substance protein A, protein disulfide isomerase (PDI, and the b'a' domain of PDI (PDIb'a', increased the solubility of hGCSF under normal conditions. Lowering the expression temperature from 30°C to 18°C also increased the solubility of thioredoxin-tagged and glutathione S-transferase-tagged hGCSF. By contrast, hexahistidine-tagged hGCSF was insoluble at both temperatures. Simple conventional chromatographic methods were used to purify hGCSF from the overexpressed PDIb'a'-hGCSF and MBP-hGCSF proteins. In total, 11.3 mg or 10.2 mg of pure hGCSF were obtained from 500 mL cultures of E. coli expressing PDIb'a'-hGCSF or MBP-hGCSF, respectively. SDS-PAGE analysis and silver staining confirmed high purity of the isolated hGCSF proteins, and the endotoxin levels were less than 0.05 EU/µg of protein. Subsequently, the bioactivity of the purified hGCSF proteins similar to that of the commercially available hGCSF was confirmed using the mouse M-NFS-60 myelogenous leukemia cell line. The EC50s of the cell proliferation dose-response curves for hGCSF proteins purified from MBP-hGCSF and PDIb'a'-hGCSF were 2.83±0.31 pM, and 3.38±0.41 pM, respectively. In summary, this study describes an efficient method for the soluble overexpression and purification of bioactive hGCSF in E. coli.

  10. Soluble prokaryotic overexpression and purification of bioactive human granulocyte colony-stimulating factor by maltose binding protein and protein disulfide isomerase.

    Science.gov (United States)

    Do, Bich Hang; Ryu, Han-Bong; Hoang, Phuong; Koo, Bon-Kyung; Choe, Han

    2014-01-01

    Human granulocyte colony-stimulating factor (hGCSF), a neutrophil-promoting cytokine, is an effective therapeutic agent for neutropenia patients who have undergone several cancer treatments. Efficient production of hGCSF using E. coli is challenging because the hormone tends to aggregate and forms inclusion bodies. This study examined the ability of seven different N-terminal fusion tags to increase expression of soluble hGCSF in E. coli. Four tag proteins, namely maltose-binding protein (MBP), N-utilization substance protein A, protein disulfide isomerase (PDI), and the b'a' domain of PDI (PDIb'a'), increased the solubility of hGCSF under normal conditions. Lowering the expression temperature from 30°C to 18°C also increased the solubility of thioredoxin-tagged and glutathione S-transferase-tagged hGCSF. By contrast, hexahistidine-tagged hGCSF was insoluble at both temperatures. Simple conventional chromatographic methods were used to purify hGCSF from the overexpressed PDIb'a'-hGCSF and MBP-hGCSF proteins. In total, 11.3 mg or 10.2 mg of pure hGCSF were obtained from 500 mL cultures of E. coli expressing PDIb'a'-hGCSF or MBP-hGCSF, respectively. SDS-PAGE analysis and silver staining confirmed high purity of the isolated hGCSF proteins, and the endotoxin levels were less than 0.05 EU/µg of protein. Subsequently, the bioactivity of the purified hGCSF proteins similar to that of the commercially available hGCSF was confirmed using the mouse M-NFS-60 myelogenous leukemia cell line. The EC50s of the cell proliferation dose-response curves for hGCSF proteins purified from MBP-hGCSF and PDIb'a'-hGCSF were 2.83±0.31 pM, and 3.38±0.41 pM, respectively. In summary, this study describes an efficient method for the soluble overexpression and purification of bioactive hGCSF in E. coli.

  11. Identification and in vitro characterization of novel nanobodies against human granulocyte colony-stimulating factor receptor to provide inhibition of G-CSF function.

    Science.gov (United States)

    Bakherad, Hamid; Gargari, Seyed Latif Mousavi; Sepehrizadeh, Zargham; Aghamollaei, Hossein; Taheri, Ramezan Ali; Torshabi, Maryam; Yazdi, Mojtaba Tabatabaei; Ebrahimizadeh, Walead; Setayesh, Neda

    2017-09-01

    It has been shown that Granulocyte colony-stimulating factor (G-CSF) has a higher expression in malignant tumors, and anti-G-CSF therapy considerably decreases tumor growth, tumor vascularization and metastasis. Thus, blocking the signaling pathway of G-CSF could be beneficial in cancer therapy. This study is aimed at designing and producing a monoclonal nanobody that could act as an antagonist of G-CSF receptor. Nanobodies are the antigen binding fragments of camelid single-chain antibodies, also known as VHH. These fragments have exceptional properties which makes them ideal for tumor imaging and therapeutic applications. We have used our previously built nanobody phage libraries to isolate specific nanobodies to the G-CSF receptor. After a series of cross-reactivity and affinity experiments, two unique nanobodies were selected for functional analysis. Proliferation assay, real-time PCR and immunofluorescence assays were used to characterize these nanobodies. Finally, VHH26 nanobody that was able to specifically bind G-CSF receptor (G-CSF-R) on the surface of NFS60 cells and efficiently block G-CSF-R downstream signaling pathway in a dose-dependent manner was selected. This nanobody could be further developed into a valuable tool in tumor therapy and it forms a basis for additional studies in preclinical animal models. Copyright © 2017. Published by Elsevier Masson SAS.

  12. Hematologic improvement in dogs with parvovirus infection treated with recombinant canine granulocyte-colony stimulating factor.

    Science.gov (United States)

    Duffy, A; Dow, S; Ogilvie, G; Rao, S; Hackett, T

    2010-08-01

    Previously, dogs with canine parvovirus-induced neutropenia have not responded to treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF). However, recombinant canine G-CSF (rcG-CSF) has not been previously evaluated for treatment of parvovirus-induced neutropenia in dogs. We assessed the effectiveness of rcG-CSF in dogs with parvovirus-induced neutropenia with a prospective, open-label, nonrandomized clinical trial. Endpoints of our study were time to recovery of WBC and neutrophil counts, and duration of hospitalization. 28 dogs with parvovirus and neutropenia were treated with rcG-CSF and outcomes were compared to those of 34 dogs with parvovirus and neutropenia not treated with rcG-CSF. We found that mean WBC and neutrophil counts were significantly higher (P parvovirus infection, but indicate the need for additional studies to evaluate overall safety of the treatment.

  13. Aggressive cutaneous vasculitis in a patient with chronic lymphatic leukemia following granulocyte colony stimulating factor injection: a case report

    OpenAIRE

    El Husseiny Noha M; Mattar Mervat M

    2011-01-01

    Abstract Introduction Vasculitis has been reported in a few cases of chronic lymphatic leukemia and with granulocytic colony-stimulating factor therapy. Those with granulocytic colony-stimulating factor occurred after prolonged therapy and there was a rise in total leukocyte count unlike that in our patient who received just a single injection for the first time. Case presentation We report the case of a 64-year-old Egyptian man with chronic lymphatic leukemia who developed progressive cutane...

  14. Curative Effect Observation of Recombinant Human Granulocyte Colony Stimulating Factor in Breast Cancer Chemotherapy%重组人粒细胞集落刺激因子在乳腺癌化疗中的疗效观察

    Institute of Scientific and Technical Information of China (English)

    徐清亮; 房黎亚; 赵春武; 赵学良; 孙伟

    2015-01-01

    Objective To observe the clinical efficacy of Recombinant Human Granulocyte Colony Stimula-ting Factor ( rhG-CSF ) in myelosuppression after postoperative chemotherapy for breast cancer .Methods The breast cancer patientswere randomly divided into 2 groups, received the postoperative TE/TEC scheme chemotherapy .Two groups of patients before chemotherapy were given antiemetic therapy , including Dexamethasoneand Palonosetron injec-tion.Then,treatment group was given "recombinant human granulocyte colony stimulating factor",after the Chemothera-py over 24~48h observed 2 groups of patients with blood routine and febrile neutropenia (febrile neutropenia,FN) inci-dence ,and analysed the statistical indicators .Results Total number of white blood cells and neutrophils in chemothera-py treatment group patients were higher than the control group ,FN rate lower than the control group ,the difference was statistically significant(P0 .05 ) .Conclusion RhG-CSF preventive treatment for breast cancer postoperative yew class and anthracycline-based drugs in combination with bone marrow suppression caused by chemotherapy has a good curative effect ,which is safe .%目的 观察重组人粒细胞集落刺激因子( rhG-CSF)对乳腺癌术后化疗骨髓抑制的临床疗效. 方法 将乳腺癌术后行TE/TEC方案化疗的患者,随机分为2组,2组患者行化疗前均给予"地塞米松片"、"帕洛诺司琼注射液",在此基础上,治疗组化疗结束24~48h后给予"重组人粒细胞集落刺激因子"治疗. 观测2组患者血常规及发热性中性粒细胞减少症( febrile neutropenia ,FN)的发生率,并对指标进行统计学分析. 结果 化疗后治疗组患者白细胞总数与中性粒细胞数均高于对照组,FN发生率低于对照组,差异均有统计学意义( P0.05). 结论 重组人粒细胞集落刺激因子治疗乳腺癌术后行紫杉类和蒽环类药物联合化疗所致的骨髓抑制具有较好疗效,安全性高.

  15. Effect of Granulocyte-Colony Stimulating Factor on Endothelial Cells and Osteoblasts

    Directory of Open Access Journals (Sweden)

    Xi Ling Liu

    2016-01-01

    Full Text Available Objectives. Some animal studies showed that granulocyte-colony stimulating factor (G-CSF provides beneficial environment for bone healing. It has been well documented that endothelial cells and osteoblasts play critical roles in multiple phases of bone healing. However, the biological effects of G-CSF on these cells remain controversial. This study aimed to investigate the influence of G-CSF at various concentrations on endothelial cells and osteoblasts. Materials and Methods. Human umbilical vein endothelial cells (HUVECs and human osteoblasts (hOBs were treated with G-CSF at 1000, 100, 10, and 0 ng/mL, respectively. The capacity of cell proliferation, migration, and tube formation of HUVECs was evaluated at 72, 8, and 6 hours after treatment, respectively. The capacity of proliferation, differentiation, and mineralization of hOBs was evaluated at 24 hours, 72 hours, and 21 days after treatment, respectively. Results. HUVECs treated with 100 and 1000 ng/mL G-CSF showed a significantly higher value comparing with controls in migration assay (p<0.001, p<0.01, resp.; the group treated with 1000 ng/mL G-CSF showed a significantly lower value on tube formation. No significant difference was detected in groups of hOBs. Conclusions. G-CSF showed favorable effects only on the migration of HUVECs, and no direct influence was found on hOBs.

  16. Structural analysis of the receptors for granulocyte colony-stimulating factor on neutrophils

    Energy Technology Data Exchange (ETDEWEB)

    Hanazono, Y.; Hosoi, T.; Kuwaki, T.; Matsuki, S.; Miyazono, K.; Miyagawa, K.; Takaku, F. (Univ. of Tokyo (Japan))

    1990-11-01

    We investigated granulocyte colony-stimulating factor (G-CSF) receptors on neutrophils from three patients with chronic myelogenous leukemia (CML) in the chronic phase, in comparison with four normal volunteers. Because we experienced some difficulties in radioiodinating intact recombinant human G-CSF, we developed a new derivative of human G-CSF termed YPY-G-CSF. It was easy to iodinate this protein using the lactoperoxidase method because of two additional tyrosine residues, and its radioactivity was higher than that previously reported. The biological activity of YPY-G-CSF as G-CSF was fully retained. Scatchard analysis demonstrated that CML neutrophils had a single class of binding sites (1400 +/- 685/cell) with a dissociation constant (Kd) of 245 +/- 66 pM. The number of sites and Kd value of CML neutrophils were not significantly different from those of normal neutrophils (p greater than 0.9). Cross-linking studies revealed two specifically labeled bands of (125I)YPY-G-CSF-receptor complexes with apparent molecular masses of 160 and 110 kd on both normal and CML neutrophils. This is the first report describing two receptor proteins on neutrophils. According to the analyses of the proteolytic process of these cross-linked complexes and proteolytic mapping, we assume that alternative splicing or processing from a single gene may generate two distinct receptor proteins that bind specifically to G-CSF but have different fates in intracellular metabolism.

  17. 重组人粒细胞刺激因子在乳癌治疗中不良反应的分析%Adverse reactions of recombinant human granulocyte colony-stimulating factor in breast cancer treatment

    Institute of Scientific and Technical Information of China (English)

    叶青青; 蔡君; 聂铮; 张立军; 王茁

    2011-01-01

    Objective : To analyze the adverse drug reaction in the clinical application of recombinant human granulocyte colony - stimulating factor ( rhG - CSF) .Methods : cases suffered from adverse drug reaction of rhG - CSF from January 2006 to November 2009 were collected and analyzed.Results : Most of adverse drug reactions induced by rhG - CSF manifested as allergic reactions and are not serious.Condusion; More attention should be paid on safety of rhG - CSF.%目的:分析在乳腺癌治疗中重组人粒细胞刺激因子注射液致药物不良反应(ADR) 发生的特点.方法:收集并分析2006年1月至2009年11月我科重组人粒细胞刺激因子注射液致不良反应病例.结果 :重组人粒细胞刺激因子注射液致不良反应,临床表现多数为过敏反应,反应较轻,尚有罕见严重的不良反应.结论:临床应重视重组人粒细胞刺激因子注射液使用的安全性问题.

  18. Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation: a multicenter randomized controlled study in southwest China.

    Science.gov (United States)

    Gao, Lei; Wen, Qin; Chen, Xinghua; Liu, Yao; Zhang, Cheng; Gao, Li; Kong, Peiyan; Zhang, Yanqi; Li, Yunlong; Liu, Jia; Wang, Qingyu; Su, Yi; Wang, Chunsen; Wang, Sanbin; Zeng, Yun; Sun, Aihua; Du, Xin; Zeng, Dongfeng; Liu, Hong; Peng, Xiangui; Zhang, Xi

    2014-12-01

    HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony-stimulating factor (rhG-CSF) or non-rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P priming group and 31 patients in the non-rhG-CSF-priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF-priming and non-rhG-CSF-priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27.1% to 56.6%; P priming conditioning regimen is an acceptable choice for HR-AML patients, especially for the patients with no M4/M5/M6 subtype who achieved CR before transplantation.

  19. Effect of granulocyte colony-stimulating factor (G-CSF) in human immunodeficiency virus-infected patients: increase in numbers of naive CD4 cells and CD34 cells makes G-CSF a candidate for use in gene therapy or to support antiretroviral therapy

    DEFF Research Database (Denmark)

    Nielsen, S D; Afzelius, P; Dam-Larsen, S

    1998-01-01

    The potential of granulocyte colony-stimulating factor (G-CSF) to mobilize CD4 cells and/or CD34 cells for use in gene therapy or to support antiretroviral therapy was examined. Ten human immunodeficiency virus-infected patients were treated with G-CSF (300 microg/day) for 5 days. Numbers of CD4....... Furthermore, the fraction of naive CD4 cells increased. These findings have implications for the design of immunotherapy or gene therapy protocols....

  20. The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity

    Directory of Open Access Journals (Sweden)

    Stephanie eWallner

    2015-08-01

    Full Text Available Granulocyte-colony stimulating factor (G-CSF is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

  1. Granulocyte-colony stimulating factor therapy to induce neovascularization in ischemic heart disease

    DEFF Research Database (Denmark)

    Ripa, Rasmus Sejersten

    2012-01-01

    Cell based therapy for ischemic heart disease has the potential to reduce post infarct heart failure and chronic ischemia. Treatment with granulocyte-colony stimulating factor (G-CSF) mobilizes cells from the bone marrow to the peripheral blood. Some of these cells are putative stem or progenitor...... cells. G-CSF is injected subcutaneously. This therapy is intuitively attractive compared to other cell based techniques since repeated catheterizations and ex vivo cell purification and expansion are avoided. Previous preclinical and early clinical trials have indicated that treatment with G-CSF leads...

  2. Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by granulocyte colony stimulating factor

    DEFF Research Database (Denmark)

    Hess, David A; Bonde, Jesper; Craft, Timothy P

    2007-01-01

    AMD3100 inhibits the interaction between SDF-1 and CXCR4, and rapidly mobilizes hematopoietic progenitors for clinical transplantation. However, the repopulating function of human cells mobilized with AMD3100 has not been characterized in comparison to cells mobilized with granulocyte-colony stim......AMD3100 inhibits the interaction between SDF-1 and CXCR4, and rapidly mobilizes hematopoietic progenitors for clinical transplantation. However, the repopulating function of human cells mobilized with AMD3100 has not been characterized in comparison to cells mobilized with granulocyte...

  3. GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) UPREGULATES β1 INTEGRIN AND INCREASES MIGRATION OF HUMAN TROPHOBLAST SWAN 71 CELLS VIA PI3K AND MAPK ACTIVATION

    Science.gov (United States)

    Furmento, Verónica A.; Marino, Julieta; Blank, Viviana C.; Cayrol, María Florencia; Cremaschi, Graciela A.; Aguilar, Rubén C.; Roguin, Leonor P.

    2017-01-01

    Multiple cytokines and growth factors expressed at the fetal-maternal interface are involved in the regulation of trophoblast functions and placental growth, but the role of G-CSF has not been completely established. Based on our previous study showing that G-CSF increases the activity of matrix metalloproteinase-2 and the release of vascular endothelial growth factor in Swan 71 human trophoblast cells, in this work we explore the possible contribution of G-CSF to cell migration and the G-CSF-triggered signaling pathway. We found that G-CSF induced morphological changes on actin cytoskeleton consistent with a migratory cell phenotype. G-CSF also up-regulated the expression levels of β1 integrin and promoted Swan 71 cell migration. By using selective pharmacological inhibitors and dominant negative mutants we showed that PI3K, Erk 1/2 and p38 pathways are required for promoting Swan 71 cell motility. It was also demonstrated that PI3K behaved as an upstream regulator of Erk 1/2 and p38 MAPK. In addition, the increase of β1 integrin expression was dependent on PI3K activation. In conclusion, our results indicate that G-CSF stimulates β1 integrin expression and Swan 71 cell migration by activating PI3K and MAPK signaling pathways, suggesting that G-CSF should be considered as an additional regulatory factor that contributes to a successful embryo implantation and to the placenta development. PMID:26992288

  4. Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Giniatullina Raisa

    2011-06-01

    Full Text Available Abstract Background Granulocyte colony stimulating factor (GCSF is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS. ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery. Methods Human mutant G93A superoxide dismutase (SOD1 ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro. Results Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS. Conclusions GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS.

  5. Granulocyte Colony-Stimulating Factor in the Treatment of Acute Radiation Syndrome: A Concise Review

    Directory of Open Access Journals (Sweden)

    Michal Hofer

    2014-04-01

    Full Text Available This article concisely summarizes data on the action of one of the principal and best known growth factors, the granulocyte colony-stimulating factor (G-CSF, in a mammalian organism exposed to radiation doses inducing acute radiation syndrome. Highlighted are the topics of its real or anticipated use in radiation accident victims, the timing of its administration, the possibilities of combining G-CSF with other drugs, the ability of other agents to stimulate endogenous G-CSF production, as well as of the capability of this growth factor to ameliorate not only the bone marrow radiation syndrome but also the gastrointestinal radiation syndrome. G-CSF is one of the pivotal drugs in the treatment of radiation accident victims and its employment in this indication can be expected to remain or even grow in the future.

  6. EXPRESSION OF cDNA FOR RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR IN ESCHERICHIA COLI AND CHARACTERIZATION OF THE PROTEIN

    Institute of Scientific and Technical Information of China (English)

    Zhang Shu; Ye Qinong

    1998-01-01

    Objective:To determine the biological activity of rhG-CSF and it's characterization. Methods: The prokaryotic expression vector pG01 containing human GCSF cDNA were constructed with DNA recombination technology. Results: We had achieved high level expression of the human G-CSF in E. Coli, where it represented at least 23.6% of the total protein as determined from SDS-PAGE gels. The human G-CSF was expressed as inclusion bodies in E. Coli. The inclusion bodies were solubilized in a solution containing 7M urea,renatured by dialysis, isolated and purified by DEAEsepharose CL-6B ion exchange and Superdex 75 gel filtration chromatography. The purified rhG-CSF was confirmed by coincidence of biological activity and protein demonstrated by SDS-PAGE. It was homogeneous with respect to mol. Wt (18400). The purity of the rhGCSF might be >90 per cent. Conclusion: The purified rhG-CSF in our laboratory had dramatically the biological activity of regulating proliferation and differentiation of the human G-CSF-dependent cell line NSF-1 and the progenitor cells of granulocytes of human bone marrow.

  7. Granulocyte colony-stimulating factor increases CD4+ T cell counts of human immunodeficiency virus-infected patients receiving stable, highly active antiretroviral therapy

    DEFF Research Database (Denmark)

    Aladdin, H; Ullum, H; Dam Nielsen, S.

    2000-01-01

    counts resulted from increases in CD45RO+ memory T cells and cells expressing the CD38 activation marker. Lymphocyte proliferative responses to phytohemagglutinin and Candida antigen decreased, whereas NK cell activity and plasma HIV RNA did not change during G-CSF treatment. After 24 weeks, all immune......Thirty human immunodeficiency virus (HIV)-infected patients with CD4+ T cell counts

  8. A Case of Neonatal Neutropenia Due to Anti-Fc Gamma Receptor IIIb Isoantibodies Treated with Recombinant Human Granulocyte Colony Stimulating Factor

    Directory of Open Access Journals (Sweden)

    Maja Tomicic

    2009-01-01

    Full Text Available Alloimmunization to granulocyte-specific antigens can occur during pregnancy. Maternal antibodies of IgG class can cross the placenta to result in alloimmune neonatal neutropenia. Antibodies to human neutrophil antigens anti-HNA-1a, HNA-1b, and HNA-2a have been most commonly reported to cause alloimmune neonatal neutropenia. Isoantibodies to Fc gamma RIIIb (CD16 if mother is a HNA-null phenotype are rarely involved in neonatal neutropenia. We report on a case of severe neutropenia (440 neutrophils/μL due to anti-Fc gamma RIIIb (CD16 isoimmunization. On day 14 severe omphalitis developed, which was treated for 7 days by an antibiotic (ceftriaxone in a dose of 80 mg/kg/d according to umbilical swab finding. Omphalitis persisted for 10 days in spite of antibiotic therapy and only resolved upon the introduction of rhG-CSF therapy. Therapy with rh-GCSF proved efficient and led to neutrophil count increase to 1970/μL and cure of omphalitis. However, therapeutic effect on granulocyte count was of transient nature, as granulocyte count fell to 760 n/μL on day 4 of therapy discontinuation. Neutropenia persisted for 2 months. The newborn was discharged from the hospital on day 26 with normal clinical status with clinical and laboratory control examinations at 2-week intervals. No additional infections were observed during the course of neutropenia.

  9. Optimization of gene transfer into primitive human hematopoietic cells of granulocyte-colony stimulating factor-mobilized peripheral blood using low-dose cytokines and comparison of a gibbon ape leukemia virus versus an RD114-pseudotyped retroviral vector.

    Science.gov (United States)

    van der Loo, Johannes C M; Liu, B L; Goldman, A I; Buckley, S M; Chrudimsky, K S

    2002-07-20

    Primitive human hematopoietic cells in granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (MPB) are more difficult to transduce compared to cells from umbilical cord blood. Based on the hypothesis that MPB cells may require different stimulation for efficient retroviral infection, we compared several culture conditions known to induce cycling of primitive hematopoietic cells. MPB-derived CD34(+) cells were stimulated in the presence or absence of the murine fetal liver cell line AFT024 in trans-wells with G-CSF, stem cell factor (SCF), and thrombopoietin (TPO) (G/S/T; 100 ng/ml) or Flt3-L, SCF, interleukin (IL)-7, and TPO (F/S/7/T; 10-20 ng/ml), and transduced using a GaLV-pseudotyped retroviral vector expressing the enhanced green fluorescence protein (eGFP). Compared to cultures without stroma, the presence of AFT024 increased the number of transduced colony-forming cells (CFC) by 3.5-fold (with G/S/T), long-term culture-initiating cells (LTC-IC) by 4.6-fold (with F/S/7/T), and nonobese diabetic/severe immunodeficiency disease (NOD/SCID)-repopulating cells (SRC) by 6.8-fold (with F/S/7/T). Similar numbers of long-term culture-initiating cells (LTC-IC) and SRC could be transduced using AFT024-conditioned medium (AFT-CM) or a defined medium that had been supplemented with factors identified in AFT-CM. Finally, using our best condition based on transduction with the gibbon ape leukemia virus (GaLV)-pseudotyped vector, we demonstrate a 33-fold higher level of gene transfer (p optimized protocol with low doses of cytokines, and transduction with an RD114 compared to a GaLV-pseudotyped retroviral vector, the overall number of transduced cells in NOD/SCID mice could be improved 144-fold, with a gene-transfer efficiency in SRC of 16.3% (13.3-19.9; n = 6).

  10. Granulocyte colony-stimulating factor protects mice during respiratory virus infections.

    Directory of Open Access Journals (Sweden)

    Tamar Hermesh

    Full Text Available A burst in the production of pro-inflammatory molecules characterizes the beginning of the host response to infection. Cytokines, chemokines, and growth factors work in concert to control pathogen replication and activate innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF mobilizes and activates hematopoietic cells from the bone marrow, and it has been shown to mediate the generation of effective immunity against bacterial and fungal infections. G-CSF is produced at high levels in the lungs during infection with influenza and parainfluenza viruses, but its role during these infections is unknown. Here we show that during infection of mice with a non-lethal dose of influenza or Sendai virus, G-CSF promotes the accumulation of activated Ly6G+ granulocytes that control the extent of the lung pro-inflammatory response. Remarkably, these G-CSF-mediated effects facilitate viral clearance and sustain mouse survival.

  11. Aggressive cutaneous vasculitis in a patient with chronic lymphatic leukemia following granulocyte colony stimulating factor injection: a case report.

    Science.gov (United States)

    El Husseiny, Noha M; Mattar, Mervat M

    2011-03-01

    Vasculitis has been reported in a few cases of chronic lymphatic leukemia and with granulocytic colony-stimulating factor therapy. Those with granulocytic colony-stimulating factor occurred after prolonged therapy and there was a rise in total leukocyte count unlike that in our patient who received just a single injection for the first time. We report the case of a 64-year-old Egyptian man with chronic lymphatic leukemia who developed progressive cutaneous vasculitic lesions following injection of a single dose of a granulocytic colony stimulating factor before a third cycle of chemotherapy to improve neutropenia. This is an unusual case and the pathogenesis is not fully understood. Our patient was not on any medical treatment except for bisoprolol for ischemic heart disease. Although aggressive management with steroids, anticoagulation and plasmapheresis had been carried out, the condition was aggressive and the patient's consciousness deteriorated. A magnetic resonance imaging scan of his brain revealed multiple ischemic foci that could be attributed to vasculitis of the brain. The aim of this case report is to highlight the importance of monitoring patients on granulocytic colony-stimulating factor therapy, especially in the context of other conditions (such as a hematological malignancy) that may lead to an adverse outcome.

  12. Aggressive cutaneous vasculitis in a patient with chronic lymphatic leukemia following granulocyte colony stimulating factor injection: a case report

    Directory of Open Access Journals (Sweden)

    El Husseiny Noha M

    2011-03-01

    Full Text Available Abstract Introduction Vasculitis has been reported in a few cases of chronic lymphatic leukemia and with granulocytic colony-stimulating factor therapy. Those with granulocytic colony-stimulating factor occurred after prolonged therapy and there was a rise in total leukocyte count unlike that in our patient who received just a single injection for the first time. Case presentation We report the case of a 64-year-old Egyptian man with chronic lymphatic leukemia who developed progressive cutaneous vasculitic lesions following injection of a single dose of a granulocytic colony stimulating factor before a third cycle of chemotherapy to improve neutropenia. This is an unusual case and the pathogenesis is not fully understood. Our patient was not on any medical treatment except for bisoprolol for ischemic heart disease. Although aggressive management with steroids, anticoagulation and plasmapheresis had been carried out, the condition was aggressive and the patient's consciousness deteriorated. A magnetic resonance imaging scan of his brain revealed multiple ischemic foci that could be attributed to vasculitis of the brain. Conclusion The aim of this case report is to highlight the importance of monitoring patients on granulocytic colony-stimulating factor therapy, especially in the context of other conditions (such as a hematological malignancy that may lead to an adverse outcome.

  13. The effect of long-term treatment with granulocyte colony-stimulating factor on hematopoiesis in HIV-infected individuals

    DEFF Research Database (Denmark)

    Nielsen, S D; Sørensen, T U; Aladdin, H;

    2000-01-01

    This randomized, placebo-controlled trial examine the long-term effect of granulocyte colony-stimulating factor (G-CSF) on absolute numbers of CD34+ progenitor cells and progenitor cell function in human immunodeficiency virus (HIV)-infected patients. G-CSF (300 microg filgrastim) or placebo...... was given three times weekly for 12 weeks to 30 HIV-infected patients that had been treated with HAART for at least 24 weeks and not yet achieved CD4 counts above 350 CD4+ cells/microl. Blood samples were collected at weeks 0, 2, 4, 8, and 12, and again 12 weeks after termination of the G-CSF treatment...... of G-CSF on in vivo function of progenitors the white-blood count was determined. Significant increase in white-blood count was found (P platelet count decreased (P = 0.001 and P = 0.013, respectively). Significant increase in the CD4 count occurred, but correlation...

  14. Radioprotective effects of granulocyte-colony stimulating factor in the jejunal mucosa of mouse

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Mi Ryeong; Chung, Su Mi; Kay, Chul Seung; Kim, Yeon Shil; Yoon, Sei Chul [College of Medicine, Catholic Univ., Seoul (Korea, Republic of)

    2001-03-01

    Granulocyte-colony stimulating factor (G-CSF) has been widely used to treat neutropenia caused by chemotherapy or radiotherapy. The efficacy of recombinant human hematopoietic growth factors in improving oral mucositis after chemotherapy or radiotherapy has been recently demonstrated in some clinical studies. This study was designed to determine whether G-CSF can modify the radiation injury of the intestinal mucosa in mice. One hundred and five BALB/c mice weighing 20 grams were divided into nine subgroups including G-CSF alone group (I: 10 {mu}g/kg or II : 100{mu}g /kg), radiation alone group (7.5 or 12 Gy on the whole body), combination group with G-CSF and radiation (G-CSF I or II plus 7.5 Gy, G-CSF I or II plus 12 Gy), and control group. Radiation was administered with a 6 MV linear accelerator (Mevatron Siemens) with a dose rate of 3 Gy/min on day O. G-CSF was injected subcutaneously for 3 days, once a day, from day -2 to day 0. Each group was sacrificed on the day 1, day 3, and day 7. The mucosal changes of jejunum were evaluated microscopically by crypt count per circumference, villi length, and histologic damage grading. In both G-CSF I and II groups, crypt counts, villi length, and histologic damage scores were not significantly different from those of the control one (p>0.05). The 7.5 Gy and 12 Gy radiation alone groups showed significantly lower crypt counts and higher histologic damage scores compared with those of control one (p<0.05). The groups exposed to 7.5 Gy radiation plus G-CSF I or II showed significantly higher crypt counts and lower histologic damage scores on the day 3, and lower histologic damage scores on the day 7 compared with those of the 7.5 Gy radiation alone one (p<0.05). The 12 Gy radiation plus G-CSF I or II group did not show significant difference in crypt counts and histologic damage scores compared with those of the 12 Gy radiation alone one (p>0.05). Most of the mice in 12 Gy radiation with or without G-CSF group showed

  15. Serum Granulocyte Colony-Stimulating Factor and Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Robert C. Barber

    2012-08-01

    Full Text Available Background: Granulocyte colony-stimulating factor (G-CSF promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis. Methods: We analyzed G-CSF levels in 197 patients with probable Alzheimer’s disease (AD and 203 cognitively normal controls (NCs from a longitudinal study by the Texas Alzheimer’s Research and Care Consortium (TARCC. Data were analyzed by regression with adjustment for age, education, gender and APOE4 status. Results: Serum G-CSF was significantly lower in AD patients than in NCs (β = –0.073; p = 0.008. However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = –0.178; p = 0.014 and higher scores on the global Clinical Dementia Rating (CDR scale (β = 0.170; p = 0.018 and CDR Sum of Boxes (β = 0.157; p = 0.035. Conclusions: G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.

  16. Granulocyte Colony-Stimulating Factor-Producing Carcinoma of Unknown Primary Site

    Directory of Open Access Journals (Sweden)

    Hirotoshi Yasui

    2014-11-01

    Full Text Available Granulocyte colony-stimulating factor (G-CSF-producing nonhematopoietic malignancies have been reported in various organs and are associated with a poor clinical outcome. Moreover, carcinoma of unknown primary site (CUP is an uncommon malignancy that occurs in about 2-6% of cancer patients. CUP also has a poor prognosis due to its missing profile. Since both G-CSF-producing carcinoma and CUP are rare, G-CSF-producing CUP (GCSF-CUP is considered to have an even poorer prognosis and is seldom encountered. Herein, we report the case of a GCSF-CUP patient. A 75-year-old man was admitted to our hospital complaining of cervical lymphadenopathy. Multiple bulky lymph nodes without a primary site were revealed by image analysis. His complete blood count showed leukocytosis, and his blood chemistry panel indicated highly elevated levels of G-CSF. Although the patient was treated with combination chemotherapy of carboplatin, paclitaxel, bevacizumab and erlotinib, he died of intestinal perforation due to tumor invasion 23 days after the start of the therapy. An autopsy confirmed that the tumor was positive for anti-G-CSF antibody, but the primary site was still not detected.

  17. Recombinant human thrombopoietin in combination with granulocyte colony-stimulating factor enhances mobilization of peripheral blood progenitor cells, increases peripheral blood platelet concentration, and accelerates hematopoietic recovery following high-dose chemotherapy.

    Science.gov (United States)

    Somlo, G; Sniecinski, I; ter Veer, A; Longmate, J; Knutson, G; Vuk-Pavlovic, S; Bhatia, R; Chow, W; Leong, L; Morgan, R; Margolin, K; Raschko, J; Shibata, S; Tetef, M; Yen, Y; Forman, S; Jones, D; Ashby, M; Fyfe, G; Hellmann, S; Doroshow, J H

    1999-05-01

    Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 micrograms/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 micrograms/kg on days -3, -1, and 1, or 0.6 micrograms/kg on days -1 and 1. G-CSF, 5 micrograms/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34(+) cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 x 10(6)/kg (range, 1.3 to 17.6) versus 0.8 x 10(6)/ kg (range, 0.3 to 4.2), P =.0003. The targeted minimum yield of 3 x 10(6) CD34(+) cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF-mobilized group versus 10% of G-CSF-mobilized patients (P =.001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P =.0001) and platelet recovery (day 9 v 10, P =.07) were accelerated, and fewer erythrocyte (3 v 4, P =.02) and platelet (4 v 5, P =.02) transfusions were needed compared with G-CSF-mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P rhTPO at 0.6 microgram/kg. rhTPO is

  18. Expression of brain derived-neurotrophic factor and granulocyte-colony stimulating factor in the urothelium: relation with voiding function

    OpenAIRE

    Yuk, Seung Mo; Shin, Ju Hyun; Song, Ki Hak; Na, Yong Gil; Lim, Jae Sung; Sul, Chong Koo

    2015-01-01

    Background We designed this experiment to elucidate the relationship between the expression of brain derived-neurotrophic factor (BDNF), the expression of granulocyte-colony stimulating factor (G-CSF), and the development of overactive bladder (OAB). In our previous study, the urothelium was observed to be more than a simple mechanosensory receptor and was found to be a potential therapeutic target for OAB. Moreover, neuregulin-1 and BDNF were found to be potential new biomarkers of OAB. Here...

  19. Granulocyte-Colony Stimulating Factor Producing Infiltrating Urothelial Carcinoma of the Left Renal Pelvis: A Case Report

    OpenAIRE

    2016-01-01

    We report a case of granulocyte-colony stimulating factor (G-CSF) producing infiltrating urothelial carcinoma of the left renal pelvis. The patient was referred to our hospital for fever and anorexia. Blood tests showed elevated level of leukocytosis without any infectious diseases. The serum concentration of G-CSF was remarkably elevated. Abdominal computed tomography (CT) revealed a huge mass in the left renal pelvis and para-aortic lymph node enlargement. He was underwent left nephroureter...

  20. Capillary Zone Electrophoresis Investigation of Interactions between Granulocyte-colony Stimulating Factor and Dextran Sulfate / Carrageenan Oligosaccharide

    Institute of Scientific and Technical Information of China (English)

    Ai Ye LIANG; Yu Guang DU; Ke Yi WANG; Bing Cheng LIN

    2005-01-01

    The interactions between granulocyte-colony stimulating factor (G-CSF) and dextran sulfate / κ-carrageenan oligosa1ccharide were studied by capillary zone electrophoresis. Dextran sulfate could strongly interact with G-CSF and the complex was detected. The binding constant and stoichiometry were determined to be 1.2x106 (mol/L)-1 and 3:1, respectively. However, the interaction between κ-carrageenan oligosaccharide and G-CSF was not found.

  1. Timing of granulocyte-colony stimulating factor treatment after acute myocardial infarction and recovery of left ventricular function: results from the STEMMI trial

    DEFF Research Database (Denmark)

    Overgaard, Mikkel; Ripa, Rasmus Sejersten; Wang, Yongzhong

    2010-01-01

    Granulocyte-colony stimulating factor (G-CSF) therapy after ST-elevation myocardial infarction (STEMI) have not demonstrated impact on systolic recovery compared to placebo. However, recent studies suggest that timing of G-CSF therapy is crucial.......Granulocyte-colony stimulating factor (G-CSF) therapy after ST-elevation myocardial infarction (STEMI) have not demonstrated impact on systolic recovery compared to placebo. However, recent studies suggest that timing of G-CSF therapy is crucial....

  2. Myeloprotective Action of Combined Application of Ukrainian Recombinant Granulocyte Colony Stimulating Factor (r-GCSF and Enterosorbent С2 in Rats with Malignant Guerin Carcinoma

    Directory of Open Access Journals (Sweden)

    Todor, I.M.

    2015-03-01

    Full Text Available The aim of the study is to analyze myeloprotective effect of novel enterosorbents alone and in combination with two recombinant granulocyte colony stimulating factors: Neupogen (Switzerland and r- GCSF (Ukraine. It is proven that Ukrainian version of recombinant granulocyte colony stimulating factor r-GCSF does not concede officinal drug Neupogen (Switzerland by its experimental therapeutic action and combined use with enterosorbent C2 significantly increases myeloprotective effect of both GCSF versions.

  3. MUTUAL INHIBITION OF MURINE ERYTHROPOIESIS AND GRANULOPOIESIS DURING COMBINED ERYTHROPOIETIN, GRANULOCYTE-COLONY-STIMULATING FACTOR, AND STEM-CELL FACTOR ADMINISTRATION - IN-VIVO INTERACTIONS AND DOSE-RESPONSE SURFACES

    NARCIS (Netherlands)

    DEHAAN, G; ENGEL, C; DONTJE, B; NIJHOF, W; LOEFFLER, M

    1994-01-01

    We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different dos

  4. Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma.

    Science.gov (United States)

    Kanno, Hiromi; Nishihara, Hiroshi; Wang, Lei; Yuzawa, Sayaka; Kobayashi, Hiroyuki; Tsuda, Masumi; Kimura, Taichi; Tanino, Mishie; Terasaka, Shunsuke; Tanaka, Shinya

    2013-07-01

    CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression. First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo. Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma.

  5. Granulocyte colony-stimulating factor use in a large British hospital: comparison with published experience

    Directory of Open Access Journals (Sweden)

    Pérez Velasco R

    2010-12-01

    Full Text Available Granulocyte colony-stimulating factors (G-CSF are high-cost agents recommended as prophylaxis of febrile neutropenia or as adjunctive treatment of severe neutropenic sepsis. Their use in high-risk situations such as acute myeloid leukaemia, acute lymphocytic leukaemia, myelodysplastic syndrome and stem cell transplantation is also indicated. Objective: This audit assessed the use of G-CSF within the Oncology and Haematology Service Delivery Unit at Guy’s and St. Thomas’ hospital (London, United Kingdom.Methods: Patients who received G-CSF in April-May 2008 were identified retrospectively from the pharmacy labelling system, and chemotherapy front sheets, clinic letters and transplantation protocols were reviewed. Patients on lenograstim, in clinical trials or under non-approved chemotherapy protocols were excluded.Results: A total of 104 G-CSF treatments were assessed. The most commonly treated malignancy was breast cancer (41.3%, with docetaxel 100 mg/m2 (34.6% being the most frequent chemotherapy regimen. The chemotherapy intent was curative in 66.3 % of cases. Pegfilgrastim was used in 73.1 % of cases and primary prophylaxis was the most common indication (54.8%. Stem cell transplantation was the first indication to meet the audit criterion (93.3%, followed by primary prophylaxis (89.5%. There was a considerable non-adherence for secondary prophylaxis (6.7%.Conclusion: The overall level of compliance with the audit criteria was 72.1%. The results for primary and secondary prophylaxis would have been different if FEC100 (fluorouracil, epirubicin, cyclophosphamide and docetaxel 100 mg/m2 had been considered a single chemotherapy regimen. Also, the lack of access to medical notes may have affected the reliability of the results for ‘therapeutic’ use.

  6. Granulocyte colony-stimulating factor administration for infertile women with thin endometrium in frozen embryo transfer program.

    Science.gov (United States)

    Li, Yu; Pan, Ping; Chen, Xiaoli; Li, Lin; Li, Yi; Yang, Dongzi

    2014-03-01

    We aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) administration for infertile women with thin endometrium in frozen embryo transfer program. Among 59 infertile patients with thin endometrium (≤7 mm), 34 patients received uterine infusion of recombinant human G-CSF (100 μg/0.6 mL) on the day of ovulation or administration of progesterone or human chorionic gonadotropin, with 40 cycles defined as G-CSF group and 49 previous cycles as self-controlled group, and 25 patients refused, with 80 cycles defined as the control group. Higher proportion of induced cycles and lower proportion of natural cycles were observed in the G-CSF group, when compared to the self-controlled group or control group (P transfer were similar in all the groups (P > .05). Our study fails to demonstrate that G-CSF has the potential to improve embryo implantation and clinical pregnancy rate of the infertile women with thin endometrium.

  7. Granulocyte-colony stimulating factor (G-CSF improves motor recovery in the rat impactor model for spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Tanjew Dittgen

    Full Text Available Granulocyte-colony stimulating factor (G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. Previously we have employed the mouse hemisection SCI model and studied motor function after subcutaneous or transgenic delivery of the protein. To further broaden confidence in animal efficacy data we sought to determine efficacy in a different model and a different species. Here we investigated the effects of G-CSF in Wistar rats using the New York University Impactor. In this model, corroborating our previous data, rats treated subcutaneously with G-CSF over 2 weeks show significant improvement of motor function.

  8. Leukocytoclastic Vasculitis as a Complication of Recombinant Granulocyte Colony-Stimulating Factor Therapy in a Heart Transplant Patient

    Directory of Open Access Journals (Sweden)

    Giovanbattista Ippoliti

    2014-01-01

    Full Text Available Recombinant granulocyte colony-stimulating factor (rG-CSF is a myeloid growth factor that is widely used in haematology to recover neutropenia secondary to myelosuppressive chemotherapy. Leukocytoclastic vasculitis is an acknowledged side effect of the above therapy. Its pathogenesis involves many mechanisms that collectively induce an increase in neutrophil function and a subsequent release of cytokines. Here, we report a case of leukocytoclastic vasculitis proven by skin biopsy, following the use of rG-CSF in a heart transplant patient with leukopenia secondary to immunosuppressive therapy.

  9. Effects of Granulocyte Colony-Stimulating Factor (GCSF) on Persistent Thin Endometrium in Frozen Embryo Transfer (FET) Cycles.

    Science.gov (United States)

    Mishra, Vineet V; Choudhary, Sumesh; Sharma, Urmila; Aggarwal, Rohina; Agarwal, Ritu; Gandhi, Khushali; Goraniya, Nilesh

    2016-10-01

    To predict the effectiveness of granulocyte colony-stimulating factor (GCSF) in the treatment of persistent thin endometrium resistant to other treatments in frozen embryo transfer (FET) cycles. This is a hospital-based prospective study. Thirty-five women with persistent thin endometrium (transfer. Of these, 3 (15.78 %) patients had chemical pregnancy, but there was no clinical pregnancy. In 16 participants, embryo transfer was canceled in view of insufficient endometrial thickness (<7 mm). GCSF caused a small increase in endometrial thickness in women with persistent thin endometrium, but there was no improvement in their pregnancy rates.

  10. Subcutaneous administration of granulocyte colony stimulating factor and stem cell factor ameliorates the outcome of acute myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    LIN Ling; ZHOU Sheng-hua; QI Shu-shan; SHEN Xiang-qian; LIU Qi-ming; FANG Zhen-fei

    2005-01-01

    @@ Orlic et al1 treated mice (splenectomized two weeks ago) with granulocyte colony stimulating factor (G-CSF) and stem cell factor (SCF) for five days before acute myocardium infarction (AMI) and three days after AMI.They found that those treatments could repair infarcted hearts,improve heart performance and decrease mortality.However,from the clinical standpoint,the work of Orlic and his co-workers has an obvious limitation.The strategy of delivering agents before infarction is not practicable because the onset of infarction is unpredictable.Therefore,we delivered the agents after infarction to modify its effect on rats closer to clinical reality.

  11. Effect of granulocyte colony-stimulating factor (G-CSF) in human immunodeficiency virus-infected patients: increase in numbers of naive CD4 cells and CD34 cells makes G-CSF a candidate for use in gene therapy or to support antiretroviral therapy

    DEFF Research Database (Denmark)

    Nielsen, S D; Afzelius, P; Dam-Larsen, S;

    1998-01-01

    The potential of granulocyte colony-stimulating factor (G-CSF) to mobilize CD4 cells and/or CD34 cells for use in gene therapy or to support antiretroviral therapy was examined. Ten human immunodeficiency virus-infected patients were treated with G-CSF (300 microg/day) for 5 days. Numbers of CD4....... Furthermore, the fraction of naive CD4 cells increased. These findings have implications for the design of immunotherapy or gene therapy protocols....... and CD34 cells were measured. To examine the numbers of naive and memory type CD4 cells, CD4 cell coexpression of CD45RA and CD45RO was measured. Functionality of mobilized CD4 cells was examined by use of the proliferation assay and interleukin-2 ELISA. The number of CD34 cells increased from 1.50 to 20...

  12. The efficiency of granulocyte colony-stimulating factor in hemorrhagic mucositis and febrile neutropenia resulted from methotrexate toxicity.

    Science.gov (United States)

    Ozkol, Hatice Uce; Toptas, Tayfur; Calka, Omer; Akdeniz, Necmettin

    2015-01-01

    Methotrexate (MTX) remains one of the most frequently used anti-metabolite agents in dermatology. MTX is an analog of folate that competitively and irreversibly inhibits dihydrofolate reductase. Oral mucositis is a common side effect of chemotherapy drugs and is characterized by erythema, pain, poor oral intake, pseudomembranous destruction, open ulceration and hemorrhage of the oral mucosa. In this paper, we report a 32-year-old female with a case of mucositis due to MTX intoxication that resulted from an overdose for rheumatoid arthritis. The patient had abdominal pain, vomiting, and nausea. During follow-up, the patient's white blood cell count was found to be 0.9 × 10(9)/L (4-10 × 10(9)/L). The patient developed fever exceeding 40 °C. The patient was consulted to the hematology service. They suggested using granulocyte colony-stimulating factor for febrile neutropenia. On the fifth day of treatment, the white blood cell count reached 5.3 × 10(9)/L and the patient's fever and mucositis started to resolve. Here, we presented a case of hemorrhagic mucositis and febrile neutropenia resulted from high-dose MTX that responded very well to granulocyte colony-stimulating factor treatment and we reviewed the literature.

  13. Patient condition affects the collection of peripheral blood progenitors after priming with recombinant granulocyte colony-stimulating factor.

    Science.gov (United States)

    Chabannon, C; Le Coroller, A G; Faucher, C; Novakovitch, G; Blaise, D; Moatti, J P; Maraninchi, D; Mannoni, P

    1995-06-01

    A total of 258 aphereses were performed in 79 patients with nonmyeloid malignancies after mobilization of peripheral blood stem cells (PBSC) with recombinant human granulocyte colony-stimulating factor (rhG-CSF). Apheresis products were examined for viable mononuclear cell (VMC), CD34+ cell, and clonogenic cell contents. The number of progenitors in aphereses differs in subgroups of patients with different diagnoses. However, the number of CD34+ or clonogenic cells is dependent on age and amount of chemotherapy delivered to patients before collection rather than on the nature of the disease itself. In addition, the actual dose of rhG-CSF used to mobilize PBSC and the number of VMC in aphereses influenced the clonogenicity of CD34+ cells, although the daily dose of rhG-CSF seems to play little role on the number of clonogenic cells in each individual apheresis product. CD34+ cell and CFU-C (or CFU-GM) numbers are related parameters, and the relation can be described as linear. However, the linear relation varies in different patient groups, and most of the linearity is induced by the highest sets of values. We conclude that mobilization with low doses of rhG-CSF alone is feasible and that the probability of collecting a high number of peripheral blood progenitors is increased in young patients undergoing apheresis early in the course of the disease. Although the relationship between CD34+ cells and CFUs can be described as linear in well-defined situations, its relevance may be limited because it is not a universal finding.

  14. Granulocyte colony-stimulating factor ameliorates coronary artery elastin breakdown in a mouse model of Kawasaki disease

    Institute of Scientific and Technical Information of China (English)

    Liu Junfeng; Chen Zhi; Du Zhongdong; Lu Dunxiang

    2014-01-01

    Background Coronary artery damage from Kawasaki disease (KD) is closely linked to the dysfunction of the endothelial progenitor cells (EPCs).The aim of the present study was to evaluate the modulatory effect of granulocyte colony stimulating factor (G-CSF) on EPCs and elastin breakdown of coronary arteries in a KD mouse model.Methods A Lactobacillus casei cell wall extract (LCWE)-induced KD model was established in C57BL/6 mice that were subsequently administrated with recombinant human G-CSF (rhG-CSF).Nω-nitro-L-arginine methyl ester (L-NAME) was administrated for the negative intervention.Evaluations included coronary artery lesions,EPC number and functions,and the plasma concentration of nitric oxide (NO).Results Elastin breakdown was found in the coronary arteries of model mice 56 days after injection of LCWE.The number of circulating EPCs,plasma concentration of NO,and functions of bone marrow EPCs,including proliferation,adhesion,and migration abilities,were all lower in the KD model group compared with those in the control group.After administration of rhG-CSF,the number of circulating EPCs and plasma concentration of NO were increased significantly compared with those in the KD model group.There were also increases in the functional indexes of EPCs.Furthermore,rhG-CSF administration improved the elastin breakdown effectively.However,these protective effects of rhG-CSF on coronary arteries were attenuated by L-NAME.Conclusion The present study indicated that the administration of G-CSF prevents elastin breakdown of the coronary arteries by enhancing the number and functions of EPCs via the NO system,and then accelerates the repair of coronary artery lesions in the KD.

  15. Granulocyte colony stimulating factor treatment of resistant thin endometrium in women with frozen-thawed blastocyst transfer.

    Science.gov (United States)

    Kunicki, Michał; Łukaszuk, Krzysztof; Liss, Joanna; Skowrońska, Patrycja; Szczyptańska, Joanna

    2017-02-01

    The aim of the study was to assess the granulocyte-colony stimulating factor (G-CSF) effect on unresponsive thin (transfer at the blastocyst stage. A total of 62 women with thin unresponsive endometrium were included in the study, of which, 29 received a G-CSF infusion and 33 who opted out of the study served as controls. Patients in both groups had similar endometrial thickness at the time of the initial evaluation: 6.50 mm (5.50-6.80) in the G-CSF and 6.40 mm (5.50-7.0) in the control group. However, after the infusion endometrial thickness increased significantly in the G-CSF group in comparison with the controls (p=0.01), (Δ) 0.5 (0.02-1.2) (p=0.005). In the G-CSF group endometrium expanded to 7.90 mm (6.58-8.70) while in the control group to 6.90 mm (6.0-7.75). Five women in each group conceived. The clinical pregnancy rate was 5/29 (17.24%) in the G-CSF treated group and 5/33 (15.15%) in the control group (p>0.05). The live birth rate was 2/29 (6.89%) in the G-CSF group and 2/33 (6.06%) in the control group (p>0.05). We concluded that G-CSF infusion leads to an improvement in endometrium thickness but not to any improvement in the clinical pregnancy and live birth rates. Until more data is available G-CSF treatment should be considered to be of limited value in increasing pregnancy rate. G-CSF: granulocyte colony-stimulating factor; M-CSF: macrophagecolony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; FET: frozen embryo transfer; IVF: in vitro fertilization.

  16. Granulocyte-Colony Stimulating Factor Producing Infiltrating Urothelial Carcinoma of the Left Renal Pelvis: A Case Report

    Directory of Open Access Journals (Sweden)

    Takamasa Horiuchi

    2017-01-01

    Full Text Available We report a case of granulocyte-colony stimulating factor (G-CSF producing infiltrating urothelial carcinoma of the left renal pelvis. The patient was referred to our hospital for fever and anorexia. Blood tests showed elevated level of leukocytosis without any infectious diseases. The serum concentration of G-CSF was remarkably elevated. Abdominal computed tomography (CT revealed a huge mass in the left renal pelvis and para-aortic lymph node enlargement. He was underwent left nephroureterectomy and para-aortic lymphadenectomy. The histological examination revealed infiltrating urothelial carcinoma with positive staining for G-CSF antibody. The postoperative course was smooth and the leukocyte count became normalized within a week postoperatively. However, multiple lung metastasis and leukocytosis were revealed about 2 months after the operation. G-CSF producing infiltrating urothelial carcinoma of the renal pelvis is reported to have a significantly poor prognosis, so it is very important to monitor closely after the operation.

  17. Two protocols to treat thin endometrium with granulocyte colony-stimulating factor during frozen embryo transfer cycles.

    Science.gov (United States)

    Xu, Bin; Zhang, Qiong; Hao, Jie; Xu, Dabao; Li, Yanping

    2015-04-01

    The efficacy of two granulocyte colony-stimulating factor (G-CSF) protocols for thin endometrium were investigated. Eighty-two patients were diagnosed with thin endometrium (transfers received intrauterine G-CSF in subsequent frozen embryo transfer (FET) cycles. Patients were divided into the G-CSF only and G-CSF with endometrial scratch subgroups. Compared with previous cycles, endometrial thickness increased from 5.7 ± 0.7 mm to 8.1 ± 2.1 mm after G-CSF treatment (P transfer cancellation and G-CSF treatment in subsequent FET cycles is beneficial. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  18. Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis

    DEFF Research Database (Denmark)

    Zohlnhofer, D.; Dibra, A.; Koppara, T.;

    2008-01-01

    OBJECTIVES: The objective of this meta-analysis was to evaluate the effect of stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) on myocardial regeneration on the basis of a synthesis of the data generated by randomized, controlled clinical trials of G-CSF after acute...... myocardial infarction (AMI). BACKGROUND: Experimental studies and early-phase clinical trials suggest that stem cell mobilization by G-CSF may have a positive impact on cardiac regeneration after AMI. The role of G-CSF in patients with AMI remains unclear considering the inconsistent results of several...... independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Eligible studies were randomized trials with stem cell mobilization by G-CSF after reperfused AMI that reported data regarding the change in left ventricular ejection fraction (LVEF...

  19. Surgical wound healing using hemostatic gauze scaffold loaded with nanoparticles containing sustained-release granulocyte colony-stimulating factor

    Directory of Open Access Journals (Sweden)

    Yuan W

    2011-12-01

    Full Text Available Weien Yuan1,2, Zhenguo Liu11Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 2School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of ChinaBackground: The therapeutic strategies for malignant melanoma are still cancer chemotherapy, radiotherapy, and tumor resection. However, these therapeutic strategies often lead to a reduced neutrophilic granulocyte count or loss of more blood after surgical tumor resection. In this study, we developed a formulation of hemostatic gauze impregnated with sustained-release granulocyte colony-stimulating factor (G-CSF with increasing of the neutrophilic granulocyte count in the blood following chemotherapy and decreasing blood loss after surgical tumor resection.Methods: We designed a formulation with both hemostatic properties and increased neutrophil content to be used in cancer chemotherapy, radiotherapy, and tumor resection, comprising a hemostatic gauze as a scaffold and (G-CSF-loaded dextran nanoparticles coated with polylactic-co-glycolic acid (PLGA solution fabricated by direct spray-painting onto the scaffold and then vacuum-dried at room temperature. The performance of this system was evaluated in vitro and in vivo.Results: Nearly zero-order release of G-CSF was recorded for 12–14 days, and the cumulative release of G-CSF retained over 90% of its bioactivity in a NFS-60 cell line proliferation assay when the scaffold was incubated in phosphate-buffered saline (pH 7.4 at 37°C. The in vivo hemostatic efficacy of this formulation was greater than that of native G-CSF, the scaffold directly spray-painted with G-CSF solution or PLGA organic solution as a coating, or when a blank scaffold was covered with the coating.Conclusion: Our results suggest that this formulation has both hemostatic properties and increased neutrophil activity.Keywords: hemostatic gauze scaffold, granulocyte colony-stimulating factor, bioactivity

  20. Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia

    NARCIS (Netherlands)

    Aarts, M.J.; Peters, F.P.; Mandigers, C.M.P.W.; Dercksen, M.W.; Stouthard, J.M.; Nortier, H.J.; Laarhoven, H.W.M. van; Warmerdam, L.J. van; Wouw, A.J. van de; Jacobs, E.M.G.; Mattijssen, V.; Rijt, C.C. van der; Smilde, T.J.; Velden, A.W. van der; Temizkan, M.; Batman, E.; Muller, E.W.; Gastel, S.M. van; Borm, G.F.; Tjan-Heijnen, V.C.

    2013-01-01

    PURPOSE: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF d

  1. Effect of recombinant murine granulocyte colony-stimulating factor with or without fluoroquinolone therapy on mixed-infection abscesses in mice.

    NARCIS (Netherlands)

    Stearne, L.E.; Vonk, A.G.; Kullberg, B.J.; Gyssens, I.C.J.

    2005-01-01

    The aim of the study was to determine if immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (G-CSF) improves the efficacy of trovafloxacin or moxifloxacin in abscesses containing Bacillus fragilis ATCC 23745 and different Escherichia coli strains varying

  2. Effect of recombinant murine granulocyte colony-stimulating factor with or without fluoroquinolone therapy on mixed-infection abscesses in mice.

    NARCIS (Netherlands)

    L.E.T. Stearne (Lorna); A.G. Vonk (Alieke); B.J. Kullberg (Bart Jan); I.C. Gyssens (Inge)

    2005-01-01

    textabstractThe aim of the study was to determine if immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (G-CSF) improves the efficacy of trovafloxacin or moxifloxacin in abscesses containing Bacillus fragilis ATCC 23745 and different Escherichia coli

  3. Effect of recombinant murine granulocyte colony-stimulating factor with or without fluoroquinolone therapy on mixed-infection abscesses in mice.

    NARCIS (Netherlands)

    L.E.T. Stearne (Lorna); A.G. Vonk (Alieke); B.J. Kullberg (Bart Jan); I.C. Gyssens (Inge)

    2005-01-01

    textabstractThe aim of the study was to determine if immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (G-CSF) improves the efficacy of trovafloxacin or moxifloxacin in abscesses containing Bacillus fragilis ATCC 23745 and different Escherichia coli strai

  4. Predicting erythroid response to recombinant erythropoietin plus granulocyte colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia.

    Science.gov (United States)

    Bowen, David; Hyslop, Ann; Keenan, Norene; Groves, Michael; Culligan, Dominic; Johnson, Peter; Shaw, Ann; Geddes, Fiona; Evans, Patricia; Porter, John; Cavill, Ivor

    2006-05-01

    We randomized 21 patients with low-risk myelodysplastic syndromes (MDS) to receive a single subcutaneous bolus of recombinant erythropoietin (epoietin) +/- granulocyte-colony stimulating factor (G-CSF), or placebo and monitored erythropoietic response over 7 days. In this small study, the reticulocyte response at day 7 was highly predictive of subsequent response to a therapeutic trial of epoietin + G-CSF.

  5. The costs of peripheral blood progenitor cell reinfusion mobilised by granulocyte colony-stimulating factor following high dose melphalan as compared with conventional therapy in multiple myeloma

    NARCIS (Netherlands)

    C.A. Uyl-de Groot (Carin); G.J. Ossenkoppele (Gert); A.A.P.M. van Riet (A. A P M); F.F.H. Rutten (Frans)

    1994-01-01

    textabstractIn a retrospective study, we calculated the treatment costs of 26 patients, who received either high dose melphalan combined with granulocyte colony-stimulating factor (G-CSF; filgrastim)(n=7) or without G-CSF (n=11) or alternatively, peripheral blood progenitor cell reinfusion (PBPC) mo

  6. Granulocyte colony-stimulating factor induces neurogenesis and improves cognition in amyloid precursor protein transgenic mouse model of Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    朱正禹

    2012-01-01

    Objective To investigate the effect of granulocyte colony-stimulating factor (G-CSF) and its effect on the cognation in the PDGF-hAPPV717I transgenic mice of Alzheimer’s disease model. Methods Totally 36 PDGF-hAPPV717I transgenic mice were randomly divided into two groups:

  7. Treatment of intra-abdominal abscesses caused by Candida albicans with antifungal agents and recombinant murine granulocyte colony-stimulating factor.

    NARCIS (Netherlands)

    Vonk, A.G.; Netea, M.G.; Krieken, J.H.J.M. van; Verweij, P.E.; Meer, J.W.M. van der; Kullberg, B.J.

    2003-01-01

    The aim of the present study was to assess the influence of immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (rmG-CSF) on intra-abdominal abscesses caused by Candida albicans. Mice received prophylaxis or therapy with 1 microg of rmG-CSF/day in the prese

  8. Use of thrombopoietin in combination with chemotherapy and granulocyte colony-stimulating factor for peripheral blood progenitor cell mobilization.

    Science.gov (United States)

    Gajewski, James L; Rondon, Gabriela; Donato, Michele L; Anderlini, Paolo; Korbling, Martin; Ippoliti, Cindy; Benyunes, Mark; Miller, Langdon L; LaTemple, Denise; Jones, Denny; Ashby, Mark; Hellmann, Sue; Durett, April; Lauppe, Jo; Geisler, Deborah; Khouri, Issa F; Giralt, Sergio A; Andersson, Borje; Ueno, Naoto T; Champlin, Richard

    2002-01-01

    This phase I/II dose-escalation study examined the safety and efficacy of recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF) for postchemotherapy mobilization of peripheral blood progenitor cells (PBPCs) in patients with advanced breast cancer. Patients received cyclophosphamide, etoposide, and cisplatin (CVP) followed by G-CSF (6 microg/kg twice a day) and rhTPO (0.6, 1.2, 2.4, or 3.6 microg/kg as a single dose on day 5 or as 3 doses on days 5, 7, and 9 after chemotherapy). PBPCs were collected by daily leukapheresis when the postnadir white blood cell count reached > or = 2 x 10(9)/L; leukapheresis was continued until acquisition of a target dose of > or = 5 x 10(6) CD34+ cells/kg. Mobilized PBPCs were transplanted into patients after additional high-dose chemotherapy with cyclophosphamide, carmustine, and thiotepa (CBT). Comparisons were made with contemporaneously treated, nonrandomized, control patients who received the same chemotherapy regimens and G-CSF support but who did not receive rhTPO. Of 32 evaluable patients receiving rhTPO and G-CSF after CVP, 91% required only 1 leukapheresis to achieve a target PBPC graft; by contrast, only 69% of 36 of the control patients achieved the target graft with just 1 leukapheresis (P = .026). A median of 26.7 x 10(6) CD34 cells/kg per leukapheresis was obtained from the rhTPO-treated patients compared with 11.5 x 10(6) cells/kg per leukapheresis from the controls (P = .09). Higher rhTPO doses appeared to yield more CD34+ cells. When PBPCs were infused after high-dose CBT chemotherapy, the median times to return of an absolute neutrophil count of 0.5 x 10(9)/L and a platelet count of 20 x 10(9)/L were 15 and 16 days, respectively; these values did not differ from those in the control group (15 days for both neutrophil and platelets). No patient developed anti-TPO antibodies. These results indicate that rhTPO safely and effectively augments the number of PBPCs mobilized with

  9. Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation

    Science.gov (United States)

    Sanzari, Jenine K.; Krigsfeld, Gabriel S.; Shuman, Anne L.; Diener, Antonia K.; Lin, Liyong; Mai, Wilfried; Kennedy, Ann R.

    2015-04-01

    Astronauts could be exposed to solar particle event (SPE) radiation, which is comprised mostly of proton radiation. Proton radiation is also a treatment option for certain cancers. Both astronauts and clinical patients exposed to ionizing radiation are at risk for loss of white blood cells (WBCs), which are the body's main defense against infection. In this report, the effect of Neulasta treatment, a granulocyte colony stimulating factor, after proton radiation exposure is discussed. Mini pigs exposed to total body proton irradiation at a dose of 2 Gy received 4 treatments of either Neulasta or saline injections. Peripheral blood cell counts and thromboelastography parameters were recorded up to 30 days post-irradiation. Neulasta significantly improved WBC loss, specifically neutrophils, in irradiated animals by approximately 60% three days after the first injection, compared to the saline treated, irradiated animals. Blood cell counts quickly decreased after the last Neulasta injection, suggesting a transient effect on WBC stimulation. Statistically significant changes in hemostasis parameters were observed after proton radiation exposure in both the saline and Neulasta treated irradiated groups, as well as internal organ complications such as pulmonary changes. In conclusion, Neulasta treatment temporarily alleviates proton radiation-induced WBC loss, but has no effect on altered hemostatic responses.

  10. Granulocyte colony-stimulating factor activating HIF-1alpha acts synergistically with erythropoietin to promote tissue plasticity.

    Directory of Open Access Journals (Sweden)

    Shih-Ping Liu

    Full Text Available Stroke and peripheral limb ischemia are serious clinical problems with poor prognosis and limited treatment. The cytokines erythropoietin (EPO and granulocyte-colony stimulating factor (G-CSF have been used to induce endogenous cell repair and angiogenesis. Here, we demonstrated that the combination therapy of EPO and G-CSF exerted synergistic effects on cell survival and functional recovery from cerebral and peripheral limbs ischemia. We observed that even under normoxic conditions, G-CSF activates hypoxia-inducible factor-1alpha (HIF-1alpha, which then binds to the EPO promoter and enhances EPO expression. Serum EPO level was significantly increased by G-CSF injection, with the exception of Tg-HIF-1alpha(+f/+f mice. The neuroplastic mechanisms exerted by EPO combined with G-CSF included enhanced expression of the antiapoptotic protein of Bcl-2, augmented neurotrophic factors synthesis, and promoted neovascularization. Further, the combination therapy significantly increased homing and differentiation of bone marrow stem cells (BMSCs and intrinsic neural progenitor cells (INPCs into the ischemic area. In summary, EPO in combination with G-CSF synergistically enhanced angiogenesis and tissue plasticity in ischemic animal models, leading to greater functional recovery than either agent alone.

  11. Delayed administration of granulocyte colony-stimulating factor after autologous bone marrow transplantation: effect on granulocyte recovery.

    Science.gov (United States)

    Vey, N; Molnar, S; Faucher, C; Le Corroller, A G; Stoppa, A M; Viens, P; Bouabdallah, R; Camerlo, J; Novakovitch, G; Mannoni, P

    1994-11-01

    Recombinant granulocyte colony-stimulating factor (rhG-CSF) has been shown to hasten granulocyte recovery after autologous BMT. In current protocols, rhG-CSF treatment starts 1 day after BM reinfusion. Our study retrospectively examined the effects on haematological recovery of a day 6 delayed administration. Seventy-eight patients receiving autologous BMT for malignant lymphoma (21 non-Hodgkin's lymphoma and 9 Hodgkin's disease) or solid tumors (33 breast carcinoma and 5 ovarian carcinoma) were split up into three study groups. Two groups receiving a 5 micrograms/kg/day of rhG-CSF starting either 1 day (day +1 group, n = 25 patients) or 6 days (day +6 group, n = 24 patients) after BM reinfusion were compared with 29 historical control patients. Granulocyte recovery to 0.5 x 10(9)/l was 12 days in day +6 and day +1 groups versus 16 days in control group (p < 0.005) without any difference in other hematological parameters, infectious complications or length of hospitalisation between the three groups. The day +6 administration allows elimination of a median of 7 days rhG-CSF. It has been concluded that the day +6 administration gives the same clinical benefit as day +1 administration with consequent cost reductions.

  12. Randomized Trial of Two Dosages of Prophylactic Granulocyte Colony-Stimulating Factor after Induction Chemotherapy in Pediatric Acute Myeloid Leukemia

    Science.gov (United States)

    Inaba, Hiroto; Cao, Xueyuan; Pounds, Stanley; Pui, Ching-Hon; Rubnit, Jeffrey E.; Ribeiro, Raul C.; Razzouk, Bassem I.

    2010-01-01

    Background Granulocyte colony-stimulating factor (G-CSF) is effective in accelerating neutrophil recovery after intensive chemotherapy for acute myeloid leukemia (AML). However, the optimal G-CSF dosage for patients with AML has not been determined. To our knowledge, G-CSF dosages have not been compared in a randomized AML study. Methods Patients enrolled on the St. Jude AML97 protocol who remained on study after window therapy were eligible to participate. The effect of the dosage of G-CSF given after induction chemotherapy courses 1 and 2 was analyzed in 46 patients randomly assigned in a double-blinded manner to receive 5 or 10 μg/kg/day of G-CSF. The number of days of G-CSF treatment, neutropenia (absolute neutrophil count < 0.5 × 109/L), and hospitalization; the number of episodes of febrile neutropenia, grade 2-4 infection, and antimicrobial therapy; transfusion requirements; the cost of supportive care; and survival were compared between the two study arms. Results We found no statistically significant difference between the two arms in any of the endpoints measured. Conclusions The higher G-CSF dosage (10 μg/kg/day) offers no greater benefit than the lower dosage (5 μg/kg/day) in patients undergoing intensive chemotherapy for AML. PMID:21381017

  13. Effect of granulocyte colony stimulating factor (G-CSF on IVF outcomes in infertile women: An RCT

    Directory of Open Access Journals (Sweden)

    Maryam Eftekhar

    2016-05-01

    Full Text Available Background: Despite major advances in assisted reproductive techniques, the implantation rates remain relatively low. Some studies have demonstrated that intrauterine infusion of granulocyte colony stimulating factor (G-CSF improves implantation in infertile women. Objective: To assess the G-CSF effects on IVF outcomes in women with normal endometrial thickness. Materials and methods: In this randomized controlled clinical trial, 100 infertile women with normal endometrial thickness who were candidate for IVF were evaluated in two groups. Exclusion criteria were positive history of repeated implantation failure (RIF, endocrine disorders, severe endometriosis, congenital or acquired uterine anomaly and contraindication for G-CSF (renal disease, sickle cell disease, or malignancy. In G-CSF group (n=50, 300 μg trans cervical intrauterine of G-CSF was administered at the oocyte retrieval day. Controls (n=50 were treated with standard protocol. Chemical, clinical and ongoing pregnancy rates, implantation rate, and miscarriage rate were compared between groups. Results: Number of total and mature oocytes (MII, two pronuclei (2PN, total embryos, transferred embryos, quality of transferred embryos, and fertilization rate did not differ significantly between two groups. So there were no significant differences between groups in chemical, clinical and ongoing pregnancy rate, implantation rate, and miscarriage rate Conclusion: our result showed in normal IVF patients with normal endometrial thickness, the intrauterine infusion of G-CSF did not improve pregnancy outcomes.

  14. Effect of granulocyte colony stimulating factor (G-CSF) on IVF outcomes in infertile women: An RCT

    Science.gov (United States)

    Eftekhar, Maryam; Hosseinisadat, Robabe; Baradaran, Ramesh; Naghshineh, Elham

    2016-01-01

    Background: Despite major advances in assisted reproductive techniques, the implantation rates remain relatively low. Some studies have demonstrated that intrauterine infusion of granulocyte colony stimulating factor (G-CSF) improves implantation in infertile women. Objective: To assess the G-CSF effects on IVF outcomes in women with normal endometrial thickness. Materials and methods: In this randomized controlled clinical trial, 100 infertile women with normal endometrial thickness who were candidate for IVF were evaluated in two groups. Exclusion criteria were positive history of repeated implantation failure (RIF), endocrine disorders, severe endometriosis, congenital or acquired uterine anomaly and contraindication for G-CSF (renal disease, sickle cell disease, or malignancy). In G-CSF group (n=50), 300 µg trans cervical intrauterine of G-CSF was administered at the oocyte retrieval day. Controls (n=50) were treated with standard protocol. Chemical, clinical and ongoing pregnancy rates, implantation rate, and miscarriage rate were compared between groups. Results: Number of total and mature oocytes (MII), two pronuclei (2PN), total embryos, transferred embryos, quality of transferred embryos, and fertilization rate did not differ significantly between two groups. So there were no significant differences between groups in chemical, clinical and ongoing pregnancy rate, implantation rate, and miscarriage rate Conclusion: our result showed in normal IVF patients with normal endometrial thickness, the intrauterine infusion of G-CSF did not improve pregnancy outcomes. PMID:27326420

  15. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

    OpenAIRE

    1995-01-01

    textabstractBACKGROUND. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia. METHODS. We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute m...

  16. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A. [Academy of Sciences of the Czech Republic, Inst. of Biophysics, Brno (Czech Republic); Znojil, V.; Vacha, J. [Masaryk Univ., Medical Faculty, Brno (Czech Republic)

    1998-03-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of {sup 60}Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au) 43 refs.

  17. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Stevenson Matt D

    2011-09-01

    Full Text Available Abstract Background Febrile neutropenia (FN occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. Methods A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. Results Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65 for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69 for filgrastim, and 0.62 (95% CI: 0.44 to 0.88 for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62. In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98. Conclusions Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

  18. Recombinant human granulocyte-colony stimulating factor for febrile neutropenia during cancer therapy: the first 20 years%重组人粒细胞集落刺激因子在肿瘤化疗中应用20年回顾

    Institute of Scientific and Technical Information of China (English)

    莫红楠; 石远凯; 孙燕

    2013-01-01

    中性粒细胞减少一直被认为是骨髓抑制性化疗最严重的血液学毒性,同时也是实体瘤和血液恶性肿瘤治疗中常见的剂量限制性毒性.重组人粒细胞集落刺激因子(recombinant human granulocyte-colony stimulating factor,rhG-CSF)主要用于抗肿瘤治疗后出现中性粒细胞减少,对癌症患者来说是重要的支持治疗.rhG-CSF的应用降低了发热性中性粒细胞减少的发生率、持续时间和严重程度,从而保证及时、足量完成抗肿瘤治疗.rhG-CSF1993年在中国上市,至今已经20年,目前临床上常用的rhG-CSF主要分为长效和短效两种制剂.本文从rhG-CSF的种类和作用机制,对化疗后出现FN的治疗和预防作用,国内外的应用经验以及相关的药物不良反应等方面,对rhG-CSF临床应用20年进行系统回顾.

  19. Granulocyte colony-stimulating factor-producing ascending colon cancer as indicated by histopathological findings: report of a case.

    Science.gov (United States)

    Fujiwara, Yushi; Yamazaki, Osamu; Takatsuka, Satoshi; Kaizaki, Ryoji; Inoue, Takeshi

    2011-12-01

    Various types of granulocyte colony-stimulating factor (G-CSF)-producing malignant tumors have been reported. However, a G-CSF-producing colorectal cancer is rare. We present a case of G-CSF-producing ascending colon cancer. An 81-year-old man was referred to our hospital with right lower abdominal pain. A colon fiberscopy revealed an ascending colon tumor, and histological examination revealed tubular adenocarcinoma. He was admitted due to worsening abdominal pain. Although laboratory data showed an elevated white blood cell (WBC) count of 17000/mm3 with 77.8% neutrophils, elevated C-reaction protein (CRP) was insignificant (1.06 mg/dL), and he was afebrile. Because computed tomography indicated that the tumor penetrated into surrounding tissue, a semi-urgent ileocecal resection was performed. An abscess was not located. The tumor was staged as T3N2aM0 and as stage IIB according to the TNM classification. Microscopically, significant neutrophil infiltration between cancer cells was observed, suggesting the presence of a G-CSF-producing tumor. Immunohistochemical staining using a G-CSF antibody revealed cytoplasmic staining in cancer cells. The serum concentration of G-CSF upon admission was 334 pg/mL. After surgical resection, the WBC count decreased to within a normal range. These findings confirmed the diagnosis of G-CSF-producing ascending colon cancer. The prognosis of G-CSF-producing tumors is considered to be poor. Early diagnosis and surgical treatment are needed for patients with G-CSF-producing tumors, and continuous careful follow-up is required.

  20. Interferon-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.

    LENUS (Irish Health Repository)

    Tajuddin, Tariq

    2012-02-01

    BACKGROUND AND AIM: Neutropenia, a major side-effect of interferon-alpha (IFN-alpha) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-alpha might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression. METHODS: Fifty-five patients who were receiving IFN-alpha\\/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- alpha or the TLR7\\/8 agonist, CL097. RESULTS: Therapeutic IFN-alpha caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-alpha treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-alpha; however, co-incubation with a TLR7\\/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls. CONCLUSIONS: Suppressed G-CSF production in the presence of IFN-alpha may contribute to IFN-alpha-induced neutropenia. However, a TLR7\\/8 agonist elicits G-CSF secretion even in the presence of IFN-alpha, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-alpha-induced neutropenia.

  1. Annual patient and caregiver burden of oncology clinic visits for granulocyte-colony stimulating factor therapy in the US.

    Science.gov (United States)

    Stephens, J Mark; Li, Xiaoyan; Reiner, Maureen; Tzivelekis, Spiros

    2016-01-01

    Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I-III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ∼$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ∼$450 per patient. Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families.

  2. Development and calibration of a standard for the protein content of granulocyte colony-stimulating factor products.

    Science.gov (United States)

    Gao, Kai; Rao, Chunming; Tao, Lei; Han, Chunmei; Shi, Xinchang; Wang, Lan; Fan, Wenhong; Yu, Lei; Wang, Junzhi

    2012-03-01

    This collaborative study characterizes a homogeneous standard for the protein content determination of granulocyte colony-stimulating factor (G-CSF) products with traceability of the measurement. The Kjeldahl method was used to determine the average protein content of G-CSF bulk as 2.505 mg/ml (95% C.I: 2.467-2.543 mg/ml, GCV 4.0%). Using G-CSF bulk as a traceability benchmark, the protein content of the final freeze-dried standard using reverse phase HPLC (RP-HPLC) was 215.4 μg protein per ampoule (95% C.I: 212.407-218.486 μg/ampoule, GCV 3.4%). A comparative study showed that there was no difference between using Filgrastim CRS (European Pharmacopeia G-CSF reference standard) and freeze-dried homogeneous standard when quantifying G-CSF protein content by RP-HPLC (P > 0.05). However, there were significant differences in the G-CSF protein content obtained using a serum albumin standard by Lowry assay and a G-CSF standard with RP-HPLC. Therefore, use of RP-HPLC with a freeze-dried homogeneous standard would eliminate the systematic errors introduced when using a serum albumin standard because of the differences in protein composition between the standard and the sample. It would also be helpful to use this method to compare the quality of G-CSF biosimilar products in situations where the protein content has been calibrated using various standards.

  3. Granulocyte colony-stimulating factor regulates JNK pathway to alleviate damage after cerebral ischemia reperfusion

    Institute of Scientific and Technical Information of China (English)

    LI Ya-guo; LIU Xiao-li; ZHENG Chao-bo

    2013-01-01

    Background Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent hematopoietic growth factor that both enhances the survival and drives the differentiation and proliferation of myeloid lineage cells.Recent studies have suggested that GM-CSF has a neuroprotective effect against cerebral ischemia injury,but the molecular mechanisms have been unclear.This study aimed to investigate the influences of a short-acting (half-life 3.5 hours) G-CSF and a long-acting (half-life 40 hours) pegylated G-CSF on the JNK signaling pathway after cerebral ischemia reperfusion.Methods A total of 52 Sprague-Dawley rats were randomly divided into four groups:a sham group (n=4),a vehicle with saline (n=16),a short-acting G-CSF treatment group (n=16) and a long-acting G-CSF treatment group (n=16).The cerebral ischemia reperfusion model was established for the sham group and G-CSF treatment groups by middle cerebral artery occlusion (MCAO).Five days post reperfusion,rats were sacrificed and the brains were removed.Changes in neurological function after cerebral ischemia reperfusion was evaluated according to Neurological Severity Score (NSS) and the lesion volume and infarct size were measured by 2,3,5-triphenyltetrazolium chloride staining.The numbers of apoptotic neurons in these ischemic areas:left cerebral cortex,striatum and hippocampus were calculated by TUNEL assay,and expression of JNK/P-JNK,c-jun/P-c-jun in these areas was detected by Western blotting.Results Compared with the saline vehicle group ((249.68±23.36) mm3,(19.27±3.37)%),G-CSF-treated rats revealed a significant reduction in lesion volume (long-acting:(10.89±1.90)%,P <0.01; short-acting G-CSF:(11.69±1.41)%,P <0.01)and infarct size (long-acting:(170.53±18.47) mm3,P <0.01; short-acting G-CSF:(180.74±16.93) mm3,P <0.01) as well as less neuron functional damage (P <0.01) and a smaller number of apoptotic neurons in ischemic areas (P <0.01).The activity of P-JNK and P-c-jun in the

  4. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Yuhang Li

    2015-01-01

    Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  5. Characterization of recombinant human granulocyte colony-stimulating factor expression by FT-IR spectroscopy: Studies on thermal induction and media formulation on the stability of the protein secondary structure.

    Science.gov (United States)

    Vemula, Sandeep; Vemula, Sushma; Dedaniya, Akshay; Kante, Rajesh Kumar; Ronda, Srinivasa Reddy

    2016-08-17

    The Fourier-transform infrared (FT-IR) spectroscopic approach has been employed to understand the recombinant human G-CSF (rhG-CSF) protein accumulation, secondary structure, and thermal stability in Escherichia coli grown under a temperature shift strategy (37 and 28°C) in various media formulations. The choline + sodium pyruvate (37°C) and sodium pyruvate (28°C) formulations have shown the highest inclusion body (IB) accumulation of 0.41 and 0.46 mg/mL, respectively. Furthermore, insights on the structure of the rhG-CSF within IBs and intact cells have been investigated through secondary structure analysis. Thermal stability experiments were also carried out to explain the pattern of the second derivative structure of rhG-CSF. The studies showed that choline + sodium pyruvate formulation has preserved the protein secondary structure even at 82°C. Overall, the FT-IR spectroscopic technique can also be adopted to accelerate the characterization of other recombinant therapeutic proteins of E. coli origin.

  6. Influence of granulocyte colony-stimulating factor on cardiac function in patients with acute myocardial infarction and leukopenia after revascularization

    Institute of Scientific and Technical Information of China (English)

    GUO Shi-zun; WANG Ning-fu; ZHOU Liang; YE Xian-hua; PAN Hao; TONG Guo-xin; YANG Jian-min; XU Jian

    2010-01-01

    Background Granulocyte colony-stimulating factor (G-CSF) seems to improve cardiac function and perfusion when used systemically through mobilization of stem cells into peripheral blood, but results of previous clinical trials remain controversial. This study was designed to investigate safety and efficacy of subcutaneous injection of G-CSF on left ventricular function in patients with impaired left ventricular function after ST-segment elevation myocardial infarction (STEMI).Methods Thirty-three patients (22 men; age, (68.5±6.1) years) with STEMI and with comorbidity of leukopenia were included after successful primary percutaneous coronary intervention within 12 hours after symptom onset. Patients were randomized into G-CSF group who received G-CSF (10 μg/kg of body weight, daily) for continuous 7 days and control group. Results of blood analyses, echocardiography and angiography were documented as well as possibly occurred adverse events.Results No severe adverse events occurred in both groups. Mean segmental wall thickening in infract segments increased significantly at 6-month follow up compared with baseline in both groups, but the longitudinal variation between two groups had no significant difference (P >0.05). The same change could also be found in longitudinal variation of wall motion score index of infarct segments (P >0.05). At 6-month follow-up, left ventricular end-diastolic volume of both groups increased to a greater extent, but there were no significant differences between the two groups when comparing the longitudinal variations (P >0.05). In both groups, left ventricular ejection fraction measured by echocardiography ameliorated significantly at 6-month follow-up (P 0.05). When pay attention to left ventricular ejection fraction measured by angiocardiography,difference of the longitudinal variation between groups was significant (P=0.046). Early diastolic mitral flow velocity deceleration time changed significantly at 6-month follow-up in both

  7. Role of granulocyte colony-stimulating factor in paclitaxel-induced intestinal barrier breakdown and bacterial translocation in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Chi; XU Yang-guang; DUAN Xue-ning; LIU Yin-hua; ZHAO Jian-xin; XU Ling; YE Jing-ming

    2011-01-01

    Background Chemotherapy causes breakdown of the intestinal barrier, which may lead to bacterial translocation. Paclitaxel, an anti-tubulin agent, has many side effects; however, its effect on the intestinal barrier is unknown. Previous studies show that granulocyte colony-stimulating factor (G-CSF) plays an important role in modulating intestinal barrier function, but these studies are not conclusive. Here, we investigated the effects of paclitaxel on the intestinal barrier, and whether G-CSF could prevent paclitaxel-induced bacterial translocation.Methods Twenty-four male Sprague-Dawley rats were divided into three groups: control group, paclitaxel group and paclitaxel + G-CSF group. Intestinal permeability was measured by the urinary excretion rates of lactulose and mannitol administered by gavage. The mesenteric lymph nodes, spleen and liver were aseptically harvested for bacterial culture. Endotoxin levels and white blood cell (WBC) counts were measured and bacterial quantification performed using relative real-time PCR. Jejunum samples were also obtained for histological observation. Intestinal apoptosis was evaluated using a fragmented DNA assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling staining. One-way analysis of variance and Fisher's exact test were used to compare differences between groups.Results Paclitaxel induced apoptosis in 12.5% of jejunum villus cells, which was reduced to 3.8% by G-CSF treatment. Apoptosis in the control group was 0.6%. Paclitaxel treatment also resulted in villus atrophy, increased intestinal permeability and a reduction in the WBC count. G-CSF treatment resulted in increased villus height and returned WBC counts to normal levels. No bacterial translocation was detected in the control group, whereas 6/8,8/8, and 8/8 rats in the paclitaxel group were culture-positive in the liver, spleen and mesenteric lymph nodes, respectively. Bacterial translocation was

  8. Sustained in vivo activity of recombinant bovine granulocyte colony stimulating factor (rbG-CSF) using HEPES buffer.

    Science.gov (United States)

    Kasraian, K; Kuzniar, A; Earley, D; Kamicker, B J; Wilson, G; Manion, T; Hong, J; Reiber, C; Canning, P

    2001-08-01

    The purpose of this study was to develop a long-acting injectable formulation of bG-CSF for veterinary use. However, in order to achieve sustained in vivo activity it was first necessary to stabilize the protein at the injection site. Preformulation studies, as well as literature, suggest that bG-CSF aggregates at neutral pH ranges (i.e., pH 6-8) and at temperatures of approximately 40 degrees C. Therefore, bG-CSF will not retain its activity for an extended period of time at the injection site. During this study we determined that HEPES buffer has a very significant impact on protein stability as well as on biological performance. Recombinant bovine granulocyte colony stimulating factor (rbG-CSF) was formulated in 1 M HEPES buffer for subcutaneous injection into cows. bG-CSF formulated in 1 M HEPES buffer resulted in sustained in vivo activity of bG-CSF compared to the "control" formulation (control formulation: 5% mannitol, 10 mM acetate buffer, 0.004% tween-80, pH 4). White blood cell (WBC) count was used as a marker to evaluate in vivo activity of the formulation. WBC numbers remained above a threshold value for only 24-30 h for the control formula. However, when bG-CSF was formulated in 1 M HEPES, the WBC remained above threshold for 3 days or 72 h. Formulating bG-CSF in 1 M HEPES at pH 7.5 also resulted in greater solution stability. This was surprising since bG-CSF is intrinsically not stable at neutral pH. The effect of 1 M HEPES on the T(M) (temperature at maximum heat flow on calorimetry scan) of bG-CSF was determined by microcalorimetry. In the absence of 1 M HEPES buffer the T(M) was 48 degrees C (onset approximately 40 degrees C), while bG-CSF formulated in 1 M HEPES buffer has a T(M) of 59 degrees C (onset approximately 50 degrees C). Similar organic buffers, such as MOPS, HEPPS, TES, and tricine, also resulted in improved solution stability as well as in sustained in vivo activity. The dramatic effect of these buffers on stability and biological

  9. Combined treatment with erythropoietin and granulocyte colony-stimulating factor enhances neovascularization and improves cardiac function after myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    Xue Jingyi; Du Guoqing; Shi Jing; Li Yue; Masahiro Yasutake; Liu Lei; Li Jianqiang

    2014-01-01

    Background Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI).However,their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial.Therefore,we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms.Methods Four groups of rats were used:control (saline injection after MI,i.h.),EPO (a single dose of 5 000 IU/kg after MI,i.h.),G-CSF (a dose of 50 μg· kg-1· d-1 for 5 days after MI,i.h.),and both EPO and G-CSF (EPO+G-CSF,using the same regiment as above).Cardiac function was assessed by echocardiography before and 1 day,7 days,14 days and 21 days after MI.CD34+/Flk-1+ cells in the peripheral blood were evaluated by flow cytometry before and 3 days,5 days and 7 days after MI.The infarct area and angiogenesis in the peri-infarct area were analyzed.The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1α (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting.Results Compared with the control and monotherapy groups,the EPO+G-CSF group had significantly increased CD34+/ Flk-1+ endothelial progenitor calls (EPCs)in the peripheral blood (P <0.05),up-regulated VEGF and SDF-1α levels in the peri-infarct region (P <0.05),enhanced capillary density (P <0.05),reduced infarct size (P <0.05) and improved cardiac structure and function (P <0.05).G-CSF alone did not dramatically increase EPCs in the peripheral blood,enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group.Conclusions Combined treatment with EPO and G-CSF increased EPCs mobilization,up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment,subsequently enhanced

  10. Anti-obesity effects of granulocyte-colony stimulating factor in Otsuka-Long-Evans-Tokushima fatty rats.

    Directory of Open Access Journals (Sweden)

    Yonggu Lee

    Full Text Available Granulocyte-colony stimulating factor (G-CSF has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF. It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long-Evans-Tokushima fatty rats (OLETF, diabetic and 12 age-matched male Long-Evans-Tokushima rats (LETO, healthy with 200 µg/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF than saline-treated OLETF (saline/OLETF following 8 weeks of treatment (-6.9±1.6% vs. -3.1±2.2%, p<0.05. G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (-32.2±3.1% vs. -20.8±6.2%, p<0.05. Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-α were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1 expression in brown adipose tissue (BAT was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment.

  11. Bacillus cereus brain abscesses occurring in a severely neutropenic patient: successful treatment with antimicrobial agents, granulocyte colony-stimulating factor and surgical drainage.

    Science.gov (United States)

    Sakai, C; Iuchi, T; Ishii, A; Kumagai, K; Takagi, T

    2001-07-01

    Multiple brain and liver abscesses developed immediately after Bacillus cereus bacteremia in a neutropenic patient with acute lymphoblastic leukemia. After even 8 weeks of antimicrobial chemotherapy together with administration of granulocyte colony-stimulating factor, every infectious process disappeared but the patient's headache has still persisted. Because the wall of one brain abscess became thin and was in danger of rupturing into the ventricle, surgical drainage was performed, resulting in disappearance of headache and resolution of brain abscess. The present case indicates that a combined medical and surgical approach is mandatory to treat patients with brain abscesses.

  12. Granulocyte colony-stimulating factor (G-CSF protects oligodendrocyte and promotes hindlimb functional recovery after spinal cord injury in rats.

    Directory of Open Access Journals (Sweden)

    Ryo Kadota

    Full Text Available BACKGROUND: Granulocyte colony-stimulating factor (G-CSF is a protein that stimulates differentiation, proliferation, and survival of cells in the granulocytic lineage. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction and we previously reported the same effect in studies of murine spinal cord injury (SCI. The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for SCI in rats. METHODS: Adult female Sprague-Dawley rats were used in the present study. Contusive SCI was introduced using the Infinite Horizon Impactor (magnitude: 200 kilodyne. Recombinant human G-CSF (15.0 µg/kg was administered by tail vein injection at 1 h after surgery and daily the next four days. The vehicle control rats received equal volumes of normal saline at the same time points. RESULTS: Using a contusive SCI model to examine the neuroprotective potential of G-CSF, we found that G-CSF suppressed the expression of pro-inflammatory cytokine (IL-1 beta and TNF- alpha in mRNA and protein levels. Histological assessment with luxol fast blue staining revealed that the area of white matter spared in the injured spinal cord was significantly larger in G-CSF-treated rats. Immunohistochemical analysis showed that G-CSF promoted up-regulation of anti-apoptotic protein Bcl-Xl on oligpodendrocytes and suppressed apoptosis of oligodendrocytes after SCI. Moreover, administration of G-CSF promoted better functional recovery of hind limbs. CONCLUSIONS: G-CSF protects oligodendrocyte from SCI-induced cell death via the suppression of inflammatory cytokines and up-regulation of anti-apoptotic protein. As a result, G-CSF attenuates white matter loss and promotes hindlimb functional recovery.

  13. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial.

    Science.gov (United States)

    Casadevall, Nicole; Durieux, Pierre; Dubois, Stéphanie; Hemery, François; Lepage, Eric; Quarré, Marie-Catherine; Damaj, Gandhi; Giraudier, Stéphane; Guerci, Agnès; Laurent, Guy; Dombret, Hervé; Chomienne, Christine; Ribrag, Vincent; Stamatoullas, Aspasia; Marie, Jean-Pierre; Vekhoff, Anne; Maloisel, Frédéric; Navarro, Robert; Dreyfus, François; Fenaux, Pierre

    2004-07-15

    In myelodysplastic syndromes (MDS), anemia responds to recombinant human erythropoietin (rHuEPO) alone and in combination with recombinant human granulocyte-colony-stimulating factor (rHuGCSF) in 10% to 20% and in 35% to 40% of patients, respectively. We randomly divided 60 patients with low-grade anemic MDS and serum EPO levels lower than 500 IU/L (500 mU/mL) into 2 groups: rHuEPO + rHuG-CSF (arm A) and supportive care (arm B). After 12 weeks, those who had erythroid responses were given rHuEPO alone for 40 additional weeks. They were also given rHuG-CSF if they had relapses. A response was considered major if the hemoglobin (Hb) level was 115 g/L (11.5 g/dL) or higher and minor Hb increase was 15 g/L (1.5 g/dL) or more or if it remained stable without transfusion. Ten of 24 patients responded in arm A, and 0 of 26 responded in arm B (P =.01). Eight patients in arm A continued rHuEPO therapy alone, and 6 had relapses. Responses were always restored when rHuG-CSF was reintroduced. Mean direct costs per patient were 26,723 euros (arm A) and 8,746 euros (arm B). Quality of life was assessed with a Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Similar percentages of patients from both arms showed significant clinical improvement. rHuEPO plus rHuG-CSF led to responses in 41.7% of MDS patients. This treatment was expensive. No effect on quality of life was demonstrated.

  14. Granulocyte colony-stimulating factor (G-CSF) depresses angiogenesis in vivo and in vitro: implications for sourcing cells for vascular regeneration therapy.

    Science.gov (United States)

    Tura, O; Crawford, J; Barclay, G R; Samuel, K; Hadoke, P W F; Roddie, H; Davies, J; Turner, M L

    2010-07-01

    The most common source of hematopoietic progenitor cells (HPCs) for hematopoietic reconstitution comprises granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs). It has been proposed that endothelial progenitor cells (EPCs) share precursors with HPCs, and that EPC release may accompany HPC mobilization to the circulation following G-CSF administration. To investigate EPC activity following HPC mobilization, and the direct effects of exogenous G-CSF administration on human umbilical vein endothelial cells (HUVECs) and endothelial outgrowth cells (EOCs), using in vitro and in vivo correlates of angiogenesis. Heparinized venous blood samples were collected from healthy volunteers and from cord blood at parturition. G-CSF-mobilized samples were collected before administration, at apheresis harvest, and at follow-up. PBSCs were phenotyped by flow cytometry, and cultured in standard colony-forming unit (CFU)-EPC and EOC assays. The effect of exogenous G-CSF was investigated by addition of it to HUVECs and EOCs in standard tubule formation and aortic ring assays, and in an in vivo sponge implantation model. Our data show that G-CSF mobilization of PBSCs produces a profound, reversible depression of circulating CFU-EPCs. Furthermore, G-CSF administration did not mobilize CD34+CD133- cells, which include precursors of EOCs. No EOCs were cultured from any mobilized PBSCs studied. Exogenous G-CSF inhibited CFU-EPC generation, HUVEC and EOC tubule formation, microvessel outgrowth, and implanted sponge vascularization in mice. G-CSF administration depresses both endothelial cell angiogenesis and monocyte proangiogenic activity, and we suggest that any angiogenic benefit observed following implantation of cells mobilized by G-CSF may come only from a paracrine effect from HPCs.

  15. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Yuhang Li; Min Jiang; Chen Xu; Jianlin Chen; Botao Li; Jun Wang; Jiangwei Hu

    2015-01-01

    Background:Steady-state bone marrow (SS-BM) and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC) are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation.Here,we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA)-identical sibling transplantation.Methods:A total of 226 patients (acute myelogenous leukemia-complete remission 1,chronic myelogenous leukemia-chronic phase 1) received SS-BM,G-BM,or G-PBSC from an HLA-identical sibling.Clinical outcomes (graft-versus-host disease [GVHD],overall survival,transplant-related mortality [TRM],and leukemia-free survival [LFS]) were analyzed.Results:When compared to SS-BM,G-BM gave faster recovery time to neutrophil or platelet (P < 0.05).Incidence of grade Ⅲ-Ⅳ acute GVHD and extensive chronic GVHD (cGVHD) was lower than seen with SS-BM (P < 0.05) and similar to G-PBSC.Although the incidence of cGVHD in the G-BM group was similar to SS-BM,both were lower than G-PBSC (P < 0.05).G-BM and G-PBSC exhibited similar survival,LFS,and TRM,but were significantly different from SS-BM (P < 0.05).There were no significant differences in leukemia relapse rates among the groups (P > 0.05).Conclusions:G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM.We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  16. Mobilization and collection of CD34+ cells for autologous transplantation of peripheral blood hematopoietic progenitor cells in children: analysis of two different granulocyte-colony stimulating factor doses

    Directory of Open Access Journals (Sweden)

    Kátia Aparecida de Brito Eid

    2015-06-01

    Full Text Available Introduction: The use of peripheral hematopoietic progenitor cells (HPCs is the cell choice in autologous transplantation. The classic dose of granulocyte-colony stimulating factor (G- CSF for mobilization is a single daily dose of 10 µg/kg of patient body weight. There is a theory that higher doses of granulocyte-colony stimulating factor applied twice daily could increase the number of CD34+ cells collected in fewer leukapheresis procedures. Objective: The aim of this study was to compare a fractionated dose of 15 µg G-CSF/kg of body weight and the conventional dose of granulocyte-colony stimulating factor in respect to the number of leukapheresis procedures required to achieve a minimum collection of 3 × 106 CD34+ cells/kg body weight. Methods: Patients were divided into two groups: Group 10 - patients who received a single daily dose of 10 µg G-CSF/kg body weight and Group 15 - patients who received a fractioned dose of 15 µg G-CSF/kg body weight daily. The leukapheresis procedure was carried out in an automated cell separator. The autologous transplantation was carried out when a minimum number of 3 × 106 CD34+ cells/kg body weight was achieved. Results: Group 10 comprised 39 patients and Group 15 comprised 26 patients. A total of 146 apheresis procedures were performed: 110 (75.3% for Group 10 and 36 (24.7% for Group 15. For Group 10, a median of three (range: 1-7 leukapheresis procedures and a mean of 8.89 × 106 CD34+ cells/kg body weight (±9.59 were collected whereas for Group 15 the corresponding values were one (range: 1-3 and 5.29 × 106 cells/kg body weight (±4.95. A statistically significant difference was found in relation to the number of apheresis procedures (p-value <0.0001. Conclusions: To collect a minimum target of 3 × 106 CD34+ cells/kg body weight, the administration of a fractionated dose of 15 µg G-CSF/kg body weight significantly decreased the number of leukapheresis procedures performed.

  17. Erythrocytic mobilization enhanced by the granulocyte colony-stimulating factor is associated with reduced anthrax-lethal-toxin-induced mortality in mice.

    Directory of Open Access Journals (Sweden)

    Hsin-Hou Chang

    Full Text Available Anthrax lethal toxin (LT, one of the primary virulence factors of Bacillus anthracis, causes anthrax-like symptoms and death in animals. Experiments have indicated that levels of erythrocytopenia and hypoxic stress are associated with disease severity after administering LT. In this study, the granulocyte colony-stimulating factor (G-CSF was used as a therapeutic agent to ameliorate anthrax-LT- and spore-induced mortality in C57BL/6J mice. We demonstrated that G-CSF promoted the mobilization of mature erythrocytes to peripheral blood, resulting in a significantly faster recovery from erythrocytopenia. In addition, combined treatment using G-CSF and erythropoietin tended to ameliorate B. anthracis-spore-elicited mortality in mice. Although specific treatments against LT-mediated pathogenesis remain elusive, these results may be useful in developing feasible strategies to treat anthrax.

  18. Granulocyte colony-stimulating factor (G-CSF): a mediator in endometrial receptivity for a patient with polycystic ovary (PCO) undergoing in vitro maturation (IVM).

    Science.gov (United States)

    Lucena, Elkin; Moreno-Ortiz, Harold

    2013-04-18

    Proliferative and secretory changes at the endometrial lining are the result of a complex intrauterine environment where sex steroid hormones and different local factors play an important role for endometrial thickening. Optimal endometrial thickness reflects an adequate maturation which is a key factor for embryo implantation. Here, we present a case of a woman with polycystic ovary who was treated using in vitro maturation (IVM) techniques. In addition, this patient showed a dyssynchrony between the endometrial phase characterised by endometrial thinning and the embryo development which had a negative impact for embryo implantation. A protocol using uterine perfusion of granulocyte colony-stimulating factor (G-CSF) was performed as an alternative treatment for the unresponsive endometrium. We found that uterine infusion of G-CSF quickly increased endometrial thickness resulting in a successful pregnancy and healthy born baby. These results suggest that G-CSF is a factor that participates during endometrial remodelling enhancing the synchronisation between uterine environment and embryo development.

  19. Granulocyte colony-stimulating factor increases extracellular glutamic acid uptake and suppresses free radicals in an experimental model of amyotrophic lateral sclerosis

    Institute of Scientific and Technical Information of China (English)

    Shengzhe Zheng; Lei Song; Lei Lu; Lina Lin; Yao Wang; Qun Liu

    2011-01-01

    Excitatory amino acid toxicity and free radical damage play important roles in amyotrophic lateral sclerosis.Granulocyte colony-stimulating factor (G-CSF) protects nerve cells exposed to high-concentrations of glutamic acid, suggesting positive effects in the treatment of amyotrophic lateral sclerosis.The present study induced in vitro motor neuron injury using glutamic acid excitotoxicity, and the biochemical effects of G-CSF on glutamic acid concentration were determined.In addition, the effects of G-CSF on superoxide dismutase, glutathione peroxidase activity in motor neurons, and malondialdehyde and nitric oxide contents were analyzed.Immunohistochemistry was performed to measure neuronal survival.Results revealed that G-CSF significantly suppressed free radical activity, inhibited excitotoxicity, and reduced apoptosis and loss of motor neurons in the anterior horn of the spinal cord.

  20. [A case of bladder cancer producing granulocyte colony-stimulating factor and interleukin-6 causing respiratory failure treated with neoadjuvant systemic chemotherapy along with sivelestat].

    Science.gov (United States)

    Matsuzaki, Kyosuke; Okumi, Masayoshi; Kishimoto, Nozomu; Yazawa, Koji; Miyagawa, Yasushi; Uchida, Kinya; Nonomura, Norio

    2013-07-01

    A 67-year-old man visited an urological clinic with a chief complaint of urination pain. Cystourethroscopy and magnetic resonance imaging (MRI) examination revealed a bladder tumor (cT3bN0M0). Marked leukocytosis and respiratory distress with pleural effusion appeared. Pulse steroid therapy improved the general condition partially. The patient was sent to our hospital for further examination. Serum granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were high and the pathological findings of bladder tumor obtained by transurethral resection (TUR) revealed an urothelial carcinoma that produced G-CSF and IL-6. Neoadjuvant systemic chemotherapy was performed along with use of steroid and sivelestat, which ameliorated the respiratory distress. After three courses of systemic chemotherapy, serum G-CSF and IL-6 normalized and cystoprostatectomy was performed. The patient has been in good health at 20 months after the surgery with no evidence of recurrence.

  1. Changes of Circulating Platelet-Derived Growth Factor and Granulocyte Colony-Stimulating Factor in Patients with Condyloma Acuminatum

    Institute of Scientific and Technical Information of China (English)

    许冰; 胡中荣

    2002-01-01

    Objective: To study the expression levels of platelet-derivedgrowth factor (PDGF) and granulocyte colony-stimulatingfactor (G-CSF) in peripheral blood and their role in thepathogenesis of Condyloma acuminatum (CA). Methods: Sera were taken from 70 patients with Condylomaacuminatum and compared with 35 healthy controls. PDGFand G-CSF in serum were quantitated using a dual antibodysandwich enzyme-linked immunoabsorbent assay (ELISA). Results: Serum concentrations of PDGF and G-CSF weresignificantly increased in patients with Condylomaacuminatum (CA) compared to controls (P<0.001 and P<0.005respectively). Serum levels of PDGF and G-CSF correlatedwith clinical severity of CA, but no significant difference wasobserved between different duration of disease groups. Asignificant positive correlation was noticed between neutrophilcount and G-CSF levels ( γ=0.38, P<0.001), and the neutrophilcount showed no significant correlation with PDGF. Conclusion: The results indicated that increased expressionof PDGF and G-CSF in peripheral blood might be involved inpathogenesis of CA.

  2. Instent neointimal hyperplasia after percutaneous intervention for ST-elevation myocardial infarction and treatment with granulocyte-colony stimulating factor. Results from the stem cells in myocardial infarction (STEMMI) trial

    DEFF Research Database (Denmark)

    2010-01-01

    Recombinant granulocyte-colony stimulating factor (G-CSF) mobilized pluripotent cells from the bone marrow are proposed to have a regenerative potential. Though, a report of excessive instent restenosis, in patients treated with G-CSF before percutaneous coronary intervention (PCI) warrants caution....

  3. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial

    DEFF Research Database (Denmark)

    Ripa, Rasmus Sejersten; Jørgensen, Erik; Wang, Yongzhong;

    2006-01-01

    BACKGROUND: Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy...

  4. Instent neointimal hyperplasia after percutaneous intervention for ST-elevation myocardial infarction and treatment with granulocyte-colony stimulating factor. Results from the stem cells in myocardial infarction (STEMMI) trial

    DEFF Research Database (Denmark)

    Jørgensen, Erik; Baldazzi, Federica; Ripa, Rasmus S

    2010-01-01

    Recombinant granulocyte-colony stimulating factor (G-CSF) mobilized pluripotent cells from the bone marrow are proposed to have a regenerative potential. Though, a report of excessive instent restenosis, in patients treated with G-CSF before percutaneous coronary intervention (PCI) warrants caution....

  5. Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line.

    Science.gov (United States)

    Sheng, Xianfu; Zhong, Hua; Wan, Haixia; Zhong, Jihua; Chen, Fangyuan

    2016-07-01

    Combining cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF) has demonstrated marked efficacy in the treatment of elderly and relapsed/refractory patients with acute myeloid leukemia (AML); however, the role of G-CSF remains poorly understood. The present study aimed to investigate the ability of G-CSF to overcome stromal-mediated drug resistance and the underlying molecular mechanism. Two types of co-culture models were established in the HS-5 human bone marrow/stromal and HL-60 human promyelocytic leukemia cell lines, in order to imitate the interactions between stromal and leukemia cells in vitro, which is mediated by the stromal cell-derived factor (SDF)-1α signaling axis. In the present study, HL-60 cells were attracted and adhered to HS-5 cells using migration assay and flow cytometry, respectively; however, these interactions were inhibited by treatment with G-CSF and/or the C-X-C chemokine receptor type 4 (CXCR4) antagonist, AMD3100. Co-culture with HS-5 cells, including direct and indirect contact, protected HL-60 cells against spontaneous apoptosis or drug-induced apoptosis; however, these protective effects were disrupted by treatment with G-CSF and/or AMD3100. Notably, G-CSF and/or AMD3100 did not alter cell viability or apoptosis when HL-60 cells were cultured with medium alone. In addition, G-CSF significantly reduced the expression levels of surface CXCR4 protein, total CXCR4 protein and CXCR4 mRNA, and significantly upregulated the expression of microRNA (miR)-146a. Conversely, AMD3100 significantly reduced surface CXCR4 expression levels, but not the total CXCR4, CXCR4 mRNA or miR-146a expression levels. The results of the present study suggested that interfering with the CXCR4/SDF-1α signaling axis via G-CSF inhibited the migration and adhesion of HL-60 cells to HS-5 cells and eliminated HS5 cell-mediated protective effects. Furthermore, G-CSF administration reduced CXCR4 expression levels by upregulating the expression of

  6. Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial

    Science.gov (United States)

    Russell, Nigel; Douglas, Kenny; Ho, Anthony D.; Mohty, Mohamad; Carlson, Kristina; Ossenkoppele, G.J.; Milone, Giuseppe; Pareja, Macarena Ortiz; Shaheen, Daniel; Willemsen, Arnold; Whitaker, Nicky; Chabannon, Christian

    2013-01-01

    In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and myeloma whose cells mobilize poorly. The purpose of this study was to further assess the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization in European patients with lymphoma or myeloma. In this multicenter, open label, single-arm study, patients received granulocyte colony-stimulating factor (10 μg/kg/day) subcutaneously for 4 days; on the evening of day 4 they were given plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 after a morning dose of granulocyte colony-stimulating factor. The primary study objective was to confirm the safety of mobilization with plerixafor. Secondary objectives included assessment of efficacy (apheresis yield, time to engraftment). The combination of plerixafor + granulocyte colony-stimulating factor was used to mobilize hematopoietic stem cells in 118 patients (90 with myeloma, 25 with non-Hodgkin's lymphoma, 3 with Hodgkin's disease). Treatment-emergent plerixafor-related adverse events were reported in 24 patients. Most adverse events occurred within 1 hour after injection, were grade 1 or 2 in severity and included gastrointestinal disorders or injection-site reactions. The minimum cell yield (≥2×106 CD34+ cells/kg) was harvested in 98% of patients with myeloma and in 80% of those with non-Hodgkin's lymphoma in a median of one apheresis. The optimum cell dose (≥5×106 CD34+ cells/kg for non-Hodgkin's lymphoma or ≥6×106 CD34+ cells/kg for myeloma) was harvested in 89% of myeloma patients and 48% of non-Hodgkin's lymphoma patients. In this prospective, multicenter European study, mobilization with plerixafor + granulocyte colony-stimulating factor allowed the majority of patients with myeloma or non-Hodgkin's lymphoma to undergo transplantation with

  7. Effects of granulocyte-colony stimulating factor (G-CSF on diabetic cardiomyopathy in Otsuka Long-Evans Tokushima Fatty rats

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    Kim Jung-Hyun

    2011-10-01

    Full Text Available Abstract Background Diabetic cardiomyopathy (CMP is a common and disabling disease in diabetic patients, however no effective treatments have been developed. Although granulocyte-colony stimulating factor (G-CSF improves heart function in myocardial infarction, its effect on non-ischemic CMP such as diabetic CMP is unknown. In the present study, we investigated the effects of G-CSF on diabetic CMP in a rat model of type II diabetes. Methods Twenty 7-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF: a rat model of diabetes rats and 10 male Long-Evans Tokushima Otsuka (LETO: normal controls rats were used. All of the LETO and 8 OLETF rats were fed on tap water while the rest were fed on sucrose-containing water. After 10 weeks, saline or recombinant human G-CSF (100 μg/kg/day was injected intraperitoneally for 5 days. Blood levels of glucose, total cholesterol and triglyceride, and Doppler echocardiograms for diastolic dysfunction were obtained just before and 4 weeks after the saline or G-CSF treatment. Light microscopy, electron microscopy (EM and immunohistochemistry for transforming growth factor-β were employed to examine myocardial histology 4 weeks after the saline or G-CSF treatment. Results Diastolic dysfunction developed at 17 weeks (before the saline or G-CSF treatment in the OLETF rats whether or not they were fed sucrose water, but were more severe in those fed sucrose water. Four weeks after saline or G-CSF treatment, diastolic function had recovered in the G-CSF-treated group regardless of sucrose water feeding, and perivascular and/or interstitial fibrosis in the G-CSF-treated group had decreased significantly. TGF-β immunoreactivity in the interstitial and perivascular tissue was also reduced in the G-CSF-treated group, and EM studies revealed less severe disruption of myofilaments and mitochondrial cristae, and decreased collagen deposition. Conclusions G-CSF can ameliorate cardiac diastolic dysfunction and morphological

  8. Effects of recombinant human granulocyte-colony stimulating factor therapy on rat pulmonary hypertension and its influence on endothelial progenitor cells%重组人粒细胞集落刺激因子治疗大鼠肺动脉高压的效果及其对内皮祖细胞的影响

    Institute of Scientific and Technical Information of China (English)

    黄军华; 刘俊峰; 牛志浩; 李宗辉; 樊青曼

    2013-01-01

    Objective To investigate the effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) therapy on pulmonary hypertension,and its influence on number and functions of circulating endothelial progenitor cells (EPCs) in rats.Methods Eight week old Sprague-Dawlay rats were randomized into model group,treatment group and control group (8 rats in each group).The rats in model group and treatment group were treated with single subcutaneous injection of 1% monocrotaline (50 mg/kg) to induce pulmonary hypertension models,while the control group was treated with phosphate buffered saline.Five days later,the rats in treatment group were administrated with 50 μg/(kg· d) rhG-CSF for 3 days.On day 21,peripheral blood was collected from caudal vein in all groups,and the percentage of EPCs in 100 000 mononuclear cells was evaluated by flow cytometry.Right ventricular systolic pressure was assessed,and the pathological changes of lung tissue and pneumoangiogram were observed by HE staining.Meanwhile,peripheral mononuclear cells collected from caudal vein were separated and cultured in vitro for EPCs.The cell ffunctions as proliferation,adhesion and migration ability were assessed.ANOVA and LSD test were applied as statistical analysis methods.Results (1) The right ventricular systolic pressure of rats in model group was higher than that in the controls [(48.13 ± 2.85) mm Hg vs (27.88 ± 3.04) mm Hg,t=2.016,P<0.01],the lesion of endothelial cells in pulmonary arteriolar was evident,and the vessel wall was thickened.The pulmonary artery pressure of rats in the treatment group [(30.38 ± 2.83) mm Hg] was lower than that in the model group and close to the level of control group (t=0.376,P>0.05) with mild pulmonary pathological changes.(2) The percentage off peripheral blood EPCs in mononuclear cells in the model group was decreased as compared to the control group [(0.016±0.007) % vs (0.031±0.011) %,t=2.617,P<0.01].After administration ofrh

  9. Using Recombinant Human Granulocyte Colony-Stimulating Factor Plus Dexamethasone Sodium Phosphate Mobilize and Apheresis Granulocyte%重组人粒细胞集落刺激因子加地塞米松磷酸钠动员单采粒细胞

    Institute of Scientific and Technical Information of China (English)

    孙琼芝

    2013-01-01

    目的 探讨采用动员剂和血细胞分离机采集粒细胞的效果.方法 选择2011年12月至2012年9月,于本血站行无偿献血的52名献血者作为研究对象.采用重组人粒细胞集落刺激因子(G-CSF)联合地塞米松磷酸钠动员献血者外周血粒细胞,用血细胞分离机采集粒细胞,分析动员剂的动员效果及影响采集效量的因素.、结果 采用动员剂动员后,献血者外周血白细胞(WBC)和中性粒细胞计数(NEUT)分别提高了4和7倍,动员前后比较,差异有统计学意义(P<0.05).本组52份粒细胞平均采集耗时为(201±83)min,处理抗凝全血为(4209±806)mL,抗凝剂枸橼酸枸橼酸钠-葡萄糖A方用量为(394±83)mL,粒细胞制品体积为(283±46)mL,制品粒细胞含量为(2.18±0.81)×1010.女性献血者粒细胞制品含量为(1.77±0.82)×1010,男性为(2.48±0.67)×1010,男性献血者粒细胞采集量高于女性献血者(t=3.331,P=0.002),单因素线形回归分析结果显示献血者采集前血细胞比容(HCT)、血红蛋白含量(Hb)、WBC计数和NEUT水平与粒细胞采集量之间呈正相关关系(P<0.05);多因素线形回归分析结果显示粒细胞采集量与献血者采集前Hb(P=0.030)和NEUT(P=0.037)相关.结论 重组人G-CSF联合地塞米松磷酸钠能有效动员献血者外周血粒细胞,采用血细胞分离机可采集足够剂量的粒细胞用于临床输注.%Objective To explore the effect of mobilization agents and blood cell separator for apheresis granulocyte.Methods From December 2011 to September 2012,52 donors who donated blood in our station were included into this study.Recombinant human granulocyte colony-stimulating factor (G-CSF) plus dexamethasone sodium phosphate were used mobilizing donors' granulocyte,and apheresis granulocyte were performed on the blood cell separator.The mobilization effective and the factors that effected product content were analyzed.Results After using mobilizing agent,the peripheral blood

  10. Effect of recombinant human granulocyte colony-stimulating factor on bone marrow depression in breast cancer patients after the chemotherapy%重组人粒细胞集落刺激因子预防乳腺癌化疗后骨髓抑制的疗效分析

    Institute of Scientific and Technical Information of China (English)

    李娇; 张晟; 张瑾

    2014-01-01

    背景与目的:骨髓抑制是化疗最严重的不良反应,以中性粒细胞减少最常见.重组人粒细胞集落刺激因子(recombinant human granulocyte colony-stimulating factor,rhG-CSF)能诱导造血祖细胞向中性粒细胞分化,并调节中性粒细胞的功能活性,可用于肿瘤化疗后严重的中性粒细胞缺乏症,以保证原计划化疗方案的完成.本文旨在了解应用rhG-CSF治疗乳腺癌化疗后骨髓抑制的疗效以及预防性作用.方法:采用回顾性调查方法,筛选出在天津医科大学肿瘤医院进行多西紫杉醇(docetaxel) 75 mg/m2、表柔比星(epirubicin)65 mg/m2与环磷酰胺(cyclophosphamide)500 mg/m2(TEC)化疗方案的浸润性乳腺癌患者,在第1个周期末次给药后24~48 h内给予rhG-CSF为预防组,以24~48 h内未给予rhG-CSF为对照组,评估2组化疗后骨髓抑制的发生情况以及用药的安全性.结果:在预防组60例患者中,外周血白细胞(white blood cell,WBC) <4.0×109/L的发生率为25.0%,中性粒细胞绝对数(absolute neutrophil count,ANC) <2.0×109/L的发生率为23.3%;在对照组60例患者中,WBC<4.0×109/L的发生率为78.3%,ANC<2.0×109/L的发生率为73.3%,差异有统计学意义(P<0.01).2组的化疗延迟率分别为5.0%和25.0% (P=0.002),化疗延迟时间分别为(2.33±0.58)d和(3.73±0.80)d (P=0.011),差异均有统计学意义.预防组发热性中性粒细胞减少症(febrile neutropenia,FN)的发生率为1.7%,对照组FN的发生率为20%,预防组明显低于对照组(P=0.001).2组对血红蛋白(hemoglobin,Hb)与血小板(platelets,PLT)水平均无显著影响(P=0.547; P=0.285).预防组rhG-CSF用药后不良反应的发生率为8.3%,而对照组为21.6%,差异有统计学意义(P=0.041).结论:对于浸润性乳腺癌患者,在第一周期化疗后24~48 h内预防性给予rhG-CSF,能降低白细胞减少症的发生,减轻骨髓抑制的程度及持续时间,降低FN的发生风险,并且能减

  11. Controlled Release of Granulocyte Colony-Stimulating Factor Enhances Osteoconductive and Biodegradable Properties of Beta-Tricalcium Phosphate in a Rat Calvarial Defect Model

    Directory of Open Access Journals (Sweden)

    Tomohiro Minagawa

    2014-01-01

    Full Text Available Autologous bone grafts remain the gold standard for the treatment of congenital craniofacial disorders; however, there are potential problems including donor site morbidity and limitations to the amount of bone that can be harvested. Recent studies suggest that granulocyte colony-stimulating factor (G-CSF promotes fracture healing or osteogenesis. The purpose of the present study was to investigate whether topically applied G-CSF can stimulate the osteoconductive properties of beta-tricalcium phosphate (β-TCP in a rat calvarial defect model. A total of 27 calvarial defects 5 mm in diameter were randomly divided into nine groups, which were treated with various combinations of a β-TCP disc and G-CSF in solution form or controlled release system using gelatin hydrogel. Histologic and histomorphometric analyses were performed at eight weeks postoperatively. The controlled release of low-dose (1 μg and 5 μg G-CSF significantly enhanced new bone formation when combined with a β-TCP disc. Moreover, administration of 5 μg G-CSF using a controlled release system significantly promoted the biodegradable properties of β-TCP. In conclusion, the controlled release of 5 μg G-CSF significantly enhanced the osteoconductive and biodegradable properties of β-TCP. The combination of G-CSF slow-release and β-TCP is a novel and promising approach for treating pediatric craniofacial bone defects.

  12. Immunomodulation Induced by Stem Cell Mobilization and Harvesting in Healthy Donors: Increased Systemic Osteopontin Levels after Treatment with Granulocyte Colony-Stimulating Factor

    Directory of Open Access Journals (Sweden)

    Guro Kristin Melve

    2016-07-01

    Full Text Available Peripheral blood stem cells from healthy donors mobilized by granulocyte colony-stimulating factor (G-CSF and harvested by leukapheresis are commonly used for allogeneic stem cell transplantation. The frequency of severe graft versus host disease is similar for patients receiving peripheral blood and bone marrow allografts, even though the blood grafts contain more T cells, indicating mobilization-related immunoregulatory effects. The regulatory phosphoprotein osteopontin was quantified in plasma samples from healthy donors before G-CSF treatment, after four days of treatment immediately before and after leukapheresis, and 18–24 h after apheresis. Myeloma patients received chemotherapy, combined with G-CSF, for stem cell mobilization and plasma samples were prepared immediately before, immediately after, and 18–24 h after leukapheresis. G-CSF treatment of healthy stem cell donors increased plasma osteopontin levels, and a further increase was seen immediately after leukapheresis. The pre-apheresis levels were also increased in myeloma patients compared to healthy individuals. Finally, in vivo G-CSF exposure did not alter T cell expression of osteopontin ligand CD44, and in vitro osteopontin exposure induced only small increases in anti-CD3- and anti-CD28-stimulated T cell proliferation. G-CSF treatment, followed by leukapheresis, can increase systemic osteopontin levels, and this effect may contribute to the immunomodulatory effects of G-CSF treatment.

  13. Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia.

    Science.gov (United States)

    Mohammadzadeh, L; Samedanifard, S H; Keshavarzi, A; Alimoghaddam, K; Larijani, B; Ghavamzadeh, A; Ahmadi, A S; Shojaeifard, A; Ostadali, M R; Sharifi, A M; Amini, M R; Mahmoudian, A; Fakhraei, H; Aalaa, M; Mohajeri-Tehrani, M R

    2013-01-01

    The efficacy and safety of transplanting autologous mesenchymal stem cells (MSCs), from granulocyte-colony-stimulating factor (G-CSF)-mobilised peripheral blood, was investigated in diabetic patients with critical limb ischaemia (CLI). After 3 months, the transplanted group of patients (n=7) showed a significant improvement in ischaemia manifestations, including pain and neurological signs, wound healing and the rate of lower-limb amputation, compared to the control group of patients (n=14). Pain was significantly reduced in the transplanted group compared to controls (P=0.014). The ankle-brachial index (ABI) and the pulse strength within ischaemic tissues of the transplanted group were significantly improved (P=0.035 and P=0.01, respectively). Importantly, 50% of the control group (7/14 patients) faced major amputation of a limb at the study's conclusion, compared to none of 7 patients in the transplanted group (P=0.047). The safety of transplantation was confirmed by observing no adverse reactions among the transplanted group, including infection and immunological rejection. Hence, this study provides further evidence that transplantation of autologous peripheral blood MSCs, mobilised by G-CSF, induces angiogenesis and improves the wound healing process in diabetic patients with CLI.

  14. Effect of granulocyte colony-stimulating factor mobilization on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire.

    Science.gov (United States)

    Xuan, Li; Wu, Xiuli; Wu, Meiqing; Zhang, Yu; Liu, Hui; Fan, Zhiping; Sun, Jing; Liu, Qifa

    2012-08-01

    The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recently, αβ(+) T cells are identified as the primary effector cells for GVHD. However, whether G-CSF could influence the repertoire of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes remains unclear. To further characterize this feature, we investigated the effect of G-CSF mobilization on the T cell receptors (TCR) of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes, as well as the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT. We found that G-CSF mobilization had an effect on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire. This alteration might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT. Copyright © 2012 Elsevier GmbH. All rights reserved.

  15. The Effect of Recombinant Granulocyte Colony-Stimulating Factor on Oral and Periodontal Manifestations in a Patient with Cyclic Neutropenia: A Case Report

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    Sergio Matarasso

    2009-01-01

    Full Text Available Cyclic Neutropenia (CN is characterized by recurrent infections, fever, oral ulcerations, and severe periodontitis as result of the reduced host defences. The previous studies have established the effectiveness of recombinant granulocyte colony-stimulating factor (GCSF to increase the number and the function of neutrophils in the peripheral blood in this disease. In a 20-year-old Caucasian female with a diagnosis of cyclic neutropenia, oral clinical examination revealed multiple painful ulcerations of the oral mucosa, poor oral hygiene conditions, marginal gingivitis, and moderate periodontitis. The patient received a treatment with G-CSF (Pegfilgrastim, 6 mg/month in order to improve her immunological status. Once a month nonsurgical periodontal treatment was carefully performed when absolute neutrophil count (ANC was ≥500/L. The treatment with G-CSF resulted in a rapid increase of circulating neutrophils that, despite its short duration, leaded to a reduction in infection related events and the resolution of the multiple oral ulcerations. The disappearance of oral pain allowed an efficacy nonsurgical treatment and a normal tooth brushing that determined a reduction of probing depth (PD≤4 mm and an improvement of the oral hygiene conditions recorded at 6-month follow-up.

  16. Evaluating the effects of buffer conditions and extremolytes on thermostability of granulocyte colony-stimulating factor using high-throughput screening combined with design of experiments.

    Science.gov (United States)

    Ablinger, Elisabeth; Hellweger, Monika; Leitgeb, Stefan; Zimmer, Andreas

    2012-10-15

    In this study, we combined a high-throughput screening method, differential scanning fluorimetry (DSF), with design of experiments (DoE) methodology to evaluate the effects of several formulation components on the thermostability of granulocyte colony stimulating factor (G-CSF). First we performed a primary buffer screening where we tested thermal stability of G-CSF in different buffers, pH values and buffer concentrations. The significance of each factor and the two-way interactions between them were studied by multivariable regression analysis. pH was identified as most critical factor regarding thermal stability. The most stabilizing buffer, sodium glutamate, and sodium acetate were determined for further investigations. Second we tested the effect of 6 naturally occurring extremolytes (trehalose, sucrose, ectoine, hydroxyectoine, sorbitol, mannitol) on the thermal stability of G-CSF, using a central composite circumscribed design. At low pH (3.8) and low buffer concentration (5 mM) all extremolytes led to a significant increase in thermal stability except the addition of ectoine which resulted in a strong destabilization of G-CSF. Increasing pH and buffer concentration led to an increase in thermal stability with all investigated extremolytes. The described systematic approach allowed to create a ranking of stabilizing extremolytes at different buffer conditions. Copyright © 2012. Published by Elsevier B.V.

  17. Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF is neuroprotective after retinal ganglion cell axotomy

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    Dietz Gunnar PH

    2009-05-01

    Full Text Available Abstract Background The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC axotomy model to compare effects of local and systemic application of neuroprotective molecules. Results We found that the G-CSF receptor is robustly expressed by RGCs in vivo and in vitro. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs in vitro. Conclusion We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.

  18. Administration of granulocyte colony stimulating factor after liver transplantation leads to an increased incidence and severity of ischemic biliary lesions in the rat model

    Institute of Scientific and Technical Information of China (English)

    Olaf Dirsch; Haidong Chi; Yuan Ji; Yan Li Gu; Christoph E Broelsch; Uta Dahmen

    2006-01-01

    AIM: Recently it has been reported that granulocyte colony stimulating factor (G-CSF) can induce hypercoagulability in healthy bone marrow donors. It is conceivable that the induction of a prothrombotic state in a recipient of an organ graft with already impaired perfusion might cause further deterioration in the transplanted organ. This study evaluated whether G-CSF treatment worsens liver perfusion following liver transplantation in the rat model.METHODS: A non-arterialized rat liver transplantation model was employed to evaluate the effect of G-CSF treatment on the liver in a syngeneic and allogeneic strain combination. Study outcomes included survival time and liver damage as investigated by liver enzymes and liver histology. Observation times were 1 d, 1 wk and 12 wk.RESULTS: Rats treated with G-CSF had increased incidence and severity of biliary damage following liver transplantation. In these animals, hepatocellular necrosis was accentuated in the centrilobular region. These lesions are indicative of impaired perfusion in G-CSF treated animals.CONCLUSION: G-CSF should be used with caution in recipients of liver transplantation, as treatment might enhance preexisting, undetected perfusion problems and ultimately lead to ischemia induced biliary complications.

  19. Tongue squamous cell carcinoma producing both parathyroid hormone-related protein and granulocyte colony-stimulating factor: a case report and literature review.

    Science.gov (United States)

    Kaneko, Naoki; Kawano, Shintaro; Matsubara, Ryota; Goto, Yuichi; Jinno, Teppei; Maruse, Yasuyuki; Sakamoto, Taiki; Hashiguchi, Yuma; Iida, Masakazu; Nakamura, Seiji

    2016-06-17

    Paraneoplastic syndrome generally results from tumor-derived hormones or peptides that cause metabolic derangements. Common metabolic conditions include hyponatremia, hypercalcemia, hypoglycemia, and Cushing's syndrome. Herein, we report a very rare case of tongue carcinoma presenting with leukocytosis and hypercalcemia. A 57-year-old man was admitted to our hospital with tongue squamous cell carcinoma (cT4aN0M0, stage IV). He underwent radical resection following preoperative chemoradiotherapy, but locoregional recurrence was detected 2 months after surgery. He presented with marked leukocytosis and hypercalcemia with elevated serum levels of granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). He was therefore managed with intravenous fluids, furosemide, prednisolone, elcatonin, and pamidronate. However, the patient died 1 month later of carcinomatous pleuritis following distant metastasis to the lung. Immunohistochemical analyses of the resected specimens revealed positive staining for PTHrP and G-CSF in the cancer cells. In this case, it was considered that tumor-derived G-CSF and PTHrP caused leukocytosis and hypercalcemia.

  20. Evaluation of a biosimilar granulocyte colony-stimulating factor (filgrastim XM02) for peripheral blood stem cell mobilization and transplantation: a single center experience in Japan

    Science.gov (United States)

    Yoshimura, Hideaki; Hotta, Masaaki; Nakanishi, Takahisa; Fujita, Shinya; Nakaya, Aya; Satake, Atsushi; Ito, Tomoki; Ishii, Kazuyoshi; Nomura, Shosaku

    2017-01-01

    Background Biosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context. Materials and methods The subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim. Results There were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation. Conclusion Biosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs. PMID:28182150

  1. Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.

    Science.gov (United States)

    Huston, Marshall W; Riegman, Adriaan R A; Yadak, Rana; van Helsdingen, Yvette; de Boer, Helen; van Til, Niek P; Wagemaker, Gerard

    2014-10-01

    Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.

  2. Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats

    Institute of Scientific and Technical Information of China (English)

    Celal Cerci; Cagri Ergin; Erol Eroglu; Canan Agalar; Fatih Agalar; Sureyya Cerci; Mahmut Bulbul

    2007-01-01

    AIM: To investigate the effects of granulocyte-colony stimulating factor (G-CSF) on peritoneal defense mechanisms and bacterial translocation after systemic 5-Fluorouracil (5-FU) administration.METHODS: Thirty Wistar albino rats were divided into three groups; the control, 5-FU and 5-FU + G-CSF groups. We measured bactericidal activity of the peritoneal fluid, phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, total peritoneal cell counts and cell types of peritoneal washing fluid.Bacterial translocation was quantified by mesenteric lymph node, liver and spleen tissue cultures.RESULTS: Systemic 5-FU reduced total peritoneal cell counts, neutrophils and macrophage numbers. It also altered bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. 5-FU also caused significant increase in frequencies of bacterial translocation at the liver and mesenteric lymph nodes. G-CSF decreased bacterial translocation, it significantly enhanced bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. It also increased total peritoneal cell counts, neutrophils and macrophage numbers.CONCLUSION: Systemic 5-FU administration caused bacterial translocation, decreased the bactericidal activity of peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. G-CSF increased both bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, and prevented the bacterial translocation. We conclude that intraperitoneal GCSF administration protects the effects of systemic 5-FU on peritoneal defense mechanisms.

  3. Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury

    Directory of Open Access Journals (Sweden)

    Hock-Kean Liew

    2015-01-01

    Full Text Available Granulocyte-colony stimulating factor (G-CSF protects brain from ischemic/reperfusion (I/R injury, and inhibition of nitric oxide (NO synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF and neurological deficit. Endothelin-1 (ET-1 microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion within the striatal region. Regional NO concentration increased rapidly (NO surge during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-NG-Nitroarginine Methyl Ester (L-NAME significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury.

  4. The effect of repeated administrations of granulocyte colony stimulating factor for blood stem cells mobilization in patients with progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy.

    Science.gov (United States)

    Pezzoli, Gianni; Tesei, Silvana; Canesi, Margherita; Sacilotto, Giorgio; Vittorio, Montefusco; Mizuno, Yoshi; Mochizuki, Hideki; Antonini, Angelo

    2010-01-01

    Granulocyte colony stimulating factor (GCSF) may boost physiological stem cell repair system in patients with cerebral lesions. Atypical parkinsonisms (PSP, CBD, MSA) are characterized by rapidly progressive course without significant benefit from current therapies. We treated 11 patients with atypical parkinsonism (MSA n=4, PSP n=5, CBD n=2) with GCSF (5mcg/kg s.c. daily for 6 days/month) for 3 months. We assessed CBC, CD34+ cells, routine biochemical and coagulation tests, UPDRS motor scores and safety. We did not observe significant adverse events during and following GCSF treatment. One patient withdrew informed consent. Three patients complained about bone pain that improved following steroid treatment. Four patients perceived a subjective benefit after treatment was completed. UPDRS motor score improved in three patients, remained stable in two and worsened in five. GCSF can be safely administered to patients with atypical parkinsonism and potentially meaningful clinical changes may be observed in some patients. These results are encouraging and warrant further studies. 2009 Elsevier B.V. All rights reserved.

  5. Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony stimulating factor.

    Science.gov (United States)

    Takeuchi, N; Hayashi, Y; Murakami, M; Alvarez, F J; Horibe, H; Iohara, K; Nakata, K; Nakamura, H; Nakashima, M

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) has been shown to have combinatorial trophic effects with dental pulp stem cells for pulp regeneration. The aim of this investigation is to examine the effects of basic fibroblast growth factor (bFGF) in vitro and in vivo compared with those of G-CSF and to assess the potential utility of bFGF as an alternative to G-CSF for pulp regeneration. Five different types of cells were examined in the in vitro effects of bFGF on cell migration, proliferation, anti-apoptosis, neurite outgrowth, angiogenesis, and odontogenesis compared with those of G-CSF. The in vivo regenerative potential of pulp tissue including vasculogenesis and odontoblastic differentiation was also compared using an ectopic tooth transplantation model. Basic fibroblast growth factor was similar to G-CSF in high migration, proliferation and anti-apoptotic effects and angiogenic and neurite outgrowth stimulatory activities in vitro. There was no significant difference between bFGF and G-CSF in the regenerative potential in vivo. The potential utility of bFGF for pulp regeneration is demonstrated as a homing/migration factor similar to the influence of G-CSF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing.

    Science.gov (United States)

    Maris, Michael B; Sandmaier, Brenda M; Storer, Barry E; Maloney, David G; Shizuru, Judith A; Agura, Edward; Kliem, Constanze; Pulsipher, Michael; Maziarz, Richard T; McSweeney, Peter A; Wade, James; Langston, Amelia A; Chauncey, Thomas R; Bruno, Benedetto; Blume, Karl G; Storb, Rainer

    2006-04-01

    We previously reported results in 71 patients with advanced hematologic malignancies given HLA-matched unrelated granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts after fludarabine 90 mg/m(2), 2 Gy of total body irradiation, and postgrafting mycophenolate mofetil (MMF) 15 mg/kg twice daily and cyclosporine 6.25 mg/kg twice daily orally. Graft rejection was 15%; the cumulative probability of acute graft-versus-host disease (GVHD) was 52%. According to MMF pharmacokinetic studies, which showed a short half-life of its active metabolite, mycophenolic acid, we increased MMF dosing from 15 mg/kg twice daily to 15 mg/kg 3 times daily to increase immunosuppression and reduce the incidence of both graft rejection and acute GVHD. Among 103 patients so treated, graft rejection occurred in 5%, whereas acute GVHD remained at 53%. Outcomes were compared with results of previous G-PBMC recipients given MMF twice daily. Infection rates were slightly higher with MMF 3 times daily than with MMF twice daily. Nevertheless, 2-year nonrelapse mortality and overall and progression-free survivals were similar for MMF 3-times-daily and twice-daily patients (19%, 58%, and 49% versus 20%, 48%, and 37%, respectively). Nonmyeloablative conditioning with postgrafting cyclosporine and MMF given 3 times daily allowed 95% durable engraftment of unrelated donor G-PBMC grafts.

  7. Effectiveness of daily versus non-daily granulocyte colony-stimulating factors in patients with solid tumours undergoing chemotherapy: a multivariate analysis of data from current practice

    Science.gov (United States)

    Almenar Cubells, D; Bosch Roig, C; Jiménez Orozco, E; Álvarez, R; Cuervo, JM; Díaz Fernández, N; Sánchez Heras, AB; Galán Brotons, A; Giner Marco, V; Codes M De Villena, M

    2013-01-01

    We conducted a multicentre, retrospective, observational study including patients with solid tumours (excluding breast cancer) that received granulocyte colony-stimulating factors (G-CSF) and chemotherapy. We investigated the effectiveness of daily vs. non-daily G-CSFs (pegfilgrastim) adjusting by potential confounders. The study included 391 patients (211 daily G-CSF; 180 pegfilgrastim), from whom 47.3% received primary prophylaxis (PP) (57.8% pegfilgrastim), 26.3% secondary prophylaxis (SP: initiation after cycle 1 and no reactive treatment in any cycle) (51.5% pegfilgrastim) and 26.3% reactive treatment (19.4% pegfilgrastim). Only 42.2% of patients with daily G-CSF and 46.2% with pegfilgrastim initiated prophylaxis within 72 h after chemotherapy, and only 10.5% of patients with daily G-CSF received it for ≥7 days. In the multivariate models, daily G-CSF was associated with higher risk of grade 3-4 neutropenia (G3-4N) vs. pegfilgrastim [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.004–2.97]. Relative to SP, PP protected against G3-4N (OR for SP vs. PP: 6.0, 95%CI: 3.2–11.4) and febrile neutropenia (OR: 3.1, 95%CI: 1.1–8.8), and was associated to less chemotherapy dose delays and reductions (OR for relative dose intensity neutropenia and its related events in the clinical practice. PMID:23331323

  8. Granulocyte colony-stimulating factor mobilized CFU-F can be found in the peripheral blood but have limited expansion potential.

    Science.gov (United States)

    Lund, Troy C; Tolar, Jakub; Orchard, Paul J

    2008-06-01

    Bone marrow mesenchymal stem cells are multipotent cells found lining the bone marrow cavity supporting the growth and differentiation of hematologic progenitors. There is growing evidence that these cells can, under the right circumstances, enter the peripheral circulation. We show that granulocyte colony-stimulating factor mobilized peripheral blood contains cells which form colonies and have a similar fibroblastic morphology (termed CFU-F) to bone marrow mesenchymal stem cells. These cells were found at a very low incidence (0.0002%). Mobilized peripheral blood CFU-F were successfully differentiated into osteogenic and adipogenic lineages. FACS analysis showed that the cells had a similar profile to bone marrow mesenchymal stem cells. Importantly, mobilized peripheral blood CFU-F had limited expansion potential and became senescent 20-25 days after isolation. Mobilized peripheral blood CFU-F also did not have any telomerase activity and displayed significant telomere shortening. The rarity of CFU-F in mobilized peripheral blood and the subsequent pressure to divide in cell culture probably contribute to early cellular senescence. Their potential for use in transplant or gene therapy is, therefore, limited.

  9. Granulocyte Colony Stimulating Factor and MT1-MMP Involved in Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

    Institute of Scientific and Technical Information of China (English)

    Su-zhen GUO; Andres J. Espinoza; Christian A. Espinoza; Terence M. Doherty; Xiao WANG

    2009-01-01

    Objectives Genetic deficiency of macrophage colony stimulating factor (M-CSF) in atherosclerosis-prone (apoE-/-) mice markedly reduces formation of atheroma. But Little is known about the potential effects of other colony stimulating factors(CSF), such as granulocyte CSF(G-CSF), on atherosclerosis. This study tested the hypothesis that G-CSF would be involved in development of atherosclerotic plaque. Methods apoE-/- mice fed with a Western-style diet (0.15% cholesterol) were injected subcutaneously with recombinant human G-CSF(10 mg/day) daily for 9 weeks then sacrificed. The matrix metalloproteinase(MMP)2 and MMP9 in serum of mice were measured by Gelatin Zymography analysis and c-kit and membrane type1-MMP(MT1-MMP) antigens were detected using fluorescence activated cell sorting (FACS). Meanwhile, complete blood counts (CBC) and serum cholesterol, relative fractions of VLDL,LDL, and HDL were evaluated by spectrophotometric techniques and high performance liquid chromatography (HPLC)respectively. Atherosclerotic Lesions of the aorta were also analyzed by histological methods. Results G-CSF treatment resulted in increased proportions of circulating monocytes (6.9±2.2% vs.3.8±0.3%;P<0.05), and decreased serum levels of total cholesterol (1225±594 vs.1991±1009;P<0.005) compared to control mice. A greater proportion of bone marrow cells from G-CSF treated mice expressed MT1-MMP (14.5±5.5% vs.6.2±5.0%, P<0.05) compared to bone marrow cells from vehicle treated mice. G-CSF treatment was also associated with smaller atheromatous plaque, and decreased oil red O staining. Conclusions G-CSF lowers serum cholesterol, increases circulating monocytes, increases bone marrow cell expression of MT1-MMP, inhibits plaque development, and decreases lipid and macrophage infiltration into developing plaque.

  10. Studies on pharmacodynamics, pharmacology, and toxicology of recombinant human serum albumin/granulocyte colony-stimulating factor fusion protein%重组人血清白蛋白/粒细胞刺激因子融合蛋白的药效学、药理学和毒理学研究

    Institute of Scientific and Technical Information of China (English)

    富岩; 尹丽莉; 顾静良; 马宪梅; 左从林; 于在林

    2012-01-01

    围内对狗呼吸和心血管系统无明显影响.实验表明 rHSA/GCSF单次皮下和静脉注射给予小鼠的最大耐受量(MTD)≥37.5 mg/kg,单次皮下注射给予食蟹猴的最大耐受剂量为 11.6 mg/kg;长期反复给药对大鼠的基本安全剂量为300 μg/kg,对食蟹猴则是≥ 150 μg/kg.结论 rHSA/GCSF 融合蛋白每 4 天给药 1 次,对放、化疗所致的动物外周血白细胞减少症具有治疗作用,与市售常规 rhGCSF 每天注射 1 次相比具有长效作用.所获得的大量药效学、药代动力学、毒理学、毒代动力学的试验数据可供正在开展的临床试验研究参考,并具有很好的指导意义.%Objective To examine the pharmacodynamics, pharmacology and toxicology of recombinant serum human albumin/granulocyte colony-stimulating factor fusion protein (rHSA/GCSF), and to obtain the pharmacokinetics and toxicokinetics data for directing the ongoing human clinical trials. Methods The rhesus monkey bone marrow cells were used for in vitro pharmacodynamics studies and the colony form unit-granulocyte macrophage (CFU-GM) numbers were counted to evaluate the influence of rHSA/GCSF. The therapeutic efficacy of rHSA/GCSF on leucopenia in mice and monkeys caused by radiation or injection of fluorouracil were evaluated. For pharmacologic study. The influence of rHSA/GCSF on central nervous system of mice and respiratory and cardiovascular systems of dogs were observed. Through acute and chronic toxicity studies, safety evaluation about rHSA/GCSF was performed in mice, rats and cynomolgus monkeys. The pharmacokinetics /toxicokinetics studies were performed to examine the PK parameters and the tissue distributions in above indicated animals. Results rHSA/GCSF stimulated the proliferation in granulocytic series of bone marrow and increased the neutrophile granulocytes. rHSA/GCSF had obvious effects on leucopenia in mice caused by fluorouracil. In the early stage of chemotherapy, it slowed down the reduction

  11. pH responsive granulocyte colony-stimulating factor variants with implications for treating Alzheimer's disease and other central nervous system disorders.

    Science.gov (United States)

    Heinzelman, Pete; Schoborg, Jennifer A; Jewett, Michael C

    2015-10-01

    Systemic injection of granulocyte colony-stimulating factor (G-CSF) has yielded encouraging results in treating Alzheimer's Disease (AD) and other central nervous system (CNS) disorders. Making G-CSF a viable AD therapeutic will, however, require increasing G-CSF's ability to stimulate neurons within the brain. This objective could be realized by increasing transcytosis of G-CSF across the blood brain barrier (BBB). An established correlation between G-CSF receptor (G-CSFR) binding pH responsiveness and increased recycling of G-CSF to the cell exterior after endocytosis motivated development of G-CSF variants with highly pH responsive G-CSFR binding affinities. These variants will be used in future validation of our hypothesis that increased BBB transcytosis can enhance G-CSF therapeutic efficacy. Flow cytometric screening of a yeast-displayed library in which G-CSF/G-CSFR interface residues were mutated to histidine yielded a G-CSF triple His mutant (L109H/D110H/Q120H) with highly pH responsive binding affinity. This variant's KD, measured by surface plasmon resonance (SPR), increases ∼20-fold as pH decreases from 7.4 to below histidine's pKa of ∼6.0; an increase 2-fold greater than for previously reported G-CSF His mutants. Cell-free protein synthesis (CFPS) enabled expression and purification of soluble, bioactive G-CSF triple His variant protein, an outcome inaccessible via Escherichia coli inclusion body refolding. This purification and bioactivity validation will enable future identification of correlations between pH responsiveness and transcytosis in BBB cell culture model and animal experiments. Furthermore, the library screening and CFPS methods employed here could be applied to developing other pH responsive hematopoietic or neurotrophic factors for treating CNS disorders.

  12. The efficacy of intrauterine instillation of granulocyte colony-stimulating factor in infertile women with a thin endometrium: A pilot study.

    Science.gov (United States)

    Lee, Dayong; Jo, Jae Dong; Kim, Seul Ki; Jee, Byung Chul; Kim, Seok Hyun

    2016-12-01

    The study aimed to investigate the efficacy of intrauterine instillation of granulocyte colony-stimulating factor (G-CSF) on the day of ovulation triggering or oocyte retrieval in infertile women with a thin endometrium. Fifty women whose endometrial thickness (EMT) was ≤8 mm at the time of triggering during at least one previous in vitro fertilization (IVF) cycle and an index IVF cycle were selected. On the day of triggering (n=12) or oocyte retrieval (n=38), 300 µg of G-CSF was instilled into the uterine cavity. In the 50 index IVF cycles, the mean EMT was 7.2±0.6 mm on the triggering day and increased to 8.5±1.5 mm on the embryo transfer day (p<0.001). The overall clinical pregnancy rate was 22.0%, the implantation rate was 15.9%, and the ongoing pregnancy rate was 20%. The clinical pregnancy rate (41.7% vs. 15.8%), the implantation rate (26.7% vs. 11.7%), and the ongoing pregnancy rate (41.7% vs. 13.2%) were higher when G-CSF was instilled on the triggering day than when it was instilled on the retrieval day, although this tendency was likewise not statistically significant. Aspects of the stimulation process and mean changes in EMT were similar in women who became pregnant and women who did not. Intrauterine instillation of G-CSF enhanced endometrial development and resulted in an acceptable pregnancy rate. Instillation of G-CSF on the triggering day showed better outcomes. G-CSF instillation should be considered as a strategy for inducing endometrial growth and good pregnancy results in infertile women with a thin endometrium.

  13. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

    NARCIS (Netherlands)

    F. Dong (Fan); R.K. Brynes; N. Tidow; K. Welte (Karl); B. Löwenberg (Bob); I.P. Touw (Ivo)

    1995-01-01

    textabstractIn severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulati

  14. NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke.

    Science.gov (United States)

    Cui, Lili; Duchamp, Nicolas S; Boston, Dakota J; Ren, Xuefang; Zhang, Xiangjian; Hu, Heng; Zhao, Li-Ru

    2015-01-01

    Chronic stroke is the phase of brain recovery and repair generally beginning 3 months after stroke onset. No pharmaceutical approach is currently available to enhance brain repair in chronic stroke. We have previously determined the therapeutic effects of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) alone or in combination (SCF+G-CSF) in an animal model of chronic stroke and demonstrated that only SCF+G-CSF induces long-term functional recovery. However, the mechanism underlying the SCF+G-CSF-induced brain repair in chronic stroke remains largely elusive. In the present study, we determined the role of nuclear factor-kappa B (NF-κB) in neurovascular network remodeling and motor function improvement by SCF+G-CSF treatment in chronic stroke. SCF+G-CSF was subcutaneously administered for 7 days beginning 17 weeks after induction of experimental stroke. To inhibit NF-κB activation, NF-κB inhibitor was infused into the brain before SCF+G-CSF treatment. We observed that NF-κB inhibitor abolished the SCF+G-CSF-induced axonal sprouting, synaptogenesis and angiogenesis in the ipsilesional somatosensorimotor cortex. In addition, blockage of NF-κB activation resulted in elimination of the SCF+G-CSF-induced motor functional restoration in chronic stroke. These data suggest that NF-κB is required for the SCF+G-CSF-induced neuron-vascular network remodeling in the ipsilesional somatosensorimotor cortex and motor functional recovery in chronic stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Combined therapy with sitagliptin plus granulocyte-colony stimulating factor in patients with acute myocardial infarction - Long-term results of the SITAGRAMI trial.

    Science.gov (United States)

    Gross, Lisa; Theiss, Hans Diogenes; Grabmaier, Ulrich; Adrion, Christine; Mansmann, Ulrich; Sohn, Hae-Young; Hoffmann, Ellen; Steinbeck, Gerhard; Franz, Wolfgang-Michael; Brenner, Christoph

    2016-07-15

    Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. The median [IQR] follow-up duration was 4.50 [3.56-5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28-1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48-1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Stem cell mobilisation by granulocyte-colony stimulating factor in patients with acute myocardial infarction. Long-term results of the REVIVAL-2 trial.

    Science.gov (United States)

    Steppich, Birgit; Hadamitzky, Martin; Ibrahim, Tareq; Groha, Philip; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Kastrati, Adnan; Ott, Ilka

    2016-04-01

    Treatment with granulocyte-colony stimulating factor (G-CSF) mobilises cells from the bone marrow to the peripheral blood. Previous preclinical and early clinical trials may suggest that treatment with G-CSF leads to improved myocardial perfusion and function in acute or chronic ischaemic heart disease. In the REVIVAL-2 study we found that stem cell mobilisation by G-CSF does not influence infarct size, left ventricular function and coronary restenosis in patients with acute myocardial infarction (MI) that underwent successful percutaneous coronary intervention. The objective of the present analysis was to assess the impact of G-CSF treatment on seven-year clinical outcomes from the REVIVAL-2 trial. In the randomized, double-blind, placebo-controlled REVIVAL-2 study, 114 patients with the diagnosis of acute myocardial infarction were enrolled five days after successful reperfusion by percutaneous coronary intervention. Patients were assigned to receive 10 µg/kg G-CSF (n=56) or placebo (n=58) for five days. The primary endpoint for this long-term outcome analysis was the composite of death, myocardial infarction or stroke seven years after randomisation. The endpoint occurred in 14.3 % of patients in the G-CSF group versus 17.2 % assigned to placebo (p=0.67). The combined incidence of death or myocardial infarction occurred in 14.3 % of the patients assigned to G-CSF and 15.5 % of the patients assigned to placebo (p=0.85). In conclusion, these long-term follow-up data show that G-CSF does not improve clinical outcomes of patients with acute myocardial infarction.

  17. Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial.

    Science.gov (United States)

    England, Timothy J; Abaei, Maryam; Auer, Dorothee P; Lowe, James; Jones, D Rhodri E; Sare, Gillian; Walker, Marion; Bath, Philip M W

    2012-02-01

    Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34(+) peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. G-CSF (10 μg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34(+) count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34(+) cells reinjected on day 6. Sixty patients were recruited at mean of 8 days (SD ± 5) post ictus, with mean age 71 years (± 12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3 ± 1.3, placebo 3.0 ± 1.3) at 90 days, or the number of injections received. G-CSF increased CD34(+) and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF-treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34(+) cells had migrated to the ischemic lesion. This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34(+) cells in patients with ischemic stroke. URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619.

  18. Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers.

    Science.gov (United States)

    Hassfurther, Renee L; TerHune, Terry N; Canning, Peter C

    2015-03-01

    To evaluate effects of various doses of polyethylene glycol (PEG)-conjugated bovine granulocyte colony-stimulating factor (bG-CSF) on the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. 211 periparturient Holstein cows and heifers. Approximately 7 days before the anticipated date of parturition (day of parturition = day 0), healthy cattle received SC injections of sterile saline (0.9% NaCl) solution (control treatment) or PEG-bG-CSF at 5, 10, or 20 μg/kg. Cattle were commingled and housed in a pen with dirt flooring, which was kept wet to maximize the incidence of naturally occurring clinical mastitis. Within 24 hours after parturition, each animal again received the assigned treatment. Mammary glands and milk were visually scored for abnormalities twice daily for 28 days after parturition. Milk samples were aseptically collected from mammary glands with an abnormal appearance or abnormal milk and submitted for microbial culture. Daily milk production was recorded, and milk composition was assessed on days 3, 5, 7, and 10. Cattle treated with PEG-bG-CSF at 10 and 20 μg/kg had significantly fewer cases of clinical mastitis (9/54 and 5/53, respectively), compared with control cattle (18/53). Administration of PEG -bG-CSF did not significantly affect daily milk production or milk composition. Results suggested that PEG-bG-CSF was effective for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. Further investigations of the use of PEG-bG-CSF as a potential preventative intervention should be conducted.

  19. 9- and 13-Hydroxy-octadecadienoic acids (9+13 HODE) are inversely related to granulocyte colony stimulating factor and IL-6 in runners after 2h running.

    Science.gov (United States)

    Nieman, David C; Meaney, Mary Pat; John, Casey S; Knagge, Kevin J; Chen, Huiyuan

    2016-08-01

    This study utilized a pro-inflammatory exercise mode to explore potential linkages between increases in 9- and 13-hydroxy-octadecadienoic acid (9+13 HODE) and biomarkers for inflammation, oxidative stress, and muscle damage. Male (N=10) and female (N=10) runners ran at ∼70% VO2max for 1.5h followed by 30min of downhill running (-10%). Blood samples were taken pre-run and immediately-, 1-h-, and 24-h post-run, and analyzed for 9+13 HODE, F2-isoprostanes, six cytokines, C-reactive protein (CRP), creatine kinase (CK), and myoglobin (MYO). Gender groups performed at comparable relative heart rate and oxygen consumption levels during the 2-h run. All outcome measures increased post-run (time effects, P⩽0.001), with levels near pre-run levels by 24h except for CRP, CK, MYO, and delayed onset of muscle soreness (DOMS). Plasma 9+13 HODE increased 314±38.4% post-run (Prun (Pincreased 50.8±8.9% post-run (Prun (P=0.006). Post-run increases were comparable between genders for all outcomes except for 9+13 HODE (interaction effect, P=0.024, post-run tending higher in females), IL-10 (P=0.006, females lower), and DOMS (P=0.029, females lower). The pre-to-post-run increase in 9+13 HODEs was not related to other outcomes except for plasma granulocyte colony stimulating factor (GCSF) (r=-0.710, Pincreases in 9+13 HODEs tended higher in females, and were not related to increases in F2-isoprostanes, muscle damage, or soreness. The negative relationships to GCSF and IL-6 suggest a linkage between 9+13 HODES and exercise-induced neutrophil chemotaxis, degranulation, and inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-oncological patients: randomized controlled trial.

    Science.gov (United States)

    Paul, Mical; Ram, Ron; Kugler, Eitan; Farbman, Laura; Peck, Anat; Leibovici, Leonard; Lahav, Meir; Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Wolach, Ofir; Itchaki, Gilad; Bar-Natan, Michal; Vidal, Liat; Gafter-Gvili, Anat; Raanani, Pia

    2014-03-01

    Intravenous (IV) granulocyte colony stimulating factor (G-CSF) might be safer and more convenient than subcutaneous (SC) administration to hospitalized hemato-oncological patients receiving chemotherapy. To compare IV vs. SC G-CSF administration, we conducted a randomized, open-label trial. We included inpatients receiving chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma or multiple myeloma, and allogeneic or autologous hematopoietic cell transplantation (HCT). Patients were randomized to 5 mcg/kg single daily dose of IV bolus versus SC filgrastim given for its clinical indications. Patients were crossed-over to the alternate study arm on the subsequent chemotherapy course. The primary outcomes were time from initiation of filgrastim to recovery of stable neutrophil count of >500 cells/µL and a composite clinical outcome of infection or death assessed for the first course post-randomization. The study was stopped on the second interim analysis. Of 120 patients randomized, 118 were evaluated in the first treatment course. The mean time to neutropenia resolution was longer with IV G-CSF [7.9 days, 95% confidence interval (CI) 6.6-9.1] compared with SC G-CSF (5.4 days, 95% CI 4.6-6.2), log-rank P = 0.001. Longer neutropenia duration was observed in all patient subgroups, except for patients undergoing autologous HCT. There was no significant difference between groups in the occurrence of infection or death, but more deaths were observed with IV (4/57, 7%) versus SC (1/61, 1.6%) G-CSF administration, P = 0.196. Similar results were observed when all 158 courses following cross-over were analyzed. Patients reported similar pain and satisfaction scores in both groups. Bolus IV administration of G-CSF results in longer neutropenia duration than SC administration, with no difference in clinical or quality-of-life measures.

  1. Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice.

    Science.gov (United States)

    Daltro, Pâmela Santana; Alves, Paula Santana; Castro, Murilo Fagundes; Azevedo, Carine M; Vasconcelos, Juliana Fraga; Allahdadi, Kyan James; de Freitas, Luiz Antônio Rodrigues; de Freitas Souza, Bruno Solano; Dos Santos, Ricardo Ribeiro; Soares, Milena Botelho Pereira; Macambira, Simone Garcia

    2015-12-03

    High fat diet (HFD) is a major contributor to the development of obesity and cardiovascular diseases due to the induction of cardiac structural and hemodynamic abnormalities. We used a model of diabetic cardiomyopathy in C57Bl/6 mice fed with a HFD to investigate the effects of granulocyte-colony stimulating factor (G-CSF), a cytokine known for its beneficial effects in the heart, on cardiac anatomical and functional abnormalities associated with obesity and type 2 diabetes. Groups of C57Bl/6 mice were fed with standard diet (n = 8) or HFD (n = 16). After 36 weeks, HFD animals were divided into a group treated with G-CSF + standard diet (n = 8) and a vehicle control group + standard diet (n = 8). Cardiac structure and function were assessed by electrocardiography, echocardiography and treadmill tests, in addition to the evaluation of body weight, fasting glicemia, insulin and glucose tolerance at different time points. Histological analyses were performed in the heart tissue. HFD consumption induced metabolic alterations characteristic of type 2 diabetes and obesity, as well as cardiac fibrosis and reduced exercise capacity. Upon returning to a standard diet, obese mice body weight returned to non-obese levels. G-CSF administration accelerated the reduction in of body weight in obese mice. Additionally, G-CSF treatment reduced insulin levels, diminished heart fibrosis, increased exercise capacity and reversed cardiac alterations, including bradycardia, elevated QRS amplitude, augmented P amplitude, increased septal wall thickness, left ventricular posterior thickening and cardiac output reduction. Our results indicate that G-CSF administration caused beneficial effects on obesity-associated cardiac impairment.

  2. Evaluation of a biosimilar granulocyte colony-stimulating factor (filgrastim XM02 for peripheral blood stem cell mobilization and transplantation: a single center experience in Japan

    Directory of Open Access Journals (Sweden)

    Yoshimura H

    2017-01-01

    Full Text Available Hideaki Yoshimura, Masaaki Hotta, Takahisa Nakanishi, Shinya Fujita, Aya Nakaya, Atsushi Satake, Tomoki Ito, Kazuyoshi Ishii, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan Background: Biosimilar granulocyte colony-stimulating factor (G-CSF has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context.Materials and methods: The subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK, or the originators, filgrastim, or lenograstim.Results: There were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation.Conclusion: Biosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs. Keywords: G-CSF, biosimilar, peripheral blood stem cell, hematological

  3. Bone marrow-derived cells mobilized by granulocyte-colony stimulating factor facilitate vascular regeneration in mouse kidney after ischemia/reperfusion injury.

    Science.gov (United States)

    Akihama, Susumu; Sato, Kazunari; Satoh, Shigeru; Tsuchiya, Norihiko; Kato, Tetsuro; Komatsuda, Atsushi; Hirokawa, Makoto; Sawada, Kenichi; Nanjo, Hiroshi; Habuchi, Tomonori

    2007-12-01

    Bone marrow-derived cells (BMDC) play crucial roles in tissue regeneration. Granulocyte-colony stimulating factor (G-CSF) mobilizes BMDC and may facilitate the repair of kidney tissues after ischemia/reperfusion (I/R) injury. The tissue protective action of resveratrol, an antioxidant, might modify the regenerating potential of BMDC in I/R renal injury. This study examined whether G-CSF and/or resveratrol affect the recruitment of BMDC into vascular endothelial cells and renal tubular cells and the kidney function after I/R injury. I/R renal injury was induced in female mice that had been lethally irradiated and transplanted with male bone marrow cells. The mice were given saline, resveratrol or G-CSF, daily for 7 days. Non-irradiated and non-bone-marrow-transplanted female mice, which underwent the same kidney injury, were included as control. White blood cell (WBC) count and serum creatinine were monitored. Immunohistologic evaluation for renal tubular cells (cytokeratin) and endothelial cells (factor VIII-related antigen), and fluorescence in situ hybridization for mouse Y chromosome were performed. Although WBC was significantly higher in the G-CSF group, there was no significant difference in creatinine levels among all groups. Factor VIII-related antigen-positive cells with a Y-chromosome signal were identified in the capillary wall between renal tubuli and most frequently seen in the G-CSF group (p cells having a Y-chromosome signal were identified. In conclusion, BMDC are recruited into endothelial cell in I/R renal injury without apparent renal tubular cell regeneration, and G-CSF facilitates the endothelial cell regeneration.

  4. Adjuvant Docetaxel and Cyclophosphamide (DC with prophylactic granulocyte colony-stimulating factor (G-CSF on days 8 &12 in breast cancer patients: a retrospective analysis.

    Directory of Open Access Journals (Sweden)

    Rinat Yerushalmi

    Full Text Available PURPOSE: Four cycles of docetaxel/cyclophosphamide (DC resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF support on days 8 and 12 of the cycle with the original DC protocol. METHODS: Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. RESULTS: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years. Thirty-three patients (26.8% were aged 65 years and older. Most of the women (87% adhered to the planned G-CSF protocol (days 8 &12. 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5% had dose reductions, 6 (5% had treatment delays due to non-medical reasons. Thirteen patients (10.6% experienced at least one event of FN (3 patients had 2 events, all requiring hospitalization. Eight patients (6.5% required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. IN CONCLUSION: Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.

  5. Effect of immobilized granulocyte colony-stimulating factor on hemopoietic precursors of various classes during cytostatic-induced myelosuppression.

    Science.gov (United States)

    Dygai, A M; Skurikhin, E G; Andreeva, T V; Madonov, P G; Vereshagin, E I; Kinsht, D N; Pershina, O V; Khmelevskaya, E S

    2010-09-01

    Experiments were performed on the model of cytostatic myelosuppression induced by cyclophosphamide. We compared the effect of immobilized granulocyte CSF (the preparation was created in Russia) and reference standard preparation of granulocyte CSF on the development of neutrophilic leukopenia and hemopoietic precursors of various classes. It was found that preparations of granulocyte CSF decreased the duration and degree of peripheral blood neutropenia. The granulocytopoiesis-stimulating effect was related to stimulation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage-megakaryocyte precursors, and granulocyte precursors. Induction of division and maturation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage-megakaryocyte precursors, and granulocyte precursors and recovery of cellularity of the granulocytic hemopoietic stem after administration of immobilized granulocyte CSF were observed at later terms compared to treatment with the reference preparation of granulocyte CSF.

  6. Alpha-1 antitrypsin and granulocyte colony-stimulating factor as serum biomarkers of disease severity in ulcerative colitis

    DEFF Research Database (Denmark)

    Soendergaard, Christoffer; Nielsen, Ole Haagen; Seidelin, Jakob Benedict

    2015-01-01

    biomarkers are currently needed for identification of patients with mild or moderate disease activity. Using a commercially available platform, we aimed at identifying serum biomarkers that are able to grade the disease severity. METHODS: Serum samples from 65 patients with UC with varying disease activity......-stimulating factor produced a predictive model with an AUC of 0.72 when differentiating mild and moderate UC, and an AUC of 0.96 when differentiating moderate and severe UC, the latter being as reliable as CRP. CONCLUSIONS: Alpha-1 antitrypsin is identified as a potential serum biomarker of mild-to-moderate disease......BACKGROUND: Initial assessment of patients with ulcerative colitis (UC) is challenging and relies on apparent clinical symptoms and measurements of surrogate markers (e.g., C-reactive protein [CRP] or similar acute phase proteins). As CRP only reliably identifies patients with severe disease, novel...

  7. [Recombinant granulocyte-colony stimulating factor (filgrastim): optimization of conditions of isolation and purification from inclusion body].

    Science.gov (United States)

    Kononova, N V; Iakovlev, A V; Zhuravko, A M; Pankeev, N N; Minaev, S V; Bobruskin, A I; Mart'ianov, V A

    2014-01-01

    We developed a unified process platform for two recombinant human GCSF medicines--one with the non-prolonged and the other with prolonged action. This unified technology led to a simpler and cheaper production while introduction of the additional pegylation stage to the technological line eased obtaining of the medicines with different action and allowed to standardize technological process documenting according to GMP requirements.

  8. Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone

    Directory of Open Access Journals (Sweden)

    Adrian Tudor Balseanu

    2014-06-01

    Full Text Available Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF. We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg or in combination with a single dose (106 cells of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration.” However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies

  9. MULTIMODAL APPROACHES FOR REGENERATIVE STROKE THERAPIES: COMBINATION OF GRANULOCYTE COLONY-STIMULATING FACTOR WITH BONE MARROW MESENCHYMAL STEM CELLS IS NOT SUPERIOR TO G-CSF ALONE

    Directory of Open Access Journals (Sweden)

    AurelPopa-Wagner

    1900-01-01

    Full Text Available Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilisation and homing by the stem cell mobiliser Granulocyte-colony Stimulating Factor (G-CSF. We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM MSCs in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 µg/kg or in combination with a single dose (106 cells of rat BM MSCs were administered intravenously to Sprague-Dawley rats at six hour safter transient occlusion (90 min of the middle cerebral artery. Infarct volume was measured by MRI at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration”. However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a

  10. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet

    Science.gov (United States)

    Pastuszko, Peter; Schears, Gregory J.; Greeley, William J.; Kubin, Joanna; Wilson, David F.; Pastuszko, Anna

    2014-01-01

    Background Ischemic brain injury continues to be of major concern in patients undergoing cardiopulmonary bypass (CPB) surgery for congenital heart disease. Striatum and hippocampus are particularly vulnerable to injury during these processes. Our hypothesis is that the neuronal injury resulting from CPB and the associated circulatory arrest can be at least partly ameliorated by pre-treatment with granulocyte colony stimulating factor (G-CSF). Material and Methods Fourteen male newborn piglets were assigned to three groups: deep hypothermic circulatory arrest (DHCA), DHCA with G-CSF, and sham-operated. The first two groups were placed on CPB, cooled to 18°C, subjected to 60 min of DHCA, re-warmed and recovered for 8-9 hrs. At the end of experiment, the brains were perfused, fixed and cut into 10 μm transverse sections. Apoptotic cells were visualized by in-situ DNA fragmentation assay (TUNEL), with the density of injured cells expressed as a mean number ± SD per mm2. Results The number of injured cells in the striatum and CA1 and CA3 regions of the hippocampus increased significantly following DHCA. In the striatum, the increase was from 0.46±0.37 to 3.67±1.57 (p=0.002); in the CA1, from 0.11±0.19 to 5.16±1.57 (p=0.001), and in the CA3, from 0.28±0.25 to 2.98±1.82 (p=0.040). Injection of G-CSF prior to bypass significantly reduced the number of injured cells in the striatum and CA1 region, by 51% and 37%, respectively. In the CA3 region, injured cell density did not differ between the G-CSF and control group. Conclusion In a model of hypoxic brain insult associated with CPB, G-CSF significantly reduces neuronal injury in brain regions important for cognitive functions, suggesting it can significantly improve neurological outcomes from procedures requiring DHCA. PMID:25082120

  11. Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease

    DEFF Research Database (Denmark)

    Wang, Yongzhong; Tägil, Kristina; Ripa, Rasmus S.

    2005-01-01

    OBJECTIVES: A phase I safety and efficacy study with granulocyte colony stimulating factor (G-CSF) mobilization of bone marrow stem cells to induce vasculogenesis in patients with severe ischemic heart disease (IHD) was conducted. DESIGN, PATIENTS AND RESULTS: 29 patients with IHD participated...... in 'mobilizers'. At the follow-up, G-CSF treated had improved in CCS classification, NTG consumption and angina attacks, but the controls only in CCS classification. No difference was seen between the two groups. The decline in NTG consumption tended to be significant in 'mobilizers' compared to controls...

  12. Uso do estimulante de colônia de granulócitos nas neutropenias em cães e gatos Granulocyte colony-stimulating factor use in neutropenias in dogs and cats

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    Cynthia de Assumpção Lucidi

    2007-06-01

    Full Text Available As neutropenias persistentes podem ser decorrentes de alterações na granulopoiese, causadas por efeitos supressivos ou tóxicos à medula óssea, predispõem o paciente a infecções comprometendo sua sobrevida. As neutropenias intensas decorrentes de toxicidade por quimioterápicos podem requerer a suspensão temporária ou permanente do medicamento, podendo gerar resistência das células neoplásicas ao tratamento. O uso de fatores de crescimento hematopoiético recombinantes em animais tem aumentado muito nos últimos anos, devido a sua crescente disponibilidade na medicina humana. O fator estimulante de colônia para granulócitos recombinante humano (rhG-CSF age aumentando o número de neutrófilos circulantes e possui grande potencial para amenizar ou reverter quadros de neutropenia associada a condições de mielotoxicidade e mielosupressão em cães e gatos.Persistent neutropenias can occur after granulopoiesis disturbances caused by myelosupressive or myelotoxic effects, and predispose patients to infections and impairs their survival. Furthermore, severe chemotherapy-induced neutropenias must require temporary or definitive treatment interruption, what may lead to drug-resistance of neoplastic cells. The use of recombinant stem cell factors in animals has been increasing due to its bigger disponibility for human beings. The human recombinant granulocyte colony-stimulating factor (rhG-CSF increases neutrophil numbers in peripheral blood and has great potential to alleviate or revert myelotoxic or myelosupression neutropenias in dogs and cats.

  13. Studies on mechanism of treatment of granulocyte colony-stimulating factor,recombinant human interleukin-11 and recombinant human interleukin-2 on hematopoietic injuries induced by 4.5 Gy γ-rays irradiation in beagles%细胞因子治疗4.5 Gyγ射线照射比格犬造血损伤的机制初探

    Institute of Scientific and Technical Information of China (English)

    李明; 王金香; 缪竞诚; 朱南康; 罗庆良; 从玉文; 张学光; 欧红玲; 邢爽; 黄海潇; 熊国林; 谢玲; 赵燕芳; 赵振虎; 王宁

    2010-01-01

    目的 探讨多种细胞因子配伍应用治疗4.5 Gyγ射线照射比格犬造血系统损伤的作用及可能机制.方法 16只比格犬均给予4.5 Gy60Coγ射线全身照射,随机分为照射对照、综合对症和细胞因子3组.细胞因子组在综合对症支持治疗的基础上应用rhG-CSF、rhIL-11和rhIL-2联合治疗,采用流式细胞术检测外周血中CD34+细胞含量、有核细胞周期及凋亡比例.结果 4.5 Gyγ射线照射犬外周血中CD34+细胞含量在照射后1 d明显下降(照射对照组和综合对症组分别为照前值的61.3%和52.1%),G0/G1期有核细胞比例增加(分别为99.27%和99.49%),且凋亡率(分别为26.93%和21.29%)和坏死率(分别为3.27%和4.14%)明显升高(与照前值比较,P<0.05);而经过细胞因子治疗后,外周血中CD34+细胞含量在照射后1 d即明显升高(为照前值的135.6%),G0/G1期有核细胞比例(99.71%)进一步增加,其凋亡率(5.66%)和坏死率(1.60%)明显低于照射对照和综合对症组.结论 本研究的细胞因子组合可能通过动员骨髓中CD34+细胞到外周血,使细胞周期阻滞在G0/G1期,减少细胞凋亡,从而促进极重度骨髓型急性放射病犬造血功能的恢复.%Objective To investigate the mechanism of treatment of granulocyte colony-stimulating factor(rhG-CSF),recombinant human interleukin-11(rhIL-11)and recombinant human interleukin-2 (rhIL-2)on hematopoietic injuries induced by 4.5 Gy60 Coγ-ray irradiation in beagles,and to provide experimental evidence for the clinical treatment of extremely severe myeloid acute radiation sickness (ARS).Methods Sixteen beagle dogs were given 4.5 Gy60 Co γ-ray total body irradiation(TBI),then randomly assigned into irradiation control group,supportive care group or cytokines+supportive care (abbreviated as cytokines)group.In addition to supportive care,rhG-CSF,rhlL-11 and rhIL-2 were administered subcutaneously to treat dogs in cytokines group.The percentage of CD34+cells,cell cycle and

  14. Treatment of severe aplastic anemia with intensified immunosuppressive therapy and two different regimens with recombinant human granulocyte colony-stimulating factor: a retrospective study based on long-term follow-up%强化免疫抑制疗法联合不同方案G-CSF治疗重型再生障碍性贫血患者的长期随访研究

    Institute of Scientific and Technical Information of China (English)

    李英梅; 李星鑫; 葛美丽; 施均; 钱林生; 王建祥; 郑以州

    2010-01-01

    目的 比较强化免疫抑制疗法(IIST)联合两种不同方案重组人粒细胞集落刺激因子(rhG-CSF)治疗重型再生障碍性贫血(SAA)患者的有效性和安全性.方法 回顾性分析1994年3月至2007年12月lIST联合rhG-CSF治疗的176例SAA患者资料.方案A:96例患者IIST后1个月始用rhG-CSF,300μg/次,每周3次、2次、1次各用1个月;方案B:80例患者IIST前始用rhG-CSF 5μg·kg-1·d-1,直至造血功能出现恢复.比较两组的治疗反应、感染相关死亡率和克隆性演变发生率.结果 ①B组患者早期治疗反应率(67.5%)显著高于A组(37.5%)(P<0.01),且其获早期治疗反应时间明显提前.B组患者IIST后4个月内感染相关死亡率(6.3%)显著低于A组(16.7%)(P=0.034).B组患者4年总体生存率[(77.7±4.9)%]显著高于A组[(57.2±5.1)%](P=0.006).②IIST后4个月无效的难治性SAA患者,A组者停用rhG-CSF,B组者继续应用,两组12个月疗效、感染相关死亡率及总体生存率差异均无统计学意义(P值分别为0.066、0.296、0.288),但B组患者转化为骨髓增生异常综合征/急性髓系白血病(MDS/AML)风险显著增高.③多因素分析发现疾病严重程度(RR=1.922,P=0.010)、是否有早期治疗反应(RR=5.749,P<0.01)为独立预后影响因素,且SAA转化为MDS/AML仅与rhG-CSF疗程相关(RR=1.004,P=0.017).结论 早期足量应用rhG-CSF联合IIST有助于造血功能恢复,并降低其感染相关死亡率,但延长rhG-CSF疗程并不能进一步提高难治性SAA患者的远期疗效,且增加其转化为MDS/AML的危险性.%Objective To compare the efficacy and safety of two different regimens with recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with intensified immunosuppressive therapy (IIST) in severe aplastic anemia (SAA). Methods Retrospectively analyzed 176 SAA treated with IIST and rhG-CSF in our hospital from March 1994 to December 2007. Regimen A (Group A, n =96) , rhG-CSF 300 (μg/d was initiated on day 31

  15. Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor

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    Kirtan Nautiyal

    2015-01-01

    Full Text Available Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS.

  16. Nerve growth factor and brain-derived neurotrophic factor but not granulocyte colony-stimulating factor, nimodipine and dizocilpine, require ATP for neuroprotective activity after oxygen-glucose deprivation of primary neurons.

    Science.gov (United States)

    Ferenz, Katja B; Gast, Ronald E; Rose, Karsten; Finger, Indra E; Hasche, Anja; Krieglstein, Josef

    2012-04-11

    In previous work, we have demonstrated by radiolabeling, mass spectrometry and site-directed mutagenesis that nerve growth factor (NGF) as well as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are capable of ATP-binding and that this binding appears to be essential for their neuroprotective activity. In this study, we attempted to shed some light on the question whether ATP is a general prerequisite for neuroprotection. Therefore, we used the non-ATP-binding granulocyte colony-stimulating factor (GCSF), the calcium antagonist nimodipine and the NMDA antagonist dizocilpine to find out whether they need ATP for neuroprotection comparable to NGF and BDNF. However, ATP was not necessary for the neuroprotective effects of GCSF, nimodipine and dizocilpine on primary cultures of rat cortical neurons damaged by oxygen-glucose deprivation whereas neuroprotection was demonstrable for NGF and BDNF only when ATP was present in the culture medium at a concentration higher than ca. 0.4nmol/l. In circular dichroism studies ATP caused changes of the secondary structure of NGF but not of GCSF. Taken together, we suggest that ATP is not a general prerequisite for neuroprotectivity but some growth factors like NGF and BDNF can stimulate their receptors only if they have bound ATP.

  17. Combination of stem cell factor and granulocyte colony-stimulating factor mobilizes the highest number of primitive haemopoietic progenitors as shown by pre-colony-forming unit (pre-CFU) assay.

    Science.gov (United States)

    Horsfall, M J; Hui, C H; To, L B; Begley, C G; Basser, R L; Simmons, P J

    2000-06-01

    Fifty-two patients with poor prognosis carcinoma of the breast underwent peripheral blood stem cell (PBSC) mobilization using five different regimens. The yields of primitive haemopoietic progenitors were quantified by a recently described pre-colony-forming unit (pre-CFU) assay using limiting dilution analysis (LDA). Results of days 14 and 35 pre-CFU were also correlated with conventional CD34+ cell enumeration, CFU-GM (granulocyte-macrophage) and long-term culture-initiating cell (LTCIC) assays. The yield of pre-CFUs with the combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) was significantly higher than with G-CSF alone, cyclophosphamide (Cyclo) and granulocyte-monocyte colony-stimulating factor (GM-CSF), interleukin (IL)-3 and GM-CSF, or Cyclo alone. No significant correlation between neutrophil engraftment and pre-CFU could be demonstrated. Furthermore, CFU-GM was shown to bear a stronger correlation with pre-CFU and LTCIC than CD34+ cell measurement; thus, CFU-GM remains a useful biological tool for haemopoietic stem cell assay. We conclude that the combination of G-CSF and SCF mobilizes the highest number of pre-CFUs as measured by functional pre-CFU assay, which provides an alternative measurement of primitive haemopoietic progenitors to the LTCIC assay.

  18. Effect of Granulocyte Colony-Stimulating Factor-Combined Conditioning in Cord Blood Transplantation for Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia: A Retrospective Study in Japan.

    Science.gov (United States)

    Konuma, Takaaki; Takahashi, Satoshi; Uchida, Naoyuki; Kuwatsuka, Yachiyo; Yamasaki, Satoshi; Aoki, Jun; Onishi, Yasushi; Aotsuka, Nobuyuki; Ohashi, Kazuteru; Mori, Takehiko; Masuko, Masayoshi; Nakamae, Hirohisa; Miyamura, Kouichi; Kato, Koji; Atsuta, Yoshiko; Kato, Seiko; Asano, Shigetaka; Takami, Akiyoshi; Miyazaki, Yasushi

    2015-09-01

    Granulocyte colony-stimulating factor (G-CSF) increases the susceptibility of dormant malignant or nonmalignant hematopoietic cells to cytarabine arabinoside (Ara-C) through the induction of cell cycle entry. Therefore, G-CSF-combined conditioning before allogeneic stem cell transplantation might positively contribute to decreased incidences of relapse and graft failure without having to increase the dose of cytotoxic drugs. We conducted a retrospective nationwide study of 336 adult patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) after single-unit cord blood transplantation (CBT) who underwent 4 different kinds of conditioning regimens: total body irradiation (TBI) ≥ 8 Gy + Ara-C/G-CSF + cyclophosphamide (CY) (n = 65), TBI ≥ 8 Gy + Ara-C + CY (n = 119), TBI ≥ 8 Gy + other (n = 104), or TBI < 8 Gy or non-TBI (n = 48). The TBI ≥ 8 Gy + Ara-C/G-CSF + CY regimen showed significantly higher incidence of neutrophil engraftment (hazard ratio, 1.52; 95% confidence interval [CI], 1.10 to 2.08; P = .009) and lower overall mortality (hazard ratio, .46; 95% CI, .26 to .82; P = .008) rates compared with those without a G-CSF regimen. This retrospective study shows that the G-CSF-combined conditioning regimen provides better engraftment and survival results in CBT for adults with MDS and sAML.

  19. Randomized study of granulocyte colony stimulating factor for childhood B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study.

    Science.gov (United States)

    Tsurusawa, Masahito; Watanabe, Tomoyuki; Gosho, Masahiko; Mori, Tetsuya; Mitsui, Tetsuo; Sunami, Shosuke; Kobayashi, Ryoji; Fukano, Reiji; Tanaka, Fumiko; Fujita, Naoto; Inada, Hiroko; Sekimizu, Masahiro; Koh, Katsuyoshi; Kosaka, Yoshiyuki; Komada, Yoshihiro; Saito, Akiko M; Nakazawa, Atsuko; Horibe, Keizo

    2016-07-01

    The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF-) based on protocols of the B-NHL03 study. The G-CSF group received 5 μg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF-. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment.

  20. Granulocyte colony-stimulating factor-producing undifferentiated carcinoma of the colon mimicking a pulmonary giant cell carcinoma: a case showing overexpression of CD44 along with highly proliferating nestin-positive tumor vessels.

    Science.gov (United States)

    Tajima, Shogo; Waki, Michihiko; Tsuchiya, Tomonori; Hoshi, Shoji

    2014-01-01

    Granulocyte colony-stimulating factor (G-CSF)-producing tumors are known for their aggressive behavior. Only four cases of G-CSF-producing colorectal carcinoma have been previously reported. Herein, we present a case of an undifferentiated carcinoma of the descending colon showing G-CSF production and giant cell carcinoma morphology in a 93-year-old woman. A tumor with a diameter of 80 mm was identified in the descending colon via computed tomography. Descending colectomy was performed involving the abdominal wall where tumor invasion was observed. The white blood cell count, which was elevated before resection, decreased to normal levels after intervention. However, local recurrence at the resected site was detected 39 days after surgery. Upon recurrence, increased white blood cell counts and serum G-CSF were seen. The patient died because of respiratory failure 98 days after colectomy. By using immunohistochemistry, G-CSF expression was detected in tumor cells in the resected specimen, along with overexpression of CD44 and highly proliferating nestin-positive tumor vessels. The poor clinical outcome of this patient is consistent with previous reports that the expression of these three molecules predict poor prognosis. While G-CSF can be a therapeutic target considering its auto/paracrine function to induce tumor growth via the G-CSF receptor, CD44 and nestin may also be possible candidate therapeutic targets. Further studies are required to assess the efficacy of treatments targeting these three molecules.

  1. A randomised study comparing granulocyte-colony stimulating factor (G-CSF) with G-CSF plus thymostimulin in the treatment of haematological toxicity in patients with advanced breast cancer after high dose mitoxantrone therapy.

    Science.gov (United States)

    Sanchiz, F; Milla, A

    1996-01-01

    54 patients with advanced breast cancer were randomised into a prospective, non-blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G-CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well-tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer.

  2. A multicenter, prospective, randomized, controlled trial evaluating the safety and efficacy of intracoronary cell infusion mobilized with granulocyte colony-stimulating factor and darbepoetin after acute myocardial infarction: study design and rationale of the 'MAGIC cell-5-combination cytokine trial'

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    Yoon Jung-Han

    2011-02-01

    Full Text Available Abstract Background Bone marrow derived stem/progenitor cell transplantation after acute myocardial infarction is safe and effective for improving left ventricular systolic function. However, the improvement of left ventricular systolic function is limited. This study will evaluate novel stem/progenitor cell therapy with combination cytokine treatment of the long-acting erythropoietin analogue, darbepoetin, and granulocyte colony-stimulating factor (G-CSF in patients with acute myocardial infarction. Methods The 'MAGIC Cell-5-Combination Cytokine Trial' is a multicenter, prospective, randomized, 3-arm, controlled trial with blind evaluation of the endpoints. A total of 116 patients will randomly receive one of the following three treatments: an intravenous darbepoetin infusion and intracoronary infusion of peripheral blood stem cells mobilized with G-CSF (n = 58, an intracoronary infusion of peripheral blood stem cells mobilized with G-CSF alone (n = 29, or conventional therapy (n = 29 at phase I. Patients with left ventricular ejection fraction Discussion This is the first study to evaluate the safety and efficacy of combination cytokine based progenitor/stem cell treatment. Trial registration http://www.ClinicalTrials.gov identifier: NCT00501917.

  3. Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A.

    Science.gov (United States)

    Iriyama, Noriyoshi; Yuan, Bo; Hatta, Yoshihiro; Horikoshi, Akira; Yoshino, Yuta; Toyoda, Hiroo; Aizawa, Shin; Takeuchi, Jin

    2012-11-01

    The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 µM) and apoptosis at high concentrations (1-2 µM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 µM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 µM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.

  4. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

    Science.gov (United States)

    Vendramin, Antonio; Gimondi, Silvia; Bermema, Anisa; Longoni, Paolo; Rizzitano, Sara; Corradini, Paolo; Carniti, Cristiana

    2014-12-01

    Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin(low/neg)HLA-DR(-)CD11b(+)CD33(+)CD14(+)) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively (P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate (P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD.

  5. Routine Primary Prophylaxis for Febrile Neutropenia with Biosimilar Granulocyte Colony-Stimulating Factor (Nivestim or Pegfilgrastim Is Cost Effective in Non-Hodgkin Lymphoma Patients undergoing Curative-Intent R-CHOP Chemotherapy.

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    Xiao Jun Wang

    Full Text Available This study aims to compare the cost-effectiveness of various strategies of myeloid growth factor prophylaxis for reducing the risk of febrile neutropenia (FN in patients with non-Hodgkin lymphoma in Singapore who are undergoing R-CHOP chemotherapy with curative intent.A Markov model was created to compare seven prophylaxis strategies: 1 primary prophylaxis (PP with nivestim (biosimilar filgrastim throughout all cycles of chemotherapy; 2 PP with nivestim during the first two cycles of chemotherapy; 3 secondary prophylaxis (SP with nivestim; 4 PP with pegfilgrastim throughout all cycles of chemotherapy; 5 PP with pegfilgrastim during the first two cycles of chemotherapy; 6 SP with pegfilgrastim; and 7 no prophylaxis (NP. The perspective of a hospital was taken and cost-effectiveness was expressed as the cost per episode of FN avoided over six cycles of chemotherapy. A probabilistic sensitivity analysis was conducted.Strategies 3, 6, and 7 were dominated in the base case analysis by strategy 5. The costs associated with strategies 2, 5, 1, and 4 were US$3,813, US$4,056, US$4,545, and US$5,331, respectively. The incremental cost-effectiveness ratios for strategy 5 vs. strategy 2, strategy 1 vs. strategy 5, and strategy 4 vs. strategy 1 were US$13,532, US$22,565, and US$30,452, respectively, per episode of FN avoided. Strategy 2 has the highest probability to be cost-effective (ranged from 48% to 60% when the willingness to pay (WTP threshold is lower than US$10,000 per FN episode prevented.In Singapore, routine PP with granulocyte colony-stimulating factor (nivestim or pegfilgrastim is cost-effective for reducing the risk of FN in patients receiving R-CHOP.

  6. Increasing aclarubicin dose in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) is efficacious as salvage chemotherapy for relapsed/refractory mixed-phenotype acute leukemia.

    Science.gov (United States)

    Liu, Limin; Qu, Qi; Jiao, Wenjing; Zhang, Yanming; Li, Xiaoli; Ding, Chao; Wu, Depei

    2015-08-01

    We treated 60 relapsed/refractory mixed-phenotype acute leukemia patients (MPAL-1) with increasing the aclarubicin dose in CAG regimen (HD-CAG, cytarabine (10 mg/m(2)/12 h, days 1-14), aclarubicin (5-7 mg/m(2)/day, days 1-14), granulocyte colony-stimulating factor (200 μg/m(2)/day, days 1-14). This was compared to 64 relapsed/refractory MPAL patients (MPAL-2) treated with DOAP regimen (daunorubicin, vincristine/vindesine, cytarabine and prednisone), 113 relapsed/refractory acute myeloid leukemia (AML) patients and 78 acute lymphocytic leukemia (ALL) patients treated with HD-CAG regimen. After one course, complete remission (CR) and overall response [OR, CR+partial remission (PR)] rates for MPAL-1 exceeded MPAL-2 (CR, 61.02% vs. 28.13%, P=0.000; OR, 72.88% vs. 34.38%, P=0.000), but these data were similar to AML and ALL (P>0.05). In MPAL-1 group, CR and OR rates of T-lymphoid+myeloid immunophenotype were higher than B-lymphoid+myeloid immunophenotype (CR, 81.82% vs. 44.12%, P=0.005; OR, 90.91% vs. 58.82%, P=0.009). The overall survival at 3 years in MPAL-1, MPAL-2, AML and ALL groups were 14.2%±6.8%, 14.1%±6.4%, 17.3%±5.0% and 15.0%±5.3% (P>0.05). Side effects were similar between HD-CAG and DOAP (P>0.05). HD-CAG regimen is efficacious for relapsed/refractory MPAL, especially for T+My patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Increased mobilization and yield of stem cells using plerixafor in combination with granulocyte-colony stimulating factor for the treatment of non-Hodgkin’s lymphoma and multiple myeloma

    Directory of Open Access Journals (Sweden)

    Louis M Pelus

    2011-02-01

    Full Text Available Louis M Pelus1, Sherif S Farag21Department of Microbiology and Immunology, 2Division of Hematology and Oncology, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IndianaAbstract: Multiple myeloma and non-Hodgkin’s lymphoma remain the most common indications for high-dose chemotherapy and autologous peripheral blood stem cell rescue. While a CD34+ cell dose of 1 × 106/kg is considered the minimum required for engraftment, higher CD34+ doses correlate with improved outcome. Numerous studies, however, support targeting a minimum CD34+ cell dose of 2.0 × 106/kg, and an “optimal” dose of 4 to 6 × 106/kg for a single transplant. Unfortunately, up to 40% of patients fail to mobilize an optimal CD34+ cell dose using myeloid growth factors alone. Plerixafor is a novel reversible inhibitor of CXCR4 that significantly increases the mobilization and collection of higher numbers of hematopoietic progenitor cells. Two randomized multi-center clinical trials in patients with non-Hodgkin’s lymphoma and multiple myeloma have demonstrated that the addition of plerixafor to granulocyte-colony stimulating factor increases the mobilization and yield of CD34+ cells in fewer apheresis days, which results in durable engraftment. This review summarizes the pharmacology and evidence for the clinical efficacy of plerixafor in mobilizing hematopoietic stem and progenitor cells, and discusses potential ways to utilize plerixafor in a cost-effective manner in patients with these diseases.Keywords: plerixafor, mobilization, stem cells, lymphoma, myeloma

  8. The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.

    Science.gov (United States)

    Lyman, Gary H; Allcott, Kim; Garcia, Jacob; Stryker, Scott; Li, Yanli; Reiner, Maureen T; Weycker, Derek

    2017-08-01

    Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs. A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines. The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes. Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.

  9. Late reperfusion of a totally occluded infarct-related artery increases granulocyte-colony stimulation factor and reduces stroma-derived factor-1alpha blood levels in patients with ongoing ischemia after acute myocardial infarction.

    Science.gov (United States)

    Kuo, Li-Tang; Chen, Shih-Jen; Cherng, Wen-Jin; Yang, Ning-I; Lee, Chen-Chin; Cheng, Chi-Wen; Verma, Subodh; Wang, Chao-Hung

    2009-07-01

    After acute myocardial infarction (AMI), reopening of a totally occluded infarct-related artery (IRA) at a subacute stage is still controversial in symptom-free patients. However, in patients with persistent ischemic symptoms and inadequate collaterals to the infarct area, recanalization is thought to provide beneficial effects. In addition to augmenting myocardial perfusion, we hypothesized that the benefit of recanalization involves the manipulation of circulating stem cell-mobilizing cytokines. This study included 30 patients with a totally occluded IRA and ongoing ischemic symptoms (the study group) and 30 patients with a partially occluded IRA (the control group). All patients underwent successful angioplasty and/or stenting. Before and immediately after the coronary intervention, blood granulocyte-colony-stimulating factor (G-CSF), stem-cell factor (SCF), vascular endothelial growth factor (VEGF), and stroma-derived factor-1 (SDF-1alpha) were measured. After recanalization, G-CSF levels significantly increased in the study group compared to the control group (P=0.03). SDF-1alpha levels in the study group decreased relative to the controls (P=0.02). However, no significant changes in VEGF or SCF levels between the two groups were found. In the multivariate analysis, reopening of a totally occluded IRA was independently and significantly associated with changes in G-CSF and SDF-1alpha levels after recanalization. In conclusion, our data suggest that the benefits of late reperfusion of a totally occluded IRA in patients with ongoing myocardial ischemia may involve mechanisms associated with stem cell-mobilizing and plaque-stabilizing cytokines. This study provides the rationale to investigate serial changes in cytokines and the numbers of circulating progenitors after reperfusion in the future.

  10. Early applications of granulocyte colony-stimulating factor (G-CSF) can stabilize the blood-optic-nerve barrier and ameliorate inflammation in a rat model of anterior ischemic optic neuropathy (rAION).

    Science.gov (United States)

    Wen, Yao-Tseng; Huang, Tzu-Lun; Huang, Sung-Ping; Chang, Chung-Hsing; Tsai, Rong-Kung

    2016-10-01

    Granulocyte colony-stimulating factor (G-CSF) was reported to have a neuroprotective effect in a rat model of anterior ischemic optic neuropathy (rAION model). However, the therapeutic window and anti-inflammatory effects of G-CSF in a rAION model have yet to be elucidated. Thus, this study aimed to determine the therapeutic window of G-CSF and investigate the mechanisms of G-CSF via regulation of optic nerve (ON) inflammation in a rAION model. Rats were treated with G-CSF on day 0, 1, 2 or 7 post-rAION induction for 5 consecutive days, and a control group were treated with phosphate-buffered saline (PBS). Visual function was assessed by flash visual evoked potentials at 4 weeks post-rAION induction. The survival rate and apoptosis of retinal ganglion cells were determined by FluoroGold labeling and TUNEL assay, respectively. ON inflammation was evaluated by staining of ED1 and Iba1, and ON vascular permeability was determined by Evans Blue extravasation. The type of macrophage polarization was evaluated using quantitative real-time PCR (qRT-PCR). The protein levels of TNF-α and IL-1β were analyzed by western blotting. A therapeutic window during which G-CSF could rescue visual function and retinal ganglion cell survival was demonstrated at day 0 and day 1 post-infarct. Macrophage infiltration was reduced by 3.1- and 1.6-fold by G-CSF treatment starting on day 0 and 1 post-rAION induction, respectively, compared with the PBS-treated group (Pmodel. © 2016. Published by The Company of Biologists Ltd.

  11. Attenuation of the bacterial load in blood by pretreatment with granulocyte-colony-stimulating factor protects rats from fatal outcome and brain damage during Streptococcus pneumoniae meningitis

    DEFF Research Database (Denmark)

    Brandt, Christian T; Lundgren, Jens D; Lund, Søren Peter

    2004-01-01

    A model of pneumococcal meningitis in young adult rats receiving antibiotics once the infection was established was developed. The intent was to mimic clinical and histopathological features of pneumococcal meningitis in humans. The primary aim of the present study was to evaluate whether medical...

  12. Prevention of febrile leucopenia after chemotherapy in high-risk breast cancer patients : no significant difference between granulocyte-colony stimulating growth factor or ciprofloxacin plus amphotericin B

    NARCIS (Netherlands)

    Schroder, CP; de Vries, EGE; Muder, NH; Willemse, PHB; Sleijfer, DT; Hospers, GAP; van der Graaf, WTA

    1999-01-01

    In a prospective randomized trial, 40 stage IV breast cancer patients undergoing intermediate high-dose chemotherapy (cyclophosphamide, 5-fluorouracil plus epirubicin or methotrexate), received either recombinant human G-CSF (rhG-CSF, group I) or ciprofloxacin and amphotericin B (CAB, group II) for

  13. [Effectiveness of Leukostim, a Russian preparation of granulocyte colony-stimulating factor, in the treatment of chemotherapy-induced neutropenia in patients with malignant tumors].

    Science.gov (United States)

    Korman, D B; Boronovskaia, L E; Maslova, I A; Andreeva, E V; Seregina, G V

    2008-01-01

    Recombinant preparation of human G-CSF-Leukostim (Russia)--(filgrastim; analog of Neupogen)--was administered in 31 patients (breast cancer--28; ovarian carcinoma--3) to treat or prevent chemotherapy-induced neutropenia. The latter was aborted after 2-6 injections. Due to use of Leukostim, another course of chemotherapy (10 cycles) was successfully used in 5 breast cancer patients: no inhibition of hemopoiesis followed although the patients had suffered acute and persistent neutropenia from previous chemotherapy. No adverse side-effects of Leukostim administration were reported.

  14. Attenuation of the bacterial load in blood by pretreatment with granulocyte-colony-stimulating factor protects rats from fatal outcome and brain damage during Streptococcus pneumoniae meningitis

    DEFF Research Database (Denmark)

    Brandt, Christian T; Lundgren, Jens D; Lund, Søren Peter

    2004-01-01

    A model of pneumococcal meningitis in young adult rats receiving antibiotics once the infection was established was developed. The intent was to mimic clinical and histopathological features of pneumococcal meningitis in humans. The primary aim of the present study was to evaluate whether medical...... of meningitis result in reduced risks of death and brain damage. This beneficial effect is most likely achieved through improved control of the systemic disease....... postinfection did not alter the clinical or histological outcome relative to that for non-G-CSF-treated rats. The magnitude of bacteremia and pretreatment with G-CSF were found to be prognostic factors for both outcome and brain damage. In summary, elevated neutrophil levels prior to the development...

  15. Granulocyte Colony Stimulating Factor and Physiotherapy after Stroke: Results of a Feasibility Randomised Controlled Trial: Stem Cell Trial of Recovery EnhanceMent after Stroke-3 (STEMS-3 ISRCTN16714730).

    Science.gov (United States)

    Sprigg, Nikola; O'Connor, Rebecca; Woodhouse, Lisa; Krishnan, Kailash; England, Timothy J; Connell, Louise A; Walker, Marion F; Bath, Philip M

    2016-01-01

    Granulocyte-colony stimulating factor (G-CSF) mobilises endogenous haematopoietic stem cells and enhances recovery in experimental stroke. Recovery may also be dependent on an enriched environment and physical activity. G-CSF may have the potential to enhance recovery when used in combination with physiotherapy, in patients with disability late after stroke. A pilot 2 x 2 factorial randomised (1:1) placebo-controlled trial of G-CSF (double-blind), and/or a 6 week course of physiotherapy, in 60 participants with disability (mRS >1), at least 3 months after stroke. Primary outcome was feasibility, acceptability and tolerability. Secondary outcomes included death, dependency, motor function and quality of life measured 90 and 365 days after enrolment. Recruitment to the trial was feasible and acceptable; of 118 screened patients, 92 were eligible and 32 declined to participate. 60 patients were recruited between November 2011 and July 2013. All participants received some allocated treatment. Although 29 out of 30 participants received all 5 G-CSF/placebo injections, only 7 of 30 participants received all 18 therapy sessions. G-CSF was well tolerated but associated with a tendency to more adverse events than placebo (16 vs 10 patients, p = 0.12) and serious adverse events (SAE) (9 vs 3, p = 0.10). On average, patients received 14 (out of 18 planned) therapy sessions, interquartile range [12, 17]. Only a minority (23%) of participants completed all physiotherapy sessions, a large proportion of sessions (114 of 540, 21%) were cancelled due to patient (94, 17%) and therapist factors (20, 4%). No significant differences in functional outcomes were detected in either the G-CSF or physiotherapy group at day 90 or 365. Delivery of G-CSF is feasible in chronic stroke. However, the study failed to demonstrate feasibility for delivering additional physiotherapy sessions late after stroke therefore a definitive study using this trial design is not supported. Future work should

  16. Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome.

    Science.gov (United States)

    Wu, Lingyun; Li, Xiao; Su, Jiying; Chang, Chunkang; He, Qi; Zhang, Xi; Xu, Li; Song, Luxi; Pu, Quan

    2009-09-01

    A total of 32 patients (25 with advanced MDS and 7 with t-AML) were enrolled in this study to evaluate the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukemia (t-AML). All the patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/day, intravenous continuous infusion, days 1-14), homoharringtonine (1 mg/day, intravenous continuous infusion, days 1-14), and G-CSF (300 microg/day, subcutaneous injection, days 0-14, interrupted when the peripheral white blood cell count reached >20 x 10(9)/L). The overall response rate was 71.9% after the administration of one course of the CHG regimen. Of the 32 patients, 15 (46.9%) achieved complete remission (CR) and 8 (25%) achieved partial remission (PR). This regimen was followed by a post-remission therapy that included conventional chemotherapy, when CR was achieved. Of the patients with CR who just received post-remission regimens as homoharringtonine and cytarabine (HA) and daunorubicin and cytarabine (DA) 6 relapsed rapidly and just had a mean 6.1 months of CR. Otherwise, the other 8 out of 14 patients with CR alternatively received subsequent chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin, or aclarubicin with cytarabine. The mean CR duration of the 8 patients had reached 10.6 months, and 5 of the 8 still kept a continuous CR. The median overall survival (OS) was 18.2 months. There were no statistically significant differences for CR, PR, and OS when the patients were grouped by age, blasts in bone marrow, and karyotypes, respectively. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-hematological toxicity was observed. Thus, a CHG priming regimen as an induction therapy was well tolerated and effective in patients with advanced MDS

  17. A patient with glycogen storage disease type Ib presenting with acute myeloid leukemia (AML bearing monosomy 7 and translocation t(3;8(q26;q24 after 14 years of treatment with granulocyte colony-stimulating factor (G-CSF: A case report

    Directory of Open Access Journals (Sweden)

    Schroeder Thomas

    2008-09-01

    Full Text Available Abstract Introduction Glycogen storage disease type Ib is an autosomal recessive transmitted disorder of glycogen metabolism caused by mutations in the glucose-6-phosphate translocase gene on chromosome 11q23 and leads to disturbed glycogenolysis as well as gluconeogenesis. Besides hepatomegaly, growth retardation, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia, patients suffer from neutropenia associated with functional defects predisposing for severe infections. In order to attenuate these complications, long-term treatment with granulocyte colony-stimulating factor is common but this is associated with an increased risk for acute myeloid leukemia or myelodysplastic syndromes in patients with inherited bone marrow failures such as severe congenital neutropenia. Onset of these myeloid malignancies is linked to cytogenetic aberrations involving chromosome 7. In addition, granulocyte colony-stimulating factor is known to stimulate proliferation of monosomy 7 cells in vitro. To our knowledge, we report for the first time a case report of a patient with glycogen storage disease type Ib, who developed acute myeloid leukemia with a classical monosomy 7 and acute myeloid leukemia-associated translocation t(3;8(q26;q24 after 14 years of continuous treatment with granulocyte colony-stimulating factor. Case presentation A 28-year-old Turkish man with glycogen storage disease type Ib was admitted to our department because of dyspnea and increasing fatigue. He also presented with gum bleeding, bone pain in his legs, night sweats, recurrent episodes of fever with temperatures up to 39°C and hepatosplenomegaly. A blood count taken on the day of admission showed pancytopenia and a differential count displayed 30% blasts. A bone marrow biopsy was taken which showed a hypercellular marrow with dysplastic features of all three cell lines, while blast count was 20%. Classical cytogenetic analyses as well as fluorescence in situ hybridization

  18. Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity.

    Science.gov (United States)

    Matsumura-Takeda, K; Kotosai, K; Ozaki, A; Hara, H; Yamashita, S

    2002-06-01

    To assess the drug-induced hematotoxicity to granulocyte progenitors, we established a modified colony-forming assay using rat bone marrow cells (BMCs). In the presence of various colony-stimulating factors (CSFs), rat BMCs were disseminated on methylcellulose at a concentration of 1.3 x 10(4) cells/cm(2) (5 x 10(4) cells/0.5 ml/well in a 12-well plate). Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) stimulated the formation of almost all macrophage colonies. Human granulocyte colony-stimulating factor (hG-CSF) alone or in combination with mouse interleukin-3 (mIL-3) did not significantly effect on the number of rat colony-forming units in culture (CFU-C). When BMCs were seeded at 5.2 x 10(4) cells/cm(2) (5 x 10(5) cells/1 ml/dish in a 35-mm dish), hG-CSF increased the number of the colonies in a dose-dependent manner, and resulted in about 50 colonies at 50 ng/ml. The constituent cells of the colonies were identified as neutrophils. Under these conditions, the effects of 5-fluorouracil (5-FU) on granulocyte colony-forming units (CFU-G) were examined in rats and mice. The inhibitory effect of 5-FU on rat CFU-G was similar to the effect on mouse CFU-G. These results indicate that the rat CFU-G induced by hG-CSF is capable of being used for the evaluation of drug-induced hematotoxicity.

  19. High Dose Granulocyte Colony-Stimulating Factor Enhances Survival and Hematopoietic Reconstruction in Canines Irradiated by 2.3 Gy Mixed Fission Neutron and Gamma Ray%大剂量粒细胞集落刺激因子对2.3Gy中子γ射线混合照射比格犬存活和造血重建的影响

    Institute of Scientific and Technical Information of China (English)

    李明; 柳晓兰; 赵振虎; 王欣茹; 从玉文; 罗庆良; 余祖胤; 邢爽; 欧红玲; 熊国林; 谢玲; 赵燕芳; 韩阿如娜; 善亚君

    2011-01-01

    This study was purposed to evaluate the effects of recombinant human granulocyte colony-stimulating factor(rhG-CSF)on hematopoietic reconstruction and survival in beagles exposed to mixed fission neutron and γ-ray.13 beagles were unilaterally exposed to single dose of 2.3 Gy 90% neutrons.The experiments were divided into 3 groups:irradiation control group(no any treatment,n=4),supportive care group(n=5)and rhG-CSF plus supportive care group(n=4,abbreviated as rhG-CSF group)in which the beagles were subcutaneously injected with 200 μg/kg of rhG-CSF early at half an hour and 24 hours post-irradiation respectively.The results showed that 2.3 Gy 90% neutron irradiation induced a severe acute radiation sickness of bone marrow type.The administration of rhG-CSF increased the survival rate from 60% in supportive care group to 100%.Twice injection of rhG-CSF in the first 24 hours reduced duration of neutropenia,enhanced neutrophil nadir and promoted neutrophil recovery when compared with control cohort administered clinical support.The number of colony-forming cells(CFU-GM,CFU-E,and BFU-E)in peripheral blood of rhG-CSF treated canines increased 2-to 5-fold relative to those of the supportive care group on day 3.All canines treated with rhG-CSF achieved hematopoietic reconstruction as evidenced by the pathological section of sternum while severe shortage of hemopoietic cells remained in the cohorts given supportive care alone.It is concluded that the combination of supportive care and high-dose rhG-CSF can accelerate hematopoietic recovery and enhance survival of dogs exposed to 2.3 Gy mixed neutron and gamma ray

  20. Allogeneic hemopoietic stem cell transplantation using mobilization with granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor%粒细胞集落刺激因子/粒-巨噬细胞集落刺激因子联合动员异基因造血干细胞移植

    Institute of Scientific and Technical Information of China (English)

    刘忠文; 郭建民; 杨靖; 张茵

    2011-01-01

    BACKGROUND: Currently, only granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) approved by Food and Drug Administration are used for the mobilization of peripheral blood hemopoietic stem cells and G-CSF alone or in combination with GM-CSF is the predominant mobilization regiments used in the allogeneic setting,but it might cause the donors some adverse events such as bone pain, muscular soreness and fever.OBJECTIVE: To retrospectively review the clinic results of allogeneic peripheral blood hemopoietic stem cell transplantation (allo-PBSCT) using mobilization with G-CSF and GM-CSF.METHODS: From January 2004 to October 2009, a total of 51 patients with hematological malignant diseases received allo-PBSCT from human leucocyte antigen-matched sibling donors mobilized with G-CSF and GM-CSF at the Department of Hematology, Henan Provincial People's Hospital. We analyzed components in the allografts, hematopoietic reconstitution and the incidence of graft versus host diseases (GVHD).RESULTS AND CONCLUSION: After mobilizing 96 hours, the percentage of CD34+ cells in mononuclear cells was (0.97+0.13)% and the percentage of CD34+/CD38- cells in CD34+ cells was (37.49+4.03)%. Rapid hematopoietic reconstruction posttransplantation was negatively associated with infused total CD34+ and CD34+/CD38- cell number. Incidences of Grades Ⅰ ,Ⅱ - Ⅳ acute GVHD were respectively 25.5% and 15.7% of patients. The incidence rates of limited and extensive chronic GVHD were 39.2% and 21.2% separately. These results suggest the combination regimen with GM-CSF and G-CSF appear to have a good effect in the mobilization of peripheral blood stem cells and be sufficient to ensure early hematopoietic reconstitution. The high doses of infused CD34+ and CD34+CD38- cells are likely beneficial to the prompt engraftment.%背景:目前FDA已批准应用于临床外周血造血干细胞移植的动员剂只有粒细胞集落刺激

  1. INTERLEUKIN-4 PREVENTS THE INDUCTION OF G-CSF MESSENGER-RNA IN HUMAN ADHERENT MONOCYTES IN RESPONSE TO ENDOTOXIN AND IL-1 STIMULATION

    NARCIS (Netherlands)

    VELLENGA, E; DOKTER, W; DEWOLF, JTM; VANDEVINNE, B; ESSELINK, MT; HALIE, MR

    Human recombinant interleukin-4 (IL-4) was studied for its effects on the expression of granulocyte-colony stimulating factor (G-CSF) mRNA in human adherent monocytes in the absence and presence of endotoxin and interleukin 1 (IL-1). IL-4 (15 ng/ml) did not induce G-CSF transcripts in monocytes but

  2. Predicting poor peripheral blood stem cell collection in patients with multiple myeloma receiving pre-transplant induction therapy with novel agents and mobilized with cyclophosphamide plus granulocyte-colony stimulating factor: results from a Gruppo Italiano Malattie EMatologiche dell'Adulto Multiple Myeloma Working Party study.

    Science.gov (United States)

    Musto, Pellegrino; Simeon, Vittorio; Grossi, Alberto; Gay, Francesca; Bringhen, Sara; Larocca, Alessandra; Guariglia, Roberto; Pietrantuono, Giuseppe; Villani, Oreste; D'Arena, Giovanni; Cuomo, Carmela; Musto, Clelia; Morabito, Fortunato; Petrucci, Maria Teresa; Offidani, Massimo; Zamagni, Elena; Tacchetti, Paola; Conticello, Concetta; Milone, Giuseppe; Palumbo, Antonio; Cavo, Michele; Boccadoro, Mario

    2015-04-17

    A still not well defined proportion of patients with multiple myeloma (MM) and eligible for autologous stem cell transplantation (AuSCT) fails to mobilize CD34+ peripheral blood stem cells (PBSC) at all or to collect an adequate number for a safe procedure or sufficient for multiple transplants. These so-called "poor-mobilizers" are difficult to be predicted, due to marked difference across previous heterogeneous studies. We aimed to develop a method based on simple clinical parameters for predicting unsuccessful (<2×10(6)/kg) or sub-optimal (<5×10(6)/kg) collections of CD34+ PBSC in newly diagnosed MM patients eligible for AuSCT, treated with novel agents and receiving an homogeneous mobilizing therapy with cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). To this purpose, 1,348 patients enrolled in five consecutive Italian clinical trials were retrospectively analysed. Age, baseline low peripheral blood cell counts, use of lenalidomide, and haematological toxicity developed during induction were taken into account as possible factors associated with poor mobilization. Overall, 280 patients (20.8%) showed either sub-optimal (167 patients, 12.4%) or unsuccessful (113 patients, 8.4%) collections. All analysed parameters negatively influenced the procedure, but only age and haematological toxicity during induction maintained their significance at multivariate analysis. Based on ordinal logistic regression model, we constructed a risk heat-map where the four parameters were pooled and weighted according to their relevance as single or combined variables. This model was predictive for different probabilities of failure, suboptimal or optimal outcomes. We found that about one fifth of newly diagnosed MM fails to collect an adequate number of PBSC. Our model, based on a large group of patients treated frontline with novel agents and receiving the most popular mobilizing approach currently employed in Europe, is applicable in individual subjects and

  3. Granulocyte and granulocyte macrophage colony-stimulating factors as therapy in human and veterinary medicine.

    Science.gov (United States)

    Fernández-Varón, Emilio; Villamayor, Lucía

    2007-07-01

    Granulocyte colony-stimulating factors (G-CSFs) and granulocyte macrophage colony-stimulating factors (GM-CSFs) are endogenous cytokines that regulate granulocyte colonies and play a major role in the stimulation of granulopoiesis (neutrophils, basophils and eosinophils) and in the regulation of microbicidal functions. There are numerous pathological conditions in which neutrophils are decreased, the most common being neutropenia associated with cancer chemotherapy, which increases the risk of serious microbial infections developing with the potential for high morbidity and mortality. New methods in molecular biology have led to the identification and cloning of CSF genes and biopharmaceutical production. Since then, CSFs have been widely used for the prevention and treatment of neutropenia associated with cancer chemotherapy, for mobilising haematopoietic cell precursors, and for other neutropenia-related pathologies. This review focuses on the use of CSFs within both human and veterinary medicine. Clinical applications, pharmacology, tolerability and the potential role of these factors in veterinary medicine are considered.

  4. Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF

    Directory of Open Access Journals (Sweden)

    Naeim Arash

    2013-01-01

    Full Text Available Abstract Background Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization. Methods This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR for hospitalization and 95% confidence intervals (CI were estimated by generalized estimating equation (GEE models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis. Results We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim. The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59 and all

  5. 毛细管电泳筛选与集落细胞刺激因子有相互作用的寡聚糖及其生物活性研究%Screening of active saccharides interacted with granulocyte colony-stimulating factor using capillary electrophoresis and their effects on leukemia cells

    Institute of Scientific and Technical Information of China (English)

    周小棉; 梁爱叶; 王秋艳; 林炳承

    2008-01-01

    out the bioactive sulfate saccharides interacted with granulocyte colony-stimulating factor (G-CSF) and provide some scientific data on their pharmacology. Methods The interactions between G-CSF and 15 sulfate saccharides with various chain lengths and extent of sulfation were studied by capillary electrophoresis. Furthermore, the effects of these G-CSF binding saccharides on the proliferation and differentiation of leukemia cell line and NFS-60 were also investigated. Results Except for the hepatosaccharide, degradable carrageenan, Dextran sulfate (DexS) with a low molecular mass the nonsulfated sancharide and alkaline chitosan oligosaccharide, the rest of saccharides had interact with G-CSF.DexS500, λ carrageenan, ι carrageenan, κ carrageenan and low molecular weight heparin-1(LMWH-1)with anticoagulant activity could inhibit the NFS-60 growth. Compared with the absorbency of the control group (100.00±3.00) after these saccharides interacted with the NPS-60 cells, their relative absorbencies were 31.33±2.08,37.67±2.08,45.00±1.20,43.00±2.65 and 74.67±1.52, respectively. Their differences had a statistical significance(t=27.94,26.71,26.42,26.61,10.54,P<0.01). The morphological analytic results showed that the LMWH and lambda carrageenan as well as DexS with a molecular mass of 500 000 induce effectively promyclocyte to transit metamyelocyte. Flow cytometry results showed enhanced expressions of CD11b, CD18 and CD45 after treatment with the LMWH, lambda carrageenan and DexS500,respectively. Cell cycle analysis indicated that the S phase population decreased after treatment with these saccharides. Conclusions Capillary electrophoresis is an effective medicine-screening technique that is used to screen some of these saccharides which could bind to G-CSF. And it is found that the interactions are correlated with the chain length, the extent and the position of sulfation of these saccharides.

  6. Uso de fatores de crescimento epidérmico e estimulador de colônias de granulócitos na prevenção e tratamento da enterocolite necrosante no recém-nascido Use of epidermic and granulocyte-colony stimulating growth factors in the prevention and treatment of necrotizing enterocolitis of the newborn

    Directory of Open Access Journals (Sweden)

    Dáfne Cardoso B. da Silva

    2008-06-01

    pathophysiology of this disease improves, new therapies, such as the administration of epidermal growth factor and granulocyte colony-stimulating factor, are being discussed. CONCLUSIONS: The use of growth factors for treatment and prevention of NEC seems promising. However, further clinics assays are needed to evaluate the effectiveness and the safety of these growth factors. At this moment, the best clinical practice is the prevention of the disease.

  7. Granulocyte colony-stimulating factor mobilizes peripheral blood CD34+ cells in patients with type 2 diabetes mellitus%粒细胞集落刺激因子动员2型糖尿病患者外周血CD34+细胞的变化

    Institute of Scientific and Technical Information of China (English)

    窦立冬; 崔晓兰; 陈建河; 王立梅; 王意忠

    2011-01-01

    背景:与正常人比较,2型糖尿病患者外周血CD34+细胞含量已有明显下降.目的:分析2型糖尿病患者外周血动员后CD34+细胞比例的变化.方法:将234例2型糖尿病患者按病程分为5组(5~<10年,10~15年和≥15年),予以粒细胞集落刺激因子动员.动员5 d后,使用流式细胞仪检测外周血CD34+细胞的含量,并利用Person简单相关及多元回归方法分析其与病程、血脂、尿酸的关系.结果与结论:糖尿病者外周血动员后CD34+细胞水平与三酰甘油相关(r=-0.202,P=0.002),与载脂蛋白B相关(r=-0.276,P=0.000),与尿酸相关(r=-0.297,P=0.000).经统计分析发现,糖尿病者外周血动员后CD34+细胞数随糖尿病病程进展而逐渐下降.%AbstractBACKGROUND: The number of mobilized peripheral blood CD34+ cells significantly decreases in type 2 diabetes mellitus patients compared with normal subjects.OBJECTIVE: To investigate the changes of mobilized peripheral blood CD34+ cells in type 2 diabetes mellitus patients. METHODS: A total of 234 patients with type 2 diabetes mellitus were divided into five categories according to disease duration, newly diagnosed type 2 diabetes (≤1 year) and diabetes duration (1-5, 5-10, 10-15, ≥15 years). CD34+ cells were mobilized with granulocyte colony-stimulating factor. Five days later, the number of peripheral blood CD34+ cells was detected with flow cytometry. Its relationship with disease duration, blood lipids and uric acid was analyzed by person-related analysis and multiple regression analysis.RESULTS AND CONCLUSION: The number of mobilized peripheral blood CD34+ cells was associated with the triacylglycerol (r=-0.202, P=0.002), the apoprotein-B (r=-0.276, P=0.000), and the uric acid (r=-0.297, P=0.000). Statistical analysis found that, the number of mobilized peripheral blood CD34+ cells decreased with development of diabetes mellitus.

  8. Combination Therapy for Radiation-Induced Bone Marrow Aplasia in Nonhuman Primates Using Synthokine SC-55494 and Recombinant Human Granulocyte Colony-Stimulating Factor

    Science.gov (United States)

    1996-05-15

    treated animals ( P < .05). t Significantly different from rhG-CSF ( P < .05). Stain; Ames Automated Slide Stainer , Elkhart, IN). Baseline levels...Grant FJ, Heipel MD, Burkhead SK, Kramer JM, Bell LA, Sprecher CA, Blumber H, Johnson R, h n k a r d D, Ching AFT, Mathewes SL, Balley MC, Forstrom...Swift S, Johnson MJ, Hsu RY, Parker VP, Suggs S, Skrine ID, Merewether LA, Clogston C, Hsu E, Hokom MM, Homkohl A, Choi E, Pangeliana M, Sun Y, Mar

  9. Impacts of erythropoietin combined with granulocyte-colony stimulating factor on neural regeneration after traumatic brain injury in rats%促红细胞生成素与粒细胞集落刺激因子联合应用对创伤性脑损伤大鼠神经再生的影响

    Institute of Scientific and Technical Information of China (English)

    路贵; 段虎斌; 郝春艳; 葛立峰; 王艳玲

    2014-01-01

    Objective To investigate the effect of erythropoietin (EPO )and granulocyte-colony stimulating factor (G-CSF )combination therapy on functional recovery and nerve cell regeneration after traumatic brain injury(TBI)in rats.Methods Total 125 male Wistar rats were randomly divided into Sham operation group (Sham group ),traumatic brain injury group (TBI group ),EPO treatment group (T +E group),G-CSF treatment group(T+G group),and EPO combined G-CSF group(T+E+G group),and then each group was sub-divided into 5 subgroups according to the time 1,3,5,7 and 14 days after TBI(each subgroups n=5 ).The rats model with TBI were prepared by Feeney′s methods.Each treatment group rats were immediately given corresponding intervention measures after TBI for 3 days.Neurological function was assessed using a modified neurological severity score(mNSS)before rats were sacrificed at 1,3,5,7 and 14 days post TBI.Immunofluorescence measurement was used to detect newly proliferation cells number and its direction of differentiation by 5′-bromo-2-deoxyuridine (BrdU ) single positive cells and BrdU/neuronal nuclear antigen(NeuN)or BrdU/glial fibrillary acidic protein(GFAP)double positive cells.The differences of mNSS,hematological indexes,and immunofluorescence staining were compared by One-Way ANOVA and LSD-t test.Results (1 )The mNSS scores of each treatment group was significantly lower than TBI group (P<0.05),and T+E+G group was also significantly lower than T+E group or T+G group at 5,7 and 14 days of surgery.(2)The BrdU positive cells number in T+E +G group was significantly higher than other groups(P<0.05 )starting from 3 days after TBI,and the peak at 7 days.Compared the groups of brain tissue BrdU/NeuN and BrdU/GFAP double positive cells number,T+E +G group were significantly higher than other groups(P<0.05 ),T+E group and T+G group were significantly higher than Sham group and TBI group(P<0.05 ).Conclusion Combined use of EPO and G-CSF can obviously improve functional

  10. Granulocyte colony-stimulating factor induces neurogenesis and improves cognition in amyloid precursor protein transgenic mouse model of Alzheimer's disease%粒细胞集落刺激因子诱导淀粉样前体蛋白转基因小鼠神经再生及对认知功能的改善

    Institute of Scientific and Technical Information of China (English)

    朱正禹; 王萍; 郭雨霁; 谢兆宏; 来超; 毕建忠

    2012-01-01

    目的 探讨粒细胞集落刺激因子(G-CSF)对淀粉样前体蛋白(APP)转基因小鼠认知功能的改善及对神经再生的影响. 方法 选用36只APP转基因小鼠作为AD动物模型,随机分为G-CSF治疗组和对照组各18只.治疗组皮下注射G-CSF,对照组给予等体积磷酸盐缓冲液(PBS)皮下注射.给药后第7d、14d、28d进行Morris水迷宫测试,计算其逃避潜伏期.水迷宫测试后取外周血,利用流式细胞术观察G-CSF对骨髓造血干细胞的诱导作用.免疫组化及免疫荧光双标观察脑内神经元再生. 结果 与对照组比较,治疗组小鼠在第7d、14 d、28 d的逃避潜伏期分别为(27.19±4.07)s、(26.48±5.29)s、(24.97±3.61)s,较对照组明显缩短(P值分别为0.000、0.010、0.002);治疗组小鼠外周血CD 34+/CD 45双阳性细胞百分率在第7d、14 d、28 d分别为0.358±0.161、0.223±0.038、0.168±0.049,较对照组明显增加(P值分别为0.007、0.000、0.003),脑内检测到CD34′阳性细胞,海马齿状回、皮质均可见BrdU+阳性细胞,同时可检测到BrdU+/Nestin+和BrdU-/MAP-2+双阳性细胞. 结论 G-CSF皮下注射可明显改善APP转基因小鼠的认知功能,可能与动员外周骨髓造血干细胞增殖、分化,并向脑内定向迁移有关.%Objective To investigate the effect of granulocyte colony-stimulating factor(G-CSF)and its effect on the cognation in the PDGF hAPPV717I transgenic mice of Alzheimer's disease model.Methods Totally 36 PDGF hAPPV717I transgenic mice were randomly divided into two groups:G-CSF group and control group.The G CSF group was subcutaneously injected with 50 μg · kg-1 · d-1 of G-CSF for 7 days.The control group was injected subcutaneously with an equal volume of PBS in parallel.The animals were tested in Morris water maze on the 7th,14th,and 28th days after the last day of the injection,and the escape latency was recorded.Once the test was completed,the peripheral blood was taken to evaluate the effect of G

  11. The effect of autologous bone marrow-derived cells mobilized by granulocyte colony stimulating factor on bleomycin-induced lung injury in mice%粒细胞集落刺激因子动员自体骨髓源性细胞对博来霉素致小鼠肺损伤的治疗作用

    Institute of Scientific and Technical Information of China (English)

    姜寒水; 李惠萍; 胡洋; 褚建新; 陈岗; 张容轩; 郑卉

    2009-01-01

    显低于未重建对照组[33.9、(56±13)×10~3、(0.49±0.08)μg/mg、(53.6±8.7)×10~(-3)、(320±98)×10~3、(409±61)×10~3和(288±75)×10~3].重建动员组在第7大肺内BMDC表达的绿色荧光蛋白阳性细胞比例(0.65±0.13)明显高于重建对照组(0.46±0.11).结论 G-CSF动员BMDC对博来霉素所敛肺损伤有一定的保护作用,本实验方法尚不能明显延长小鼠的存活时间.%Objective To investigate the contribution of mobilized autologous bone marrow-derived cells ( BMDC) to lung repair after lung injury induced by bleomycin, and the mechanisms of any protective effects conferred by BMDC. Methods Sixty marrow-reconstructed mice were randomly divided into 2 groups: group A [bleomycin + granulocyte colony stimulating factor( G-CSF) ] and group B (bleomycin +saline). Seventy-five normal mice were randomly divided into 3 groups: group C (bleomycin + G-CSF) :group D (bleomycin + saline) and group N (saline only). Each group was further divided into 3 subgroups,which were sacrificed respectively on days 3, 7 and 14. Therapeutic evaluations were made by means of HE stain, Masson' s trichrome stain, hydroxyproline concentration and pulmonary permeability index. The expressions of TGF-β_1, IFN-γ, MMP-9 and TIMP-1 in the lung tissue were detected by immunohistochemistry. Intrapulmonary BMDC was evaluated by flow cytometry and laser scanning confocal microscope. Another 20 mice were randomly divided into 2 groups including group E ( bleomycin + G-CSF) and group F (bleomycin + saline). The survival time of each mouse was observed without end point Results The alveolitis score ( mean rank 15.3 ) , the pulmonary fibrosis score (46 ±8 ) , the hydroxyproline concentrations (0.44 ±0.09) μg/mg, the TGF-β_1, level (111 ±23), the IFN-γ level (250 ±72) and the MMP-9 level (59±19) were significantly decreased in reconstructed treatment group on day 7 as compared to reconstructed control group, which was respectively (mean rank 28.0) , (73 ± 10) , (0. 52 ±0. 07)

  12. Comparación de la eficacia y seguridad de la terapia combinada de cardiomioplastia celular con el factor estimulante de colonias de granulocitos en pacientes con cardiopatía isquémica en dos vías de implatación Comparison of efficacy and safety of combined therapy of cellular cardiomyoplasty and granulocyte colony stimulating factor in patients with ischemic cardiomyopathy in two routes of implantation

    Directory of Open Access Journals (Sweden)

    Juan M Senior

    2011-04-01

    ía sostenida de la fracción de eyección y los MET más allá de los beneficios que se logran con la revascularización y la terapia farmacológica óptima.The objective of this study is to assess efficacy and safety of combined therapy of cellular cardiomyoplasty and granulocyte colony stimulating factor in patients with ischemic cardiomyopathy and explore possible differences between the implantation routes. METHODOLOGY: we performed a before and after study for longitudinal data comparing echocardiographic variables and number of Met achieved in the stress test before and at two, six and twelve months after the procedure. Likewise, mortality and adverse therapy effects were evaluated. Differences in the results were analyzed according to the intracoronary vs. epicardiac route of implantation. RESULTS: eighteen patients were included; 62,3% men, with mean age 49.4 ± 11,7 years. Mean ejection fraction was 31% ± 0,04. In twelve patients implantation was performed by intracoronary route and in six by epicardiac route. Mean ejection fraction before cell implantation was 30% with an interquartil range (IQR of 28-35%, and MET average was 6 with an interquartil rage of 5-7. Both variables as well as end-systolic and end-diastolic volumes increased significantly after the procedure, with a tendency to greater increase in ejection fraction in the group of patients whose route was epicardial implantation compared with intracoronary route; however, the number of patients in each subgroup prevented to make a definitive analysis. One patient had surgical wound infection and three died two months after implantation (one of septic shock and two of cardiogenic shock. CONCLUSION: in our environment the performance of combination therapy with cellular cardiomyoplasty and granulocyte colony stimulating factor is feasible. This is a safe procedure that achieved a sustained improvement in ejection fraction and MET beyond benefits achieved with revascularization and optimal pharmacological

  13. Reviewing non clinical data for a granulocyte colony stimulatory factor product: experience in Brazil.

    Science.gov (United States)

    Castanheira, Laura Gomes

    2011-09-01

    Non clinical studies are one of the requirements for the Brazilian National Regulatory Authority, ANVISA, for licensing a similar biotherapeutic product. During the WHO/KFDA workshop on implementing WHO guidelines on evaluating similar biotherapeutic products (SBP) in Seoul, Republic of Korea, the Brazilian experience with the non clinical studies of a Granulocyte Colony Stimulatory Factor (G-CSF), filgrastim, was presented. The applicant presented a reduced non clinical data package, but the key studies with relevant species were conducted and the non-clinical studies were considered sufficient for approval. Using the comparability exercise, these studies were taken together with the appropriate quality and clinical packages presented. Copyright © 2011. Published by Elsevier Ltd.

  14. 单次大剂量足叶乙甙联合G-CSF用于恶性血液病患者自体外周血造血干细胞动员的临床研究%Clinical study on high-dose etoposide with granulocyte colony-stimulating factor for mobilization of autologous peripheral blood stem cells in patients with hematologic malignancies

    Institute of Scientific and Technical Information of China (English)

    沈文怡; 吴汉新; 李建勇; 洪鸣; 张闰; 陆化; 刘澎; 钱思轩; 徐卫; 仇红霞

    2012-01-01

    目的 探讨单次大剂量足叶乙甙(Vp16)静脉注射联合粒细胞集落刺激因子(G-CSF)用于恶性血液病患者自体外周血造血干细胞(APBSC)动员的有效性和安全性.方法 80例恶性血液病患者包括急性白血病(AL)20例、多发性骨髓瘤(MM)23例、非霍奇金淋巴瘤(NHL)35例、霍奇金淋巴瘤(HL)2例,均采用Vp16 1.6 g /m2匀速持续静脉注射10 h,外周血中性粒细胞计数(ANC)降至1×109/L时开始给予G-CSF 10 μg·kg-1·d-1皮下注射,至采集结束.WBC>5.0×109/L时开始APBSC采集,目标值:单个核细胞(MNC)≥6.0×108/kg且CD34+细胞≥2.0×106/kg.患者经预处理后回输自体外周血干细胞.观察动员采集过程中血液学指标变化、采集细胞数量、造血重建时间、不良反应等.结果 足叶乙甙应用后11(7~25) d开始干细胞采集,中位采集次数为2(1~5)次.80例患者中,APBSC动员失败3例,均为急性非淋巴细胞白血病(ANLL)患者;既往其他方案动员自体干细胞失败的6例患者中5例动员成功,1例既往阿糖胞苷动员失败的ANLL-M5患者足叶乙甙动员仍失败;77例患者CD34+细胞中位数为4(1.59~24.68)×106/kg,其中3例患者CD34+细胞未达2×106/kg,但移植后造血顺利重建.对20例AL和23例MM患者采集物行微量残留病检测,未发现采集物残留肿瘤细胞污染.所有患者均良好耐受动员、采集过程.80例患者在干细胞动员过程中,Ⅳ度白细胞减少发生率为36.25%(29/80),感染发生率为23.75%(19/80).结论 单次大剂量足叶乙甙联合G-CSF动员APBSC总体成功率高,不良反应可控,是恶性血液病患者动员采集APBSC安全有效的方案.%Objective To explore the effectivity and safety of single high-dose(HD) etoposide(Vp16) with granulocyte colony-stimulating factor(G-CSF) for mobilization of autologous peripheral blood stem cells(PBSC) in patients with hematologic malignancies. Methods 80 patients of hematologic malignancies including 20 patients

  15. O fator estimulador de colônias granulocitárias (G-CSF para isquemia cerebral: uma nova aplicação terapêutica? Granulocyte colony-stimulating factor (G-CSF for ischemic stroke: a new therapeutic modality?

    Directory of Open Access Journals (Sweden)

    Angelo Luiz Maset

    2007-12-01

    Full Text Available G-CSF is a FDA-approved drug, commonly utilized in neutropenic patients, long knows for its anti-inflammatory and angiogenic properties and also for its capacity to mobilize stem cells, hematopoiethic and endogen precursors and progenitor cells. Recently neuroprotective effects have been shown in animals and humans and there are publications mentioning its potential therapeutic role in focal ischemia (medial cerebral artery territory. We describe a case of a 74-year-old male patient, victim of a subarachnoid hemorrhage and brain ischemia due to bilateral involvement of medial cerebral arteries and vertebrobasilar vasospasms (overall ischemia, who was submitted to G-C5F therapy. G-CSF did not cause adverse effects, mobilized cells (as was seen by the exponential increase in leukocytes and possibly contributed to a progressive clinical improvement confirmed using GCS and NIHSS scales. Clinical improvements did not reflect in eithrt CT, MNR or SPECT examinations. This initial experience opens the perspective for G-CSF studies in brain ischemia.

  16. 131I对Graves病外周血粒细胞集落刺激因子和白细胞的影响%Effects of 131I treatment on the circulating granulocyte colony-stimulating factor and leucocyte levels in patients with Graves' disease

    Institute of Scientific and Technical Information of China (English)

    蔡强军; 潘芙蓉; 张琦; 李焕斌; 夏玉祥; 谢克俭

    2011-01-01

    Objective To observe the effects of 131I treatment on circulating granulocyte colonystimulating factor (G-CSF) and leucocyte levels of patients with Graves' disease (GD).Methods Enzyme-linked immunosorbent assay (ELISA),coulter three assortments,and radioimmunoassay were used to test the levels of circulating G-CSF,leucocytes and thyroid hormones of 65 incipient and untreated GD patients,all females,aged 21 -50,43 with normal leucocyte level and 22 with leucopenia before and after 131I treatment.Thirty age-matched healthy female subjects were used as controls.Results Before 131I treatment,the serous G-CSF level of the GD patients with normal leucocyte level was (28.4 ± 11.7)μg/L,significantly higher than that of the control [ ( 18.3 ± 6.98) μg/L,t =2.376,P < 0.05 ].The serous G-CSF level of the GD patients with leucopenia was (40.1 ± 13.8 ) μg/L,significantly higher than that of the patients with normal leucocyte level ( t =2.788,P < 0.01 ) and that of the control ( t =3.672,P<0.01 ).180 d after the initiation of 131 I treatment,the G-CSF level of the patients with normal leucocyte level was (18.9 ± 8.32) μg/L,not significantly different from that of the normal controls,however,the G-CSF level of the GD patients with leucopenia was (25.7 ± 11.5) μg/L,still significantly higher than that of the normal control (t =2.103,P < 0.05).The serous G-CSF level was negatively correlated with the titer of leucocyte ( r =- 0.38,P < 0.05 ),however,not significantly correlated with such clinical parameters,as free triiodothyronine (FT3),free thyroxine (FT4) and thyrotropin-stimulating hormone (TSH).Conclusions Abnormal increment of G-CSF is observed in the GD patients,which may be related to the decrease of leucocyte.Effectively suppressing the auto-immune status in the GD patients,131I treatment is a safe and reliable therapy for GD patients with leucopenia and should be used as early as possible.%目的 探讨131I治疗Graves病(GD)对患者外周血粒细

  17. The preparation of 6x His-tagged granulocyte colony stimulating ...

    African Journals Online (AJOL)

    Jane

    This was done to overcome the problems associated ... pIVEX 2.4d vector and transformation of the produced construct in chemically competent ..... This organization allows RNA to ... According to our cloning strategy, a restriction enzyme .... mase secreted by resistant bacterial cells. .... the design of an industrial process.

  18. Granulocyte-colony stimulating factor improves MDX mouse response to peripheral nerve injury.

    Directory of Open Access Journals (Sweden)

    Gustavo Ferreira Simões

    Full Text Available BACKGROUND: G-CSF has been shown to increase neuronal survival, which may positively influence the spinal cord microenvironment during the course of muscular dystrophies. METHODOLOGY/PRINCIPAL FINDINGS: Male MDX mice that were six weeks of age received a left sciatic nerve transection and were treated with intraperitoneal injections of 200 µg/kg/day of G-CSF 7 days before and 7 days after the transection. The axotomy was performed after the cycles of muscular degeneration/regeneration, consistent with previous descriptions of this model of muscular dystrophy. C57BL/10 mice were used as control subjects. Seven days after the surgery, the animals were sacrificed and their lumbar spinal cords were processed for immunohistochemistry (anti-MHC I, anti-Synaptophysin, anti-GFAP and anti-IBA-1 and transmission electron microscopy. MHC I expression increased in both strains of mice after the axotomy. Nevertheless, the MDX mice displayed a significantly smaller MHC I upregulation than the control mice. Regarding GFAP expression, the MDX mice showed a stronger astrogliosis compared with the C57BL/10 mice across all groups. Both groups that were treated with G-CSF demonstrated preservation of synaptophysin expression compared with the untreated and placebo groups. The quantitative analysis of the ultrastructural level showed a preservation of the synaptic covering for the both groups that were treated with G-CSF and the axotomized groups showed a smaller loss of synaptic contact in relation to the treated groups after the lesion. CONCLUSIONS/SIGNIFICANCE: The reduction of active inputs to the alpha-motoneurons and increased astrogliosis in the axotomized and control groups may be associated with the cycles of muscle degeneration/regeneration that occur postnatally. The G-CSF treated group showed a preservation of the spinal cord microenvironment after the lesion. Moreover, the increase of MHC I expression in the MDX mice that were treated with G-CSF may indicate that this drug performs an active role in regenerative potential after lesions.

  19. 转人粒细胞集落刺激因子(hG-CSF)基因的鱼腥藻的构建%Construction of Anabaena Transferred the Gene Encoding the Human Granulocyte Colony-stimulating Factor

    Institute of Scientific and Technical Information of China (English)

    陈翠丽; 施定基

    2005-01-01

    本研究目的是构建转G-CSF基因的工程鱼腥藻Anabaena sp..首先将b型G-CSF克隆于中间载体pRL 439和穿梭表达载体pDC-8上.通过三亲接合转移将穿梭表达载体pDCG-CSF转入鱼腥藻内.通过PCR扩增的方法在转基因鱼腥藻中检测到G-CSF基因的存在.

  20. The Potential Role of Recombinant Hematopoietic Colony-Stimulating Factors in Preventing Infections in the Immunocompromised Host

    Directory of Open Access Journals (Sweden)

    James Rusthoven

    1991-01-01

    Full Text Available Hematopoietic colony-stimulating factors coordinate the proliferation and maturation of bone marrow and peripheral blood cells during normal hematopoiesis. Most of these factors are now available as recombinant human colony-stimulating factors, and preclinical and clinical testing is proceeding rapidly. Granulocyte and granulocyte/macrophage colony-stimulating factors have been the most extensively studied to date. In human clinical trials, granulocyte colony-stimulating factor improves neutrophil counts and function, reduces episodes of febrile neutropenia, improves neutrophil recovery after disease- or treatment-induced myelosuppression, and reduces the number of serious infections in several neutropenic disease states. Granulocyte/macrophage colony-stimulating factor has similar biological properties but may also improve eosinophil proliferation and function, and platelet cell recovery after myelotoxic bone marrow injury, Interleukin-1 boosts the effects of granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, but also may promote the resolution of established infections in conjunction with antibiotics. The therapeutic realities and future therapeutic implications of these agents for the therapy of infections, cancer and hemopoietic disorders are discussed.

  1. Recombinant human IL-3 and G-CSF act synergistically in stimulating the growth of acute myeloid leukemia cells.

    Science.gov (United States)

    Pébusque, M J; Faÿ, C; Lafage, M; Sempéré, C; Saeland, S; Caux, C; Mannoni, P

    1989-03-01

    The effects of combinations of recombinant human growth factors (colony-stimulating factor (CSF], interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF) for inducing proliferation of leukemic cells were compared in 27 acute myeloid leukemias (AMLs). While functional heterogeneity of AML was clearly shown, we further demonstrated that optimal growth may be obtained with combinations of CSF. The most striking feature was that, in both suspension and semisolid cultures, IL-3 and G-CSF acted synergistically in supporting AML cell proliferation except in cases for which G-CSF was found to be an inhibitory factor. In the majority of cases, the proliferative effects of the IL-3 and GM-CSF combination were significantly higher than the most potent of either factor present alone in the cultures. Finally, preincubation with IL-3 greatly potentiated the responsiveness of AML cells to subsequent addition of either GM-CSF or G-CSF. These results indicate that AML cells respond to growth factor in the same way as normal hemopoietic cells and that stimulation by a second late-acting growth factor such as G-CSF is also required to yield optimal growth.

  2. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia

    NARCIS (Netherlands)

    Lowenberg, B; van Putten, W; Theobald, M; Gmur, J; Verdonck, L; Sonneveld, P; Fey, M; de Greef, G; Ferrant, A; Kovacsovics, T; Gratwohl, A; Daenen, S; Huijgens, P; Boogaerts, M

    2003-01-01

    BACKGROUND Sensitization of leukemic cells with hematopoietic growth factors may enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML). METHODS In a multicenter randomized trial, we assigned patients (age range, 18 to 60 years) with newly diagnosed AML to receive cytarabine plus i

  3. Clinical outcome after stem cell mobilization with granulocyte-colony-stimulating factor after acute ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Ripa, Rasmus Sejersten; Jørgensen, Erik; Kastrup, Jens

    2013-01-01

    cardiovascular-related hospital admittance, (3) first major cardiovascular event, and (4) death. Results. One patient (1%) was lost to follow-up. Four patients (4%) died in the follow-up period, three in the G-CSF group and one in the placebo group (p = 0.4). Hazard ratio for all cause hospital admittance was 0.......7 (95% CI 0.38-1.29). The incidence of both new myocardial infarction (p = 1.0) and revascularization procedures (p = 0.4) were similar in the two groups. Survival analyses showed no differences in the occurrence of any of the four prespecified composite endpoints between the two groups (p = 0.6; 0.5; 0...

  4. OK-432 reduces mortality and bacterial translocation in irradiated and granulocyte-colony stimulating factor (G-CSF)-treated mice

    Energy Technology Data Exchange (ETDEWEB)

    Nose, Masako; Uzawa, Akiko; Ogyu, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan); Suzuki, Gen

    2001-06-01

    Acute radiation induces bacterial translocation from the gut, followed by systemic infection and sepsis. In order to reduce the mortality after acute whole body irradiation, it is essential to control bacterial translocation. In this study, we established a bacterial translocation assay as a sensitive method to detect minor mucosal injury by radiation. By utilizing this assay, we evaluated the adverse effects, if any, of hematopoietic reagents on the mucosal integrity in the respiratory and gastro-intestinal tracts. Bacterial translocation to the liver and spleen occurred after whole-body irradiation if the dose exceeded 6 Gy. The administration of G-CSF unexpectedly increased the bacterial translocation in 8 Gy-irradiated mice. The pharmaceutical preparation of low-virulent Streptococcus pyogenes, OK-432, significantly reduced the endotoxin levels in peripheral blood without any reduction of bacterial translocation. A combined treatment with G-CSF and OK-432 decreased bacterial translocation and prevented death. This result indicates that the early administration of G-CSF has an adverse effect on bacterial translocation, and that a combined treatment of G-CSF and OK-432 attenuates the adverse effect of G-CSF and improves the survival rate after acute irradiation. (author)

  5. Mobilization of bone marrow stem cells by granulocyte colony-stimulating factor ameliorates radiation-induced damage to salivary glands

    NARCIS (Netherlands)

    Lombaert, IMA; Wierenga, PK; Kok, T; Kampinga, HH; deHaan, G; Coppes, RP

    2006-01-01

    Purpose: One of the major reasons for failure of radiotherapeutic cancer treatment is the limitation in dose that can be applied to the tumor because of coirradiation of the normal healthy tissue. Late radiation-induced damage reduces the quality of life of the patient and may even be life threateni

  6. Human Tissue Stimulator

    Science.gov (United States)

    1982-01-01

    Neurodyne Corporation Human Tissue Stimulator (HTS) is a totally implantable system used for treatment of chronic pain and involuntary motion disorders by electrical stimulation. It was developed by Pacesetter Systems, Inc. in cooperation with the Applied Physics Laboratory. HTS incorporates a nickel cadmium battery, telemetry and command systems technologies of the same type as those used in NASA's Small Astronomy Satellite-3 in microminiature proportions so that the implantable element is the size of a deck of cards. The stimulator includes a rechargeable battery, an antenna and electronics to receive and process commands and to report on its own condition via telemetry, a wireless process wherein instrument data is converted to electrical signals and sent to a receiver where signals are presented as usable information. The HTS is targeted to nerve centers or to particular areas of the brain to provide relief from intractable pain or arrest involuntary motion. The nickel cadmium battery can be recharged through the skin. The first two HTS units were implanted last year and have been successful. Extensive testing is required before HTS can be made available for general use.

  7. 聚乙二醇化重组人粒细胞刺激因子注射液Ⅰ期临床耐受性试验%Phase Ⅰ clinical trail tolerance of pegylated recombinant human granulocyte colony-stimulating factor injection

    Institute of Scientific and Technical Information of China (English)

    孙成春; 王宝成; 毕经旺; 吕伟伟; 胡君莉; 康长清; 张立志

    2013-01-01

    目的:评价聚乙二醇化重组人粒细胞刺激因子(PEG-rhG-CSF)用于肿瘤患者的安全性和耐受性,初步观察化疗后PEG-rhG-CSF升高外周血中性粒细胞的效果.方法:本研究为单中心、开放性剂量递增试验.所有受试者采用1d化疗方案,于化疗药物给药结束后48 h给予PEG-rhG-CSF.PEG-rhG-CSF的初始剂量为30 μg/kg,递增剂量依次为60、100、150、200 μg/kg,每一剂量组3例受试患者.结果:入组15例患者均可评价疗效和安全性.与PEG-rhG-CSF相关的不良反应主要有乏力4例(4/15),肌肉酸痛1例(1/15),均为1度,无需特殊处理.无PEG-rhG-CSF的剂量限制性毒性.PEG-rhG-CSF对中性粒细胞的升高均有较为明确的效果,维持时间较长,有明显的量效关系.结论:PEG-rhG-CSF显示良好的耐受性,未出现严重不良事件.%To evaluate the safety and tolerance of PEG-rhG-CSF in tumor patients, and to explore its efficacy of enhancing absolute neutrphil count(ANC). METHODS: This study was open-labeled, dose-escalation trial. All patients received 1 day chemotherapy. Patients received a single injection of PEG-rhG-CSF (30, 60,100,150, or 200 jug/kg) 48 h after administration of chemotherapy drug. Each dose group had 3 patients. RESULTS: All the 15 patients enrolled were evaluable for safety and efficacy of PEG-rhG-CSF. Main adverse events related to PEG-rhG-CSF were fatigue ( 4/15 ), musculo-skeletal pain (1/15). All adverse events were mild, and they were reversible without treatment. PEG-rhG-CSF enhanced ANC in a dose-dependent manner to some extent. CONCLUSION: PEG-rhG-CSF is well tolerated, with no serious adverse event in this trial.

  8. 聚乙二醇化重组人粒细胞集落刺激因子预防化疗后中性粒细胞减少症临床疗效观察%A Randomized Controlled Clinical Study of Pegylated Recombinant Human Granulocyte Colony-stimulating Factor in Chemotherapy-induced Neutropenia Shiyong

    Institute of Scientific and Technical Information of China (English)

    周世勇; 崔秀珍; 王华庆; 张会来; 邱立华; 钱正子; 李维; 侯芸; 付凯; 刘贤明

    2011-01-01

    目的:比较聚乙二醇化重组人粒细胞集落刺激因子 (PEG-rhG-CSF) 和重组人粒细胞集落刺激因子 (rhG-CSF) 预防化疗后中性粒细胞减少症的有效性和安全性.方法:采用随机自身交叉对照,选择初治恶性肿瘤患者接受2个周期相同方案的化疗,其中试验周期给予PEG-rhG-CSF 100 μg/kg皮下注射一次,对照周期每日一次皮下注射rhG-CSF 5 μg/kg,直至外周血中性粒细胞绝对值 (ANC) 在低谷后连续两次检查≥5.0×109/L.结果:入组78例患者,在76个试验周期和74个对照周期中,ANC 5.0 ×109/L twice post nadir, whichever occurred first. The efficacy and safety parameters were monitored. Results: The incidence of ANC < 1.5 × 109/L in 76 evaluable study cycles and 74 evaluable control cycles were 30.00% and 21.00%, with durations of 2.34 days and 2.31 days, respectively Additionally, those with grade 4 neutropenia were 3.80% and 3.00%, respectively, in the trial and control cycles. The differences above were not statistically significant. None of the patients experienced febrile neutropenia after receiving PEG-rhG-CSF and rhG-CSF. Compared with that of rhG-CSF, the ANC profile of PEG-rhG-CSF exhibited limited "overshoot" of neutrophils after the nadir. Subgroup analysis according to disease type yielded similar results. The safety profiles of PEG-rhG-CSF and rhG-CSF were similar. Musculoskeletal pain or arthralgias occurred in 16.5% of the cases during the study cycles and 26.00% in the control cycles ( P= 0.963 ), which were mostly mild or moderate. Other adverse effects, such as fever, fatigue, dizziness, gastrointestinal effects and injection-site pain, were transient and easily manageable. Conclusion: A single subcutaneous injection of 100 ug/kg PEG-rhG-CSF provides neutrophil support and a safety profile comparable to daily subcutaneous injections of 5 ug/kg/d rhG-CSF in Chinese patients receiving a variety of myelosuppressive chemotherapy regimens.

  9. Consensus on the use of neutrophil-stimulating hematopoietic growth factors in clinical practice : An international viewpoint

    NARCIS (Netherlands)

    Rusthoven, JJ; deVries, EGE; Dale, DC; Piccart, M; Glaspy, J; Hamilton, A

    1997-01-01

    Hematopoietic growth factors (CSFs) are now available for use in patients with myelosuppression due to congenital, acquired and therapy-induced conditions. Variations in the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in differen

  10. HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors.

    Science.gov (United States)

    Hakki, Morgan; Goldman, Devorah C; Streblow, Daniel N; Hamlin, Kimberly L; Krekylwich, Craig N; Fleming, William H; Nelson, Jay A

    2014-01-01

    Human cytomegalovirus (HCMV) infection, including primary infection resulting from transmission from a seropositive donor to a seronegative recipient (D(+)/R(-)), remains a significant problem in the setting of peripheral blood stem cell transplantation (PBSCT). The lack of a suitable animal model for studying HCMV transmission after PBSCT is a major barrier to understanding this process and, consequently, developing novel interventions to prevent HCMV infection. Our previous work demonstrated that human CD34(+) progenitor cell-engrafted NOD-scid IL2Rγc(null) (NSG) mice support latent HCMV infection after direct inoculation and reactivation after treatment with granulocyte colony-stimulating factor. To more accurately recapitulate HCMV infection in the D(+)/R(-) PBSCT setting, granulocyte colony-stimulating factor-mobilized peripheral blood stem cells from seropositive donors were used to engraft NSG mice. All recipient mice demonstrated evidence of HCMV infection in liver, spleen, and bone marrow. These findings validate the NSG mouse model for studying HCMV transmission during PBSCT.

  11. Enhancement of innate immunity with granulocyte colony-stimulating factor did not mitigate disease in pigs infected with a highly pathogenic Chinese PRRSV strain

    Science.gov (United States)

    Porcine reproductive and respiratory syndrome virus (PRRSV) is responsible for one of the most economically important diseases in swine worldwide. It causes reproductive failure in sows and pneumonia in pigs that predisposes them to secondary bacterial infections. Methods to control PRRSV and/or lim...

  12. Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial

    National Research Council Canada - National Science Library

    England, Timothy J; Abaei, Maryam; Auer, Dorothee P; Lowe, James; Jones, D Rhodri E; Sare, Gillian; Walker, Marion; Bath, Philip M W

    2012-01-01

    ...(+) peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. G-CSF (10 μg/kg) or placebo (ratio 2:1...

  13. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

    NARCIS (Netherlands)

    Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C.; Graux, Carlos; Vekemans, Marie-Christiane; Biemond, Bart; Sonneveld, Peter; Passweg, Jakob; Verdonck, Leo; Legdeur, Marie-Cecile; Theobald, Matthias; Jacky, Emanuel; Bargetzi, Mario; Maertens, Johan; Ossenkoppele, Gert Jan; Lowenberg, Bob

    2012-01-01

    The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cyta

  14. A randomized study of granulocyte colony-stimulating factor applied during and after chemotherapy in patients with poor risk myelodysplastic syndromes : a report from the HOVON Cooperative Group

    NARCIS (Netherlands)

    Ossenkoppele, GJ; van der Holt, B; Verhoef, GEG; Daenen, SMGJ; Verdonck, LF; Sonneveld, P; Wijermans, PW; van der Lelie, J; van Putten, WLJ; Lowenberg, B

    1999-01-01

    The purpose of this study was to determine the safety and efficacy of filgrastim as an adjunct to induction and consolidation chemotherapy in poor risk patients with myelodysplastic syndrome (MDS). Filgrastim was given both during and after chemotherapy with the objective to accelerate hematopoietic

  15. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor

    NARCIS (Netherlands)

    J.H. Jansen (Joop); M.C. de Breems-de Ridder (Marleen); W.M. Geertsma; C.A.J. Erpelinck (Claudia); K. van Lom (Kirsten); R. Slater (Rosalyn); B.A. van der Reijden (Bert); G.E. de Greef (Georgine); P. Sonneveld (Pieter); B. Löwenberg (Bob); E.M.E. Smit (Elisabeth)

    1999-01-01

    textabstractThe combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted

  16. Pretransplant mobilization with granulocyte colony-stimulating factor improves b-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice

    NARCIS (Netherlands)

    M.W. Huston (Marshall W.); A.R.A. Riegman (Adriaan R.A.); R. Yadak (Rana); Y.M. van Helsdingen (Yvette); H. De Boer (Helen); N.P. van Til (Niek); G. Wagemaker (Gerard)

    2014-01-01

    textabstractHematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to impr

  17. Febrile Neutropenia Risk Assessment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens

    DEFF Research Database (Denmark)

    Salar, Antonio; Haioun, Corinne; Rossi, Francesca Gaia

    2009-01-01

    at lower risk), and only around two-thirds of patients received optimal chemotherapy RDI. Our data suggest that improvements in neutropenia management are required. More consistent use of G-CSF primary prophylaxis may further reduce FN and assist in optimal chemotherapy delivery. Sponsored by Amgen...... Disclosures: Salar: Amgen: Honoraria. Haioun: Roche: Research Funding; Amgen: Other, Research Funding; Celgene: Other, Research Funding; Mundipharma: Research Funding. Pettengell: Amgen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jaeger: Amgen: Research...

  18. Response to recombinant erythropoietin alpha, without the adjunct of granulocyte-colony stimulating factor, is associated with a longer survival in patients with transfusion-dependent myelodysplastic syndromes.

    Science.gov (United States)

    Musto, Pellegrino; Villani, Oreste; Martorelli, Maria Carmen; Pietrantuono, Giuseppe; Guariglia, Roberto; Mansueto, Giovanna; D'Auria, Fiorella; Grieco, Vitina; Bianchino, Gabriella; Sparano, Anna; Zonno, Antonia; Lerose, Rosa; Sanpaolo, Grazia; Falcone, Antonietta

    2010-08-01

    This was a retrospective, comparative study focused on the extended follow-up of 192 transfusion-dependent patients with myelodysplastic syndromes treated (n. 83) or not treated (n. 109) with recombinant erythropoietin alpha (r-EPO) as single agent during the course of their disease. The results supported the safety of this treatment in the long term and also showed a significant survival advantage (median 52 months vs. 31 months, p<0.0095) in responding patients as compared to non-responding ones or to subjects never treated with r-EPO. At multivariate analysis, response to r-EPO maintained an independent prognostic value on OS.

  19. The treatment of skin ulcers in systemic sclerosis: use of granulocyte-colony stimulating factor (G-CSF in 26 patients

    Directory of Open Access Journals (Sweden)

    Andrea Caruso

    2011-09-01

    Full Text Available Objectives: To verify the effectiveness of G-CSF in the treatment of non-healing skin lesions in SSc patients. Methods: 26 SSc patients (23 F and 3 M, age 54 ±13,6 yrs with skin ulcers were enrolled in a pilot study. Prior to the treatment with G-CSF, all ulcers failed to heal with conventional therapies carried out for a period of 1-5 years. All patients were treated with 5μg/kg G-CSF subcutaneously for 5 days. Healing time, quality of wounds, VAS and HAQ-DI were used to evaluate the efficacy of the treatment. Results: An improvement of skin ulcers was observed in 24/26 patients; in particular, 22/26 wounds completely healed, 2/26 showed a partial healing, in only 2 patients skin ulcers did not change during the 6-month follow-up. The quality of life improves as showed by VAS (from 88±13 to 55±28; p<.0001 and HAQ (from 2.12 ±0.45 to 1.28±0.30; p<.0001. The eradication of pathogens from the infected ulcers was also observed in 12/12 patients; while no adverse side effects related to G-CSF were recorded. Our study suggests that G-CSF may be usefully employed in scleroderma skin ulcers refractory to conventional treatments.

  20. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

    NARCIS (Netherlands)

    F. Dong (Fan); R.K. Brynes; N. Tidow; K. Welte (Karl); B. Löwenberg (Bob); I.P. Touw (Ivo)

    1995-01-01

    textabstractBACKGROUND. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction

  1. Acute iritis induced by granulocyte colony-stimulating factor used for mobilization in a volunteer unrelated peripheral blood progenitor cell donor.

    Science.gov (United States)

    Parkkali, T; Volin, L; Sirén, M K; Ruutu, T

    1996-03-01

    We describe a volunteer unrelated peripheral blood progenitor cell donor with previously diagnosed dermatitis herpetiformis in whom the administration of G-CSF for the mobilization of precursor cells induced acute iritis. G-CSF has been administered to healthy people with minimal side-effects but when used in patients with autoimmune disorders worsening of symptoms or new manifestations may be a potential concern.

  2. Febrile Neutropenia Risk Assessment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens

    DEFF Research Database (Denmark)

    Salar, Antonio; Haioun, Corinne; Rossi, Francesca Gaia;

    2009-01-01

    Disclosures: Salar: Amgen: Honoraria. Haioun: Roche: Research Funding; Amgen: Other, Research Funding; Celgene: Other, Research Funding; Mundipharma: Research Funding. Pettengell: Amgen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jaeger: Amgen: Research...

  3. The anti-inflammatory role of granulocyte colony-stimulating factor in macrophage-dendritic cell crosstalk after Lactobacillus rhamnosus GR-1 exposure.

    Science.gov (United States)

    Martins, Andrew J; Spanton, Sarah; Sheikh, Haroon I; Kim, Sung Ouk

    2011-06-01

    MΦs are important sensory cells of the innate immune system and regulate immune responses through releasing different combinations of cytokines. In this study, we examined whether cytokines released by MΦs in response to the probiotic bacterial strain GR-1 modulate the responses of DCs. The cytokine profile released by GR-1-treated MΦs was characterized by low levels of TNF-α, GM-CSF, IL-6, and IL-12 but very high levels of G-CSF. GR-1 CM did not induce expression of the shared p40 subunit of IL-12 and IL-23 and costimulatory molecules CD80 or CD86 or increase T cell stimulatory capacity in DCs. However, in G-CSFR-deficient DCs or after antibody-mediated neutralization of G-CSF, GR-1 CM induced IL-12/23 p40 production significantly, indicating that G-CSF within the GR-1 CM inhibits IL-12/23 p40 production induced by other CM components. GR-1 CM and rG-CSF also inhibited LPS-induced IL-12 production at the mRNA and protein levels. The inhibition of IL-12 production by G-CSF was at least in part mediated through inhibition of JNK activation. Finally, splenic DCs of GR-1-injected mice produced less IL-12/23 p40 than those of PBS-injected mice in response to LPS ex vivo, and this was at least partially dependent on exposure to GR-1-induced G-CSF in vivo. Altogether, these results suggest that G-CSF modulates the IL-12/23 p40 response of DCs in the context of the probiotic GR-1 through MΦ-DC crosstalk.

  4. A Kunjin replicon vector encoding granulocyte macrophage colony-stimulating factor for intra-tumoral gene therapy

    NARCIS (Netherlands)

    Hoang-Le, D.; Smeenk, L.; Anraku, I.; Pijlman, G.P.; Wang, X.J.; Vrij, de J.; Liu, W.J.; Le, T.T.; Schroder, W.A.; Khromykh, A.A.; Suhrbier, A.

    2009-01-01

    We have recently developed a non-cytopathic RNA replicon-based viral vector system based on the flavivirus Kunjin. Here, we illustrate the utility of the Kunjin replicon system for gene therapy. Intra-tumoral injections of Kunjin replicon virus-like particles encoding granulocyte colony-stimulating

  5. [Clinical use of recombinant human thrombopoietin. Status and perspectives].

    Science.gov (United States)

    Hansen, P B; Hasselbalch, H C

    2001-05-07

    Thrombopoietin (TPO) is primarily produced by hepatocytes and regulates the production and differentiation of megakaryocytes and platelets in the bone marrow. The endogenous TPO level is increased when the megakaryocyte count is low, and high in aplastic anaemia and after myeloablative chemotherapy. TPO is cloned and manufactured by a recombinant technique for clinical use. Treatment with recombinant human TPO (rhTPO) after intensive chemotherapy may reduce the need for platelet transfusions. Administration of granulocyte colony-stimulating factor in combination with rhTPO has enhanced the mobilisation and harvest product of haematopoietic stem cells. Whether rhTPO is effective in the treatment of the myelodysplastic syndrome, aplastic anaemia, and other conditions with bone marrow insufficiency (including AIDS) is not yet known. In liver cirrhosis, the endogenous TPO level rapidly increases after liver transplantation. Accordingly, substitution of rhTPO may be indicated in advanced liver failure complicated by thrombocytopenia and bleeding.

  6. Gene expression profiling of human erythroid progenitors by micro-serial analysis of gene expression.

    Science.gov (United States)

    Fujishima, Naohito; Hirokawa, Makoto; Aiba, Namiko; Ichikawa, Yoshikazu; Fujishima, Masumi; Komatsuda, Atsushi; Suzuki, Yoshiko; Kawabata, Yoshinari; Miura, Ikuo; Sawada, Ken-ichi

    2004-10-01

    We compared the expression profiles of highly purified human CD34+ cells and erythroid progenitor cells by micro-serial analysis of gene expression (microSAGE). Human CD34+ cells were purified from granulocyte colony-stimulating factor-mobilized blood stem cells, and erythroid progenitors were obtained by cultivating these cells in the presence of stem cell factor, interleukin 3, and erythropoietin. Our 10,202 SAGE tags allowed us to identify 1354 different transcripts appearing more than once. Erythroid progenitor cells showed increased expression of LRBA, EEF1A1, HSPCA, PILRB, RANBP1, NACA, and SMURF. Overexpression of HSPCA was confirmed by real-time polymerase chain reaction analysis. MicroSAGE revealed an unexpected preferential expression of several genes in erythroid progenitor cells in addition to the known functional genes, including hemoglobins. Our results provide reference data for future studies of gene expression in various hematopoietic disorders, including myelodysplastic syndrome and leukemia.

  7. Alpha-1-antitrypsin is produced by human neutrophil granulocytes and their precursors and liberated during granule exocytosis

    DEFF Research Database (Denmark)

    Clemmensen, Stine N; Jacobsen, Lars C; Rørvig, Sara

    2011-01-01

    1AT is produced at all stages of myeloid maturation in the bone marrow. The production increases as neutrophils enter circulation and increases further upon migration to tissues as observed in skin windows and when blood neutrophils are incubated with granulocyte colony-stimulating factor...

  8. Transcranial electrical stimulation accelerates human sleep homeostasis.

    Directory of Open Access Journals (Sweden)

    Davide Reato

    Full Text Available The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO in the human electro-encephalogram (EEG. A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep.

  9. rhCSF3 accelerates the proliferation of human melanocytes in culture through binding CSF3R and the expression of CSF3R transcripts.

    Science.gov (United States)

    Lu, Yan; Guo, Ze; Zhou, Mei-Hua; Li, Xue; Sun, Jie; Gong, Qing-Li; Zhu, Wen-Yuan

    2015-05-01

    Melanogenic paracrine and autocrine cytokine networks have recently been discovered in vitro between melanocytes and other types of skin cells. Granulocyte colony-stimulating factor receptor (CSF3R) controls the survival, proliferation and differentiation of many kinds of cells, including neutrophils. To understand the function of CSF3R and recombinant human granulocyte colony-stimulating factor (rhCSF3) on melanocyte proliferation, this study compared the expression of CSF3R and the effects of rhCSF3 in primary human melanocytes, neutrophils and HEL 92.1.7 cells. The results show that CSF3R is localized in the cytoplasm and on cell membranes of melanocytes and neutrophils. The percentage of CSF3R(+) melanocytes was higher than CSF3R(+) HEL 92.1.7 cells, but was lower than CSF3R(+) neutrophils. Both CSF3R mRNA and CSF3R protein levels in melanocytes were higher than in HEL 92.1.7 cells, but were lower than in neutrophils. Treatment with rhCSF3 increased the proliferation of human melanocytes, but not their tyrosinase activity. Transcripts of CSF3R in human melanocytes, M14, A375 melanoma and A431 squamous cell carcinoma cells were also detected. Expression of the CSF3R V3 transcript was lower in melanocytes than in M14, A375 melanoma and A431 squamous cell carcinoma cells. In conclusion, rhCSF3 can promote melanocyte proliferation through CSF3R without affecting tyrosinase activity.

  10. Transcranial magnetic stimulation and the human brain

    Science.gov (United States)

    Hallett, Mark

    2000-07-01

    Transcranial magnetic stimulation (TMS) is rapidly developing as a powerful, non-invasive tool for studying the human brain. A pulsed magnetic field creates current flow in the brain and can temporarily excite or inhibit specific areas. TMS of motor cortex can produce a muscle twitch or block movement; TMS of occipital cortex can produce visual phosphenes or scotomas. TMS can also alter the functioning of the brain beyond the time of stimulation, offering potential for therapy.

  11. Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5)

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, H.D.; Tucker, W.Q.J.; Hort, Y.; Martinson, M.E.; Mayo, G.; Clutterbuck, E.J.; Sanderson, C.J.; Young, I.G.

    1987-10-01

    The human eosinophil differentiation factor (EDF) gene was cloned from a genomic library in lambda phage EMBL3A by using a murine EDF cDNA clone as a probe. The DNA sequence of a 3.2-kilobase BamHI fragment spanning the gene was determined. The gene contains three introns. The predicted amino acid sequence of 134 amino acids is identical with that recently reported for human interleukin 5 but shows no significant homology with other known hemopoietic growth regulators. The amino acid sequence shows strong homology (approx. 70% identity) with that of murine EDF. Recombinant human EDF, expressed from the human EDF gene after transfection into monkey COS cells, stimulated the production of eosinophils and eosinophil colonies from normal human bone marrow but had no effect on the production of neutrophils or mononuclear cells (monocytes and lymphoid cells). The apparent specificity of human EDF for the eosinophil lineage in myeloid hemopoiesis contrasts with the properties of human interleukin 3 and granulocyte/macrophage and granulocyte colony-stimulating factors but is directly analogous to the biological properties of murine EDF. Human EDF therefore represents a distinct hemopoietic growth factor that could play a central role in the regulation of eosinophilia.

  12. The Gottingen Minipig Is a Model of the Hematopoietic Acute Radiation Syndrome: G-Colony Stimulating Factor Stimulates Hematopoiesis and Enhances Survival From Lethal Total-Body γ-Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Moroni, Maria, E-mail: maria.moroni@usuhs.edu [Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Ngudiankama, Barbara F. [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (United States); Christensen, Christine [Division of Comparative Pathology, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Olsen, Cara H. [Biostatistics Consulting Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Owens, Rossitsa [Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Lombardini, Eric D. [Veterinary Medicine Department, Armed Forces Research Institute of Medical Sciences, Bangkok (Thailand); Holt, Rebecca K. [Veterinary Science Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Whitnall, Mark H. [Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States)

    2013-08-01

    Purpose: We are characterizing the Gottingen minipig as an additional large animal model for advanced drug testing for the acute radiation syndrome (ARS) to enhance the discovery and development of novel radiation countermeasures. Among the advantages provided by this model, the similarities to human hematologic parameters and dynamics of cell loss/recovery after irradiation provide a convenient means to compare the efficacy of drugs known to affect bone marrow cellularity and hematopoiesis. Methods and Materials: Male Gottingen minipigs, 4 to 5 months old and weighing 9 to 11 kg, were used for this study. We tested the standard off-label treatment for ARS, rhG-CSF (Neupogen, 10 μg/kg/day for 17 days), at the estimated LD70/30 total-body γ-irradiation (TBI) radiation dose for the hematopoietic syndrome, starting 24 hours after irradiation. Results: The results indicated that granulocyte colony stimulating factor (G-CSF) enhanced survival, stimulated recovery from neutropenia, and induced mobilization of hematopoietic progenitor cells. In addition, the administration of G-CSF resulted in maturation of monocytes/macrophages. Conclusions: These results support continuing efforts toward validation of the minipig as a large animal model for advanced testing of radiation countermeasures and characterization of the pathophysiology of ARS, and they suggest that the efficacy of G-CSF in improving survival after total body irradiation may involve mechanisms other than increasing the numbers of circulating granulocytes.

  13. Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: A double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial).

    Science.gov (United States)

    Brenner, Christoph; Adrion, Christine; Grabmaier, Ulrich; Theisen, Daniel; von Ziegler, Franz; Leber, Alexander; Becker, Alexander; Sohn, Hae-Young; Hoffmann, Ellen; Mansmann, Ulrich; Steinbeck, Gerhard; Franz, Wolfgang-Michael; Theiss, Hans Diogenes

    2016-02-15

    In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI. At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS. Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation). Copyright © 2015. Published by Elsevier Ireland Ltd.

  14. Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens

    Science.gov (United States)

    Bassi, Simona; Stroppa, Elisa M.; Moroni, Carlo F.; Arbasi, Maria C.; Trabacchi, Elena; Di Franco, Anna; Lazzaro, Antonio; Bernuzzi, Patrizia; Moretto, Mauro; Arcari, Annalisa; Bosi, Costanza; Riva, Alessandra; Cavanna, Luigi; Vallisa, Daniele

    2015-01-01

    Background Filgrastim biosimilars have recently been introduced into clinical practice. To date biosimilars have demonstrated comparable efficacy and safety as the originator in chemotherapy-induced neutropenia. Published experience in engraftment after autologous stem cell transplantation (ASCT) is limited and concerns relatively few patients. Materials and methods With the aim of assessing the efficacy and the safety of filgrastim biosimilars in post-ASCT bone marrow recovery, we conducted a single institution, retrospective study in 56 lymphoma and myeloma patients who received filgrastim biosimilars (Tevagrastim® and Zarzio®) at standard doses from day 5. We compared our results with recently published data on the originator. A cost analysis of each biosimilar was performed. Results Neutrophil counts recovered in 55 patients. The median number of filgrastim biosimilar vials injected was seven per patient. The median time to neutrophil and platelet recovery was 10 and 12 days, respectively. Twenty-six patients had febrile neutropenia, in half of whom the agent involved was identified. In the cost analysis, the use of Tevagrastim® and Zarzio® was associated with cost reductions of 56% and of 86%, respectively. Discussion Despite differences in CD34+ cell counts and time of starting filgrastim, our results in terms of time to engraftment and median number of vials injected are similar to published data. Comparing our results by single conditioning regimen to recent literature data, the time to engraftment and duration of hospitalisation were equivalent. Significant differences were observed in the incidence of febrile neutropenia, perhaps due to different preventive and prophylactic protocols for infections. Although prospective studies should be performed to confirm our results, filgrastim biosimilars were found to be effective and safe in engraftment after ASCT. PMID:25761321

  15. Problems in early diagnosis of bladder cancer in a spinal cord injury patient: Report of a case of simultaneous production of granulocyte colony stimulating factor and parathyroid hormone-related protein by squamous cell carcinoma of urinary bladder

    Directory of Open Access Journals (Sweden)

    Singh Gurpreet

    2002-08-01

    Full Text Available Abstract Background Typical symptoms and signs of a clinical condition may be absent in spinal cord injury (SCI patients. Case presentation A male with paraplegia was passing urine through penile sheath for 35 years, when he developed urinary infections. There was no history of haematuria. Intravenous urography showed bilateral hydronephrosis. The significance of abnormal outline of bladder was not appreciated. As there was large residual urine, he was advised intermittent catheterisation. Serum urea: 3.5 mmol/L; creatinine: 77 umol/L. A year later, serum urea: 36.8 mmol/l; creatinine: 632 umol/l; white cell count: 22.2; neutrophils: 18.88. Ultrasound: bilateral hydronephrosis. Bilateral nephrostomy was performed. Subsequently, blood tests showed: Urea: 14.2 mmol/l; Creatinine: 251 umol/l; Adjusted Calcium: 3.28 mmol/l; Parathyroid hormone: A repeat ultrasound scan demonstrated a tumour arising from right lateral wall; biopsy revealed squamous cell carcinoma. In view of persistently high white cell count and high calcium level, immunohistochemistry for G-CSF and PTHrP was performed. Dense staining of tumour cells for G-CSF and faintly positive staining for C-terminal PTHrP were observed. This patient expired about five months later. Conclusion This case demonstrates how delay in diagnosis of bladder cancer could occur in a SCI patient due to absence of characteristic symptoms and signs.

  16. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial

    DEFF Research Database (Denmark)

    Ripa, Rasmus Sejersten; Jørgensen, Erik; Wang, Yongzhong

    2006-01-01

    of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction. METHODS AND RESULTS: Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention ... hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 microg/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core...

  17. Prophylactic administration of vector-encoded porcine granulocyte-colony stimulating factor reduces Salmonella shedding,tonsil colonization,& microbiota alterations of the gastrointestinal tract in Salmonella-challenged swine

    Science.gov (United States)

    Salmonella colonization of food animals is a concern for animal health and public health as a food safety risk. Various obstacles impede the effort to reduce asymptomatic Salmonella carriage in food animals, including the existence of numerous serovars and the ubiquitous nature of Salmonella. To d...

  18. Efficacy and toxicity of decitabine versus CHG regimen (low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor) in patients with higher risk myelodysplastic syndrome: a retrospective study.

    Science.gov (United States)

    Wu, Lingyun; Li, Xiao; Chang, Chunkang; Xu, Feng; He, Qi; Wu, Dong; Zhang, Zheng; Su, Jiying; Zhou, Liyu; Song, Luxi; Chao, Xiao; Zhao, Youshan

    2016-01-01

    Decitabine and CHG regimen (low-dose cytarabine and homoharringtonine with G-CSF) have been used for treating higher risk myelodysplastic syndrome (MDS). In this study, we retrospectively compared the efficacy and toxicity of the two regimens in 132 MDS patients. Complete remission (CR) was not significantly different between the groups (27.1% with decitabine vs. 30.6% with CHG, p = 0.657). The CR rate with decitabine (58.8%) was significantly higher than that with CHG (7.7%) (p = 0.007) among the patients with poor karyotypes. Five of 23 (21.7%) patients who failed to respond to decitabine achieved CR with CHG, while one of two patients achieved CR with decitabine after failure with CHG. Overall and relapse-free survival were not different between the groups. In conclusion, both decitabine and CHG regimen are effective for higher risk MDS; there is no cross resistance between the regimens. Decitabine might be a better choice for patients with poor karyotypes.

  19. Heavy Metals Stimulate Human LINE-1 Retrotransposition

    Directory of Open Access Journals (Sweden)

    Astrid M. Roy-Engel

    2005-04-01

    Full Text Available L1 and Alu elements are among the most active retroposons (mobile elements in the human genome. Several human diseases, including certain forms of breast cancer and leukemia, are associated with L1 and Alu insertions in functionally important areas of the genome. We present data demonstrating that environmental pollutants, such as heavy metals, can stimulate L1 retrotransposition in a tissue culture system using two different types of assays. The response to these agents was equivalent when using a cell line with a stably integrated L1 vector (genomic or a by introducing the L1 vector by transient transfection (episomal of the cell. Reproducible results showed that mercury (HgS, cadmium (CdS, and nickel (NiO increase the activity of L1 by an average of three (3 fold p<0.001. This observation is the first to link several carcinogenic agents with the increased retrotransposition activity of L1 as an alternate mechanism of generating genomic instability contributing to the process of carcinogenesis. Our results demonstrate that mobile element activation must be considered as one of the mechanisms when evaluating genomic damage/instability in response to environmental agents.

  20. Harmine stimulates proliferation of human neural progenitors

    Science.gov (United States)

    Dakic, Vanja; Maciel, Renata de Moraes; Drummond, Hannah; Nascimento, Juliana M.; Trindade, Pablo

    2016-01-01

    Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo. PMID:27957390

  1. Harmine stimulates proliferation of human neural progenitors

    Directory of Open Access Journals (Sweden)

    Vanja Dakic

    2016-12-01

    Full Text Available Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A, which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY, and an irreversible selective inhibitor of monoamine oxidase (MAO but not DYRK1A (pargyline. INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

  2. Arecoline increases basic fibroblast growth factor but reduces expression of IL-1, IL-6, G-CSF and GM-CSF in human umbilical vein endothelium.

    Science.gov (United States)

    Ullah, Mafaz; Cox, Stephen; Kelly, Elizabeth; Moore, Malcolm A S; Zoellner, Hans

    2015-09-01

    Areca nut chewing is associated with oral submucous fibrosis (OSF). Raised vascular basic fibroblast growth factor may induce fibrosis. Arecoline is a muscarinic alkaloid in areca nut, which we earlier reported causes injury and necrosis of human endothelium. Human umbilical vein endothelial cells were exposed to arecoline with or without tumor necrosis factor-α, and separately to acetylcholine, muscarine, or nicotine. Protein levels of basic fibroblast growth factor, as well as the inflammatory cytokines: granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor, and Interleukins-6, 1-α and 1-β, were determined by enzyme-linked immunosorbent assay. mRNA levels were established by real-time reverse transcription polymerase chain reaction. Basic fibroblast growth factor was released into the culture medium at arecoline levels causing necrosis (P arecoline on levels of the inflammatory cytokines (P arecoline reduced this stimulated expression (P Arecoline had no effect on mRNA for basic fibroblast growth factor, although there was reduced mRNA for the separate inflammatory cytokines studied. The effect of acetylcholine, muscarine, and nicotine was minimal and dissimilar to that of arecoline. Data raise the possibility that arecoline-induced, vascular basic fibroblast growth factor contributes to OSF, by combining increased growth factor expression with endothelial necrosis, and thus driving fibroblast proliferation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Nanoscale Mechanical Stimulation of Human Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    H Nikukar

    2014-05-01

    We observed significant responses after 1 and 2-week stimulations in cell number, cell shapes and phenotypical markers. Microarray was performed for all groups. Cell count showed normal cell growth with stimulation. However, cell surface area, cell perimeter, and arboration after 1-week stimulation showed significant increases. Immunofluorescent studies have showed significant increase in osteocalcin production after stimulation. Conclusions: Nanoscale mechanical vibration showed significant changes in human mesenchymal stem cell behaviours. Cell morphology changed to become more polygonal and increased expression of the osteoblast markers were noted. These findings with gene regulation changes suggesting nanoscale mechanostimulation has stimulated osteoblastogenesis.  Keywords:  Mesenchymal, Nanoscale, Stem Cells.

  4. Transcranial laser stimulation improves human cerebral oxygenation

    OpenAIRE

    2016-01-01

    Background and Objective Transcranial laser stimulation of the brain with near‐infrared light is a novel form of non‐invasive photobiomodulation or low‐level laser therapy (LLLT) that has shown therapeutic potential in a variety of neurological and psychological conditions. Understanding of its neurophysiological effects is essential for mechanistic study and treatment evaluation. This study investigated how transcranial laser stimulation influences cerebral hemodynamics and oxygenation in th...

  5. In vitro differentiation of cultured human CD34+ cells into astrocytes

    Directory of Open Access Journals (Sweden)

    Katari Venkatesh

    2013-01-01

    Full Text Available Background: Astrocytes are abundantly present as glial cells in the brain and play an important role in the regenerative processes. The possible role of stem cell derived astrocytes in the spinal cord injuries is possible related to their influence at the synaptic junctions. Aim: The present study is focused on in vitro differentiation of cultured human CD34+ cells into astrocytes. Materials and Methods: Granulocyte-colony stimulating factor mobilized human CD34+ cells were isolated from peripheral blood using apheresis method from a donor. These cells were further purified by fluorescence-activated cell sorting and cultured in Dulbecco′s modified eagle′s medium. Thus, cultured cells were induced with astrocyte defined medium (ADM and in the differentiated astrocytes serine/threonine protein kinases (STPK and glutamine synthetase (GLUL activities were estimated. The expression of glial fibrillary acidic protein (GFAP and GLUL were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR. Results: The cultured human CD34+ cells differentiated into astrocytes after 11 h of incubation in ADM. The RT-PCR experiment showed the expression of GLUL (1.5 kb and GFAP (2.9 kb in differentiated astrocytes. The high enzyme activities of GLUL and STPK in differentiated astrocytes compared with cultured human CD34+ cells confirmed astrocyte formation. Conclusion: In the present study, in vitro differentiation of stem cells with retinoic acid induction may result in the formation of astrocytes.

  6. Stimulation of the human auditory nerve with optical radiation

    Science.gov (United States)

    Fishman, Andrew; Winkler, Piotr; Mierzwinski, Jozef; Beuth, Wojciech; Izzo Matic, Agnella; Siedlecki, Zygmunt; Teudt, Ingo; Maier, Hannes; Richter, Claus-Peter

    2009-02-01

    A novel, spatially selective method to stimulate cranial nerves has been proposed: contact free stimulation with optical radiation. The radiation source is an infrared pulsed laser. The Case Report is the first report ever that shows that optical stimulation of the auditory nerve is possible in the human. The ethical approach to conduct any measurements or tests in humans requires efficacy and safety studies in animals, which have been conducted in gerbils. This report represents the first step in a translational research project to initiate a paradigm shift in neural interfaces. A patient was selected who required surgical removal of a large meningioma angiomatum WHO I by a planned transcochlear approach. Prior to cochlear ablation by drilling and subsequent tumor resection, the cochlear nerve was stimulated with a pulsed infrared laser at low radiation energies. Stimulation with optical radiation evoked compound action potentials from the human auditory nerve. Stimulation of the auditory nerve with infrared laser pulses is possible in the human inner ear. The finding is an important step for translating results from animal experiments to human and furthers the development of a novel interface that uses optical radiation to stimulate neurons. Additional measurements are required to optimize the stimulation parameters.

  7. Infrared neural stimulation of human spinal nerve roots in vivo.

    Science.gov (United States)

    Cayce, Jonathan M; Wells, Jonathon D; Malphrus, Jonathan D; Kao, Chris; Thomsen, Sharon; Tulipan, Noel B; Konrad, Peter E; Jansen, E Duco; Mahadevan-Jansen, Anita

    2015-01-01

    Infrared neural stimulation (INS) is a neurostimulation modality that uses pulsed infrared light to evoke artifact-free, spatially precise neural activity with a noncontact interface; however, the technique has not been demonstrated in humans. The objective of this study is to demonstrate the safety and efficacy of INS in humans in vivo. The feasibility of INS in humans was assessed in patients ([Formula: see text]) undergoing selective dorsal root rhizotomy, where hyperactive dorsal roots, identified for transection, were stimulated in vivo with INS on two to three sites per nerve with electromyogram recordings acquired throughout the stimulation. The stimulated dorsal root was removed and histology was performed to determine thermal damage thresholds of INS. Threshold activation of human dorsal rootlets occurred in 63% of nerves for radiant exposures between 0.53 and [Formula: see text]. In all cases, only one or two monitored muscle groups were activated from INS stimulation of a hyperactive spinal root identified by electrical stimulation. Thermal damage was first noted at [Formula: see text] and a [Formula: see text] safety ratio was identified. These findings demonstrate the success of INS as a fresh approach for activating human nerves in vivo and providing the necessary safety data needed to pursue clinically driven therapeutic and diagnostic applications of INS in humans.

  8. Modeling of electromagnetic stimulation of the human brain.

    Science.gov (United States)

    Lazutkin, Dmitry; Husar, Peter

    2010-01-01

    The World Health Organization estimates depression as a serious threat to the health of millions of people worldwide. The purpose of this paper is to introduce the ongoing research devoted to the investigation of a possibility to use low-field electromagnetic stimulation of the human brain in the treatment of depressive disorder. In the course of the work the 3D models of transcranial magnetic stimulation and low-field magnetic stimulation based upon the use of a layered sphere head model have been developed. An initial approach towards the realistic human head reconstruction has been made. The revealed order of the stimulating electromagnetic field suitable for operation makes it possible to draft a technical specification for the stimulation device.

  9. Neuroethics of deep brain stimulation for mental disorders: brain stimulation reward in humans.

    Science.gov (United States)

    Oshima, Hideki; Katayama, Yoichi

    2010-01-01

    The theoretical basis of some deep brain stimulation (DBS) trials undertaken in the early years was the phenomenon of "brain stimulation reward (BSR)," which was first identified in rats. The animals appeared to be rewarded by pleasure caused by the stimulation of certain brain regions (reward system), such as the septal area. "Self-stimulation" experiments, in which rats were allowed to stimulate their own brain by pressing a freely accessible lever, they quickly learned lever pressing and sometimes continued to stimulate until they exhausted themselves. BSR was also observed with DBS of the septal area in humans. DBS trials in later years were undertaken on other theoretical bases, but unexpected BSR was sometimes induced by stimulation of some areas, such as the locus coeruleus complex. When BSR was induced, the subjects experienced feelings that were described as "cheerful," "alert," "good," "well-being," "comfort," "relaxation," "joy," or "satisfaction." Since the DBS procedure is equivalent to a "self-stimulation" experiment, they could become "addicted to the stimulation itself" or "compulsive about the stimulation," and stimulate themselves "for the entire day," "at maximum amplitude" and, in some instances, "into convulsions." DBS of the reward system has recently been applied to alleviate anhedonia in patients with refractory major depression. Although this approach appears promising, there remains a difficult problem: who can adjust their feelings and reward-oriented behavior within the normal range? With a self-stimulation procedure, the BSR may become uncontrollable. To develop DBS to the level of a standard therapy for mental disorders, we need to discuss "Who has the right to control the mental condition?" and "Who makes decisions" on "How much control is appropriate?" in daily life.

  10. Phorbol ester-treated human acute myeloid leukemia cells secrete G-CSF, GM-CSF and erythroid differentiation factor into serum-free media in primary culture.

    Science.gov (United States)

    Scher, W; Eto, Y; Ejima, D; Den, T; Svet-Moldavsky, I A

    1990-12-10

    Upon treatment with the phorbol ester, tetradecanoylphorbol 13-acetate (PMA), peripheral mononuclear blood cells from patients with acute myeloid leukemia secrete into serum-free cell-conditioned media (PMA-CCM) at least three distinct nondialysable 'hematopoietic' factors: granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage-colony-stimulating factor (GM-CSF) and erythroid differentiation factor (EDF, activin A). G-CSF was identified by its stimulation of [3H]thymidine incorporation into a G-CSF-responsive cell line, NSF-60, and the inhibition of its stimulation by a G-CSF-specific monoclonal antibody (MAB). GM-CSF was identified by its stimulation of [3H]thymidine incorporation into a GM-CSF-responsive line, TALL-101, and the inhibition of its stimulation by a GM-CSF-specific MAB. EDF was identified by its ability to stimulate erythroid differentiation in mouse erythroleukemia cell lines, its identical retention times to those of authentic EDF on three successive reverse-phase HPLC columns and characterization of its penultimate N-terminal residue as leucine which is the same as that of authentic EDF. Both authentic EDF and the erythroid-stimulating activity in PMA-CCM were found to act synergistically with a suboptimal inducing concentration of a well-studied inducing agent, dimethyl sulfoxide, in inducing erythroid differentiation. In addition, a fourth activity was observed in PMA-CCM: normal human fetal bone marrow cell-proliferation stimulating activity (FBMC-PSA). FBMC-PSA was identified by its ability to stimulate the growth of granulocytes and macrophages in FBMC suspension cultures, which neither recombinant G-CSF or GM-CSF were found to do.

  11. Human RECQL5beta stimulates flap endonuclease 1

    DEFF Research Database (Denmark)

    Speina, Elzbieta; Dawut, Lale; Hedayati, Mohammad

    2010-01-01

    Human RECQL5 is a member of the RecQ helicase family which is implicated in genome maintenance. Five human members of the family have been identified; three of them, BLM, WRN and RECQL4 are associated with elevated cancer risk. RECQL1 and RECQL5 have not been linked to any human disorder yet; cells...... dramatically stimulates the rate of FEN1 cleavage of flap DNA substrates. Moreover, we show that RECQL5beta and FEN1 interact physically and co-localize in the nucleus in response to DNA damage. Our findings, together with the previous literature on WRN, BLM and RECQL4's stimulation of FEN1, suggests...

  12. Interaction of transcranial magnetic stimulation and electrical transmastoid stimulation in human subjects

    DEFF Research Database (Denmark)

    Taylor, Janet L; Petersen, Nicolas Caesar; Butler, Jane E

    2002-01-01

    Transcranial magnetic stimulation activates corticospinal neurones directly and transsynaptically and hence, activates motoneurones and results in a response in the muscle. Transmastoid stimulation results in a similar muscle response through activation of axons in the spinal cord. This study...... was designed to determine whether the two stimuli activate the same descending axons. Responses to transcranial magnetic stimuli paired with electrical transmastoid stimuli were examined in biceps brachii in human subjects. Twelve interstimulus intervals (ISIs) from -6 ms (magnet before transmastoid) to 5 ms......-wave, facilitation still occurred at ISIs of -6 and -5 ms and depression of the paired response at ISIs of 0, 1, 4 and 5 ms. The interaction of the response to transmastoid stimulation with the multiple descending volleys elicited by magnetic stimulation of the cortex is complex. However, depression of the response...

  13. Neutrophil-induced transmigration of tumour cells treated with tumour-conditioned medium is facilitated by granulocyte-macrophage colony-stimulating factor.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    OBJECTIVE: To investigate the effect of different cytokines that are present in tumour-conditioned medium on human neutrophil (PMN)-induced tumour cell transmigration. DESIGN: Laboratory study. SETTING: University hospital, Ireland. MATERIAL: Isolated human PMN and cultured human breast tumour cell line, MDA-MB-231. Interventions: Human PMN treated with either tumour-conditioned medium or different media neutralised with monoclonal antibodies (MoAb), and MDA-MB-231 cells were plated on macrovascular and microvascular endothelial monolayers in collagen-coated transwells to assess migration of tumour cells. MAIN OUTCOME MEASURES: Cytokines present in tumour-conditioned medium, PMN cytocidal function and receptor expression, and tumour cell transmigration. RESULTS: tumour-conditioned medium contained high concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8), but not granulocyte colony-stimulating factor (G-CSF) and interleukin 3 (IL-3). Anti-GM-CSF MoAb significantly reduced PMN-induced transmigration of tumour cells treated with tumour-conditioned medium (p < 0.05), whereas anti-VEGF and anti-IL-8 MoAbs did not affect their migration. In addition, anti-GM-CSF MoAb, but not anti-VEGF or anti-IL-8 MoAb, reduced PMN CD11b and CD18 overexpression induced by tumour-conditioned medium (p < 0.05). CONCLUSION: These results indicate that the GM-CSF that is present in tumour-conditioned medium may be involved, at least in part, in alterations in PMN function mediated by the medium and subsequently PMN-induced transmigration of tumour cells.

  14. Erythropoietic Potential of CD34+ Hematopoietic Stem Cells from Human Cord Blood and G-CSF-Mobilized Peripheral Blood

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    Honglian Jin

    2014-01-01

    Full Text Available Red blood cell (RBC supply for transfusion has been severely constrained by the limited availability of donor blood and the emergence of infection and contamination issues. Alternatively, hematopoietic stem cells (HSCs from human organs have been increasingly considered as safe and effective blood source. Several methods have been studied to obtain mature RBCs from CD34+ hematopoietic stem cells via in vitro culture. Among them, human cord blood (CB and granulocyte colony-stimulating factor-mobilized adult peripheral blood (mPB are common adult stem cells used for allogeneic transplantation. Our present study focuses on comparing CB- and mPB-derived stem cells in differentiation from CD34+ cells into mature RBCs. By using CD34+ cells from cord blood and G-CSF mobilized peripheral blood, we showed in vitro RBC generation of artificial red blood cells. Our results demonstrate that CB- and mPB-derived CD34+ hematopoietic stem cells have similar characteristics when cultured under the same conditions, but differ considerably with respect to expression levels of various genes and hemoglobin development. This study is the first to compare the characteristics of CB- and mPB-derived erythrocytes. The results support the idea that CB and mPB, despite some similarities, possess different erythropoietic potentials in in vitro culture systems.

  15. Extending the Serum Half-Life of G-CSF via Fusion with the Domain III of Human Serum Albumin

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    Shuqiang Zhao

    2013-01-01

    Full Text Available Protein fusion technology is one of the most commonly used methods to extend the half-life of therapeutic proteins. In this study, in order to prolong the half-life of Granulocyte colony stimulating factor (G-CSF, the domain III of human serum albumin (3DHSA was genetically fused to the N-terminal of G-CSF. The 3DHSA-G-CSF fusion gene was cloned into pPICZαA along with the open reading frame of the α-factor signal under the control of the AOX1 promoter. The recombinant expression vector was transformed into Pichia pastoris GS115, and the recombinant strains were screened by SDS-PAGE. As expected, the 3DHSA-G-CSF showed high binding affinity with HSA antibody and G-CSF antibody, and the natural N-terminal of 3DHSA was detected by N-terminal sequencing. The bioactivity and pharmacokinetic studies of 3DHSA-G-CSF were respectively determined using neutropenia model mice and human G-CSF ELISA kit. The results demonstrated that 3DHSA-G-CSF has the ability to increase the peripheral white blood cell (WBC counts of neutropenia model mice, and the half-life of 3DHSA-G-CSF is longer than that of native G-CSF. In conclusion, 3DHSA can be used to extend the half-life of G-CSF.

  16. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

    Science.gov (United States)

    Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

    1992-06-01

    A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

  17. The lymphokine eosinophil stimulation promoter and human schistosomiasis mansoni.

    Science.gov (United States)

    Kazura, J W; Mahmoud, A A; Karb, K S; Warren, K S

    1975-12-01

    An in vitro assay for the new lymphokine eosinophil stimulation promoter has been adapted for use with human material. Peripheral eosinophils from patients with schistosomiasis mansoni were specifically induced to migrate on incubation with egg antigen. Furthermore, the peripheral lymphocytes of these patients on incubation with the egg antigen secreted the lymphokine eosinophil stimulation promoter, which enhanced the migration of purified eosinophils from patients with or without schistosomiasis. The test can be easily performed with human target cells and may be helpful for diagnostic or investigative purposes.

  18. Interleukin-10 inhibits burst-forming unit-erythroid growth by suppression of endogenous granulocyte-macrophage colony-stimulating factor production from T cells.

    Science.gov (United States)

    Oehler, L; Kollars, M; Bohle, B; Berer, A; Reiter, E; Lechner, K; Geissler, K

    1999-02-01

    Numerous cytokines released from accessory cells have been shown to exert either stimulatory or inhibitory growth signals on burst-forming unit-erythroid (BFU-E) growth. Because of its cytokine synthesis-inhibiting effects on T cells and monocytes, interleukin-10 (IL-10) may be a potential candidate for indirectly affecting erythropoiesis. We investigated the effects of IL-10 on BFU-E growth from normal human peripheral blood mononuclear cells (PBMC) using a clonogenic progenitor cell assay. The addition of recombinant human IL-10 to cultures containing recombinant human erythropoietin suppressed BFU-E growth in a dose-dependent manner (by 55.2%, range 47.3-63.3%, p cultivating highly enriched CD34+ cells. BFU-E growth from PBMC also was markedly suppressed in the presence of a neutralizing anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (by 48.7%, range 32.9-61.2% inhibition,p < 0.01), but not by neutralizing antibodies against granulocyte colony-stimulating factor and interleukin-3. This suggests a stimulatory role of endogenously released GM-CSF on BFU-E formation. Also, the addition of exogenous GM-CSF completely restored IL-10-induced suppression of BFU-E growth. To determine the cellular source of GM-CSF production, we analyzed GM-CSF levels in suspension cultures containing PBMC that were either depleted of monocytes or T cells. Monocyte-depleted PBMC showed spontaneous production of increasing amounts of GM-CSF on days 3, 5, and 7, respectively, which could be suppressed by IL-10, whereas GM-CSF levels did not increase in cultures containing T-cell-depleted PBMC. Our data indicate that IL-10 inhibits the growth of erythroid progenitor cells in vitro, most likely by suppression of endogenous GM-CSF production from T cells.

  19. External Dentin Stimulation Induces ATP Release in Human Teeth.

    Science.gov (United States)

    Liu, X; Wang, C; Fujita, T; Malmstrom, H S; Nedergaard, M; Ren, Y F; Dirksen, R T

    2015-09-01

    ATP is involved in neurosensory processing, including nociceptive transduction. Thus, ATP signaling may participate in dentin hypersensitivity and dental pain. In this study, we investigated whether pannexins, which can form mechanosensitive ATP-permeable channels, are present in human dental pulp. We also assessed the existence and functional activity of ecto-ATPase for extracellular ATP degradation. We further tested if ATP is released from dental pulp upon dentin mechanical or thermal stimulation that induces dentin hypersensitivity and dental pain and if pannexin or pannexin/gap junction channel blockers reduce stimulation-dependent ATP release. Using immunofluorescence staining, we demonstrated immunoreactivity of pannexin 1 and 2 in odontoblasts and their processes extending into the dentin tubules. Using enzymatic histochemistry staining, we also demonstrated functional ecto-ATPase activity within the odontoblast layer, subodontoblast layer, dental pulp nerve bundles, and blood vessels. Using an ATP bioluminescence assay, we found that mechanical or cold stimulation to the exposed dentin induced ATP release in an in vitro human tooth perfusion model. We further demonstrated that blocking pannexin/gap junction channels with probenecid or carbenoxolone significantly reduced external dentin stimulation-induced ATP release. Our results provide evidence for the existence of functional machinery required for ATP release and degradation in human dental pulp and that pannexin channels are involved in external dentin stimulation-induced ATP release. These findings support a plausible role for ATP signaling in dentin hypersensitivity and dental pain.

  20. Fructose ingestion acutely stimulates circulating FGF21 levels in humans

    OpenAIRE

    Dushay, Jody R.; Toschi, Elena; Mitten, Emilie K.; Fisher, ffolliott M.; Herman, Mark A.; Maratos-Flier, Eleftheria

    2014-01-01

    Objective Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element...

  1. Environmental Stimulation, Parental Nurturance and Cognitive Development in Humans

    Science.gov (United States)

    Farah, Martha J.; Betancourt, Laura; Shera, David M.; Savage, Jessica H.; Giannetta, Joan M.; Brodsky, Nancy L.; Malmud, Elsa K.; Hurt, Hallam

    2008-01-01

    The effects of environmental stimulation and parental nurturance on brain development have been studied extensively in animals. Much less is known about the relations between childhood experience and cognitive development in humans. Using a longitudinally collected data set with ecologically valid in-home measures of childhood experience and later…

  2. Large-Scale Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells Provides Granulocytes or Macrophages for Cell Replacement Therapies

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    Nico Lachmann

    2015-02-01

    Full Text Available Interleukin-3 (IL-3 is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF and macrophage CSF (M-CSF represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34+ clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45+CD11b+CD15+CD16+CD66b+ granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45+CD11b+CD14+CD163+CD68+ monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications.

  3. Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer.

    Science.gov (United States)

    Orecchioni, Stefania; Gregato, Giuliana; Martin-Padura, Ines; Reggiani, Francesca; Braidotti, Paola; Mancuso, Patrizia; Calleri, Angelica; Quarna, Jessica; Marighetti, Paola; Aldeni, Chiara; Pruneri, Giancarlo; Martella, Stefano; Manconi, Andrea; Petit, Jean-Yves; Rietjens, Mario; Bertolini, Francesco

    2013-10-01

    Obesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer. We found that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45(-)CD34(+)CD31(+)CD13(-)CCRL2(+) endothelial cells can generate mature endothelial cells and capillaries. Their cancer-promoting effect in the breast was limited in the absence of CD45(-)CD34(+)CD31(-)CD13(+)CD140b(+) mesenchymal progenitors/adipose stromal cells (ASC), which generated pericytes and were more efficient than endothelial cells in promoting local tumor growth. Both endothelial cells and ASCs induced epithelial-to-mesenchymal transition (EMT) gene expression in luminal breast cancer cells. Endothelial cells (but not ASCs) migrated to lymph nodes and to contralateral nascent breast cancer lesions where they generated new vessels. In vitro and in vivo, endothelial cells were more efficient than ASCs in promoting tumor migration and in inducing metastases. Granulocyte colony-stimulating factor (G-CSF) effectively mobilized endothelial cells (but not ASCs), and the addition of chemotherapy and/or of CXCR4 inhibitors did not increase endothelial cell or ASC blood mobilization. Our findings suggest that adipose tissue progenitor cells cooperate in driving progression and metastatic spread of breast cancer.

  4. Staphylococcal superantigens stimulate immortalized human adipocytes to produce chemokines.

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    Bao G Vu

    Full Text Available BACKGROUND: Human adipocytes may have significant functions in wound healing and the development of diabetes through production of pro-inflammatory cytokines after stimulation by gram-negative bacterial endotoxin. Diabetic foot ulcers are most often associated with staphylococcal infections. Adipocyte responses in the area of the wound may play a role in persistence and pathology. We studied the effect of staphylococcal superantigens (SAgs on immortalized human adipocytes, alone and in the presence of bacterial endotoxin or staphylococcal α-toxin. METHODOLOGY/PRINCIPAL FINDINGS: Primary non-diabetic and diabetic human preadipocytes were immortalized by the reverse transcriptase component of telomerase (TERT and the E6/E7 genes of human papillomavirus. The immortal cells were demonstrated to have properties of non-immortalized pre-adipocytes and could be differentiated into mature and functional adipocytes. Differentiated adipocytes exposed to staphylococcal SAgs produced robust levels of cytokines IL-6 and IL-8, but there were no significant differences in levels between the non-diabetic and diabetic cells. Cytokine production was increased by co-incubation of adipocytes with SAgs and endotoxin together. In contrast, α-toxin alone was cytotoxic at high concentrations, but, at sub-cytotoxic doses, did not stimulate production of IL-6 and IL-8. CONCLUSIONS/SIGNIFICANCE: Endotoxin has been proposed to contribute to diabetes through enhanced insulin resistance after chronic exposure and stimulation of adipocytes to produce cytokines. Our data indicate staphylococcal SAgs TSST-1 and SEB alone and in combination with bacterial endotoxin also stimulate adipocytes to produce cytokines and thus may contribute to the inflammatory response found in chronic diabetic ulcers and in the systemic inflammation that is associated with the development and persistence of diabetes. The immortal human pre-adipocytes reported here will be useful for studies to

  5. Modulating human auditory processing by transcranial electrical stimulation

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    Kai eHeimrath

    2016-03-01

    Full Text Available Transcranial electrical stimulation (tES has become a valuable research tool for the investigation of neurophysiological processes underlying human action and cognition. In recent years, striking evidence for the neuromodulatory effects of transcranial direct current stimulation (tDCS, transcranial alternating current stimulation (tACS, and transcranial random noise stimulation (tRNS has emerged. However, while the wealth of knowledge has been gained about tES in the motor domain and, to a lesser extent, about its ability to modulate human cognition, surprisingly little is known about its impact on perceptual processing, particularly in the auditory domain. Moreover, while only a few studies systematically investigated the impact of auditory tES, it has already been applied in a large number of clinical trials, leading to a remarkable imbalance between basic and clinical research on auditory tES. Here, we review the state of the art of tES application in the auditory domain focussing on the impact of neuromodulation on acoustic perception and its potential for clinical application in the treatment of auditory related disorders.

  6. Direct Electrical Stimulation in the Human Brain Disrupts Melody Processing.

    Science.gov (United States)

    Garcea, Frank E; Chernoff, Benjamin L; Diamond, Bram; Lewis, Wesley; Sims, Maxwell H; Tomlinson, Samuel B; Teghipco, Alexander; Belkhir, Raouf; Gannon, Sarah B; Erickson, Steve; Smith, Susan O; Stone, Jonathan; Liu, Lynn; Tollefson, Trenton; Langfitt, John; Marvin, Elizabeth; Pilcher, Webster H; Mahon, Bradford Z

    2017-09-11

    Prior research using functional magnetic resonance imaging (fMRI) [1-4] and behavioral studies of patients with acquired or congenital amusia [5-8] suggest that the right posterior superior temporal gyrus (STG) in the human brain is specialized for aspects of music processing (for review, see [9-12]). Intracranial electrical brain stimulation in awake neurosurgery patients is a powerful means to determine the computations supported by specific brain regions and networks [13-21] because it provides reversible causal evidence with high spatial resolution (for review, see [22, 23]). Prior intracranial stimulation or cortical cooling studies have investigated musical abilities related to reading music scores [13, 14] and singing familiar songs [24, 25]. However, individuals with amusia (congenitally, or from a brain injury) have difficulty humming melodies but can be spared for singing familiar songs with familiar lyrics [26]. Here we report a detailed study of a musician with a low-grade tumor in the right temporal lobe. Functional MRI was used pre-operatively to localize music processing to the right STG, and the patient subsequently underwent awake intraoperative mapping using direct electrical stimulation during a melody repetition task. Stimulation of the right STG induced "music arrest" and errors in pitch but did not affect language processing. These findings provide causal evidence for the functional segregation of music and language processing in the human brain and confirm a specific role of the right STG in melody processing. VIDEO ABSTRACT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Transcranial focused ultrasound stimulation of human primary visual cortex

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    Lee, Wonhye; Kim, Hyun-Chul; Jung, Yujin; Chung, Yong An; Song, In-Uk; Lee, Jong-Hwan; Yoo, Seung-Schik

    2016-09-01

    Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

  8. Human vascular model with defined stimulation medium - a characterization study.

    Science.gov (United States)

    Huttala, Outi; Vuorenpää, Hanna; Toimela, Tarja; Uotila, Jukka; Kuokkanen, Hannu; Ylikomi, Timo; Sarkanen, Jertta-Riina; Heinonen, Tuula

    2015-01-01

    The formation of blood vessels is a vital process in embryonic development and in normal physiology. Current vascular modelling is mainly based on animal biology leading to species-to-species variation when extrapolating the results to humans. Although there are a few human cell based vascular models available these assays are insufficiently characterized in terms of culture conditions and developmental stage of vascular structures. Therefore, well characterized vascular models with human relevance are needed for basic research, embryotoxicity testing, development of therapeutic strategies and for tissue engineering. We have previously shown that the in vitro vascular model based on co-culture of human adipose stromal cells (hASC) and human umbilical vein endothelial cells (HUVEC) is able to induce an extensive vascular-like network with high reproducibility. In this work we developed a defined serum-free vascular stimulation medium (VSM) and performed further characterization in terms of cell identity, maturation and structure to obtain a thoroughly characterized in vitro vascular model to replace or reduce corresponding animal experiments. The results showed that the novel vascular stimulation medium induced intact and evenly distributed vascular-like network with morphology of mature vessels. Electron microscopic analysis assured the three-dimensional microstructure of the network containing lumen. Additionally, elevated expressions of the main human angiogenesis-related genes were detected. In conclusion, with the new defined medium the vascular model can be utilized as a characterized test system for chemical testing as well as in creating vascularized tissue models.

  9. Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

    Science.gov (United States)

    Cash, Robin F H; Murakami, Takenobu; Chen, Robert; Thickbroom, Gary W; Ziemann, Ulf

    2016-01-01

    Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans. In Experiment 1, patterned repetitive TMS was applied to left M1, consisting of 6 trains (intertrain interval, 8 s) of 4 doublets (interpulse interval equal to individual peak I-wave facilitation, 1.3-1.5 ms) spaced by the individual peak LCD (interdoublet interval (IDI), 200-250 ms). This intervention (total of 48 pulses applied over ∼45 s) increased motor-evoked potential amplitude, a marker of corticospinal excitability, in a right hand muscle by 147% ± 4%. Control experiments showed that IDIs shorter or longer than LCD did not result in LTP-like plasticity. Experiment 2 indicated topographic specificity to the M1 hand region stimulated by TMS and duration of the LTP-like plasticity of 60 min. In conclusion, GABA(B)ergic LCD offers a powerful new approach for augmenting LTP-like plasticity induction in human cortex. We refer to this protocol as disinhibition stimulation (DIS).

  10. Differential Constitutive and Cytokine-Modulated Expression of Human Toll-like Receptors in Primary Neutrophils, Monocytes, and Macrophages

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    D. Shane O'Mahony, Uyenvy Pham, Ramesh Iyer, Thomas R. Hawn, W. Conrad Liles

    2008-01-01

    Full Text Available Human Toll-like receptors (TLRs comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the human innate immune system. Proinflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF, macrophage colony-stimulating factor (M-CSF, and interferon-γ (IFN-γ, have been shown to up-regulate microbicidal activity in these effector cells of innate immunity. Currently, the cellular and molecular mechanisms responsible for these effects are not completely understood. We hypothesized that these cytokines may up-regulate TLR expression as a mechanism to facilitate microbial recognition and augment the innate immune response. Using quantitative realtime rt-PCR technology, we examined constitutive expression of TLR2, TLR4, TLR5, and TLR9 mRNA and the effects of G-CSF, GM-CSF, M-CSF, and IFN-γ on TLR mRNA expression in purified populations of normal human neutrophils, monocytes, and monocyte-derived macrophages. Relative constitutive expression of TLR2, TLR4, and TLR9 was similar in neutrophils and monocytes. Constitutive expression of TLR5 was less in neutrophils compared to monocytes. Constitutive expression of TLR4 was greater and that of TLR9 lower in monocyte-derived macrophages compared to monocytes. Of the cytokines examined, IFN-γ and GM-CSF caused the greatest effects on TLR expression. IFN- γ up-regulated TLR2 and TLR4 in neutrophils and monocytes. GM-CSF up-regulated expression of TLR2 and TLR4 in neutrophils and TLR2 in monocytes. TLR5 was down-regulated by inflammatory cytokines in monocytes. These results suggest a potential role for IFN- γ and/or GM-CSF as therapeutic immunomodulators of the host defense to infection.

  11. Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip.

    Science.gov (United States)

    Herland, Anna; van der Meer, Andries D; FitzGerald, Edward A; Park, Tae-Eun; Sleeboom, Jelle J F; Ingber, Donald E

    2016-01-01

    Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel's inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types.

  12. Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

    Science.gov (United States)

    FitzGerald, Edward A.; Park, Tae-Eun; Sleeboom, Jelle J. F.; Ingber, Donald E.

    2016-01-01

    Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types. PMID:26930059

  13. Modeling and percept of transcorneal electrical stimulation in humans.

    Science.gov (United States)

    Xie, John; Wang, Gene-Jack; Yow, Lindy; J Cela, Carlos; Humayun, Mark S; Weiland, James D; Lazzi, Gianluca; Jadvar, Hossein

    2011-07-01

    Retinal activation via transcorneal electrical stimulation (TcES) in normal humans was investigated by comparing subject perception, model predictions, and brain activation patterns. The preferential location of retinal stimulation was predicted from 3-D admittance modeling. Visual cortex activation was measured using positron emission tomography (PET) and (18)F-fluorodeoxyglucose (FDG). Two different corneal electrodes were investigated: DTL-Plus and ERG-Jet. Modeling results predicted preferential stimulation of the peripheral, inferior, nasal retina during right eye TcES using DTL-Plus, but more extensive activation of peripheral, nasal hemiretina using ERG-Jet. The results from human FDG PET study using both corneal electrodes showed areas of visual cortex activation that consistently corresponded with the reported phosphene percept and modeling predictions. ERG-Jet was able to generate brighter phosphene percept than DTL-Plus and elicited retinotopically mapped primary visual cortex activation. This study demonstrates that admittance modeling and PET imaging consistently predict the perceived location of electrically elicited phosphenes produced during TcES.

  14. Human neural progenitor cells promote photoreceptor survival in retinal explants.

    Science.gov (United States)

    Englund-Johansson, Ulrica; Mohlin, Camilla; Liljekvist-Soltic, Ingela; Ekström, Per; Johansson, Kjell

    2010-02-01

    Different types of progenitor and stem cells have been shown to provide neuroprotection in animal models of photoreceptor degeneration. The present study was conducted to investigate whether human neural progenitor cells (HNPCs) have neuroprotective properties on retinal explants models with calpain- and caspase-3-dependent photoreceptor cell death. In the first experiments, HNPCs in a feeder layer were co-cultured for 6 days either with postnatal rd1 mouse or normal rat retinas. Retinal histological sections were used to determine outer nuclear layer (ONL) thickness, and to detect the number of photoreceptors with labeling for calpain activity, cleaved caspase-3 and TUNEL. The ONL thickness of co-cultured rat and rd1 retinas was found to be almost 10% and 40% thicker, respectively, compared to controls. Cell counts of calpain activity, cleaved caspase-3 and TUNEL labeled photoreceptors in both models revealed a 30-50% decrease when co-cultured with HNPCs. The results represent significant increases of photoreceptor survival in the co-cultured retinas. In the second experiments, for an identification of putative survival factors, or a combination of them, a growth factor profile was performed on conditioned medium. The relative levels of various growth factors were analyzed by densitometric measurements of growth factor array membranes. Following growth factors were identified as most potential survival factors; granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GMCSF), insulin-like growth factor II (IGF-II), neurotrophic factor 3 (NT-3), placental growth factor (PIGF), transforming growth factors (TGF-beta1 and TGF-beta2) and vascular endothelial growth factor (VEGF-D). HNPCs protect both against calpain- and caspase-3-dependent photoreceptor cell death in the rd1 mouse and against caspase-3-dependent photoreceptor cell death in normal rat retinas in vitro. The protective effect is possibly achieved by a variety of

  15. Human very small embryonic-like cells generate skeletal structures, in vivo.

    Science.gov (United States)

    Havens, Aaron M; Shiozawa, Yusuke; Jung, Younghun; Sun, Hongli; Wang, Jincheng; McGee, Samantha; Mishra, Anjali; Taichman, L Susan; Danciu, Theodora; Jiang, Yajuan; Yavanian, Gregory; Leary, Elizabeth; Krebsbach, Paul H; Rodgerson, Denis; Taichman, Russell S

    2013-02-15

    Human very small embryonic-like (hVSEL) cells are a resident population of multipotent stem cells in the bone marrow involved in the turnover and regeneration of tissues. The levels of VSEL cells in blood are greatly increased in response to injury, and they have been shown to repair injured tissues. Adult hVSEL cells, SSEA-4(+)/CD133(+)/CXCR4(+)/Lin(-)/CD45(-), express the pluripotency markers (Oct-4 and Nanog) and may be able to differentiate into cells from all 3 germ lineages. hVSEL cells isolated from blood by apheresis following granulocyte-colony-stimulating factor mobilization were fractionated and enriched by elutriation and fluorescence activated cell sorting. Collagen sponge scaffolds containing 2,000-30,000 hVSEL cells were implanted into cranial defects generated in SCID mice. Analysis by microcomputed tomography showed that a cell population containing VSEL cells produced mineralized tissue within the cranial defects compared with controls at 3 months. Histologic studies showed significant bone formation and cellular organization within the defects compared with cellular or scaffold controls alone. Antibodies to human leukocyte antigens demonstrated that the newly generated tissues were of human origin. Moreover, human osteocalcin was identified circulating in the peripheral blood. There was evidence that some level of hVSEL cells migrated away from the defect site, using quantitative real-time polymerase chain reaction to detect for human-specific Alu sequences. This study demonstrates that hVSEL cells are able to generate human bone tissue in a mouse model of skeletal repair. These studies lay the foundation for future cell-based regenerative therapies for osseous and connective tissue disorders, including trauma and degenerative conditions, such as osteoporosis, fracture repair, and neoplastic repair.

  16. Sphingosylphosphorylcholine stimulates human monocyte-derived dendritic cell chemotaxis

    Institute of Scientific and Technical Information of China (English)

    Ha-young LEE; Eun-ha SHIN; Yoe-sik BAE

    2006-01-01

    Aim: To investigate the effects of Sphingosylphosphorylcholine (SPC) on human monocyte-derived dendritic cell (DC) chemotaxis. Methods: Human DC were generated from peripheral blood monocytes by culturing them with granulocyte macrophage-colony stimulating factor and interleukin-4. The effect of SPC on the DC chemotactic migration was measured by chemotaxis assay. Intracellular signaling event involved in the SPC-induced DC chemotaxis was investigated with several inhibitors for specific kinase. The expression of the SPC receptors was examined by reverse transcription polymerase chain reaction. Results: We found that SPC induced chemotactic migration in immature DC (iDC) and mature DC (mDC). In terms of SPC-induced signaling events, mitogen activated protein kinase activation and Akt activation in iDC and mDC were stimulated. SPC-induced chemotaxis was mediated by extracellular signal-regulated protein kinase and phosphoino-sitide-3-kinase, but not by calcium in both iDC and mDC. Although mDC express ovarian cancer G protein-coupled receptor 1, but not G protein-coupled receptor 4, iDC do not express any of these receptors. To examine the involvement of sphin-gosine-1-phosphate (SIP) receptors, we checked the effect of an SIP receptor antagonist (VPC23019) on SPC-induced DC chemotaxis. VPC23019 did not affect SPC-induced DC chemotaxis. Conclusion: The results suggest that SPC may play a role in regulating DC trafficking during phagocytosis and the T cell-stimulating phase, and the unique SPC receptor, which is different from SIP receptors, is involved in SPC-induced chemotaxis.

  17. What’s Normal? Immune Profiling of Human Milk from Healthy Women Living in Different Geographical and Socioeconomic Settings

    Science.gov (United States)

    Ruiz, Lorena; Espinosa-Martos, Irene; García-Carral, Cristina; Manzano, Susana; McGuire, Michelle K.; Meehan, Courtney L.; McGuire, Mark A.; Williams, Janet E.; Foster, James; Sellen, Daniel W.; Kamau-Mbuthia, Elizabeth W.; Kamundia, Egidioh W.; Mbugua, Samwel; Moore, Sophie E.; Kvist, Linda J.; Otoo, Gloria E.; Lackey, Kimberly A.; Flores, Katherine; Pareja, Rossina G.; Bode, Lars; Rodríguez, Juan M.

    2017-01-01

    Human milk provides a very wide range of nutrients and bioactive components, including immune factors, human milk oligosaccharides, and a commensal microbiota. These factors are essential for interconnected processes including immunity programming and the development of a normal infant gastrointestinal microbiome. Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL1β, IL6, IL12, INFγ, TNFα), acquired immunity factors (IL2, IL4, IL10, IL13, IL17), chemokines (IL8, Groα, MCP1, MIP1β), growth factors [IL5, IL7, epidermal growth factor (EGF), granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, TGFβ2], and immunoglobulins (IgA, IgG, IgM), in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors, IgA, IgG, IgM, EGF, TGFβ2, IL7, IL8, Groα, and MIP1β were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as the “core” soluble immune factors in milk produced by healthy women worldwide. This approach may help define which immune factors are (or are not) common in milk produced by women living in various conditions, and to identify host, lifestyle, and environmental factors that affect the immunological composition of this complex biological fluid. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02670278. PMID:28713365

  18. What’s Normal? Immune Profiling of Human Milk from Healthy Women Living in Different Geographical and Socioeconomic Settings

    Directory of Open Access Journals (Sweden)

    Lorena Ruiz

    2017-06-01

    Full Text Available Human milk provides a very wide range of nutrients and bioactive components, including immune factors, human milk oligosaccharides, and a commensal microbiota. These factors are essential for interconnected processes including immunity programming and the development of a normal infant gastrointestinal microbiome. Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL1β, IL6, IL12, INFγ, TNFα, acquired immunity factors (IL2, IL4, IL10, IL13, IL17, chemokines (IL8, Groα, MCP1, MIP1β, growth factors [IL5, IL7, epidermal growth factor (EGF, granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, TGFβ2], and immunoglobulins (IgA, IgG, IgM, in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors, IgA, IgG, IgM, EGF, TGFβ2, IL7, IL8, Groα, and MIP1β were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as the “core” soluble immune factors in milk produced by healthy women worldwide. This approach may help define which immune factors are (or are not common in milk produced by women living in various conditions, and to identify host, lifestyle, and environmental factors that affect the immunological composition of this complex biological fluid.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02670278.

  19. Transcranial static magnetic field stimulation of the human motor cortex.

    Science.gov (United States)

    Oliviero, Antonio; Mordillo-Mateos, Laura; Arias, Pablo; Panyavin, Ivan; Foffani, Guglielmo; Aguilar, Juan

    2011-10-15

    The aim of the present study was to investigate in healthy humans the possibility of a non-invasive modulation of motor cortex excitability by the application of static magnetic fields through the scalp. Static magnetic fields were obtained by using cylindrical NdFeB magnets. We performed four sets of experiments. In Experiment 1, we recorded motor potentials evoked by single-pulse transcranial magnetic stimulation (TMS) of the motor cortex before and after 10 min of transcranial static magnetic field stimulation (tSMS) in conscious subjects. We observed an average reduction of motor cortex excitability of up to 25%, as revealed by TMS, which lasted for several minutes after the end of tSMS, and was dose dependent (intensity of the magnetic field) but not polarity dependent. In Experiment 2, we confirmed the reduction of motor cortex excitability induced by tSMS using a double-blind sham-controlled design. In Experiment 3, we investigated the duration of tSMS that was necessary to modulate motor cortex excitability. We found that 10 min of tSMS (compared to 1 min and 5 min) were necessary to induce significant effects. In Experiment 4, we used transcranial electric stimulation (TES) to establish that the tSMS-induced reduction of motor cortex excitability was not due to corticospinal axon and/or spinal excitability, but specifically involved intracortical networks. These results suggest that tSMS using small static magnets may be a promising tool to modulate cerebral excitability in a non-invasive, painless, and reversible way.

  20. Substance P stimulation of cultured human smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Mitsuhashi, M.; Payan, D.G.

    1986-03-01

    Substance P (SP) has been shown to be mitogenic for cells active in the inflammatory response, such as lymphocytes and macrophages, and demonstrates vasodilatory and bronchoconstrictor properties, implicating SP receptor-mediated responses on smooth muscle cells. The effects of SP on cultured human vascular smooth muscle cell (HSMC) proliferative responses and protein synthesis were assessed by measuring the incorporation of (/sup 3/H)thymidine into DNA and (/sup 3/H)leucine into intracellular proteins, respectively. SP at concentrations of 10/sup -6/ to 10/sup -5/M stimulated a 40-50% increase in the incorporation of (/sup 3/H)thymidine in HMSC. In addition, the uptake of (/sup 3/H)leucine into HSMC proteins was increased significantly by SP over the concentration range 10/sup -11/ to 10/sup -6/M. Moreover, an enhancement of protein synthesis in HSMC by 10/sup -9/M SP was demonstrated by an increased incorporation of (/sup 35/S)methionine into cellular proteins of MW 40-30,000 daltons as assessed by autoradiographic analysis of HSMC lysates analyzed by SDS-PAGE. Furthermore, the uptake of (/sup 3/H)inositol into HSMC membrane phospholipid was increased significantly by SP in a dose-dependent manner over the concentration range 10/sup -11/ to 10/sup -6/M. Peptides such as SP which stimulate smooth muscle contraction, also demonstrate mitogenic properties on HSMC, suggesting that these cellular response shares common pathways of activation.

  1. Differential activation of nerve fibers with magnetic stimulation in humans

    Directory of Open Access Journals (Sweden)

    Olree Kenneth S

    2006-07-01

    Full Text Available Abstract Background Earlier observations in our lab had indicated that large, time-varying magnetic fields could elicit action potentials that travel in only one direction in at least some of the myelinated axons in peripheral nerves. The objective of this study was to collect quantitative evidence for magnetically induced unidirectional action potentials in peripheral nerves of human subjects. A magnetic coil was maneuvered to a location on the upper arm where physical effects consistent with the creation of unidirectional action potentials were observed. Electromyographic (EMG and somatosensory evoked potential (SEP recordings were then made from a total of 20 subjects during stimulation with the magnetic coil. Results The relative amplitudes of the EMG and SEP signals changed oppositely when the current direction in the magnetic coil was reversed. This effect was consistent with current direction in the coil relative to the arm for all subjects. Conclusion A differential evocation of motor and sensory fibers was demonstrated and indicates that it may be possible to induce unidirectional action potentials in myelinated peripheral nerve fibers with magnetic stimulation.

  2. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  3. A Method for Functional Quantification of the Reflex Effect of Human Peripheral Nerve Stimulation

    OpenAIRE

    Zehr, E. P.; Komiyama, Tomoyushi; Stein, R B

    2000-01-01

    E.P. Zehr, KOMIYAMA, T. and R.B. Stein. A Method for Functional Quantification of the Reflex Effect of Human Peripheral Nerve Stimulation. Adv. Exerc. Sports Physiol., Vol.6, No.1 pp25-32, 2000. We have developed simple method that accounts for the overrall function of reflex effects occurring in the surface electrimyogran (EMG) after human nerve stimulation. This method involves the subtraction of pre-stimulus EMG levels from EMG modulation curves obtained after human peripheral nerve stimul...

  4. IL-17A potentiates TNFα-induced secretion from human endothelial cells and alters barrier functions controlling neutrophils rights of passage.

    Science.gov (United States)

    Bosteen, Markus H; Tritsaris, Katerina; Hansen, Anker J; Dissing, Steen

    2014-05-01

    Interleukin-17A (IL-17A) is an important pro-inflammatory cytokine that regulates leukocyte mobilization and recruitment. To better understand how IL-17A controls leukocyte trafficking across capillaries in the peripheral blood circulation, we used primary human dermal microvascular endothelial cells (HDMEC) to investigate their secretory potential and barrier function when activated with IL-17A and TNFα. Activation by TNFα and IL-17A causes phosphorylation of p38 as well as IκBα whereby NFκB subsequently becomes phosphorylated, a mechanism that initiates transcription of adhesion molecules such as E-selectin. Members of the neutrophil-specific GRO-family chemokines were significantly up-regulated upon IL-17A stimulation on the mRNA and protein level, whereas all tested non-neutrophil-specific chemokines remained unchanged in comparison. Moreover, a striking synergistic effect in the induction of granulocyte colony-stimulating factors (G-CSF) was elicited when IL-17A was used in combination with TNFα, and IL-17A was able to significantly augment the levels of TNFα-induced E-selectin and ICAM-1. In accordance with this observation, IL-17A was able to markedly increase TNFα-induced neutrophil adherence to HDMEC monolayers in an in vitro adhesion assay. Using a trans-well migration assay with an HDMEC monolayer as a barrier, we here show that pre-stimulating the endothelial cells with TNFα and IL-17A together enhances the rate of neutrophil transmigration compared to TNFα or IL-17A alone. These results show that IL-17A and TNFα act in cooperation to facilitate neutrophil migration across the endothelial cell barrier. In addition, the synergistic actions of IL-17A with TNFα to secrete G-CSF appear to be important for mobilizing neutrophils from the bone marrow to the blood stream.

  5. Maturation of Human Fetal Responses to Vibroacoustic Stimulation.

    Science.gov (United States)

    Kisilevsky, Barbara S.; And Others

    1992-01-01

    Fetuses received vibroacoustic stimulation while movement and heart rate were monitored. From 29 weeks, at least 83 percent of fetuses responded to stimulation with heart rate acceleration. Between 26 and 36 weeks, the percentage of fetuses responding to stimulation with movement increased from 58 to 100 percent. (BC)

  6. 粒细胞集落刺激因子及其受体对人黑素细胞增殖及酪氨酸酶活性的影响%Effect of granulocyt e colony-stimulating factor and its receptor on the proliferation and tyrosinase activity of human melanocytes

    Institute of Scientific and Technical Information of China (English)

    周梅华; 李雪; 吴迪; 朱文元; 鲁严

    2012-01-01

    目的 探讨粒细胞集落刺激因子受体(G-CSFR)在人黑素细胞中的表达及重组人粒细胞集落刺激因子(rhG-CSF)对人黑素细胞生物学作用的影响.方法 分别用普通的合成培养基与添加一定浓度rhG-CSF的合成培养基培养健康人的黑素细胞,并对黑素细胞的生长情况及形态进行观察.应用流式细胞仪检测人黑素细胞、中性粒细胞及红白血病细胞( HEL 92.1.7)中G-CSFR的表达率.Western印迹、逆转录聚合酶链反应( RT-PCR)方法分别检测黑素细胞、中性粒细胞及HEL 92.1.7中G-CSFR蛋白及G-CSFR mRNA的表达情况;噻唑蓝比色法(MTT法)检测不上浓度rhG-CSF( 200、400、600、800 μg/L)对黑素细胞增殖作用.多巴氧化法检测黑素细胞的酪氨酸酶活性.结果 黑素细胞G-CSFR的表达率(76.81%±10.70%)较HEL92.1.7 (2.53%±1.54%)明显升高(P<0.01),略低于中性粒细胞(85.76%±15.71%,P<0.05);黑素细胞可表达G-CSFR蛋白和mRNA,不同浓度rhG-CSF处理组间比较,差异无统计学意义(P>0.05).黑素细胞G-CSFR蛋白和mRNA的表达水平明显高于HEL 92.1.7 (P< 0.01),低于中性粒细胞(P< 0.05或P<0.01).rhG-CSF在200~800μg/L时均有促黑素细胞增殖的能力,与空白对照组相比,差异有统计学意义(P< 0.01或P<0.05);在200~ 600 μg/L范围内呈浓度依赖性(P<0.01),600μg/L时的效应( 164.04%±13.0%)与20 μg/L的TPA作用(165.62%±10.6%)相当(P> 0.05);200~800 μg/L的rhG-CSF对黑素细胞酪氨酸酶活性的影响与空白对照组相比差异无统计学意义(P>0.05).结论 人黑素细胞可表达G-CSFR;rhG-CSF具有促进黑素细胞增殖的作用,但对酪氨酸酶活性无影响.%Objective To measure the expression of granulocyte colony-stimulating factor receptor (G-CSFR) in human melanocytes and to evaluate the biologic effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on human melanocytes

  7. Activation of GPR119 Stimulates Human β-Cell Replication and Neogenesis in Humanized Mice with Functional Human Islets

    Science.gov (United States)

    Ansarullah; Free, Colette; Christopherson, Jenica; Chen, Quanhai; Gao, Jie; Liu, Chengyang; Naji, Ali; Rabinovitch, Alex; Guo, Zhiguang

    2016-01-01

    Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human β-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts. Immunostaining for insulin, glucagon, and BrdU or Ki67 was performed in islet grafts to evaluate α- and β-cell replication. Insulin and CK19 immunostaining was performed to evaluate β-cell neogenesis. Four weeks after human islet transplantation, 71% of PSN632408-treated mice achieved normoglycaemia compared with 24% of vehicle-treated mice. Also, oral glucose tolerance was significantly improved in the PSN632408-treated mice. PSN632408 treatment significantly increased both human α- and β-cell areas in islet grafts and stimulated α- and β-cell replication. In addition, β-cell neogenesis was induced from pancreatic duct cells in the islet grafts. Our results demonstrated that activation of GPR119 increases β-cell mass by stimulating human β-cell replication and neogenesis. Therefore, GPR119 activators may qualify as therapeutic agents to increase human β-cell mass in patients with diabetes. PMID:27413754

  8. Intravenous Glucose Acutely Stimulates Intestinal Lipoprotein Secretion in Healthy Humans.

    Science.gov (United States)

    Xiao, Changting; Dash, Satya; Morgantini, Cecilia; Lewis, Gary F

    2016-07-01

    Increased production of intestinal triglyceride-rich lipoproteins (TRLs) contributes to dyslipidemia and increased risk of atherosclerotic cardiovascular disease in insulin resistance and type 2 diabetes. We have previously demonstrated that enteral glucose enhances lipid-stimulated intestinal lipoprotein particle secretion. Here, we assessed whether glucose delivered systemically by intravenous infusion also enhances intestinal lipoprotein particle secretion in humans. On 2 occasions, 4 to 6 weeks apart and in random order, 10 healthy men received a constant 15-hour intravenous infusion of either 20% glucose to induce hyperglycemia or normal saline as control. Production of TRL-apolipoprotein B48 (apoB48, primary outcomes) and apoB100 (secondary outcomes) was assessed during hourly liquid-mixed macronutrient formula ingestion with stable isotope enrichment and multicompartmental modeling, under pancreatic clamp conditions to limit perturbations in pancreatic hormones (insulin and glucagon) and growth hormone. Compared with saline infusion, glucose infusion induced both hyperglycemia and hyperinsulinemia, increased plasma triglyceride levels, and increased TRL-apoB48 concentration and production rate (Plipoprotein production. Hyperglycemia may contribute to intestinal lipoprotein overproduction in type 2 diabetes. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02607839. © 2016 American Heart Association, Inc.

  9. Mechanical stimulation improves tissue-engineered human skeletal muscle

    Science.gov (United States)

    Powell, Courtney A.; Smiley, Beth L.; Mills, John; Vandenburgh, Herman H.

    2002-01-01

    Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

  10. Mechanical stimulation improves tissue-engineered human skeletal muscle

    Science.gov (United States)

    Powell, Courtney A.; Smiley, Beth L.; Mills, John; Vandenburgh, Herman H.

    2002-01-01

    Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

  11. Enhancement of human cognitive performance using transcranial magnetic stimulation (TMS).

    Science.gov (United States)

    Luber, Bruce; Lisanby, Sarah H

    2014-01-15

    Here we review the usefulness of transcranial magnetic stimulation (TMS) in modulating cortical networks in ways that might produce performance enhancements in healthy human subjects. To date over sixty studies have reported significant improvements in speed and accuracy in a variety of tasks involving perceptual, motor, and executive processing. Two basic categories of enhancement mechanisms are suggested by this literature: direct modulation of a cortical region or network that leads to more efficient processing, and addition-by-subtraction, which is disruption of processing which competes or distracts from task performance. Potential applications of TMS cognitive enhancement, including research into cortical function, rehabilitation therapy in neurological and psychiatric illness, and accelerated skill acquisition in healthy individuals are discussed, as are methods of optimizing the magnitude and duration of TMS-induced performance enhancement, such as improvement of targeting through further integration of brain imaging with TMS. One technique, combining multiple sessions of TMS with concurrent TMS/task performance to induce Hebbian-like learning, appears to be promising for prolonging enhancement effects. While further refinements in the application of TMS to cognitive enhancement can still be made, and questions remain regarding the mechanisms underlying the observed effects, this appears to be a fruitful area of investigation that may shed light on the basic mechanisms of cognitive function and their therapeutic modulation.

  12. Burkholderia pseudomallei Capsule Exacerbates Respiratory Melioidosis but Does Not Afford Protection against Antimicrobial Signaling or Bacterial Killing in Human Olfactory Ensheathing Cells.

    Science.gov (United States)

    Dando, Samantha J; Ipe, Deepak S; Batzloff, Michael; Sullivan, Matthew J; Crossman, David K; Crowley, Michael; Strong, Emily; Kyan, Stephanie; Leclercq, Sophie Y; Ekberg, Jenny A K; St John, James; Beacham, Ifor R; Ulett, Glen C

    2016-07-01

    Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an often severe infection that regularly involves respiratory disease following inhalation exposure. Intranasal (i.n.) inoculation of mice represents an experimental approach used to study the contributions of bacterial capsular polysaccharide I (CPS I) to virulence during acute disease. We used aerosol delivery of B. pseudomallei to establish respiratory infection in mice and studied CPS I in the context of innate immune responses. CPS I improved B. pseudomallei survival in vivo and triggered multiple cytokine responses, neutrophil infiltration, and acute inflammatory histopathology in the spleen, liver, nasal-associated lymphoid tissue, and olfactory mucosa (OM). To further explore the role of the OM response to B. pseudomallei infection, we infected human olfactory ensheathing cells (OECs) in vitro and measured bacterial invasion and the cytokine responses induced following infection. Human OECs killed >90% of the B. pseudomallei in a CPS I-independent manner and exhibited an antibacterial cytokine response comprising granulocyte colony-stimulating factor, tumor necrosis factor alpha, and several regulatory cytokines. In-depth genome-wide transcriptomic profiling of the OEC response by RNA-Seq revealed a network of signaling pathways activated in OECs following infection involving a novel group of 378 genes that encode biological pathways controlling cellular movement, inflammation, immunological disease, and molecular transport. This represents the first antimicrobial program to be described in human OECs and establishes the extensive transcriptional defense network accessible in these cells. Collectively, these findings show a role for CPS I in B. pseudomallei survival in vivo following inhalation infection and the antibacterial signaling network that exists in human OM and OECs.

  13. Interleukin-6 production by human monocytes stimulated with Cryptococcus neoformans components.

    Science.gov (United States)

    Delfino, D; Cianci, L; Lupis, E; Celeste, A; Petrelli, M L; Curró, F; Cusumano, V; Teti, G

    1997-06-01

    In order to ascertain if Cryptococcus neoformans components can induce interleukin-6 (IL-6) production, we stimulated human whole blood with purified capsular products. Their potencies in stimulating IL-6 release were mannoproteins > galactoxylomannan = glucuronoxylomannan > alpha(1-3)glucan. IL-6 production was tumor necrosis factor alpha independent and required the presence of monocytes and plasma. Since IL-6 can stimulate replication of the human immunodeficiency virus in monocytic cells, these findings may be clinically relevant.

  14. Repetitive electric brain stimulation reduces food intake in humans

    National Research Council Canada - National Science Library

    Jauch-Chara, Kamila; Kistenmacher, Alina; Herzog, Nina; Schwarz, Marianka; Schweiger, Ulrich; Oltmanns, Kerstin M

    2014-01-01

    ...)) from 20 to 25 were examined during 8 d of daily tDCS or a sham stimulation. After tDCS or sham stimulation on the first and the last day of both experimental conditions, participants consumed food ad libitum from a standardized test buffet...

  15. Improving human plateaued motor skill with somatic stimulation.

    Directory of Open Access Journals (Sweden)

    Shintaro Uehara

    Full Text Available Procedural motor learning includes a period when no substantial gain in performance improvement is obtained even with repeated, daily practice. Prompted by the potential benefit of high-frequency transcutaneous electrical stimulation, we examined if the stimulation to the hand reduces redundant motor activity that likely exists in an acquired hand motor skill, so as to further upgrade stable motor performance. Healthy participants were trained until their motor performance of continuously rotating two balls in the palm of their right hand became stable. In the series of experiments, they repeated a trial performing this cyclic rotation as many times as possible in 15 s. In trials where we applied the stimulation to the relaxed thumb before they initiated the task, most reported that their movements became smoother and they could perform the movements at a higher cycle compared to the control trials. This was not possible when the dorsal side of the wrist was stimulated. The performance improvement was associated with reduction of amplitude of finger displacement, which was consistently observed irrespective of the task demands. Importantly, this kinematic change occurred without being noticed by the participants, and their intentional changes of motor strategies (reducing amplitude of finger displacement never improved the performance. Moreover, the performance never spontaneously improved during one-week training without stimulation, whereas the improvement in association with stimulation was consistently observed across days during training on another week combined with the stimulation. The improved effect obtained in stimulation trials on one day partially carried over to the next day, thereby promoting daily improvement of plateaued performance, which could not be unlocked by the first-week intensive training. This study demonstrated the possibility of effectively improving a plateaued motor skill, and pre-movement somatic stimulation

  16. T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART

    DEFF Research Database (Denmark)

    Aladdin, H; Von Essen, M; Schjerling, P;

    2001-01-01

    The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G-CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)-infected individuals...

  17. Enhancement of the amplitude of somatosensory evoked potentials following magnetic pulse stimulation of the human brain.

    Science.gov (United States)

    Seyal, M; Browne, J K; Masuoka, L K; Gabor, A J

    1993-01-01

    In this study we have demonstrated an enhancement of cortically generated wave forms of the somatosensory evoked potential (SEP) following magnetic pulse stimulation of the human brain. Subcortically generated activity was unaltered. The enhancement of SEP amplitude was greatest when the median nerve was stimulated 30-70 msec following magnetic pulse stimulation over the contralateral parietal scalp. We posit that the enhancement of the SEP is the result of synchronization of pyramidal cells in the sensorimotor cortex resulting from the magnetic pulse.

  18. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans.

    Science.gov (United States)

    Nitsche, M A; Paulus, W

    2001-11-27

    The authors show that in the human transcranial direct current stimulation is able to induce sustained cortical excitability elevations. As revealed by transcranial magnetic stimulation, motor cortical excitability increased approximately 150% above baseline for up to 90 minutes after the end of stimulation. The feasibility of inducing long-lasting excitability modulations in a noninvasive, painless, and reversible way makes this technique a potentially valuable tool in neuroplasticity modulation.

  19. Lipopolysaccharide-Induced Profiles of Cytokine, Chemokine, and Growth Factors Produced by Human Decidual Cells Are Altered by Lactobacillus rhamnosus GR-1 Supernatant.

    Science.gov (United States)

    Li, Wei; Yang, Siwen; Kim, Sung O; Reid, Gregor; Challis, John R G; Bocking, Alan D

    2014-07-01

    The aim of this study was to assess the effects of bacterial lipopolysaccharide (LPS) and Lactobacillus rhamnosus GR-1 supernatant (GR-1SN) on secretion profiles of cytokines, chemokines, and growth factors from primary cultures of human decidual cells. Lipopolysaccharide significantly increased the output of proinflammatory cytokines (interleukin [IL]-1B, IL-2, IL-6, IL-12p70, IL-15, IL-17A, interferon gamma [IFN-γ], and tumor necrosis factor [TNF]); anti-inflammatory cytokines (IL-1RN, IL-4, IL-9, and IL-10); chemokines (IL-8, eotaxin, IFN-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1α [MIP-1α], macrophage inflammatory protein-1β [MIP-1β], and regulated on activation normal T cell expressed and secreted [RANTES]); and growth factors (granulocyte colony-stimulating factor [CSF] 3, CSF-2, and vascular endothelial growth factor A [VEGFA]). Lactobacillus rhamnosus GR-1SN alone significantly increased CSF-3, MIP-1α MIP-1β, and RANTES but decreased IL-15 and IP-10 output. The GR-1SN also significantly or partially reduced LPS-induced proinflammatory cytokines TNF, IFN-γ, IL-1β, IL-2 IL-6, IL-12p70, IL-15, IL-17, and IP-10; partially reduced LPS-induced anti-inflammatory cytokines IL-1RN, IL-4 and IL-10, and LPS-induced VEGFA output but did not affect CSF-3, MIP-1α, MIP-1β, MCP-1, IL-8, and IL-9. Our results demonstrate that GR-1SN attenuates the inflammatory responses to LPS by human decidual cells, suggesting its potential role in ameliorating intrauterine infection.

  20. Vestibular implantation and longitudinal electrical stimulation of the semicircular canal afferents in human subjects.

    Science.gov (United States)

    Phillips, James O; Ling, Leo; Nie, Kaibao; Jameyson, Elyse; Phillips, Christopher M; Nowack, Amy L; Golub, Justin S; Rubinstein, Jay T

    2015-06-01

    Animal experiments and limited data in humans suggest that electrical stimulation of the vestibular end organs could be used to treat loss of vestibular function. In this paper we demonstrate that canal-specific two-dimensionally (2D) measured eye velocities are elicited from intermittent brief 2 s biphasic pulse electrical stimulation in four human subjects implanted with a vestibular prosthesis. The 2D measured direction of the slow phase eye movements changed with the canal stimulated. Increasing pulse current over a 0-400 μA range typically produced a monotonic increase in slow phase eye velocity. The responses decremented or in some cases fluctuated over time in most implanted canals but could be partially restored by changing the return path of the stimulation current. Implantation of the device in Meniere's patients produced hearing and vestibular loss in the implanted ear. Electrical stimulation was well tolerated, producing no sensation of pain, nausea, or auditory percept with stimulation that elicited robust eye movements. There were changes in slow phase eye velocity with current and over time, and changes in electrically evoked compound action potentials produced by stimulation and recorded with the implanted device. Perceived rotation in subjects was consistent with the slow phase eye movements in direction and scaled with stimulation current in magnitude. These results suggest that electrical stimulation of the vestibular end organ in human subjects provided controlled vestibular inputs over time, but in Meniere's patients this apparently came at the cost of hearing and vestibular function in the implanted ear.

  1. Cultured rat and purified human Pneumocystis carinii stimulate intra- but not extracellular free radical production in human neutrophils

    DEFF Research Database (Denmark)

    Jensen, T; Aliouat, E M; Lundgren, B

    1998-01-01

    The production of free radicals in human neutrophils was studied in both Pneumocystis carinii derived from cultures of L2 rat lung epithelial-like cells and Pneumocystis carinii purified from human lung. Using the cytochrome C technique, which selectively measured extracellular superoxide....... It was established that 1) P. carinii stimulated intra- but not extracellular free radical production in human neutrophils, 2) opsonized cultured rat-derived P. carinii stimulated human neutrophils to a strong intracellular response of superoxide production, and 3) opsonized P. carinii, purified from human lung also...

  2. Efficacy and safety analysis of the combination of cladribine, cytarabine, granulocyte colony-stimulating factor (CLAG) regime in patients with refractory or relapsed acute myeloid leukemia%CLAG方案治疗33例难治复发急性髓系白血病的疗效及安全性

    Institute of Scientific and Technical Information of China (English)

    段明辉; 张岩; 张梅; 韩潇; 张炎; 杨辰; 冯俊; 张路; 张薇

    2016-01-01

    Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia (AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three patients (16 males and 17 females) with refractory or relapsed AML were treated with one course of CLAG with a median age of 49 (14-68) years.According to FAB subtype,there were 22 patients with M2,and 11 with other types.According to NCCN criteria,there were 6,18 and 9 patients with favorable,intermediate and unfavorable risk respectively,including 5 with FLT3-ITD mutation.Of 16 refractory and 17 relapsed patients;the median previous chemotherapy courses were 2 (1-36).After one course of CLAG,78.8% (26/ 33) patients achieved hematological complete response (CR),with 93.8 %(15/16) in relapsed and 64.7 % (11/17) in refractory groups respectively.All five patients with FLT3-ITD mutation achieved CR.All patients had grade 4 neutropenia and thrombocytopenia and infection in different sites;three patients died early from infections.Five patients received allogeneic hematopoietic stem cell transplantation (alloHSCT).Ten patients relapsed and thirteen patients died after the median follow-up 142 (9-525) days.The median EFS and OS were 230 (9-525) and 419 (9-525) days respectively,which in CR group (n=26) were significantly longer than those in NR one (n=7) [447(165-525)d vs 52 (9-162)d,P< 0.001].Conclusions CLAG regimen was effective and well tolerable in patients with refractory or relapsed AML,with the CR rate in relapsed patients higher than in refractory counterparts.Control of infections was imperative for treatment.%目的 分析CLAG方案(克拉屈滨+阿糖胞苷+G-CSF)对难治复发急性髓系白血病(AML)的疗效及安全性.方法 回顾性分析2014年4月1日至2015年12月9日采用1个疗程CLAG方案治疗的33例难治复发AML患者的临床资料.结果 33例难治复发AML患者中,男16例,女17例,中位年龄49(14~68)岁.按照WHO分类(第4版)诊断:伴有重现性遗传学异常AML7例(21.2%),伴有多系病态造血AML 5例(15.2%),治疗相关AML 2例(6.1%),其他类型19例(57.5%).NCCN危险分层低危、中危、高危组分别为6、18、9例,其中FLT3-1TD基因突变5例.复发16例,难治17例,既往化疗疗程中位数为2(1~36)个.经CLAG方案1个疗程化疗后,26例(78.8%)获得完全缓解(CR),难治组CR率低于复发组[64.7%(11/17)对93.8%(15/16),P=0.041].5例FLT3-ITD基因突变患者均获CR.所有患者均出现4级白细胞减少和血小板减少和不同部位感染,3例因感染而早期死亡.5例患者CR后接受异基因造血干细胞移植.中位随访142(9~525)d,复发10例,死亡13例,中位无事件生存期为230(9~525)d,中位总生存期为419(9~525)d.获CR患者(26例)中位总生存期长于未缓解患者(7例)[447(165~525)d对52(9~162)d,P< 0.001].结论 CLAG方案对难治复发AML疗效肯定,复发患者CR率高于难治患者.控制感染是治疗成功的关键.

  3. 粒系集落刺激因子对进展型多发性硬化患者造血干细胞的动员效果及安全性%Efficacy and safety of hematopoietic stem cell mobilization by granulocyte colony-stimulation factor in patients with progressive multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    徐娟; 冀冰心; 苏力; 孔雪静; 刘聪艳

    2008-01-01

    目的: 观察粒系集落刺激因子(G-CSF)对进展型多发性硬化(MS)患者造血干细胞动员效果及安全性.方法: 34例继发进展型MS患者纳入研究,给予G-CSF 5μg/(kg·d)4~6 d动员自体造血干细胞.动员后经血细胞分离机收集外周血单个核细胞.应用流式细胞术检测CD34+细胞和单个核细胞绝对数,并观察应用G-CSF后不良反应的类型和发生率.于动员前及动员后分别评定患者的扩展残疾状态评分(expanded disability status scale,EDSS).结果:采集物中CD34+细胞为(2.68±0.89)×106/kg,单个核细胞为(2.98±1.19)×108/kg.移植后中性粒细胞恢复至>0.5×109/L的中位时间为13 d(9~17d),血小板恢复至>50×109/L的中位时间为16 d(11~21 d).移植相关死亡率为0.在G-CSF动员过程中有17例患者(50%)出现肌痛及乏力症状,未用药物治疗症状消退.2例患者在用药期间EDSS评分增加0.5分,与动员前相比差异无统计学意义(P=0.16).结论: 对于自体造血干细胞移植治疗进展型多发性硬化患者,单用G-CSF动员可以达到有效安全的临床要求.

  4. Paired pulse TMS stimulation and human tongue corticomotor pathways

    DEFF Research Database (Denmark)

    Kothari, Mohit; Svensson, Peter; Nielsen, Jørgen Feldbæk

    Objectives: Paired pulse transcranial magnetic stimulation (ppTMS) can be used to assess short-term interval intra-cortical inhibitory (SICI) and facilitatory (ICF) networks. The degree of SICI and ICF varies with interstimulus intervals (ISI) and stimulus intensities of the conditioning stimulus...... intensities (P = 0.984). Post-hoc tests revealed that there was significant SICI with ppTMS ISI of 2, 2.5, 3, and 3.5 ms compared with single pulse stimulation (Pstimulation (P=0.988). There was no interaction between...

  5. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans.

    Science.gov (United States)

    Batsikadze, G; Moliadze, V; Paulus, W; Kuo, M-F; Nitsche, M A

    2013-04-01

    Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm(2) has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI

  6. Fatigue of intermittently stimulated human quadriceps during imposed cyclical lower leg movements

    NARCIS (Netherlands)

    Franken, Henry M.; Veltink, Peter H.; Fidder, Marc; Boom, Herman B.K.

    1993-01-01

    In this study the torque output of intermittently stimulated paralyzed human knee extensor muscles during imposed isokinetic cyclical lower leg movements was investigated in four paraplegic subjects. During prolonged (10 min) experiments the influence of knee angular velocity and stimulation paramet

  7. Nanostructural change of human melanocytes stimulated with α-melanocyte stimulating hormone observed by atomic force microscopy.

    Science.gov (United States)

    Shin, Min Kyung; Lim, Hee Kyeong; Kang, Boo Kyoung; Lee, Gi-Ja; Uhm, Yun-Kyung; Lee, Mu-Hyoung

    2014-01-01

    It is well known that α-melanocyte stimulating hormone (α-MSH) induces melanization, but structural changes of melanocytes after α-MSH exposure are not well known. This study investigated the serial morphologic changes of human cultured melanocytes after stimulation with α-MSH using atomic force microscopy (AFM). Cultured human melanocytes were treated with α-MSH for 7 days. Contact mode AFM images were obtained using a NANOstation II and fixed melanocytes were scanned in PBS solution at a resolution of 512 × 512 pixels, at a scan speed of 0.4 line/s. The surface roughness and pore-like structures of the melanocytes were measured from topographic images using the Scanning Probe Imaging Processor. The surface roughness of cell body did not change significantly over time. All three roughness parameters (Sa, Sq, Sz) inside the pore-like structures on the dendrites increased significantly. The number of pore-like structures increased and the length and the breadth of pore-like structures also increased gradually. Pore-like structures changed statistically significantly in response to α-MSH stimulation. Further study will be needed to clarify whether the nature of pore-like structures is related to movement of melanosomes.

  8. Fluoride stimulates ( sup 3 H)thymidine incorporation and alkaline phosphatase production by human osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Khokher, M.A.; Dandona, P. (Royal Free Hospital, London (England))

    1990-11-01

    The effect of sodium fluoride on alkaline phosphatase (ALP) release and ({sup 3}H)thymidine uptake by human osteoblasts in culture was investigated. Sodium fluoride stimulated both ALP release and ({sup 3}H)thymidine uptake at concentrations of sodium fluoride greater than 250 mumol/L. This stimulation was similar in magnitude to that induced by 1,25-dihydroxycholecalciferol. The fluoride-induced increase in ALP was inhibited by verapamil, a calcium channel blocker. We conclude that sodium fluoride stimulates osteoblasts to proliferate and to release ALP. This stimulation by fluoride is dependent on calcium influx. Fluoride-induced stimulation of human osteoblasts may be relevant to its effect in enhancing bone formation in patients with osteoporosis.

  9. Vertical torque responses to vestibular stimulation in standing humans.

    Science.gov (United States)

    Reynolds, Raymond F

    2011-08-15

    The effects of electrical vestibular stimulation upon movement and perception suggest two evoked sensations: head roll and inter-aural linear acceleration. The head roll vector causes walking subjects to turn in a direction dependent on head pitch, requiring generation of torque around a vertical axis. Here the effect of vestibular stimulation upon vertical torque (T(z)) was investigated during quiet stance. With the head tilted forward, square-wave stimuli applied to the mastoid processes evoked a polarity-specific T(z) response accompanied by trunk yaw. Stochastic vestibular stimulation (SVS) was used to investigate the effect of head pitch with greater precision; the SVS–T(z) cross-correlation displayed a modulation pattern consistent with the head roll vector and this was also reflected by changes in coherence at 2–3 Hz. However, a separate response at 7–8 Hz was unaffected by head pitch. Head translation (rather than rotation) had no effect upon this high frequency response either, suggesting it is not caused by a sense of body rotation induced by an inter-aural acceleration vector offset from the body. Instead, high coherence between medio-lateral shear force and T(z) at the same frequency range suggests it is caused by mechanical coupling to evoked medio-lateral sway. Consistent with this explanation, the 7–8 Hz response was attenuated by 90 deg head roll or yaw, both of which uncouple the inter-aural axis from the medio-lateral sway axis. These results demonstrate two vertical torque responses to electrical vestibular stimulation in standing subjects. The high frequency response can be attributed to mechanical coupling to evoked medio-lateral sway. The low frequency response is consistent with a reaction to a sensation of head roll, and provides a novel method for investigating proprioceptive-vestibular interactions during stance.

  10. Transcutaneous electrical spinal-cord stimulation in humans

    OpenAIRE

    Gerasimenko, Yury; Gorodnichev, Ruslan; Moshonkina, Tatiana; Sayenko, Dimitry; Gad, Parag; Edgerton, V. Reggie

    2015-01-01

    Locomotor behavior is controlled by specific neural circuits called central pattern generators primarily located at the lumbosacral spinal cord. These locomotor-related neuronal circuits have a high level of automaticity; that is, they can produce a “stepping” movement pattern also seen on electromyography (EMG) in the absence of supraspinal and/or peripheral afferent inputs. These circuits can be modulated by epidural spinal-cord stimulation and/or pharmacological intervention. Such interven...

  11. Controlled Pseudopod Extension of Human Neutrophils Stimulated with Different Chemoattractants

    OpenAIRE

    Zhelev, Doncho V.; Alteraifi, Abdullatif M.; Chodniewicz, David

    2004-01-01

    The formation of pseudopods and lamellae after ligation of chemoattractant sensitive G-protein coupled receptors (GPCRs) is essential for chemotaxis. Here, pseudopod extension was stimulated with chemoattractant delivered from a micropipet. The chemoattractant diffusion and convection mass transport were considered, and it is shown that when the delivery of chemoattractant was limited by diffusion there was a strong chemoattractant gradient along the cell surface. The diffusion-limited delive...

  12. Optogenetic stimulation of a meso-scale human cortical model

    Science.gov (United States)

    Selvaraj, Prashanth; Szeri, Andrew; Sleigh, Jamie; Kirsch, Heidi

    2015-03-01

    Neurological phenomena like sleep and seizures depend not only on the activity of individual neurons, but on the dynamics of neuron populations as well. Meso-scale models of cortical activity provide a means to study neural dynamics at the level of neuron populations. Additionally, they offer a safe and economical way to test the effects and efficacy of stimulation techniques on the dynamics of the cortex. Here, we use a physiologically relevant meso-scale model of the cortex to study the hypersynchronous activity of neuron populations during epileptic seizures. The model consists of a set of stochastic, highly non-linear partial differential equations. Next, we use optogenetic stimulation to control seizures in a hyperexcited cortex, and to induce seizures in a normally functioning cortex. The high spatial and temporal resolution this method offers makes a strong case for the use of optogenetics in treating meso scale cortical disorders such as epileptic seizures. We use bifurcation analysis to investigate the effect of optogenetic stimulation in the meso scale model, and its efficacy in suppressing the non-linear dynamics of seizures.

  13. Transcutaneous electrical spinal-cord stimulation in humans.

    Science.gov (United States)

    Gerasimenko, Yury; Gorodnichev, Ruslan; Moshonkina, Tatiana; Sayenko, Dimitry; Gad, Parag; Reggie Edgerton, V

    2015-09-01

    Locomotor behavior is controlled by specific neural circuits called central pattern generators primarily located at the lumbosacral spinal cord. These locomotor-related neuronal circuits have a high level of automaticity; that is, they can produce a "stepping" movement pattern also seen on electromyography (EMG) in the absence of supraspinal and/or peripheral afferent inputs. These circuits can be modulated by epidural spinal-cord stimulation and/or pharmacological intervention. Such interventions have been used to neuromodulate the neuronal circuits in patients with motor-complete spinal-cord injury (SCI) to facilitate postural and locomotor adjustments and to regain voluntary motor control. Here, we describe a novel non-invasive stimulation strategy of painless transcutaneous electrical enabling motor control (pcEmc) to neuromodulate the physiological state of the spinal cord. The technique can facilitate a stepping performance in non-injured subjects with legs placed in a gravity-neutral position. The stepping movements were induced more effectively with multi-site than single-site spinal-cord stimulation. From these results, a multielectrode surface array technology was developed. Our preliminary data indicate that use of the multielectrode surface array can fine-tune the control of the locomotor behavior. As well, the pcEmc strategy combined with exoskeleton technology is effective for improving motor function in paralyzed patients with SCI. The potential impact of using pcEmc to neuromodulate the spinal circuitry has significant implications for furthering our understanding of the mechanisms controlling locomotion and for rehabilitating sensorimotor function even after severe SCI. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Human milk proresolving mediators stimulate resolution of acute inflammation.

    Science.gov (United States)

    Arnardottir, H; Orr, S K; Dalli, J; Serhan, C N

    2016-05-01

    Human milk contains nutrients and bioactive products relevant to infant development and immunological protection. Here, we investigated the proresolving properties of milk using human milk lipid mediator isolates (HLMIs) and determined their impact on resolution programs in vivo and with human macrophages. HLMIs reduced the maximum neutrophil numbers (14.6±1.2 × 10(6)-11.0±1.0 × 10(6) cells per exudate) and shortened the resolution interval (Ri; 50% neutrophil reduction) by 54% compared with peritonitis. Using rigorous liquid-chromatography tandem-mass spectrometry (LC-MS-MS)-based lipid mediator (LM) metabololipidomics, we demonstrated that human milk possesses a proresolving LM-specialized proresolving mediator (LM-SPM) signature profile, containing SPMs (e.g. resolvins (Rv), protectins (PDs), maresins (MaRs), and lipoxins (LXs)) at bioactive levels (pico-nanomolar concentrations) that enhanced human macrophage efferocytosis and bacterial containment. SPMs identified in human milk included D-series Rvs (e.g., RvD1, RvD2, RvD3, AT-RvD3, and RvD4), PD1, MaR1, E-series Rvs (e.g. RvE1, RvE2, and RvE3), and LXs (LXA4 and LXB4). Of the SPMs identified in human milk, RvD2 and MaR1 (50 ng per mouse) individually shortened Ri by ∼75%. Milk from mastitis gave higher leukotriene B4 and prostanoids and lower SPM levels. Taken together, these findings provide evidence that human milk has proresolving actions via comprehensive LM-SPM profiling, describing a potentially novel mechanism in maternal-infant biochemical imprinting.

  15. Controlled pseudopod extension of human neutrophils stimulated with different chemoattractants.

    Science.gov (United States)

    Zhelev, Doncho V; Alteraifi, Abdullatif M; Chodniewicz, David

    2004-07-01

    The formation of pseudopods and lamellae after ligation of chemoattractant sensitive G-protein coupled receptors (GPCRs) is essential for chemotaxis. Here, pseudopod extension was stimulated with chemoattractant delivered from a micropipet. The chemoattractant diffusion and convection mass transport were considered, and it is shown that when the delivery of chemoattractant was limited by diffusion there was a strong chemoattractant gradient along the cell surface. The diffusion-limited delivery of chemoattractant from a micropipet allowed for maintaining an almost constant chemoattractant concentration at the leading edge of single pseudopods during their growth. In these conditions, the rate of pseudopod extension was dependent on the concentration of chemoattractant in the pipet delivering chemoattractant. The pseudopod extension induced using micropipets was oscillatory even in the presence of a constant delivery of chemoattractant. This oscillatory pseudopod extension was controlled by activated RhoA and its downstream effector kinase ROCK and was abolished after the inhibition of RhoA activation with Clostridium botulinium C3 exoenzyme (C3) or the blocking of ROCK activation with Y-27632. The ability of the micropipet assay to establish a well-defined chemoattractant distribution around the activated cell over a wide range of molecular weights of the used chemoattractants allowed for comparison of the effect of chemoattractant stimulation on the dynamics of pseudopod growth. Pseudopod growth was stimulated using N-formylated peptide (N-formyl-methionyl-leucyl-phenylalanine (fMLP)), platelet activating factor (PAF), leukotriene B4 (LTB(4)), C5a anaphylotoxin (C5a), and interleukin-8 (IL-8), which represent the typical ligands for G-protein coupled chemotactic receptors. The dependence of the rate of pseudopod extension on the concentration of these chemoattractants and their equimolar mixture was measured and shown to be similar for all chemoattractants. The

  16. Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    1999-01-01

    following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91...... young controls aged 19-31 years. Levels of TNF-alpha and IL-1 beta were significantly lower in elderly humans compared with young controls, whereas no difference was detected with regard to IL-6. Elderly humans with low body mass index had the lowest levels of IL-1 beta. Young women had lower levels...

  17. Transcutaneous spinal direct current stimulation modulates human corticospinal system excitability.

    Science.gov (United States)

    Bocci, Tommaso; Marceglia, Sara; Vergari, Maurizio; Cognetto, Valeria; Cogiamanian, Filippo; Sartucci, Ferdinando; Priori, Alberto

    2015-07-01

    This study aimed to assess the effects of thoracic anodal and cathodal transcutaneous spinal direct current stimulation (tsDCS) on upper and lower limb corticospinal excitability. Although there have been studies assessing how thoracic tsDCS influences the spinal ascending tract and reflexes, none has assessed the effects of this technique over upper and lower limb corticomotor neuronal connections. In 14 healthy subjects we recorded motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) from abductor hallucis (AH) and hand abductor digiti minimi (ADM) muscles before (baseline) and at different time points (0 and 30 min) after anodal or cathodal tsDCS (2.5 mA, 20 min, T9-T11 level). In 8 of the 14 subjects we also tested the soleus H reflex and the F waves from AH and ADM before and after tsDCS. Both anodal and cathodal tsDCS left the upper limb MEPs and F wave unchanged. Conversely, while leaving lower limb H reflex unchanged, they oppositely affected lower limb MEPs: whereas anodal tsDCS increased resting motor threshold [(mean ± SE) 107.33 ± 3.3% increase immediately after tsDCS and 108.37 ± 3.2% increase 30 min after tsDCS compared with baseline] and had no effects on MEP area and latency, cathodal tsDCS increased MEP area (139.71 ± 12.9% increase immediately after tsDCS and 132.74 ± 22.0% increase 30 min after tsDCS compared with baseline) without affecting resting motor threshold and MEP latency. Our results show that tsDCS induces polarity-specific changes in corticospinal excitability that last for >30 min after tsDCS offset and selectively affect responses in lower limb muscles innervated by lumbar and sacral motor neurons.

  18. [Thyroid stimulating immunoglobulin bioassay using cultured normal human thyroid cells].

    Science.gov (United States)

    Ando, M; Yamauchi, K; Tanaka, H; Mori, Y; Takatsuki, K; Yamamoto, M; Matsui, N; Tomita, A

    1985-08-20

    It is currently believed that the thyroid stimulating immunoglobulin (TSI) of Graves' disease is involved in the pathogenesis of hyperthyroidism through the stimulation of the adenylate cyclase-cyclic AMP system. To evaluate this mechanism, TSI in the serum of patients with Graves' disease was determined by its ability to generate cyclic AMP (cAMP) in monolayer cells prepared from a normal thyroid gland. The thyroid tissue was digested with collagenase, and the liberated follicles were collected from the supernatant and cultured for 7 days. One gram of thyroid tissue yielded more than 1 X 10(7) monolayer cells which were stored in aliquots at -80C. Cells (1 approximately 2 X 10(4)/0.28 cm2 microtiter well) were incubated for 4 hours in 0.2 ml Hanks solution poor in NaCl, with various amounts of bovine TSH (bTSH) or 1.5 mg/ml Graves' serum IgG extracted by polyethylene glycol. cAMP accumulated in medium and cells was measured by RIA. Total cAMP (both medium and cells) was about 4 times higher when NaCl was deleted from Hanks solution. Moreover, as more than 90% of the cAMP was released into the medium, it was possible to omit the measurement of cellular cAMP, which requires extraction. The increase in medium cAMP concentration was dependent upon the number of cells, incubation time, and dose of bTSH. Time course and dose response curves in medium cAMP stimulated by IgG from 3 Graves' patients paralleled those of bTSH equivalent units. Accordingly, TSI activity could be expressed in bTSH equivalent units (bTSH microUeq). The assay could detect 1.0 or 3.3 microU/ml of bTSH and was highly reproducible. TSI activity in all of 16 IgGs from normal subjects was under 3.3 bTSH microUeq/ml, while it was greater than 3.3 bTSH microUeq/ml in IgGs from 33 of 37 (89%) untreated patients with Graves disease. Of the 13 patients followed for 2 to 7 months while on antithyroid drugs, 12 had greater than 3.3 bTSH microUeq/ml and, with the exception of one, all showed a decrease in

  19. Mechanical Stimulation Protocols of Human Derived Cells in Articular Cartilage Tissue Engineering - A Systematic Review.

    Science.gov (United States)

    Khozoee, Baktash; Mafi, Pouya; Mafi, Reza; Khan, Wasim S

    2017-01-01

    Mechanical stimulation is a key factor in articular cartilage generation and maintenance. Bioreactor systems have been designed and built in order to deliver specific types of mechanical stimulation. The focus has been twofold, applying a type of preconditioning in order to stimulate cell differentiation, and to simulate in vivo conditions in order to gain further insight into how cells respond to different stimulatory patterns. Due to the complex forces at work within joints, it is difficult to simulate mechanical conditions using a bioreactor. The aim of this review is to gain a deeper understanding of the complexities of mechanical stimulation protocols by comparing those employed in bioreactors in the context of tissue engineering for articular cartilage, and to consider their effects on cultured cells. Allied and Complementary Medicine 1985 to 2016, Ovid MEDLINE[R] 1946 to 2016, and Embase 1974 to 2016 were searched using key terms. Results were subject to inclusion and exclusion criteria, key findings summarised into a table and subsequently discussed. Based on this review it is overwhelmingly clear that mechanical stimulation leads to increased chondrogenic properties in the context of bioreactor articular cartilage tissue engineering using human cells. However, given the variability and lack of controlled factors between research articles, results are difficult to compare, and a standardised method of evaluating stimulation protocols proved challenging. With improved standardisation in mechanical stimulation protocol reporting, bioreactor design and building processes, along with a better understanding of joint behaviours, we hope to perform a meta-analysis on stimulation protocols and methods.

  20. Transcranial alternating current stimulation enhances individual alpha activity in human EEG.

    Directory of Open Access Journals (Sweden)

    Tino Zaehle

    Full Text Available Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity.The present findings are the first direct electrophysiological evidence of an interaction of tACS and ongoing oscillatory activity in the human cortex. The data demonstrate the ability of tACS to specifically modulate oscillatory brain activity and show its potential both at fostering knowledge on the functional significance of brain oscillations and for therapeutic application.

  1. Ovarian response to recombinant human follicle-stimulating hormone

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; Andersen, Anders Nyboe; Fernández-Sánchez, Manuel

    2014-01-01

    OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrat......OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH......) concentrations. DESIGN: Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-infertility centers in four countries. PATIENT(S): Two hundred sixty-five women aged ≤37 years. INTERVENTION(S): Controlled...

  2. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat...... and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis...

  3. Uraemic sera stimulate lipolysis in human adipocytes: role of perilipin.

    Science.gov (United States)

    Axelsson, Jonas; Aström, Gaby; Sjölin, Eva; Qureshi, Abdul Rashid; Lorente-Cebrián, Silvia; Stenvinkel, Peter; Rydén, Mikael

    2011-08-01

    Although chronic kidney disease (CKD) is associated with dyslipidaemia and insulin resistance, the exact cause(s) are unknown. Since adipose tissue plays an important role in the development of these complications, we investigated the effect of uraemic sera on human adipocytes in vitro. Cultured human adipocytes were incubated for 48 h with media containing sera from eight CKD Stage 5 patients or four (matched for age, sex and body mass index) healthy controls. Glycerol release (an index of lipolysis) was determined in conditioned media. RNA was isolated from the cells and quantitative polymerase chain reaction of genes involved in lipolysis was performed. In vivo lipolysis was determined by the plasma glycerol/total fat mass (from dual energy X-ray absorptiometry) ratio in 28 CKD patients and 28 matched controls. Incubation with uraemic, but not control, sera resulted in a significant ∼30% increase in spontaneous (basal) lipolysis (P lipolysis in human adipocytes in vitro, probably by attenuating the expression of the lipolytic regulator PLIN. Since in vivo lipolysis is a well-established risk factor for insulin resistance and cardiovascular disease, these effects may promote increased morbidity and mortality in CKD.

  4. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing.

    Science.gov (United States)

    Koob, Thomas J; Rennert, Robert; Zabek, Nicole; Massee, Michelle; Lim, Jeremy J; Temenoff, Johnna S; Li, William W; Gurtner, Geoffrey

    2013-10-01

    Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In this study, PURION® (MiMedx, Marietta, GA) processed dehydrated human amnion/chorion tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for the presence of growth factors, interleukins (ILs) and tissue inhibitors of metalloproteinases (TIMPs). Enzyme-linked immunosorbent assays (ELISA) were performed on samples of dHACM and showed quantifiable levels of the following growth factors: platelet-derived growth factor-AA (PDGF-AA), PDGF-BB, transforming growth factor α (TGFα), TGFβ1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), placental growth factor (PLGF) and granulocyte colony-stimulating factor (GCSF). The ELISA assays also confirmed the presence of IL-4, 6, 8 and 10, and TIMP 1, 2 and 4. Moreover, the relative elution of growth factors into saline from the allograft ranged from 4% to 62%, indicating that there are bound and unbound fractions of these compounds within the allograft. dHACM retained biological activities that cause human dermal fibroblast proliferation and migration of human mesenchymal stem cells (MSCs) in vitro. An in vivo mouse model showed that dHACM when tested in a skin flap model caused mesenchymal progenitor cell recruitment to the site of implantation. The results from both the in vitro and in vivo experiments clearly established that dHACM contains one or more soluble factors capable of stimulating MSC migration and recruitment. In summary, PURION® processed dHACM retains its biological activities related to wound healing, including the potential to positively affect four distinct and pivotal physiological processes intimately involved in wound healing: cell proliferation, inflammation, metalloproteinase activity and recruitment of progenitor cells. This suggests

  5. Functional magnetic resonance imaging of the human spinal cord during vibration stimulation of different dermatomes.

    Science.gov (United States)

    Lawrence, Jane M; Stroman, Patrick W; Kollias, Spyros S

    2008-03-01

    We investigated noninvasively areas of the healthy human spinal cord that become active in response to vibration stimulation of different dermatomes using functional magnetic resonance imaging (fMRI). The objectives of this study were to: (1) examine the patterns of consistent activity in the spinal cord during vibration stimulation of the skin, and (2) investigate the rostrocaudal distribution of active pixels when stimulation was applied to different dermatomes. FMRI of the cervical and lumbar spinal cord of seven healthy human subjects was carried out during vibration stimulation of six different dermatomes. In separate experiments, vibratory stimulation (about 50 Hz) was applied to the right biceps, wrist, palm, patella, Achilles tendon and left palm. The segmental distribution of activity observed by fMRI corresponded well with known spinal cord neuroanatomy. The peak number of active pixels was observed at the expected level of the spinal cord with some activity in the adjacent segments. The rostrocaudal distribution of activity was observed to correspond to the dermatome being stimulated. Cross-sectional localization of activity was primarily in dorsal areas but also spread into ventral and intermediate areas of the gray matter and a distinct laterality ipsilateral to the stimulated limb was not observed. We demonstrated that fMRI can detect a dermatome-dependent pattern of spinal cord activity during vibratory stimulation and can be used as a passive stimulus for the noninvasive assessment of the functional integrity of the human spinal cord. Demonstration of cross-sectional selectivity of the activation awaits further methodological and experimental refinements.

  6. Functional magnetic resonance imaging of the human spinal cord during vibration stimulation of different dermatomes

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence, Jane M. [University Hospital of Zurich, Institute of Neuroradiology, Zurich (Switzerland); University of Manitoba, Department of Physiology, Winnipeg, Manitoba (Canada); Stroman, Patrick W. [Queen' s University, Department of Diagnostic Radiology, Kingston, Ontario (Canada); Kollias, Spyros S. [University Hospital of Zurich, Institute of Neuroradiology, Zurich (Switzerland)

    2008-03-15

    We investigated noninvasively areas of the healthy human spinal cord that become active in response to vibration stimulation of different dermatomes using functional magnetic resonance imaging (fMRI). The objectives of this study were to: (1) examine the patterns of consistent activity in the spinal cord during vibration stimulation of the skin, and (2) investigate the rostrocaudal distribution of active pixels when stimulation was applied to different dermatomes. FMRI of the cervical and lumbar spinal cord of seven healthy human subjects was carried out during vibration stimulation of six different dermatomes. In separate experiments, vibratory stimulation (about 50 Hz) was applied to the right biceps, wrist, palm, patella, Achilles tendon and left palm. The segmental distribution of activity observed by fMRI corresponded well with known spinal cord neuroanatomy. The peak number of active pixels was observed at the expected level of the spinal cord with some activity in the adjacent segments. The rostrocaudal distribution of activity was observed to correspond to the dermatome being stimulated. Cross-sectional localization of activity was primarily in dorsal areas but also spread into ventral and intermediate areas of the gray matter and a distinct laterality ipsilateral to the stimulated limb was not observed. We demonstrated that fMRI can detect a dermatome-dependent pattern of spinal cord activity during vibratory stimulation and can be used as a passive stimulus for the noninvasive assessment of the functional integrity of the human spinal cord. Demonstration of cross-sectional selectivity of the activation awaits further methodological and experimental refinements. (orig.)

  7. Interleukin-6 stimulates lipolysis and fat oxidation in humans

    DEFF Research Database (Denmark)

    van Hall, Gerrit; Steensberg, Adam; Sacchetti, Massimo

    2003-01-01

    Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n = 6) or a high dose (High-rhIL6; n = 6) or a low dose (Low-rhIL6; n = 6) of rec...... in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia. Comment in...

  8. Suppression of EMG activity by transcranial magnetic stimulation in human subjects during walking

    DEFF Research Database (Denmark)

    Petersen, Nicolas Caesar; Butler, Jane E; Marchand-Pauvert, Veronique

    2001-01-01

    1. The involvement of the motor cortex during human walking was evaluated using transcranial magnetic stimulation (TMS) of the motor cortex at a variety of intensities. Recordings of EMG activity in tibialis anterior (TA) and soleus muscles during walking were rectified and averaged. 2. TMS of low...... intensity (below threshold for a motor-evoked potential, MEP) produced a suppression of ongoing EMG activity during walking. The average latency for this suppression was 40.0 +/- 1.0 ms. At slightly higher intensities of stimulation there was a facilitation of the EMG activity with an average latency of 29.......5 +/- 1.0 ms. As the intensity of the stimulation was increased the facilitation increased in size and eventually a MEP was clear in individual sweeps. 3. In three subjects TMS was replaced by electrical stimulation over the motor cortex. Just below MEP threshold there was a clear facilitation at short...

  9. Illicit stimulant use is associated with abnormal substantia nigra morphology in humans.

    Directory of Open Access Journals (Sweden)

    Gabrielle Todd

    Full Text Available Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed 'hyperechogenicity' when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs and cannabis users (n = 12; 25±7 yrs. Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm(2 than in the control (0.201±0.054 cm(2; P<0.001 and cannabis (0.202±0.045 cm(2; P<0.007 groups. 53% of stimulant users exhibited echogenicity that exceeded the 90(th percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system.

  10. Corticospinal activity evoked and modulated by non-invasive stimulation of the intact human motor cortex.

    Science.gov (United States)

    Di Lazzaro, Vincenzo; Rothwell, John C

    2014-10-01

    A number of methods have been developed recently that stimulate the human brain non-invasively through the intact scalp. The most common are transcranial magnetic stimulation (TMS), transcranial electric stimulation (TES) and transcranial direct current stimulation (TDCS). They are widely used to probe function and connectivity of brain areas as well as therapeutically in a variety of conditions such as depression or stroke. They are much less focal than conventional invasive methods which use small electrodes placed on or in the brain and are often thought to activate all classes of neurones in the stimulated area. However, this is not true. A large body of evidence from experiments on the motor cortex shows that non-invasive methods of brain stimulation can be surprisingly selective and that adjusting the intensity and direction of stimulation can activate different classes of inhibitory and excitatory inputs to the corticospinal output cells. Here we review data that have elucidated the action of TMS and TES, concentrating mainly on the most direct evidence available from spinal epidural recordings of the descending corticospinal volleys. The results show that it is potentially possible to test and condition specific neural circuits in motor cortex that could be affected differentially by disease, or be used in different forms of natural behaviour. However, there is substantial interindividual variability in the specificity of these protocols. Perhaps in the future it will be possible, with the advances currently being made to model the electrical fields induced in individual brains, to develop forms of stimulation that can reliably target more specific populations of neurones, and open up the internal circuitry of the motor cortex for study in behaving humans.

  11. Anatomical and functional characteristics of carotid sinus stimulation in humans

    Science.gov (United States)

    Querry, R. G.; Smith, S. A.; Stromstad, M.; Ide, K.; Secher, N. H.; Raven, P. B.

    2001-01-01

    Transmission characteristics of pneumatic pressure to the carotid sinus were evaluated in 19 subjects at rest and during exercise. Either a percutaneous fluid-filled (n = 12) or balloon-tipped catheter (n = 7) was placed at the carotid bifurcation to record internal transmission of external neck pressure/neck suction (NP/NS). Sustained, 5-s pulses, and rapid ramping pulse protocols (+40 to -80 Torr) were recorded. Transmission of pressure stimuli was less with the fluid-filled catheter compared with that of the balloon-tipped catheter (65% vs. 82% negative pressure, 83% vs. 89% positive pressure; P Anatomical location of the carotid sinus averaged 3.2 cm (left) and 3.6 cm (right) from the gonion of the mandible with a range of 0-7.5 cm. Transmission was not altered by exercise or Valsalva maneuver, but did vary depending on the position of the carotid sinus locus beneath the sealed chamber. These data indicate that transmission of external NP/NS was higher than previously recorded in humans, and anatomical variation of carotid sinus location and equipment design can affect transmission results.

  12. Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    1999-01-01

    host defence against infections in the elderly and be of importance in elderly humans with underlying health disorders. However, the clinical relevance is questionable in healthy elderly people because decreased levels were found compared with young men but not compared with young women....... following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91...... young controls aged 19-31 years. Levels of TNF-alpha and IL-1 beta were significantly lower in elderly humans compared with young controls, whereas no difference was detected with regard to IL-6. Elderly humans with low body mass index had the lowest levels of IL-1 beta. Young women had lower levels...

  13. Spatial Attention Changes Excitability of Human Visual Cortex to Direct Stimulation

    OpenAIRE

    Bestmann, Sven; Ruff, Christian C; Blakemore, Colin; Driver, Jon; Thilo, Kai V.

    2007-01-01

    Summary Conscious perception depends not only on sensory input, but also on attention [1, 2]. Recent studies in monkeys [3–6] and humans [7–12] suggest that influences of spatial attention on visual awareness may reflect top-down influences on excitability of visual cortex. Here we tested this specifically, by providing direct input into human visual cortex via cortical transcranial magnetic stimulation (TMS) to produce illusory visual percepts, called phosphenes. We found that a lower TMS in...

  14. Anodal transcranial direct current stimulation reduces psychophysically measured surround suppression in the human visual cortex.

    Directory of Open Access Journals (Sweden)

    Daniel P Spiegel

    Full Text Available Transcranial direct current stimulation (tDCS is a safe, non-invasive technique for transiently modulating the balance of excitation and inhibition within the human brain. It has been reported that anodal tDCS can reduce both GABA mediated inhibition and GABA concentration within the human motor cortex. As GABA mediated inhibition is thought to be a key modulator of plasticity within the adult brain, these findings have broad implications for the future use of tDCS. It is important, therefore, to establish whether tDCS can exert similar effects within non-motor brain areas. The aim of this study was to assess whether anodal tDCS could reduce inhibitory interactions within the human visual cortex. Psychophysical measures of surround suppression were used as an index of inhibition within V1. Overlay suppression, which is thought to originate within the lateral geniculate nucleus (LGN, was also measured as a control. Anodal stimulation of the occipital poles significantly reduced psychophysical surround suppression, but had no effect on overlay suppression. This effect was specific to anodal stimulation as cathodal stimulation had no effect on either measure. These psychophysical results provide the first evidence for tDCS-induced reductions of intracortical inhibition within the human visual cortex.

  15. UV-stimulation of DNA-mediated transformation of human cells.

    NARCIS (Netherlands)

    M. van Duin (Mark); A. Westerveld (Andries); J.H.J. Hoeijmakers (Jan)

    1985-01-01

    textabstractIrradiation of dominant marker DNA with UV light (150 to 1,000 J/m2) was found to stimulate the transformation of human cells by this marker from two- to more than fourfold. This phenomenon is also displayed by xeroderma pigmentosum cells (complementation groups A and F), which are defic

  16. Nanosecond UV lasers stimulate transient Ca2+ elevations in human hNT astrocytes

    Science.gov (United States)

    Raos, B. J.; Graham, E. S.; Unsworth, C. P.

    2017-06-01

    Objective. Astrocytes respond to various stimuli resulting in intracellular Ca2+ signals that can propagate through organized functional networks. Recent literature calls for the development of techniques that can stimulate astrocytes in a fast and highly localized manner to emulate more closely the characteristics of astrocytic Ca2+ signals in vivo. Approach. In this article we demonstrate, for the first time, how nanosecond UV lasers are capable of reproducibly stimulating Ca2+ transients in human hNT astrocytes. Main results. We report that laser pulses with a beam energy of 4-29 µJ generate transient increases in cytosolic Ca2+. These Ca2+ transients then propagate to adjacent astrocytes as intercellular Ca2+ waves. Significance. We propose that nanosecond laser stimulation provides a valuable tool for enabling the study of Ca2+ dynamics in human astrocytes at both a single cell and network level. Compared to previously developed techniques nanosecond laser stimulation has the advantage of not requiring loading of photo-caged or -sensitising agents, is non-contact, enables stimulation with a high spatiotemporal resolution and is comparatively cost effective.

  17. Simultaneous application of slow-oscillation transcranial direct current stimulation and theta burst stimulation prolongs continuous theta burst stimulation-induced suppression of corticomotor excitability in humans.

    Science.gov (United States)

    Doeltgen, Sebastian H; McAllister, Suzanne M; Ridding, Michael C

    2012-09-01

    The objective of this study was to assess whether the simultaneous application of slow-oscillation transcranial direct current stimulation enhances the neuroplastic response to transcranial magnetic theta burst stimulation. Motor evoked potential amplitude was assessed at baseline and at regular intervals up to 60 min following continuous theta burst stimulation, slow-oscillation transcranial direct current stimulation, and the simultaneous application of these paradigms. In addition, the electroencephalographic power spectra of slow and fast delta, and theta frequency bands recorded over the motor cortex were analyzed prior to and up to 5 min following each intervention. There was longer-lasting motor evoked potential suppression following the simultaneous application of continuous theta burst stimulation and slow-oscillation transcranial direct current stimulation compared with when continuous theta burst stimulation was applied alone. Slow-oscillation transcranial direct current stimulation applied alone did not modulate the motor evoked potential amplitude. No significant changes in spectral power were observed following slow-oscillation transcranial direct current stimulation. Simultaneous application of continuous theta burst stimulation and slow-oscillation transcranial direct current stimulation may provide an approach to prolong the induction of neuroplastic changes in motor cortical circuits by repetitive transcranial magnetic brain stimulation.

  18. Establishment of a novel in vitro test setup for electric and magnetic stimulation of human osteoblasts.

    Science.gov (United States)

    Grunert, P C; Jonitz-Heincke, A; Su, Y; Souffrant, R; Hansmann, D; Ewald, H; Krüger, A; Mittelmeier, W; Bader, R

    2014-11-01

    When large defects occur, bone regeneration can be supported by bone grafting and biophysical stimuli like electric and magnetic stimulation (EMS). Clinically established EMS modes are external coils and surgical implants like an electroinductive screw system, which combines a magnetic and electric field, e.g., for the treatment of avascular bone necrosis or pseudarthrosis. For optimization of this implant system, an in vitro test setup was designed to investigate effects of EMS on human osteoblasts on different 3D scaffolds (based on calcium phosphate and collagen). Prior to the cell experiments, numerical simulations of the setup, as well as experimental validation, via measurements of the electric parameters induced by EMS were conducted. Human osteoblasts (3 × 10(5) cells) were seeded onto the scaffolds and cultivated. After 24 h, screw implants (Stryker ASNIS III s-series) were centered in the scaffolds, and EMS was applied (3 × 45 min per day at 20 Hz) for 3 days. Cell viability and collagen type 1 (Col1) synthesis were determined subsequently. Numerical simulation and validation showed an adequate distribution of the electric field within the scaffolds. Experimental measurements of the electric potential revealed only minimal deviation from the simulation. Cell response to stimulation varied with scaffold material and mode of stimulation. EMS-stimulated cells exhibited a significant decrease of metabolic activity in particular on collagen scaffolds. In contrast, the Col1/metabolic activity ratio was significantly increased on collagen and non-sintered calcium phosphate scaffolds after 3 days. Exclusive magnetic stimulation showed similar but nonsignificant tendencies in metabolic activity and Col1 synthesis. The cell tests demonstrate that the new test setup is a valuable tool for in vitro testing and parameter optimization of the clinically used electroinductive screw system. It combines magnetic and electric stimulation, allowing in vitro investigations

  19. An endoscopic method for thermal and chemical stimulation of the human oesophagus.

    Science.gov (United States)

    Olesen, S S; Olesen, A E; Gravesen, F; Poulsen, J L; Funch-Jensen, P; Gregersen, H; Drewes, A M

    2009-12-01

    Previous methods for visceral thermal stimulation have lacked control of the temperature rate and visual inspection of the organ. The aims of this study was to develop a method for linear control of heat stimulation in the human oesophagus combined with endoscopy, to assess the reproducibility of this method and to investigate sensitivity to thermal stimulation of the distal oesophagus before and after acid perfusion. A probe with a 2.8 mm endoscope inside was constructed permitting heat and chemical stimulation. Three different temperature ramps were applied in the distal oesophagus in 12 healthy subjects by recirculation of heated water in a bag. Endoscopy of the oesophageal mucosa was performed prior to experimental stimulation. The temperature, the time of stimulation and the area under the temperature curve (AUC) were measured at the pain detection threshold. Thermal stimulation was repeated after perfusion of the oesophagus with acid. The method was tested on two subsequent days to assess reproducibility. All subjects had a normal endoscopic examination. Day-to-day reproducibility was good for the three temperature ramps (intra-class correlations >0.6). The subjects tolerated less heat stimulation, a decrease in AUC (P = 0.0003), a decrease in time to pain detection threshold (P = 0.005) and decreased temperature at pain detection threshold (P = 0.0001) after acid perfusion. The slow ramp was the most sensitive, showing a decrease in AUC of 29%. The present method was easily implemented and showed good reproducibility. It can potentially be used in basic experiments, drug and clinical studies as it provides a controllable thermal stimulus.

  20. Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans

    Directory of Open Access Journals (Sweden)

    Scholz Markus

    2012-07-01

    Full Text Available Abstract Background The human granulocyte colony-stimulating factor (G-CSF is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim. Results Model equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which

  1. A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment.

    Science.gov (United States)

    Schirm, Sibylle; Engel, Christoph; Loeffler, Markus; Scholz, Markus

    2014-05-26

    Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in healthy volunteers

  2. Muramyl dipeptide-Lys stimulates the function of human dendritic cells.

    Science.gov (United States)

    Todate, A; Suda, T; Kuwata, H; Chida, K; Nakamura, H

    2001-11-01

    Muramyl dipeptide (MDP)-Lys (L18), a synthetic MDP analogue derived from bacterial cell walls, has been reported to be a potent immunoadjuvant that enhances protective immunity against pathogens and tumors by stimulating immune-competent cells, such as monocytes and macrophages. However, it is not known whether MDP-Lys modulates the function of dendritic cells (DCs), which are the most potent antigen-presenting cells and play a crucial role in initiating T cell-mediated immunity. Therefore, we examined the effects of MDP-Lys on the expression of surface molecules, cytokine production, and antigen-presenting function of human DCs generated from peripheral blood cells in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. We found that MDP-Lys markedly up-regulated the expression of CD80, CD83, CD86, and CD40, but not human leukocyte antigen-DR, and stimulated the production of tumor necrosis factor-alpha, IL-6, IL-8, IL-10, and IL-12 (p40) by human DCs in a dose-dependent manner. Furthermore, MDP-Lys-treated DCs showed enhanced antigen-presenting function compared with untreated DCs, as assessed by an allogeneic mixed lymphocyte reaction. These results suggested that the immunoadjuvant activity of MDP-Lys in vivo is mediated, in part, by its stimulation of DC function.

  3. Role of macrophage colony-stimulating factor (M-CSF) in human granulosa cells.

    Science.gov (United States)

    Xu, Song; Zhang, Zhifen; Xia, Li-Xia; Huang, Jian

    2016-12-01

    Macrophage colony-stimulating factor (M-CSF) has been proved to have a positive role in the follicular development. We investigated its effect on human granulosa cells and found that M-CSF could stimulate the production of E2. The production of FSH receptors was enhanced by M-CSF in vitro in a dose-dependent manner with or without the addition of tamoxifen (p M-CSF and its receptor (p M-CSF (p M-CSF has a role in regulating the response of granulosa cells to gonadotropins. Its function is associated with JAK/STAT-signaling pathway.

  4. An implantable, designed-for-human-use peripheral nerve stimulation and recording system for advanced prosthetics.

    Science.gov (United States)

    Lachapelle, John R; Bjune, Caroline K; Kindle, Alexander L; Czarnecki, Andrew; Burns, John R; Grainger, Julianne E; Segura, Carlos A; Nugent, Brian D; Sriram, Tirunelveli S; Parks, Philip D; Keefer, Edward; Cheng, Jonathan

    2016-08-01

    Complex suture prostheses that deliver sensory and position feedback require a more sophisticated integration with the human user. Here a micro-size active implantable system that provides many-degree-of-freedom neural feedback in both sensory stimulation and motor control is shown, as one potential human-use solution in DARPA's HAPTIX program. Various electrical and mechanical challenge and solutions in meeting both sensory /motor performance as well as ISO 14708 FDA-acceptable human use in an aspirin-size active implementation are discussed.

  5. Human milk effects on neutrophil calcium metabolism: blockade of calcium influx after agonist stimulation.

    Science.gov (United States)

    Chacon-Cruz, E; Oelberg, D G; Buescher, E S

    1999-08-01

    Neutrophils are the predominant cellular mediators of acute inflammation, and human milk suppresses multiple neutrophil functions. We sought to determine whether these effects were mediated through disruption of normal intracellular Ca2+ homeostasis. Exposure of human neutrophils to human milk, followed by washing, resulted in altered Ca2+ transient responses to formyl-peptide stimulation in which the peak cytosolic free Ca2+ concentration ([free Ca]) was the same as in unexposed cells, but the postpeak decline in [free Ca] was more rapid. This effect was observed after human milk exposures as brief as 10 s, persisted for up to 4 h after human milk removal, and was concentration dependent. On the basis of experiments examining Ca2+-free conditions followed by Ca2+ supplementation, and experiments examining spontaneous and stimulated manganese and barium influx into neutrophils, the human milk effect was due to blockade of Ca2+ influx. Decreased Ca2+ transient responses to other physiologic stimuli (IL-8, opsonized Staphylococcus aureus, and immune complexes) were observed after human milk exposures. Rat intestinal epithelial cells and HL-60 cells failed to show these effects, suggesting a selective effect on mature inflammatory cells. Characterization of the Ca2+-blocking activity showed it was heat and acid stable in human milk with a molecular mass between 30-100 kD. Commercial human milk lactoferrin exhibited Ca2+ influx blockade activity, but recombinant human lactoferrin showed none. Separation of the activity by heparin affinity chromatography showed that it was distinct from lactoferrin. Human milk-induced blockade of Ca2+ influx provides a potential mechanism for broad suppression of neutrophil functions that may contribute to the antiinflammatory properties of human milk.

  6. Spacial isolation of protein kinase C activation in thrombin stimulated human platelets.

    Science.gov (United States)

    Crouch, M F; Lapetina, E G

    1988-10-14

    Thrombin stimulation of human platelets is associated with turnover of inositol phospholipids, mobilization of intracellular Ca2+ stores, and activation of protein kinase C. However, within 5 minutes, the thrombin receptor desensitizes, but can be re-coupled to its effectors by stimulation of alpha 2-adrenergic receptors (Crouch and Lapetina, J. Biol. Chem. 263, 3363-3371, 1988). This effect of epinephrine was found to be inhibited by preincubation of platelets with phorbol ester, suggesting that protein kinase C was inhibitory. However, since thrombin also activated protein kinase C and epinephrine was active following thrombin stimulation of platelets, this implied that thrombin activation of protein kinase C may have been spacially isolated near the thrombin receptor and could not inactivate alpha 2-receptor activity. In the present paper, we have tested this possibility, and we present evidence which strongly favours the possibility that protein kinase C activation by receptors induces its local translocation to the cell membrane.

  7. Drug: D10242 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available LANTS L03A IMMUNOSTIMULANTS L03AA Colony stimulating factors L03AA14 Lipegfilgrastim D10242 Lip...d pegylated G-CSF [HSA:1440] [KO:K05423] granulocyte colony stimulating factor (G...(ATC) classification [BR:br08303] L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS L03 IMMUNOSTIMU...ceptors (hematopoietin family receptors) granulocyte colony stimulating factor (G

  8. Aspirin inhibits tumor necrosis factor-α-stimulated fractalkine expression in human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    JIANG De-qian; LIU Hong; ZHANG She-bing; ZHANG Xiao-lian

    2009-01-01

    Background Fractalkine is an important chemokine mediating local monocyte accumulation and inflammatory reactions in the vascular wall. Aspirin inhibits inflammatory cytokine expression closely related to atherosclerosis through the way independent of platelet and cyclooxygenase (COX). There has been no report about the effect of aspirin on fractalkine expression. We aimed to determine the fractalkine expression in human umbilical vein endothelial cell (HUVEC) stimulated by tumor necrosis factor (TNF)-α and the effect of aspirin intervention.Methods Six of 8 HUVEC groups received either different concentrations of aspirin (0.02, 0.2, 1.0, 5.0 mmol/L) or 40 μmol/L pyrrolidinecarbodithioc acid (PDTC) or 0.5 μmol/L NS-398. The other two groups were negative control and positive control (TNF-α-stimulated). After being incubated for 24 hours, cells of the 8 groups except the negative control one were stimulated with TNF-a (4 ng/ml) for another 24 hours. After that, the cells were collected for RNA isolation and protein extraction.Results Both mRNA and protein expressions of fractalkine in HUVEC were upregulated by 4 ng/ml TNF-α stimulation,Aspirin inhibited fractalkine expression in a dose-dependent manner at mRNA and protein levels. Nuclear factor-kappa B inhibitor, PDTC, effectively decreased the fractalkine expression. Fractalkine expression was not influenced by COX-2 selective inhibitor NS-398. COX-1 protein expression was not changed by either TNF-α stimulation or aspirin, PDTC,NS-398 intervention. Both mRNA and protein expression of COX-2 in HUVEC were upregulated by 4 ng/ml TNF-α stimulation. Aspirin decreased COX-2 expression in a dose-dependent manner at mRNA and protein levels.Conclusions TNF-α-stimulated fractalkine expression is suppressed by aspirin in a dose-dependent manner through the nuclear factor-kappa B p65 pathway.

  9. A novel approach to mechanical foot stimulation during human locomotion under body weight support.

    Science.gov (United States)

    Gravano, S; Ivanenko, Y P; Maccioni, G; Macellari, V; Poppele, R E; Lacquaniti, F

    2011-04-01

    Input from the foot plays an essential part in perceiving support surfaces and determining kinematic events in human walking. To simulate adequate tactile pressure inputs under body weight support (BWS) conditions that represent an effective form of locomotion training, we here developed a new method of phasic mechanical foot stimulation using light-weight pneumatic insoles placed inside the shoes (under the heel and metatarsus). To test the system, we asked healthy participants to walk on a treadmill with different levels of BWS. The pressure under the stimulated areas of the feet and subjective sensations were higher at high levels of BWS and when applied to the ball and toes rather than heels. Foot stimulation did not disturb significantly the normal motor pattern, and in all participants we evoked a reliable step-synchronized triggering of stimuli for each leg separately. This approach has been performed in a general framework looking for "afferent templates" of human locomotion that could be used for functional sensory stimulation. The proposed technique can be used to imitate or partially restore surrogate contact forces under body weight support conditions.

  10. Hydrogen peroxide stimulates the active transport of serotonin into human platelets

    Energy Technology Data Exchange (ETDEWEB)

    Bosin, T.R. (Indiana Univ., Bloomington (United States))

    1991-03-11

    The effect of hydrogen peroxide on the active transport of serotonin (5-HT) by human platelets was investigated. Platelets were exposed to either a single dose of H{sub 2}O{sub 2} or to H{sub 2}O{sub 2} generated by the glucose/glucose oxidase or xanthine/xanthine oxidase enzyme systems. H{sub 2}{sub 2} produced a rapid, dose-dependent and time-dependent increase in 5-HT transport which was maximal after a 2 min incubation and decreased with continued incubation. Catalase completely prevented H{sub 2}O{sub 2}-induced stimulation and fluoxetine totally blocked 5-HT uptake into stimulated platelets. The glucose/glucose oxidase and the xanthine/xanthine oxidase generating systems produced a similar response to that of H{sub 2}O{sub 2}. In the xanthine/xanthine oxidase system, superoxide dismutase failed to alter the stimulation, while catalase effectively prevented the response. The kinetics of 5-HT transport indicated that H{sub 2}O{sub 2} treatment did not alter the K{sub m} of 5-HT transport but significantly increased the maximal rate of 5-HT transport. These data demonstrated that exposure of human platelets to H{sub 2}O{sub 2} resulted in a stimulation of the active transport of 5-HT and suggested that H{sub 2}O{sub 2} may function to regulate this process.

  11. Cytotoxic Effects of Re-Activated Lunar Dust Stimulant on Human Lung Cells

    Science.gov (United States)

    Upadhyaya, Krishna

    2009-01-01

    Lunar dust has been of significant concern due to various problems observed on the Apollo missions. Reports from astronauts have shown that the dust may have caused eye and nasal irritation as well as possible hay fever like symptoms. As NASA hopes to go to the Moon within the next few years, we hope to understand the possible toxic effects the dust might have. In these studies, we are looking at the effect of "re-activated" lunar dust stimulant on human bronchial cells. A simple grinding analog as a method of simulating micrometeorite crushing on the moon is used to "activate" the dust stimulant, i.e. capable of producing hydroxyl radicals. These radicals could then interact with human cells and may lead to a loss in membrane integrity and cell death. (Castranova, 1994) Cells are exposed to the dust for 6 and 24 hour intervals to assess cytotoxicity. Cytotoxicity is measured by looking at the production of inflammatory cytokines. Cells are exposed to ground and unground stimulant and compared to cytokine production from cells exposed to quartz which have a known toxicity. Here we look at the cytotoxicity of the lunar dust stimulant relative to quartz by measuring the production of inflammatory cytokines.

  12. Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation

    Science.gov (United States)

    Huang, Yu; Liu, Anli A; Lafon, Belen; Friedman, Daniel; Dayan, Michael; Wang, Xiuyuan; Bikson, Marom; Doyle, Werner K; Devinsky, Orrin; Parra, Lucas C

    2017-01-01

    Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimated electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.4 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r = 0.89) and depth (r = 0.84) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials. DOI: http://dx.doi.org/10.7554/eLife.18834.001 PMID:28169833

  13. Visceral response to acute retrograde gastric electrical stimulation in healthy human

    Institute of Scientific and Technical Information of China (English)

    Shu-Kun Yao; Mei-Yun Ke; Zhi-Feng Wang; Da-Bo Xu; Yan-Li Zhang

    2005-01-01

    AIM: To investigate the visceral response to acute retrograde gastric electrical stimulation (RGES) in healthy humans and to derive optimal parameters for treatment of patients with obesity.METHODS: RGES with a series of effective parameters were performed via a bipolar mucosal electrode implanted along the great curvature 5 cm above pylorus of stomach in 12 healthy human subjects. Symptoms associated with dyspepsia and other discomfort were observed and graded during RGES at different settings, including long pulse and pulse train. Gastric myoelectrical activity at baseline and during different settings of stimulation was recorded by a multi-channel electrogastrography.RESULTS: The gastric slow wave was entrained in all the subjects at the pacing parameter of 9 cpm in frequency, 500 ms in pulse width, and 5 mA in amplitude.The frequently appeared symptoms during stimulation were satiety, bloating, discomfort, pain, sting, and nausea. The total symptom score for each subject significantly increased as the amplitude or pulse width was adjusted to a higher scale in both long pulse and pulse train. There was a wide diversity of visceral responses to RGES among individuals.CONCLUSION: Acute RGES can result in a series of symptoms associated with dyspepsia, which is beneficial to the treatment of obesity. Optimal parameter should be determined according to the individual sensitivity to electrical stimulation.

  14. Innervation of the Human Cavum Conchae and Auditory Canal: Anatomical Basis for Transcutaneous Auricular Nerve Stimulation

    Science.gov (United States)

    Bermejo, P.; López, M.; Larraya, I.; Chamorro, J.; Cobo, J. L.; Ordóñez, S.

    2017-01-01

    The innocuous transcutaneous stimulation of nerves supplying the outer ear has been demonstrated to be as effective as the invasive direct stimulation of the vagus nerve for the treatment of some neurological and nonneurological disturbances. Thus, the precise knowledge of external ear innervation is of maximal interest for the design of transcutaneous auricular nerve stimulation devices. We analyzed eleven outer ears, and the innervation was assessed by Masson's trichrome staining, immunohistochemistry, or immunofluorescence (neurofilaments, S100 protein, and myelin-basic protein). In both the cavum conchae and the auditory canal, nerve profiles were identified between the cartilage and the skin and out of the cartilage. The density of nerves and of myelinated nerve fibers was higher out of the cartilage and in the auditory canal with respect to the cavum conchae. Moreover, the nerves were more numerous in the superior and posterior-inferior than in the anterior-inferior segments of the auditory canal. The present study established a precise nerve map of the human cavum conchae and the cartilaginous segment of the auditory canal demonstrating regional differences in the pattern of innervation of the human outer ear. These results may provide additional neuroanatomical basis for the accurate design of auricular transcutaneous nerve stimulation devices.

  15. Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation.

    Science.gov (United States)

    Huang, Yu; Liu, Anli A; Lafon, Belen; Friedman, Daniel; Dayan, Michael; Wang, Xiuyuan; Bikson, Marom; Doyle, Werner K; Devinsky, Orrin; Parra, Lucas C

    2017-02-07

    Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimated electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.4 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r = 0.89) and depth (r = 0.84) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials.

  16. Entrainment of perceptually relevant brain oscillations by non-invasive rhythmic stimulation of the human brain

    Directory of Open Access Journals (Sweden)

    Gregor eThut

    2011-07-01

    Full Text Available The notion of driving brain oscillations by directly stimulating neuronal elements with rhythmic stimulation protocols has become increasingly popular in research on brain rhythms. Induction of brain oscillations in a controlled and functionally meaningful way would likely prove highly beneficial for the study of brain oscillations, and their therapeutic control. We here review conventional and new non-invasive brain stimulation protocols as to their suitability for controlled intervention into human brain oscillations. We focus on one such type of intervention, the direct entrainment of brain oscillations by a periodic external drive. We review highlights of the literature on entraining brain rhythms linked to perception and attention, and point out controversies. Behaviourally, such entrainment seems to alter specific aspects of perception depending on the frequency of stimulation, informing models on the functional role of oscillatory activity. This indicates that human brain oscillations and function may be promoted in a controlled way by focal entrainment, with great potential for probing into brain oscillations and their causal role.

  17. Entrainment of perceptually relevant brain oscillations by non-invasive rhythmic stimulation of the human brain.

    Science.gov (United States)

    Thut, Gregor; Schyns, Philippe G; Gross, Joachim

    2011-01-01

    The notion of driving brain oscillations by directly stimulating neuronal elements with rhythmic stimulation protocols has become increasingly popular in research on brain rhythms. Induction of brain oscillations in a controlled and functionally meaningful way would likely prove highly beneficial for the study of brain oscillations, and their therapeutic control. We here review conventional and new non-invasive brain stimulation protocols as to their suitability for controlled intervention into human brain oscillations. We focus on one such type of intervention, the direct entrainment of brain oscillations by a periodic external drive. We review highlights of the literature on entraining brain rhythms linked to perception and attention, and point out controversies. Behaviourally, such entrainment seems to alter specific aspects of perception depending on the frequency of stimulation, informing models on the functional role of oscillatory activity. This indicates that human brain oscillations and function may be promoted in a controlled way by focal entrainment, with great potential for probing into brain oscillations and their causal role.

  18. Recombinant human thrombopoietin augments mobilization of peripheral blood progenitor cells for autologous transplantation.

    Science.gov (United States)

    Linker, Charles; Anderlini, Paolo; Herzig, Roger; Christiansen, Neal; Somlo, George; Bensinger, William; Fay, Joseph; Lynch, Joseph P; Goodnough, Lawrence T; Ashby, Mark; Benyunes, Mark C; Jones, Dennie V; Yang, Timothy A; Miller, Langdon L; Weaver, Charles

    2003-06-01

    This study assessed the ability of various schedules of recombinant human thrombopoietin (rhTPO) to enhance mobilization of peripheral blood progenitor cells (PBPCs) in 134 patients with cancer undergoing high-dose chemotherapy and autologous PBPC transplantation. Patients received the study drug on days 1, 3, and 5 before initiation of granulocyte colony-stimulating factor (G-CSF) 10 microg/kg/day on day 5 and pheresis starting on day 9. Randomly assigned treatments on days 1, 3, and 5 were: group 1 (n=27) placebo, placebo, rhTPO 1.5 microg/kg; group 2 (n=27) rhTPO 1.5 microg/kg, placebo, placebo; groups 3 (n=28) and 4 (n=22) rhTPO 0.5 microg/kg on all 3 treatment days; and group 5 (n=30) placebo on all 3 treatment days. After high-dose chemotherapy and PBPC transplantation, groups 1 through 4 received rhTPO 1.5 microg/kg days 0, +2, +4, and +6 with either G-CSF 5 microg/kg/day (groups 1-3) or granulocyte-macrophage colony-stimulating factor 250 microg/m(2)/day (group 4). Group 5 received placebo plus G-CSF 5 microg/kg/day. The addition of rhTPO to G-CSF increased median CD34+ cell yield/pheresis in cohorts in which rhTPO was started before day 5, with higher yields in groups 2 (2.67 x 10(6)/kg) and groups 3 and 4 (3.10 x 10(6)/kg) than in group 1 (1.86 x 10(6)/kg) or group 5 (1.65 x 10(6)/kg) (P=.006 across groups). Comparing rhTPO to placebo, higher percentages of patients achieved the minimum yield of CD34+ > or =2 x 10(6)/kg (92% v 75%; P=.050) as well as the target yield of CD34+ > or =5 x 10(6)/kg (73% v 46%; P= .041). rhTPO-treated patients required fewer phereses to achieve minimum (P= .011) and target (P= .015) CD34+ cell values. rhTPO given after transplantation did not speed platelet recovery. No neutralizing antibodies were observed. We conclude that rhTPO can safely enhance mobilization of PBPC, reduce the number of leukapheresis, and allow more patients to meet minimal cell yield requirements to receive high-dose chemotherapy with PBPC

  19. Augmenting LTP-Like Plasticity in Human Motor Cortex by Spaced Paired Associative Stimulation.

    Directory of Open Access Journals (Sweden)

    Florian Müller-Dahlhaus

    Full Text Available Paired associative stimulation (PASLTP of the human primary motor cortex (M1 can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30 min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1 induced strong LTP-like plasticity lasting for 30-60 min. The effect of a second identical PASLTP protocol (PAS2 critically depended on the time between PAS1 and PAS2. At 10 min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30 min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60 min and 180 min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30 min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60 min and 180 min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30 min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.

  20. Expression of prolactin receptor and response to prolactin stimulation of human NK cell lines

    Institute of Scientific and Technical Information of China (English)

    Rui SUN; Ai Ling LI; Hai Ming WEI; Zhi Gang TIAN

    2004-01-01

    We have previously shown a critical role of prolactin (PRL) during maturation and anti-tumor effects of murine natural killer (NK) cells in vitro and in vivo. We extended that study by exploring the ability of human NK cell lines (NK-92 and YT cell) to express PRL receptor (PRL-R) and to respond to PRL stimulation in vitro. Both human NK cell lines constitutively expressed PRL-R on membrane and mRNA transcripts,NK-92 cells contained higher level of PRL-R than YT cells,which correlated to the enhanced capacity of the cells to proliferate and to lyse target cells in response to PRL stimulation in the presence of trace amount of IL-2 or IL-15 in vitro. Two differences between IL-2 and IL-15 in functioning on human NK cells were for the first time observed. PRL synergized with IL-15 to improve proliferation of NK cells in a dose-dependent manner without double peak manifesting like IL-2. Although PRL enhanced the cytotoxicity of IL-2 or IL- 15 activated NK cells,it exerted the function through up-regulating gene expression of perforin without influence of FasL in IL-2-stimulated NK cells,while in IL-15-stimulated NK cells,PRL did the function through up-regulating gene expression of both perforin and FasL but not IFNγ. PRL increased expressions of IL-2Rα on membrane and of IL-2 mRNA in cells,indicating that PRL up-regulated NK cell function by improving positive feedback between IL-2 and IL-2R. The similar results were also observed in network between IL-15 and IL-15R. These data indicate a potential role of PRL in human NK cell modulation.

  1. Augmenting LTP-Like Plasticity in Human Motor Cortex by Spaced Paired Associative Stimulation.

    Science.gov (United States)

    Müller-Dahlhaus, Florian; Lücke, Caroline; Lu, Ming-Kuei; Arai, Noritoshi; Fuhl, Anna; Herrmann, Eva; Ziemann, Ulf

    2015-01-01

    Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30 min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60 min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10 min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30 min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60 min and 180 min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30 min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60 min and 180 min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30 min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.

  2. Investigation of Fe and Ca in non-stimulated human saliva using NAA

    Science.gov (United States)

    de Medeiros, J. A. G.; Zamboni, C. B.; Kovacs, L.; Lewgoy, H. R.

    2015-07-01

    In this study we investigated non-stimulated human whole saliva of healthy subjects and patients with periodontal disease using Neutron Activation Analysis technique (NAA). The measurements were performed in the IEA-R1 nuclear reactor at IPEN-CNEN/SP. We found considerable metabolic changes mainly in Fe and Ca concentration in whole saliva of periodontal patients. These data are useful for identifying or preventing this oral disease in the Brazilian population.

  3. Biological stimulation of the Human skin applying health promoting light and plasma sources

    Energy Technology Data Exchange (ETDEWEB)

    Awakowicz, P.; Bibinov, N. [Center for Plasma Science and Technology, Ruhr-University, Bochum (Germany); Born, M.; Niemann, U. [Philips Research, Aachen (Germany); Busse, B. [Zell-Kontakt GmbH, Noerten-Hardenberg (Germany); Gesche, R.; Kuehn, S.; Porteanu, H.E. [Ferdinand-Braun-Institut fuer Hoechstfrequenztechnik, Berlin (Germany); Helmke, A. [University of Applied Sciences and Arts, Goettingen (Germany); Kaemling, A.; Wandke, D. [CINOGY GmbH, Duderstadt (Germany); Kolb-Bachofen, V.; Liebmann, J. [Institute for Immunobiology, Heinrich-Heine University, Duesseldorf (Germany); Kovacs, R.; Mertens, N.; Scherer, J. [Aurion Anlagentechnik GmbH, Seligenstadt (Germany); Oplaender, C.; Suschek, C. [Clinic for Plastic Surgery, University Clinic, Aachen (Germany); Vioel, W. [Laser-Laboratorium, Goettingen (Germany); University of Applied Sciences and Arts, Goettingen (Germany)

    2009-10-15

    In the frame of BMBF project ''BioLiP'', new physical treatment techniques aiming at medical treatment of the human skin have been developed. The acronym BioLiP stands for ''Desinfektion, Entkeimung und biologische Stimulation der Haut durch gesundheitsfoerdernde Licht- und Plasmaquellen'' (Disinfection, germ reduction and biological stimulation of the human skin by health promoting light and plasma sources). A source applying a low-temperature dielectric barrier discharge plasma (DBD) has been investigated on its effectiveness for skin disinfection and stimulation of biological material. Alternatively an atmospheric plasma source consisting of a microwave resonator combined with a solid state power oscillator has been examined. This concept which allows for a compact and efficient design avoiding external microwave power supply and matching units has been optimized with respect to nitrogen monoxide (NO) production in high yields. In both cases various application possibilities in the medical and biological domain are opened up. Light sources in the visible spectral range have been investigated with respect to the proliferation of human cell types. Intensive highly selective blue light sources based on LED technology can slow down proliferation rates without inducing toxic effects which offers new opportunities for treatments of so-called hyperproliferative skin conditions (e.g. with psoriasis or in wound healing) using UV-free light. (copyright 2009 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  4. Comparative In Vitro Immune Stimulation Analysis of Primary Human B Cells and B Cell Lines

    Science.gov (United States)

    Van Belle, Kristien; Herman, Jean; Boon, Louis; Waer, Mark

    2016-01-01

    B cell specific immunomodulatory drugs still remain an unmet medical need. Utilisation of validated simplified in vitro models would allow readily obtaining new insights in the complexity of B cell regulation. For this purpose we investigated which human B lymphocyte stimulation assays may be ideally suited to investigate new B lymphocyte immunosuppressants. Primary polyclonal human B cells underwent in vitro stimulation and their proliferation, production of immunoglobulins (Igs) and of cytokines, and expression of cell surface molecules were analysed using various stimuli. ODN2006, a toll-like receptor 9 (TLR9) agonist, was the most potent general B cell stimulus. Subsequently, we investigated on which human B cell lines ODN2006 evoked the broadest immunostimulatory effects. The Namalwa cell line proved to be the most responsive upon TLR9 stimulation and hence may serve as a relevant, homogeneous, and stable B cell model in an in vitro phenotypic assay for the discovery of new targets and inhibitors of the B cell activation processes. As for the read-out for such screening assay, it is proposed that the expression of activation and costimulatory surface markers reliably reflects B lymphocyte activation. PMID:28116319

  5. DT56a stimulates gender-specific human cultured bone cells in vitro.

    Science.gov (United States)

    Somjen, Dalia; Katzburg, Sara; Lieberherr, M; Hendel, David; Yoles, Israel

    2006-01-01

    DT56a found to have SERM-like properties is used for the treatment of menopausal symptoms and osteoporosis. In vivo experiments demonstrated that DT56a displayed selective estrogenic activity; it stimulated creatine kinase (CK) specific activity in the skeletal tissues but not on the uterus of ovariectomized rats. DT56a, when applied together with estradiol-17beta (E(2)), completely inhibited the E(2)-stimulated CK, as demonstrated by other SERMs. DT56a stimulated bone formation in a rat model as measured by histological and histomorphometrical parameters. In a clinical study, administration of DT56a (Femarelle) resulted in a considerable elevation of bone mineral density and relief of menopausal symptoms. The aim of the present study was to analyze the effects of DT56a in vitro on human-derived bone cultured osteoblasts (Ob), by measuring its effects, at different concentrations, on DNA synthesis, CK and alkaline phosphatase (ALP) specific activities as well as changes in intracellular [Ca(2+)](i) concentrations. DT56a stimulated CK and DNA synthesis in both pre- and post-menopausal female Ob with maximal effect at 100 ng/ml for both age groups. In addition, DT56a stimulated ALP in Ob from both pre- and post-menopausal women with maximal effect at lower dose of 50 ng/ml, with higher response of pre-menopausal cells. Raloxifene (Ral) inhibited all DT56a-stimulated changes in Ob from both age groups. DT56a, when given together with E(2), completely antagonized E(2)-stimulated effects demonstrating its nature as a phyto-SERM. DT56a also, dose dependency, stimulated the intracellular levels of [Ca(2+)](i) with maximal effect at 10 ng/ml. Male-derived Ob did not respond to DT56a in any parameter. In summary, DT56a stimulated sex-specifically female-derived Ob, indicating its unique nature compared to the compounds currently used for postmenopausal osteoporosis by being bone-forming and not only an anti-resorptive agent.

  6. Homeostatic modulation of stimulation-dependent plasticity in human motor cortex.

    Science.gov (United States)

    Ilić, N V; Milanović, S; Krstić, J; Bajec, D D; Grajić, M; Ilić, T V

    2011-01-01

    Since recently, it is possible, using noninvasive cortical stimulation, such as the protocol of paired associative stimulation (PAS), to induce the plastic changes in the motor cortex, in humans that mimic Hebb's model of learning. Application of TMS conjugated with peripheral electrical stimulation at strictly coherent temporal manner lead to convergence of inputs in the sensory-motor cortex, with the consequent synaptic potentiation or weakening, if applied repetitively. However, when optimal interstimulus interval (ISI) for induction of LTP-like effects is applied as a single pair, Motor evoked potential (MEP) amplitude inhibition is observed, the paradigm known as short-latency afferent inhibition (SLAI). Aiming to resolve this paradox, PAS protocols were applied, with 200 repetitions of TMS pulses paired with median nerve electrical stimulation, at ISI equal to individual latencies of evoked response of somatosensory cortex (N(20)) (PAS(LTP)), and at ISI of N(20) shortened for 5 msec (PAS(LTD)) - protocols that mimic LTP-like changes in the human motor cortex. MEP amplitudes before, during and after interventions were measured as an indicator based on output signals originating from the motor system. Post-intervention MEP amplitudes following the TMS protocols of PAS(LTP) and PAS(LTD) were facilitated and depressed, respectively, contrary to MEP amplitudes during intervention. During PAS(LTP) MEP amplitudes were significantly decreased in case of PAS(LTP), while in the case of PAS(LTD) an upward trend was observed. In conclusions, a possible explanation for the seemingly paradoxical effect of PAS can be found in the mechanism of homeostatic modulation of plasticity. Those findings indicate the existence of complex relationships in the development of plasticity induced by stimulation, depending on the level of the previous motor cortex excitability.

  7. Human skeletal muscle fibroblasts stimulate in vitro myogenesis and in vivo muscle regeneration.

    Science.gov (United States)

    Mackey, Abigail L; Magnan, Mélanie; Chazaud, Bénédicte; Kjaer, Michael

    2017-08-01

    Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia. The extent of cross-talk between fibroblasts, as the source of matrix protein, and satellite cells in humans is unknown. We studied this in human muscle biopsies and cell-culture studies. We observed a strong stimulation of myogenesis by human fibroblasts in cell culture. In biopsies collected 30 days after a muscle injury protocol, fibroblast number increased to four times control levels, where fibroblasts were found to be preferentially located immediately surrounding regenerating muscle fibres. These novel findings indicate an important role for fibroblasts in supporting the regeneration of muscle fibres, potentially through direct stimulation of satellite cell differentiation and fusion, and contribute to understanding of cell-cell cross-talk during physiological and pathological muscle remodelling. Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia. In addition to the indispensable role satellite cells play in muscle regeneration, there is emerging evidence in rodents for a regulatory influence on fibroblast activity. However, the influence of fibroblasts on satellite cells and muscle regeneration in humans is unknown. The purpose of this study was to investigate this in vitro and during in vivo regeneration in humans. Following a muscle injury protocol in young healthy men (n = 7), the number of fibroblasts (TCF7L2+), satellite cells (Pax7+), differentiating myogenic cells (myogenin+) and regenerating fibres (neonatal/embryonic myosin+) was determined from biopsy cross-sections. Fibroblasts and myogenic precursor cells (MPCs) were also isolated from human skeletal muscle (n = 4) and co-cultured using different cell ratios, with the two cell populations either in direct contact with each other or separated by a permeable

  8. Hyaluronic acid abrogates nitric oxide-dependent stimulation of collagen degradation in cultured human chondrocytes.

    Science.gov (United States)

    Surazynski, Arkadiusz; Miltyk, Wojciech; Czarnomysy, Robert; Grabowska, Joanna; Palka, Jerzy

    2009-07-01

    Experimental inflammation induced in cultured chondrocytes by inflammatory cytokine IL-1 beta stimulates collagen degradation by metalloproteinases. We propose that nitric oxide (NO) may represent down stream signaling molecule of IL-1-induced collagen degradation in chondrocytes. It was found that IL-1 beta induced the activity of MMP-2 and MMP-9 during the 48 h time course of the experiment, especially after 24h incubation, while DETA/NO, donor of NO, stimulated the process at 12h incubation. The mechanism of IL-1-dependent stimulation of NO production was found at the level of iNOS expression and activation of NF-kappaB. We found that hyaluronic acid (HA) counteracted IL-induced degradation of collagen in chondrocytes. Although, HA by itself had no effect on the metaloproteinases activity, when added to IL-1 beta or DETA/NO treated chondrocytes it contributed to the restoration of the MMPs activity to the control level. The mechanism of this phenomenon involves inhibition of NF-kappaB activation. The data suggest that NO may represent a target molecule for protective effect of hyaluronic acid on interleukin-1-induced stimulation of metaloproteinases activity in cultured human chondrocytes.

  9. Image-Guided Transcranial Focused Ultrasound Stimulates Human Primary Somatosensory Cortex

    Science.gov (United States)

    Lee, Wonhye; Kim, Hyungmin; Jung, Yujin; Song, In-Uk; Chung, Yong An; Yoo, Seung-Schik

    2015-03-01

    Focused ultrasound (FUS) has recently been investigated as a new mode of non-invasive brain stimulation, which offers exquisite spatial resolution and depth control. We report on the elicitation of explicit somatosensory sensations as well as accompanying evoked electroencephalographic (EEG) potentials induced by FUS stimulation of the human somatosensory cortex. As guided by individual-specific neuroimage data, FUS was transcranially delivered to the hand somatosensory cortex among healthy volunteers. The sonication elicited transient tactile sensations on the hand area contralateral to the sonicated hemisphere, with anatomical specificity of up to a finger, while EEG recordings revealed the elicitation of sonication-specific evoked potentials. Retrospective numerical simulation of the acoustic propagation through the skull showed that a threshold of acoustic intensity may exist for successful cortical stimulation. The neurological and neuroradiological assessment before and after the sonication, along with strict safety considerations through the individual-specific estimation of effective acoustic intensity in situ and thermal effects, showed promising initial safety profile; however, equal/more rigorous precautionary procedures are advised for future studies. The transient and localized stimulation of the brain using image-guided transcranial FUS may serve as a novel tool for the non-invasive assessment and modification of region-specific brain function.

  10. Millicurrent stimulation of human articular chondrocytes cultivated in a collagen type-I gel and of human osteochondral explants

    Directory of Open Access Journals (Sweden)

    Silny Jiri

    2010-08-01

    Full Text Available Abstract Background Here we investigate the effect of millicurrent treatment on human chondrocytes cultivated in a collagen gel matrix and on human osteochondral explants. Methods Human chondrocytes from osteoarthritic knee joints were enzymatically released and transferred into a collagen type-I gel. Osteochondral explants and cell-seeded gel samples were cultivated in-vitro for three weeks. Samples of the verum groups were stimulated every two days by millicurrent treatment (3 mA, sinusoidal signal of 312 Hz amplitude modulated by two super-imposed signals of 0.28 Hz, while control samples remained unaffected. After recovery, collagen type-I, type-II, aggrecan, interleukin-1β, IL-6, TNFα and MMP13 were examined by immunohistochemistry and by real time PCR. Results With regard to the immunostainings 3 D gel samples and osteochondral explants did not show any differences between treatment and control group. The expression of all investigated genes of the 3 D gel samples was elevated following millicurrent treatment. While osteochondral explant gene expression of col-I, col-II and Il-1β was nearly unaffected, aggrecan gene expression was elevated. Following millicurrent treatment, IL-6, TNFα, and MMP13 gene expression decreased. In general, the standard deviations of the gene expression data were high, resulting in rarely significant results. Conclusions We conclude that millicurrent stimulation of human osteoarthritic chondrocytes cultivated in a 3 D collagen gel and of osteochondral explants directly influences cell metabolism.

  11. Localized stimulation of the human brain and spinal cord by a pair of opposing pulsed magnetic fields

    Science.gov (United States)

    Ueno, S.; Matsuda, T.; Hiwaki, O.

    1990-05-01

    A method of localized stimulation of the human brain and spinal cord is proposed. The basic idea is to concentrate induced eddy currents locally in the vicinity of a target by a pair of opposing pulsed magnetic fields. A pair of coils are positioned outside the head in the opposite directions around a target. The eddy currents induced at the target are expected to flow together, which results in an increased current flow at the target. A figure-eight coil is designed, and the magnetic brain stimulation is carried out using ourselves as volunteers. The results show that the selective stimulation of the brain is realized with a 5-mm resolution. The functional mapping of the human motor cortex related to the hand, arm, and foot areas is obtained. It is also obtained that an optimum direction of stimulating currents for neural excitation exists in each functional area in the cortex. Magnetic stimulation of the spinal cord is carried out by the same method as used in the brain stimulation. Rabbits are used in the experiments. A figure-eight coil is positioned on the surface of the spine. Shifting the stimulating points on the spine, electromyographic (EMG) signals are recorded from limb muscles. The EMG signals are clearly responding to the stimulation at a segment which innervates limb muscles, whereas no EMG signals are obtained by stimulation of segments higher than the critical segment. It is also obtained that the amplitude of the EMG signals varies with the direction of stimulating currents.

  12. ATF-2 stimulates the human insulin promoter through the conserved CRE2 sequence.

    Science.gov (United States)

    Hay, Colin W; Ferguson, Laura A; Docherty, Kevin

    2007-02-01

    The insulin promoter contains a number of dissimilar cis-acting regulatory elements that bind a range of tissue specific and ubiquitous transcription factors. Of the regulatory elements within the insulin promoter, the cyclic AMP responsive element (CRE) binds by far the most diverse array of transcription factors. Rodent insulin promoters have a single CRE site, whereas there are four CREs within the human insulin gene, of which CRE2 is the only one conserved between species. The aim of this study was to characterise the human CRE2 site and to investigate the effects of the two principal CRE-associated transcription factors; CREB-1 and ATF-2. Co-transfection of INS-1 pancreatic beta-cells with promoter constructs containing the human insulin gene promoter placed upstream of the firefly luciferase reporter gene and expression plasmids for ATF-2 or CREB-1 showed that ATF-2 stimulated transcriptional activity while CREB-1 elicited an inhibitory effect. Mutagenesis of CRE2 diminished the effect of ATF-2 but not that of CREB-1. ATF-2 was shown to bind to the CRE2 site by electrophoretic mobility shift assay and by chromatin immunoprecipitation, while siRNA mediated knockdown of ATF-2 diminished the stimulatory effects of cAMP related signalling on promoter activity. These results suggest that ATF-2 may be a key regulator of the human insulin promoter possibly stimulating activity in response to extracellular signals.

  13. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Raufman, Jean-Pierre, E-mail: jraufman@medicine.umaryland.edu [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States); Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  14. Functional stochastic resonance in human baroreflex induced by 1/f-type noisy galvanic vestibular stimulation

    Science.gov (United States)

    Soma, Rika; Kwak, Shin; Yamamoto, Yoshiharu

    2003-05-01

    We hypothesized that 1/f noise is more beneficial than the conventional white noise in optimizing the brain's response to a weak input signal, and showed that externally added 1/f noise outperforms white noise in sensitizing human baroreflex centers in the brain. We examined the compensatory heart rate response to weak periodic signal introduced at the venous blood pressure receptor, while adding either 1/f or white noise with the same variance to the brain stem by electrically stimulating the bilateral vestibular afferents cutaneously. This stochastic galvanic vestibular stimulation, activating the vestibulo-sympathetic pathway in the brain stem, optimized covariance between weak input signals and the heart rate responses both with 1/f and white noise. Further, the optimal noise level with 1/f noise was significantly lower than that with white noise, suggesting the functional benefit of 1/f noise for the neuronal information transfer in the brain.

  15. Stimulation of human embryonic stem cell-derived cardiomyocytes on thin-film microelectrodes.

    Science.gov (United States)

    Viitanen, Jouko; Heimala, Päivi; Hokkanen, Ari; Iljin, Kristiina; Kerkelä, Erja; Kolari, Kai; Kattelus, Hannu

    2011-05-01

    We describe successful long-term stimulation of human embryonic stem cell-derived cardiomyocyte clusters on thin-film microelectrode structures in vitro. Interdigitated electrode structures were constructed using plain titanium on glass as the electrode material. Titanium rapidly oxidizes in atmospheric conditions to produce an insulating TiO(χ) layer with high relative permittivity. Capacitive coupling to the incubation medium and to the cells adherent to the electrodes was still efficient, and the dielectric layer prevented electrolysis, allowing a wider window of possible stimulation amplitudes to be used, relative to conducting surfaces. A common hypothesis suggests that to achieve proper differentiation of electroactive cells from the stem cells electrical stimuli are also needed. Spontaneously beating cardiomyocyte clusters were seeded on the glass-electrode surfaces, and we successfully altered and resynchronized a clearly different beat interval. The new pace was reliably maintained for extended periods of several tens of minutes.

  16. Human transcriptional coactivator PC4 stimulates DNA end joining and activates DSB repair activity.

    Science.gov (United States)

    Batta, Kiran; Yokokawa, Masatoshi; Takeyasu, Kunio; Kundu, Tapas K

    2009-01-23

    Human transcriptional coactivator PC4 is a highly abundant nuclear protein that is involved in diverse cellular processes ranging from transcription to chromatin organization. Earlier, we have shown that PC4, a positive activator of p53, overexpresses upon genotoxic insult in a p53-dependent manner. In the present study, we show that PC4 stimulates ligase-mediated DNA end joining irrespective of the source of DNA ligase. Pull-down assays reveal that PC4 helps in the association of DNA ends through its C-terminal domain. In vitro nonhomologous end-joining assays with cell-free extracts show that PC4 enhances the joining of noncomplementary DNA ends. Interestingly, we found that PC4 activates double-strand break (DSB) repair activity through stimulation of DSB rejoining in vivo. Together, these findings demonstrate PC4 as an activator of nonhomologous end joining and DSB repair activity.

  17. Human PSF concentrates DNA and stimulates duplex capture in DMC1-mediated homologous pairing

    Science.gov (United States)

    Morozumi, Yuichi; Ino, Ryohei; Takaku, Motoki; Hosokawa, Mihoko; Chuma, Shinichiro; Kurumizaka, Hitoshi

    2012-01-01

    PSF is considered to have multiple functions in RNA processing, transcription and DNA repair by mitotic recombination. In the present study, we found that PSF is produced in spermatogonia, spermatocytes and spermatids, suggesting that PSF may also function in meiotic recombination. We tested the effect of PSF on homologous pairing by the meiosis-specific recombinase DMC1, and found that human PSF robustly stimulated it. PSF synergistically enhanced the formation of a synaptic complex containing DMC1, ssDNA and dsDNA during homologous pairing. The PSF-mediated DMC1 stimulation may be promoted by its DNA aggregation activity, which increases the local concentrations of ssDNA and dsDNA for homologous pairing by DMC1. These results suggested that PSF may function as an activator for the meiosis-specific recombinase DMC1 in higher eukaryotes. PMID:22156371

  18. Decrease in platelet activating factor stimulated phosphoinositide turnover during storage of human platelets in plasma

    Energy Technology Data Exchange (ETDEWEB)

    Carter, M.G.; Shukla, S.D. (Univ. of Missouri School of Medicine, Columbia (USA))

    1987-05-01

    Human platelet concentrate from the American Red Cross Blood Center was stored at 24{degree}C in a shaker and aliquots were taken out at time intervals aseptically. Platelet activating factor (PAF) stimulated turnover of phosphoinositide (PPI) was monitored by assaying {sup 32}P incorporation into phosphoinositides using platelet rich plasma (PRP). Platelets in PRP were incubated with 1 {times} 10{sup {minus}7} M PAF at 37{degree}C with gentle shaking and after 5 min their lipids were extracted and analysed by TLC for {sup 32}P-phosphoinositides. The percent stimulation of {sup 32}P incorporation by PAF (over control) into PPI was approximately 250, 100, 60, 25 and 20 on days 1, 2, 3, 5 and 6, respectively. This indicated a dramatic decrease in PAF responsive turnover of platelet PPI during storage. These findings have important implications in relation to PAF receptor activity and viability of platelets at different periods of storage.

  19. Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes

    DEFF Research Database (Denmark)

    Clementsen, P; Bisgaard, H; Pedersen, M

    1989-01-01

    Mediator release was examined from superficially lying cells in the airway epithelium obtained by bronchoalveolar lavage (BAL) in 13 non-atopic individuals. The BAL-cells were incubated (20 min, 37 degrees C) with Staphylococcus (Staph.) aureus or with human influenza A virus Staph. aureus...... was found to release histamine from cells from 7 of the 13 individuals and influenza A virus in 3 of 5 persons. Furthermore, Staph, aureus stimulated the BAL-cells to release leukotriene B4 in 7 of 11 subjects, whereas no release was found by influenza A virus in 7 examined persons. When cells from 4...... persons were stimulated with Staph. aureus no release of leukotriene C4 was found. The mediator release caused by bacteria and virus might be of importance for the exacerbation of bronchial asthma in upper respiratory tract infections, since histamine is assumed to increase the epithelial permeability...

  20. The anti-inflammatory effects of asiatic acid in lipopolysaccharide-stimulated human corneal epithelial cells

    Science.gov (United States)

    Chen, Hao; Hua, Xiao-Min; Ze, Bai-Chen; Wang, Bin; Wei, Li

    2017-01-01

    AIM To investigate the anti-inflammatory effects of asiatic acid (AA) on lipopolysaccharide (LPS)-induced inflammatory response in human corneal epithelial cells (HCECs). METHODS Cell viability was measured using a cell counting kit-8 (CCK-8) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA expression of interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β (TGF-β) in HCECs. Intracellular reactive oxygen species (ROS) was measured using the ROS assay kit. Glutathione (GSH) concentration was measured using the total GSH assay kit. Akt1 and Akt phosphorylation (p-Akt1) levels were measured by Western blotting and immunofluorescence. RESULTS AA induced toxicity at high concentrations and significantly stimulated the proliferation of HCECs at concentrations of 20 µmol/L for 1h. LPS at concentrations of 300 ng/mL for 1h significantly stimulated the mRNA expression of IL-8, IL-6, IL-1β, TNF-α, and TGF-β in HCECs, while the stimulation effects were significantly inhibited by AA (20 µmol/L). In addition, AA was found to decrease the content of ROS, increase GSH generation, and also inhibit LPS-induced p-Akt in HCECs. CONCLUSION AA decreases the generation of inflammatory factors IL-8, IL-6, IL-1β, TNF-α, and TGF-β in LPS-stimulated HCECs. AA significantly inhibites the intracellular concentrations of ROS and increases GSH generation. AA also inhibites LPS-induced p-Akt in HCECs. These findings reveal that AA has anti-inflammation effects in LPS-stimulated HCECs.

  1. Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans.

    Directory of Open Access Journals (Sweden)

    Enrico Rejc

    Full Text Available Sensory and motor complete spinal cord injury (SCI has been considered functionally complete resulting in permanent paralysis with no recovery of voluntary movement, standing or walking. Previous findings demonstrated that lumbosacral spinal cord epidural stimulation can activate the spinal neural networks in one individual with motor complete, but sensory incomplete SCI, who achieved full body weight-bearing standing with independent knee extension, minimal self-assistance for balance and minimal external assistance for facilitating hip extension. In this study, we showed that two clinically sensory and motor complete participants were able to stand over-ground bearing full body-weight without any external assistance, using their hands to assist balance. The two clinically motor complete, but sensory incomplete participants also used minimal external assistance for hip extension. Standing with the least amount of assistance was achieved with individual-specific stimulation parameters, which promoted overall continuous EMG patterns in the lower limbs' muscles. Stimulation parameters optimized for one individual resulted in poor standing and additional need of external assistance for hip and knee extension in the other participants. During sitting, little or negligible EMG activity of lower limb muscles was induced by epidural stimulation, showing that the weight-bearing related sensory information was needed to generate sufficient EMG patterns to effectively support full weight-bearing standing. In general, electrode configurations with cathodes selected in the caudal region of the array at relatively higher frequencies (25-60 Hz resulted in the more effective EMG patterns for standing. These results show that human spinal circuitry can generate motor patterns effective for standing in the absence of functional supraspinal connections; however the appropriate selection of stimulation parameters is critical.

  2. Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans.

    Science.gov (United States)

    Rejc, Enrico; Angeli, Claudia; Harkema, Susan

    2015-01-01

    Sensory and motor complete spinal cord injury (SCI) has been considered functionally complete resulting in permanent paralysis with no recovery of voluntary movement, standing or walking. Previous findings demonstrated that lumbosacral spinal cord epidural stimulation can activate the spinal neural networks in one individual with motor complete, but sensory incomplete SCI, who achieved full body weight-bearing standing with independent knee extension, minimal self-assistance for balance and minimal external assistance for facilitating hip extension. In this study, we showed that two clinically sensory and motor complete participants were able to stand over-ground bearing full body-weight without any external assistance, using their hands to assist balance. The two clinically motor complete, but sensory incomplete participants also used minimal external assistance for hip extension. Standing with the least amount of assistance was achieved with individual-specific stimulation parameters, which promoted overall continuous EMG patterns in the lower limbs' muscles. Stimulation parameters optimized for one individual resulted in poor standing and additional need of external assistance for hip and knee extension in the other participants. During sitting, little or negligible EMG activity of lower limb muscles was induced by epidural stimulation, showing that the weight-bearing related sensory information was needed to generate sufficient EMG patterns to effectively support full weight-bearing standing. In general, electrode configurations with cathodes selected in the caudal region of the array at relatively higher frequencies (25-60 Hz) resulted in the more effective EMG patterns for standing. These results show that human spinal circuitry can generate motor patterns effective for standing in the absence of functional supraspinal connections; however the appropriate selection of stimulation parameters is critical.

  3. Somatotopic organization of the white matter tracts underpinning motor control in humans: an electrical stimulation study.

    Science.gov (United States)

    Rech, Fabien; Herbet, Guillaume; Moritz-Gasser, Sylvie; Duffau, Hugues

    2016-09-01

    The somatotopic organization of the primary motor cortex is well documented. However, a possible somatotopy of the network involved in motor control, i.e., eliciting negative motor phenomena during electrostimulation, is unknown in humans, particularly at the subcortical level. Here, we performed electrical stimulation mapping in awake patients operated for gliomas, to study the distribution of the white matter tracts subserving movement control of the lower limb, upper limb(s), and speech. Eighteen patients underwent awake surgery for frontal low-grade gliomas, by using intraoperative subcortical electrostimulation mapping to search interference with movement of the leg, arm(s), and face. We assessed the negative motor responses and their distribution throughout the tracts located under premotor areas. The corresponding stimulation sites were reported on a standard brain template for visual analysis and between-subjects comparisons. During stimulation of the white matter underneath the dorsal premotor cortex and supplementary motor area, rostral to the corticospinal tracts, all patients experienced cessation of the movement of lower and upper limbs, of bimanual coordination, and/or speech. These subcortical sites were somatotopically distributed. Indeed, stimulation of the fibers from mesial to lateral directions and from posterior to anterior directions evoked arrest of movement of the lower limb (mesially and posteriorly), upper limb(s), and face/speech (laterally and anteriorly). There were no postoperative permanent deficits. This is the first evidence of a somatotopic organization of the white matter bundles underpinning movement control in humans. A better knowledge of the distribution of this motor control network may be helpful in neurosciences and neurosurgery.

  4. Stimulation of osteogenic differentiation in human osteoprogenitor cells by pulsed electromagnetic fields: an in vitro study

    Directory of Open Access Journals (Sweden)

    Jansen Justus HW

    2010-08-01

    Full Text Available Abstract Background Although pulsed electromagnetic field (PEMF stimulation may be clinically beneficial during fracture healing and for a wide range of bone disorders, there is still debate on its working mechanism. Mesenchymal stem cells are likely mediators facilitating the observed clinical effects of PEMF. Here, we performed in vitro experiments to investigate the effect of PEMF stimulation on human bone marrow-derived stromal cell (BMSC metabolism and, specifically, whether PEMF can stimulate their osteogenic differentiation. Methods BMSCs derived from four different donors were cultured in osteogenic medium, with the PEMF treated group being continuously exposed to a 15 Hz, 1 Gauss EM field, consisting of 5-millisecond bursts with 5-microsecond pulses. On culture day 1, 5, 9, and 14, cells were collected for biochemical analysis (DNA amount, alkaline phosphatase activity, calcium deposition, expression of various osteoblast-relevant genes and activation of extracellular signal-regulated kinase (ERK signaling. Differences between treated and control groups were analyzed using the Wilcoxon signed rank test, and considered significant when p Results Biochemical analysis revealed significant, differentiation stage-dependent, PEMF-induced differences: PEMF increased mineralization at day 9 and 14, without altering alkaline phosphatase activity. Cell proliferation, as measured by DNA amounts, was not affected by PEMF until day 14. Here, DNA content stagnated in PEMF treated group, resulting in less DNA compared to control. Quantitative RT-PCR revealed that during early culture, up to day 9, PEMF treatment increased mRNA levels of bone morphogenetic protein 2, transforming growth factor-beta 1, osteoprotegerin, matrix metalloproteinase-1 and -3, osteocalcin, and bone sialoprotein. In contrast, receptor activator of NF-κB ligand expression was primarily stimulated on day 14. ERK1/2 phosphorylation was not affected by PEMF stimulation

  5. LIF is a contraction-induced myokine stimulating human myocyte proliferation

    DEFF Research Database (Denmark)

    Broholm, Christa; Laye, Matthew J; Brandt, Claus

    2011-01-01

    Background: The cytokine leukemia inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of myoblasts. We hypothesized that LIF is a contraction-induced myokine functioning in an autocrine fashion to activate gene regulation of human muscle satellite cell proliferation....... Methods: Skeletal muscle LIF expression, regulation and action were examined in two models: 1) Young men performing a bout of heavy resistance exercise of the quadriceps muscle and 2) cultured primary human satellite cells. Results: Resistance exercise induced a 9-fold increase in LIF mRNA content...... in skeletal muscle, but LIF was not detectable in plasma of the subjects. However, electrically stimulated cultured human myotubes produced and secreted LIF, suggesting that LIF is a myokine with local effects. The well-established exercise-induced signaling molecules PI3K, Akt and mTor contributed...

  6. Functional asymmetry between the left and right human fusiform gyrus explored through electrical brain stimulation.

    Science.gov (United States)

    Rangarajan, Vinitha; Parvizi, Josef

    2016-03-01

    The ventral temporal cortex (VTC) contains several areas with selective responses to words, numbers, faces, and objects as demonstrated by numerous human and primate imaging and electrophysiological studies. Our recent work using electrocorticography (ECoG) confirmed the presence of face-selective neuronal populations in the human fusiform gyrus (FG) in patients implanted with intracranial electrodes in either the left or right hemisphere. Electrical brain stimulation (EBS) disrupted the conscious perception of faces only when it was delivered in the right, but not left, FG. In contrast to our previous findings, here we report both negative and positive EBS effects in right and left FG, respectively. The presence of right hemisphere language dominance in the first, and strong left-handedness and poor language processing performance in the second case, provide indirect clues about the functional architecture of the human VTC in relation to hemispheric asymmetries in language processing and handedness.

  7. Generation and characterization of human B lymphocyte stimulator blocking monoclonal antibody.

    Science.gov (United States)

    Zhuang, Weiliang; Zhang, Jianjun; Pei, Lili; Fang, Shuping; Liu, Honghao; Wang, Ruixue; Su, Yunpeng

    2016-09-01

    The cytokine, B lymphocyte stimulator (Blys) is essential for activation and proliferation of B cells and is involved in the pathogenesis of B-cell mediated autoimmune diseases. Based on its essential activity, Blys may be a potential therapeutic target for human autoimmune diseases. In this article, we have described the development of a novel humanized anti-Blys antibody, NMB04, that binds with high affinity and specificity to both soluble and membrane bound Blys. This monoclonal antibody has the potential to block Blys binding to all its three receptors, TACI, BCMA and BR-3. Further in vivo studies revealed that NMB04 possessed more potent inhibitory activity against human Blys as compared to an existing antibody, Belimumab. Therefore, NMB04 may have potential as a therapeutic candidate targeting autoimmune diseases.

  8. Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes.

    Science.gov (United States)

    Kwak, Hyo-Bum; Thalacker-Mercer, Anna; Anderson, Ethan J; Lin, Chien-Te; Kane, Daniel A; Lee, Nam-Sihk; Cortright, Ronald N; Bamman, Marcas M; Neufer, P Darrell

    2012-01-01

    Statins, the widely prescribed cholesterol-lowering drugs for the treatment of cardiovascular disease, cause adverse skeletal muscle side effects ranging from fatigue to fatal rhabdomyolysis. The purpose of this study was to determine the effects of simvastatin on mitochondrial respiration, oxidative stress, and cell death in differentiated primary human skeletal muscle cells (i.e., myotubes). Simvastatin induced a dose-dependent decrease in viability of proliferating and differentiating primary human muscle precursor cells, and a similar dose-dependent effect was noted in differentiated myoblasts and myotubes. Additionally, there were decreases in myotube number and size following 48 h of simvastatin treatment (5 μM). In permeabilized myotubes, maximal ADP-stimulated oxygen consumption, supported by palmitoylcarnitine+malate (PCM, complex I and II substrates) and glutamate+malate (GM, complex I substrates), was 32-37% lower (P<0.05) in simvastatin-treated (5 μM) vs control myotubes, providing evidence of impaired respiration at complex I. Mitochondrial superoxide and hydrogen peroxide generation were significantly greater in the simvastatin-treated human skeletal myotube cultures compared to control. In addition, simvastatin markedly increased protein levels of Bax (proapoptotic, +53%) and Bcl-2 (antiapoptotic, +100%, P<0.05), mitochondrial PTP opening (+44%, P<0.05), and TUNEL-positive nuclei in human skeletal myotubes, demonstrating up-regulation of mitochondrial-mediated myonuclear apoptotic mechanisms. These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis in primary human skeletal myotubes, suggesting that mitochondrial dysfunction may underlie human statin-induced myopathy. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. A novel method for the culture and polarized stimulation of human intestinal mucosa explants.

    Science.gov (United States)

    Tsilingiri, Katerina; Sonzogni, Angelica; Caprioli, Flavio; Rescigno, Maria

    2013-05-01

    Few models currently exist to realistically simulate the complex human intestine's micro-environment, where a variety of interactions take place. Proper homeostasis directly depends on these interactions, as they shape an entire immunological response inducing tolerance against food antigens while at the same time mounting effective immune responses against pathogenic microbes accidentally ingested with food. Intestinal homeostasis is preserved also through various complex interactions between the microbiota (including food-associated beneficial bacterial strains) and the host, that regulate the attachment/degradation of mucus, the production of antimicrobial peptides by the epithelial barrier, and the "education" of epithelial cells' that controls the tolerogenic or immunogenic phenotype of unique, gut-resident lymphoid cells' populations. These interactions have been so far very difficult to reproduce with in vitro assays using either cultured cell lines or peripheral blood mononuclear cells. In addition, mouse models differ substantially in components of the intestinal mucosa (mucus layer organization, commensal bacteria community) with respect to the human gut. Thus, studies of a variety of treatments to be brought in the clinics for important stress-related or pathological conditions such as irritable bowel syndrome, inflammatory bowel disease or colorectal cancer have been difficult to carry out. To address these issues, we developed a novel system that enables us to stimulate explants of human intestinal mucosa that retain their in situ conditioning by the host microbiota and immune response, in a polarized fashion. Polarized apical stimulation is of great importance for the outcome of the elicited immune response. It has been repeatedly shown that the same stimuli can produce completely different responses when they bypass the apical face of the intestinal epithelium, stimulating epithelial cells basolaterally or coming into direct contact with lamina

  10. High and low frequency transcutaneous electrical nerve stimulation inhibits nociceptive responses induced by CO2 laser stimulation in humans.

    Science.gov (United States)

    de Tommaso, Marina; Fiore, Pietro; Camporeale, Alfonso; Guido, Marco; Libro, Giuseppe; Losito, Luciana; Megna, Marisa; Puca, Francomichele; Megna, Gianfranco

    2003-05-15

    The aim of the study was to evaluate the effects of transcutaneous electric nerve stimulation (TENS) on CO(2) laser evoked potentials (LEPs) in 16 normal subjects. The volar side of the forearm was stimulated by 10 Hz TENS in eight subjects and by 100 Hz TENS in the remainder; the skin of the forearm was stimulated by CO(2) laser and the LEPs were recorded in basal conditions and soon after and 15 min after TENS. Both low and high frequency TENS significantly reduced the subjective rating of heat stimuli and the LEPs amplitude, although high frequency TENS appeared more efficacious. TENS seemed to exert a mild inhibition of the perception and processing of pain induced by laser Adelta fibres activation; the implications of these effects in the clinical employment of TENS remain to be clarified.

  11. Influence of mechanical stimulation on human dermal fibroblasts derived from different body sites.

    Science.gov (United States)

    Kuang, Ruixia; Wang, Zhiguo; Xu, Quanchen; Liu, Su; Zhang, Weidong

    2015-01-01

    Mechanical stimulation is highly associated with pathogenesis of human hypertrophic scar. Although much work has focused on the influence of mechanical stress on fibroblast populations from various tissues and organs in the human body, their effects on cultured dermal fibroblasts by the area of the body have not been as well studied. In this study, cultures of skin fibroblasts from two different body sites were subjected to cyclic mechanical stimulation with a 10% stretching amplitude at a frequency of 0.1 Hz for 24, 36 and 48 hours, respectively, and thereafter harvested for experimental assays. Fibroblasts from scapular upper back skin, subjected to mechanical loads for 36 and 48 hours, respectively, were observed to proliferate at a higher rate and reach confluent more rapidly during in vitro culturing, had higher expression levels of mRNA and protein production of integrin β1, p130Cas and TGF β1 versus those from medial side of upper arm. These data indicate that skin fibroblasts, with regard to originated body sites studied in the experiments, display a diversity of mechanotransduction properties and biochemical reactions in response to applied mechanical stress, which contributes to the increased susceptibility to hypertrophic scars formation at certain areas of human body characterized by higher skin and muscle tension.

  12. IL-8 and MCP Gene Expression and Production by LPS-Stimulated Human Corneal Stromal Cells

    Directory of Open Access Journals (Sweden)

    Roni M. Shtein

    2012-01-01

    Full Text Available Purpose. To determine time course of effect of lipopolysaccharide (LPS on production of interleukin-8 (IL-8 and monocyte chemotactic protein (MCP by cultured human corneal stromal cells. Methods. Human corneal stromal cells were harvested from donor corneal specimens, and fourth to sixth passaged cells were used. Cell cultures were stimulated with LPS for 2, 4, 8, and 24 hours. Northern blot analysis of IL-8 and MCP gene expression and ELISA for IL-8 and MCP secretion were performed. ELISA results were analyzed for statistical significance using two-tailed Student's t-test. Results. Northern blot analysis demonstrated significantly increased IL-8 and MCP gene expression after 4 and 8 hours of exposure to LPS. ELISA for secreted IL-8 and MCP demonstrated statistically significant increases (P<0.05 after corneal stromal cell stimulation with LPS. Conclusions. This paper suggests that human corneal stromal cells may participate in corneal inflammation by secreting potent leukocyte chemotactic and activating proteins in a time-dependent manner when exposed to LPS.

  13. In situ electric fields causing electro-stimulation from conductor contact of charged human.

    Science.gov (United States)

    Nagai, Toshihiro; Hirata, Akimasa

    2010-08-01

    Contact currents flow from/into a human body when touching an object such as a metal structure with a different electric potential. These currents can stimulate muscle and peripheral nerves. In this context, computational analyses of in situ electric fields caused by the contact current have been performed, while their effectiveness for transient contact currents has not well been investigated. In the present study, using an anatomically based human model, a dispersive finite-difference time-domain model was utilised to computed transient contact current and in situ electric fields from a charged human. Computed in situ electric fields were highly localised in the hand. In order to obtain an insight into the relationship between in situ electric field and electro-stimulation, cell-maximum and 5-mm averaged in situ electric fields were computed and compared with strength-duration curves. The comparison suggests that both measures could be larger than thresholds derived from the strength-duration curves with parameters used in previous studies.

  14. Beer and wine but not whisky and pure ethanol do stimulate release of gastrin in humans.

    Science.gov (United States)

    Singer, M V; Eysselein, V; Goebell, H

    1983-01-01

    In humans, the action of ethanol on gastrin release is still unclear and that of alcoholic beverages greatly unknown. We studied the effect of a drink of various concentrations of pure ethanol and several commonly ingested alcoholic beverages on plasma levels of immunoreactive gastrin in 6 healthy human volunteers and compared the results to a protein-rich meal. A drink of distilled water (250 ml) and of pure ethanol (250 ml or 125 ml in the case of 40% v/v ethanol) in concentrations (4, 10, 20 and 40% v/v) normally present in beer, wine, liquor and whisky did not stimulate plasma gastrin levels above basal. Of the alcoholic beverages given only whisky (125 ml) did not stimulate gastrin release. Beer, red and white wine (250 ml each) caused a rapid increase in plasma gastrin concentrations with a peak at 15-20 min, basal levels being reached 60 min after starting the drink. The 60-min integrated plasma gastrin response to beer, red and white wine was about 50% of the gastrin response to the protein-rich (steak) meal (883 +/- 297 pmol X min X 1(-1); mean +/- SE). A drink of 250 ml of white wine together with the meal did not cause a significantly higher integrated gastrin response than the protein meal with 250 ml of distilled water. We conclude that commonly ingested alcoholic beverages such as beer, red and white wine, but not whisky, are potent stimulants of gastrin release in humans. The ethanol content of these beverages cannot be responsible for the increase in plasma gastrin levels, since oral ingestion of pure ethanol in equivalent concentrations and amounts did not elicit a rise in plasma gastrin levels. Some unknown ingredients present in beer and wine are most likely responsible for the gastrin release by both alcoholic beverages.

  15. Human macrophage colony-stimulating factor induces the differentiation of trophoblast.

    Science.gov (United States)

    Saito, S; Saito, M; Enomoto, M; Ito, A; Motoyoshi, K; Nakagawa, T; Ichijo, M

    1993-01-01

    When human cytotrophoblastic cells in the early stage of pregnancy were cultured in a serum-free medium in the presence of human macrophage colony-stimulating factor (M-CSF), the cytotrophoblastic cells fused and formed a typical syncytiotrophoblast which had a dense distribution of microvilli revealed under an electron microscope. On the other hand, cytotrophoblasts incubated with anti-M-CSF antibody showed hardly any syncytiotrophoblast formation. Following this finding, we studied the differentiation of chorionic cells from the viewpoint of hormone secretion. When cytotrophoblasts were incubated in the presence of M-CSF, the supernatant of the culture showed an increase in human chorionic gonadotropin and human placental lactogen levels in proportion to the concentration of M-CSF added. When cytotrophoblasts were incubated in the presence of anti-M-CSF antibody or anti-fms antibody, human chorionic gonadotropin and human placental lactogen secretion were suppressed. Thus, M-CSF was morphologically and endocrinologically found to induce the differentiation of chorionic cells.

  16. Responses of the human motor system to observing actions across species: A transcranial magnetic stimulation study.

    Science.gov (United States)

    White, Nicole C; Reid, Connor; Welsh, Timothy N

    2014-10-22

    Ample evidence suggests that the role of the mirror neuron system (MNS) in monkeys is to represent the meaning of actions. The MNS becomes active in monkeys during execution, observation, and auditory experience of meaningful, object-oriented actions, suggesting that these cells represent the same action based on a variety of cues. The present study sought to determine whether the human motor system, part of the putative human MNS, similarly represents and reflects the meaning of actions rather than simply the mechanics of the actions. To this end, transcranial magnetic stimulation (TMS) of primary motor cortex was used to generate motor-evoked potentials (MEPs) from muscles involved in grasping while participants viewed object-oriented grasping actions performed by either a human, an elephant, a rat, or a body-less robotic arm. The analysis of MEP amplitudes suggested that activity in primary motor cortex during action observation was greatest during observation of the grasping actions of the rat and elephant, and smallest for the human and robotic arm. Based on these data, we conclude that the human action observation system can represent actions executed by non-human animals and shows sensitivity to species-specific differences in action mechanics.

  17. Twitch potentiation induced by stimulated and voluntary isometric contractions at various torque levels in human knee extensor muscles.

    Science.gov (United States)

    Miyamoto, Naokazu; Yanai, Toshimasa; Kawakami, Yasuo

    2011-03-01

    The purpose of this study was to compare the extent of twitch potentiation (TP) after stimulated or voluntary contractions at identical intensities for the human knee extensor muscles. Isometric knee extensions of 10 s were performed at 20%, 40%, and 60% of maximal voluntary contraction (MVC) torque level, through percutaneous electrical stimulation of the quadriceps at 80 Hz or voluntary contraction. Twitch responses were evoked by stimulating the femoral nerve percutaneously with supramaximal intensity. The extent of TP after the stimulated contraction was greater than that after the voluntary contraction at the 20% MVC torque level, whereas a stimulated contraction induced a smaller extent of TP than did a voluntary contraction at contraction intensities higher than 40% MVC. We suggest that this contraction intensity dependence of differences in TP after stimulated and voluntary isometric conditioning contractions is responsible for differences in the recruitment pattern of motor units during the conditioning contractions.

  18. Study of intracranial pressure in human brain during transcranial magnetic stimulation.

    Science.gov (United States)

    Honrath, Marc; Sabouni, Abas

    2015-01-01

    This paper presents the results of cranial force in human brain due to electromagnetic pulse during transcranial magnetic stimulation. To model the force in a realistic brain, we used three dimensional magnetic resonance image of the 26 years old female subject. Simulation results show that during TMS procedure, there is a small force generated within the cranial tissue layers along with a torque value in different layers of brain tissues. The force depends on the magnitude of the magnetic field generated by the TMS coil.

  19. fMRI assessment of somatotopy in human Brodmann area 3b by electrical finger stimulation.

    Science.gov (United States)

    Kurth, R; Villringer, K; Mackert, B M; Schwiemann, J; Braun, J; Curio, G; Villringer, A; Wolf, K J

    1998-01-26

    Functional magnetic resonance imaging (fMRI) is capable of detecting focal brain activation induced by electrical stimulation of single fingers in human subjects. In eight subjects somatotopic arrangement of the second and fifth finger was found in Brodmann area 3b of the primary somatosensory cortex. In four subjects the representation area of the second finger was located lateral and inferior to the fifth finger; in one subject the somatotopy was reversed. In three subjects representation areas of the two fingers in Brodmann area 3b were found overlapping. Additional activated areas were found on the crown of ipsilateral and contralateral postcentral gyrus (Brodmann areas 1 and 2) and posterior parietal cortex.

  20. Adenosine receptors in rat and human pancreatic ducts stimulate chloride transport

    DEFF Research Database (Denmark)

    Novak, Ivana; Hede, Susanne; Hansen, Mette

    2007-01-01

    these could be involved in secretory processes, which involve cystic fibrosis transmembrane regulator (CFTR) Cl(-) channels or Ca(2+)-activated Cl(-) channels and [Formula: see text] transporters. Reverse transcriptase polymerase chain reaction analysis on rat pancreatic ducts and human duct cell......, plasma membrane of many PANC-1 cells, but only a few CFPAC-1 cells. Taken together, our data indicate that A(2A) receptors open Cl(-) channels in pancreatic ducts cells with functional CFTR. We propose that adenosine can stimulate pancreatic secretion and, thereby, is an active player in the acini...

  1. Granulocyte macrophage colony stimulating factor (GM-CSF biological actions on human dermal fibroblasts

    Directory of Open Access Journals (Sweden)

    S Montagnani

    2009-12-01

    Full Text Available Fibroblasts are involved in all pathologies characterized by increased ExtraCellularMatrix synthesis, from wound healing to fibrosis. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF is a cytokine isolated as an hemopoietic growth factor but recently indicated as a differentiative agent on endothelial cells. In this work we demonstrated the expression of the receptor for GM-CSF (GMCSFR on human normal skin fibroblasts from healthy subjects (NFPC and on a human normal fibroblast cell line (NHDF and we try to investigate the biological effects of this cytokine. Human normal fibroblasts were cultured with different doses of GM-CSF to study the effects of this factor on GMCSFR expression, on cell proliferation and adhesion structures. In addition we studied the production of some Extra-Cellular Matrix (ECM components such as Fibronectin, Tenascin and Collagen I. The growth rate of fibroblasts from healthy donors (NFPC is not augmented by GM-CSF stimulation in spite of increased expression of the GM-CSFR. On the contrary, the proliferation of normal human dermal fibroblasts (NHDF cell line seems more influenced by high concentration of GM-CSF in the culture medium. The adhesion structures and the ECM components appear variously influenced by GM-CSF treatment as compared to fibroblasts cultured in basal condition, but newly only NHDF cells are really induced to increase their synthesis activity. We suggest that the in vitro treatment with GM-CSF can shift human normal fibroblasts towards a more differentiated state, due or accompanied by an increased expression of GM-CSFR and that such “differentiation” is an important event induced by such cytokine.

  2. Hypothalamic-pituitary-thyroid axis hormones stimulate mitochondrial function and biogenesis in human hair follicles.

    Science.gov (United States)

    Vidali, Silvia; Knuever, Jana; Lerchner, Johannes; Giesen, Melanie; Bíró, Tamás; Klinger, Matthias; Kofler, Barbara; Funk, Wolfgang; Poeggeler, Burkhard; Paus, Ralf

    2014-01-01

    Thyroid hormones regulate mitochondrial function. As other hypothalamic-pituitary-thyroid (HPT) axis hormones, i.e., thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), are expressed in human hair follicles (HFs) and regulate mitochondrial function in human epidermis, we investigated in organ-cultured human scalp HFs whether TRH (30 nM), TSH (10 mU ml(-1)), thyroxine (T4) (100 nM), and triiodothyronine (T3) (100 pM) alter intrafollicular mitochondrial energy metabolism. All HPT-axis members increased gene and protein expression of mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin. All hormones also stimulated intrafollicular complex I/IV activity and mitochondrial biogenesis. The TSH effects on MTCO1, TFAM, and porin could be abolished by K1-70, a TSH-receptor antagonist, suggesting a TSH receptor-mediated action. Notably, as measured by calorimetry, T3 and TSH increased follicular heat production, whereas T3/T4 and TRH stimulated ATP production in cultured HF keratinocytes. HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable.

  3. Interleukin-1 beta stimulates glucose uptake of human peritoneal mesothelial cells in vitro.

    Science.gov (United States)

    Kruse, M; Mahiout, A; Kliem, V; Kurz, P; Koch, K M; Brunkhorst, R

    1996-01-01

    To investigate whether the glucose uptake (GU) of human peritoneal mesothelial cells (HPMC) is mediated by glucose transporters and whether this uptake is influenced by interleukin 1-beta (IL-1 beta), we measured 2-deoxy-(3H)-GU of HPMC in vitro, after exposing the cells for different times (two and 12 hours) to increasing concentrations (0.1, 1.0, and 2.0 ng/mL) of IL-1 beta. To exclude a noncarrier-mediated transport, GU was also tested in the presence of cytochalasin B. All experiments were performed in triplicate in the cells of two donors. Cytochalasin B inhibits GU of HPMC almost completely. GU of HPMC is not stimulated by insulin. GU is stimulated by IL-1 beta in a dose-dependent manner. These data indicate a GU of HPMC, which is mediated by a glucose transporter and stimulated by IL-1 beta. The increased uptake of glucose from the dialysate in patients with peritonitis may be mediated by a (cytokine-induced) increased activity of HPMC glucose transporters.

  4. Synthesis of nitric oxide in human osteoblasts in response to physiologic stimulation of electrotherapy.

    Science.gov (United States)

    Hamed, Ayman; Kim, Paul; Cho, Michael

    2006-12-01

    Electrotherapy for bone healing, remodeling and wound healing may be mediated by modulation of nitric oxide (NO). Using NO-specific fluorophore (DAF-2), we report here that application of non-invasive, physiologic electrical stimulation induces NO synthesis in human osteoblasts, and that such NO generation is comparable to that induced by estrogen treatment. For example, application of a sinusoidal 1 Hz, 2 V/cm (peak to peak) electrical stimulation (ES) increases NO-bound DAF-2 fluorescence intensity by a 2-fold within 60 min exposure by activating nitric oxide synthase (NOS). Increase in the NO level is found to depend critically on the frequency and strength of ES. While the frequency of 1 Hz ES seems optimal, the ES strength >0.5 V/cm is required to induce significant NO increase, however. Nitric oxide synthesis in response to ES is completely prevented by blocking estrogen receptors using a competitive inhibitor, suggesting that NO generation is likely initiated by activation of estrogen receptors at the cell surface. Based on these findings, physiologic stimulation of electrotherapy appears to represent a potential non-invasive, non-genomic, and novel physical technique that could be used to regulate NO-mediated bone density and facilitate bone remodeling without adverse effects associated with hormone therapy.

  5. Stimulation of differentiated functions in human melanoma cells by tumor-promoting agents and dimethyl sulfoxide

    Energy Technology Data Exchange (ETDEWEB)

    Huberman, E.; Heckman, C.; Langenbach, R.

    1979-07-01

    Treatment of cultured human HO melanoma cells with the mouse skin tumor promoter phorbol-12-myristate-13-acetate (PMA) at 5 x 10/sup -10/ to 5 x 10/sup -7/ M resulted in a dose-related inhibition of growth and a stimulation of differentiated functions. These included melanin synthesis and formation of dendrite-like structues. Higher doses of phorbol dibutyrate, a less potent tumor promoter, were required to produce an effect comparable to that of PMA for dendrite induction. Phorbol and two other phorbal esters, which lack tumor-promoting activity, were either inactive or elicited a poor response. In addition to morphological changes, treatment with PMA altered glucosamine incorporation into membrane gangliosides. After PMA treatment, glucosamine incorporation increased 8- to 10 fold in the G/sub m3/ ganglioside and decreased 2-fold in the G/sub m1/ ganglioside, as compared to phorbol or untreated control. Inhibition of cell growth and stimulation of melanin synthesis were also observed after treatment of the HO cells with dimethyl sulfoxide. Unlike the tumor-promoting agents, dimethyl sulfoxide did not induce the formation of dendrite-like structures in the cells. These findings indicate that HO melanoma cells can be stimulated into terminally differentiated cells after treatment with tumor-promoting agents such as phorbol diesters.

  6. Enterococcus faecium stimulates human neutrophils via the formyl-peptide receptor 2.

    Directory of Open Access Journals (Sweden)

    Dominik Alexander Bloes

    Full Text Available The human formyl-peptide receptor 2 (FPR2/ALX senses phenol-soluble modulin (PSM peptide toxins produced by pathogenic staphylococcal species and plays a crucial role in directing neutrophil influx during staphylococcal infection. However, it has remained unclear if FPR2 responds also to molecules from other bacterial pathogens. Here we analyzed a variety of gram-positive and gram-negative pathogens and found that apart from staphylococci only certain enterococcal strains have the capacity to stimulate FPR2/ALX. Most of the analyzed Enterococcus faecium but only sporadic Enterococcus faecalis strains released FPR2/ALX-stimulating molecules leading to neutrophil calcium ion fluxes, chemotaxis, and complement receptor upregulation. Among ten test strains vancomycin-resistant E. faecium had a significantly higher capacity to stimulate FPR2/ALX than vancomycin-susceptible strains, suggesting an association of strong FPR2/ALX activation with health-care associated strains. The enterococcal FPR2/ALX agonists were found to be peptides or proteins, which appear, however, to be unrelated to staphylococcal PSMs in sequence and physicochemical properties. Enterococci are among the most frequent invasive bacterial pathogens but the basis of enterococcal virulence and immune activation has remained incompletely understood. Our study indicates that previously unrecognized proteinaceous agonists contribute to Enterococcus-host interaction and underscores the importance of FPR2/ALX in host defense against major endogenous bacterial pathogens.

  7. Pulsed ultrasound differentially stimulates somatosensory circuits in humans as indicated by EEG and FMRI.

    Directory of Open Access Journals (Sweden)

    Wynn Legon

    Full Text Available Peripheral somatosensory circuits are known to respond to diverse stimulus modalities. The energy modalities capable of eliciting somatosensory responses traditionally belong to mechanical, thermal, electromagnetic, and photonic domains. Ultrasound (US applied to the periphery has also been reported to evoke diverse somatosensations. These observations however have been based primarily on subjective reports and lack neurophysiological descriptions. To investigate the effects of peripherally applied US on human somatosensory brain circuit activity we recorded evoked potentials using electroencephalography and conducted functional magnetic resonance imaging of blood oxygen level-dependent (BOLD responses to fingertip stimulation with pulsed US. We found a pulsed US waveform designed to elicit a mild vibration sensation reliably triggered evoked potentials having distinct waveform morphologies including a large double-peaked vertex potential. Fingertip stimulation with this pulsed US waveform also led to the appearance of BOLD signals in brain regions responsible for somatosensory discrimination including the primary somatosensory cortex and parietal operculum, as well as brain regions involved in hierarchical somatosensory processing, such as the insula, anterior middle cingulate cortex, and supramarginal gyrus. By changing the energy profile of the pulsed US stimulus waveform we observed pulsed US can differentially activate somatosensory circuits and alter subjective reports that are concomitant with changes in evoked potential morphology and BOLD response patterns. Based on these observations we conclude pulsed US can functionally stimulate different somatosensory fibers and receptors, which may permit new approaches to the study and diagnosis of peripheral nerve injury, dysfunction, and disease.

  8. Effects of frontal transcranial direct current stimulation on emotional processing and mood in healthy humans

    Directory of Open Access Journals (Sweden)

    Michael A. Nitsche

    2012-06-01

    Full Text Available The prefrontal cortex is involved in mood and emotional processing. In patients suffering from depression, the left dorsolateral prefrontal cortex is hypoactive, while activity of the right dorsolateral prefrontal cortex is enhanced. Counterbalancing these pathological excitability alterations by repetitive transcranial magnetic stimulation (rTMS or transcranial direct current stimulation (tDCS improves mood in these patients. In healthy subjects, however, rTMS of the same areas has no major effect, and the effects of tDCS are mixed. We aimed to evaluate the effects of prefrontal tDCS on mood and mood-related cognitive processing in healthy humans. In a first study, we administered excitability-enhancing anodal, excitability-diminishing cathodal and placebo tDCS to the left dorsolateral prefrontal cortex, combined with antagonistic stimulation of the right frontopolar cortex, and tested acute mood changes by an adjective checklist. Subjective mood was not influenced by tDCS. Emotional face identification, however, which was explored in a second experiment, was subtly improved by a tDCS-driven excitability modulation of the prefrontal cortex, markedly by anodal tDCS of the left dorsolateral prefrontal cortex for positive emotional content. We conclude that tDCS of the prefrontal cortex improves mood processing in healthy subjects, but does not influence subjective mood state.

  9. Preferential Th1 cytokine profile of phosphoantigen-stimulated human Vγ9Vδ2 T cells.

    LENUS (Irish Health Repository)

    Dunne, Margaret R

    2010-01-01

    Human Vγ9Vδ2 T cells recognise pyrophosphate-based antigens (phosphoantigens) and have multiple functions in innate and adaptive immunity, including a unique ability to activate other cells of the immune system. We used flow cytometry and ELISA to define the early cytokine profiles of Vγ9Vδ2 T cells stimulated in vitro with isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP) in the absence and presence of IL-2 and IL-15. We show that fresh Vγ9Vδ2 T cells produce interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) within 4 hours of stimulation with phosphoantigen, but neither IL-10, IL-13, nor IL-17 was detectable up to 72 hours under these conditions. Cytokine production was not influenced by expression or lack, thereof, of CD4 or CD8. Addition of IL-2 or IL-15 caused expansion of IFN-γ-producing Vγ9Vδ2 T cells, but did not enhance IFN-γ secretion after 24-72 hours. Thus, phosphoantigen-stimulated Vγ9Vδ2 T cells have potential as Th1-biasing adjuvants for immunotherapy.

  10. Lobohedleolide induces interleukin-8 production in LPS-stimulated human monocytic cell line THP-1

    Directory of Open Access Journals (Sweden)

    T Oda

    2011-09-01

    Full Text Available Summary: Lobohedleolide (1 has been isolated from a soft coral, Sarcophyton sp., as one of three responsible substances for observed inhibitory activity against TNF-a production in lipopolysaccharide (LPS-stimulated murine macrophage-like RAW 264.7 cells. During the examination of other inflammatory cytokines, we found that only 1 induced the production of interleukin (IL-8 in LPS-stimulated human monocytic THP-1 cells, while the other two compounds did not affect the production of IL-8. Although 1 showed an inhibitory effect on nuclear factor-kappaB (NF-kB activation, this compound induced IL-8 promoter activity, which led to the induction of IL-8 production in LPS-stimulated THP-1 cells. Industrial Relevance: Marine organisms are a rich resource of biologically active secondary metabolites. Two marine natural products and two derivatives of marine sponge compounds have been utilized for medical treatment, and marked numbers of marine natural products and their derivatives are now in clinical and pre-clinical trials. Therefore, marine natural products are attractive sources of medicines and their lead compounds, and elucidation of new bioactivity and the mechanism of action of marine natural products are also a very important study for drug discovery. This report describes a new bioactivity of a diterpene previously obtained from an Indonesian soft corral.

  11. Reversal of adaptive left ventricular atrophy following electrically-stimulated exercise training in human tetraplegics.

    Science.gov (United States)

    Nash, M S; Bilsker, S; Marcillo, A E; Isaac, S M; Botelho, L A; Klose, K J; Green, B A; Rountree, M T; Shea, J D

    1991-11-01

    Left ventricular (LV) myocardial atrophy and diminished cardiac function have been shown to accompany chronic human tetraplegia. These changes are attributable both to physical immobilisation and abnormal autonomic circulatory regulation imposed by a spinal cord injury (SCI). To test whether exercise training increases LV mass following chronic SCI, 8 neurologically complete quadriplegic males at 2 SCI rehabilitation and research centres underwent one month of electrically-stimulated quadriceps strengthening followed by 6 months of electrically-stimulated cycling exercise. Resting M-mode and 2-D echocardiograms were measured before and after exercise training to quantify the interventricular septal and posterior wall thicknesses at end-diastole (IVSTED and PWTED, respectively), and the LV internal dimension at end-diastole (LVIDED). LV mass was computed from these measurements using standard cube function geometry. Results showed a 6.5% increase in LVIDED following exercise training (p less than 0.02), with increases in IVSTED and PWTED of 17.8 (p less than 0.002) and 20.3% (p less than 0.01), respectively. Computed LV mass increased by 35% following exercise training (p = 0.002). These data indicate that myocardial atrophy is reversed in tetraplegics following electrically-stimulated exercise training, and that the changes in cardiac architecture are likely to be the result of both pressure and volume challenge to the heart imposed by exercise.

  12. Gram-Negative Bacterial Lipopolysaccharide Stimulates Activin A Secretion from Human Amniotic Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Yumiko Abe

    2013-01-01

    Full Text Available Activin A is involved in inflammation. The present study was performed to clarify if lipopolysaccharide, a component of Gram-negative bacteria, stimulates activin A secretion from human amniotic epithelial cells and to determine if activin A plays a role in amnionitis. Fetal membranes were obtained during elective cesarean sections performed in full-term pregnancies of patients without systemic disease, signs of premature delivery, or fetal complications. Amniotic epithelial cells were isolated by trypsinization. The activin A concentrations in the culture media were measured by enzyme-linked immunosorbent assay, and cell proliferation was assessed by 5-bromo-2′-deoxyuridine incorporation. Amniotic epithelial cells secreted activin A in a cell density-dependent manner, and lipopolysaccharide (10 μg/mL enhanced the secretion at each cell density. Lipopolysaccharide (10–50 μg/mL also stimulated activin A secretion in a dose-dependent manner. Contrary to the effect of activin A secretion, lipopolysaccharide inhibited cell proliferation in amniotic epithelial cells. The present study suggests that lipopolysaccharide stimulation of activin A secretion may be a mechanism in the pathogenesis of amnionitis.

  13. Conditional Electrical Stimulation in Animal and Human Models for Neurogenic Bladder: Working Toward a Neuroprosthesis.

    Science.gov (United States)

    Powell, C R

    2016-12-01

    Sacral neuromodulation has had a tremendous impact on the treatment of urinary incontinence and lower urinary tract symptoms for patients with neurologic conditions. This stimulation does not use real-time data from the body or input from the patient. Incorporating this is the goal of those pursuing a neuroprosthesis to enhance bladder function for these patients. Investigators have demonstrated the effectiveness of conditional (also called closed-loop) feedback in animal models as well as limited human studies. Dorsal genital nerve, pudendal nerve, S3 afferent nerve roots, S1 and S2 ganglia have all been used as targets for stimulation. Most of these have also been used as sources of afferent nerve information using sophisticated nerve electrode arrays and filtering algorithms to detect significant bladder events and even to estimate the fullness of the bladder. There are problems with afferent nerve sensing, however. Some of these include sensor migration and low signal to noise ratios. Implantable pressure sensors have also been investigated that have their own unique challenges, such as erosion and sensor drift. As technology improves, an intelligent neuroprosthesis with the ability to sense significant bladder events and stimulate as needed will evolve.

  14. Is the human mirror neuron system plastic? Evidence from a transcranial magnetic stimulation study.

    Science.gov (United States)

    Mehta, Urvakhsh Meherwan; Waghmare, Avinash V; Thirthalli, Jagadisha; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

    2015-10-01

    Virtual lesions in the mirror neuron network using inhibitory low-frequency (1Hz) transcranial magnetic stimulation (TMS) have been employed to understand its spatio-functional properties. However, no studies have examined the influence of neuro-enhancement by using excitatory high-frequency (20Hz) repetitive transcranial magnetic stimulation (HF-rTMS) on these networks. We used three forms of TMS stimulation (HF-rTMS, single and paired pulse) to investigate whether the mirror neuron system facilitates the motor system during goal-directed action observation relative to inanimate motion (motor resonance), a marker of putative mirror neuron activity. 31 healthy individuals were randomized to receive single-sessions of true or sham HF-rTMS delivered to the left inferior frontal gyrus - a component of the human mirror system. Motor resonance was assessed before and after HF-rTMS using three TMS cortical reactivity paradigms: (a) 120% of resting motor threshold (RMT), (b) stimulus intensity set to evoke motor evoked potential of 1-millivolt amplitude (SI1mV) and (c) a short latency paired pulse paradigm. Two-way RMANOVA showed a significant group (true versus sham) X occasion (pre- and post-HF-rTMS motor resonance) interaction effect for SI1mV [F(df)=6.26 (1, 29), p=0.018] and 120% RMT stimuli [F(df)=7.01 (1, 29), p=0.013] indicating greater enhancement of motor resonance in the true HF-rTMS group than the sham-group. This suggests that HF-rTMS could adaptively modulate properties of the mirror neuron system. This neuro-enhancement effect is a preliminary step that can open translational avenues for novel brain stimulation therapeutics targeting social-cognition deficits in schizophrenia and autism. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. A chemical compound that stimulates the human homologous recombination protein RAD51.

    Science.gov (United States)

    Jayathilaka, Krishanthi; Sheridan, Sean D; Bold, Tyler D; Bochenska, Katarzyna; Logan, Hillary L; Weichselbaum, Ralph R; Bishop, Douglas K; Connell, Philip P

    2008-10-14

    RAD51 and other members of the RecA family of strand exchange proteins assemble on ssDNA to form presynaptic filaments, which carry out the central steps of homologous recombination. A microplate-based assay was developed for high-throughput measurement of hRAD51 filament formation on ssDNA. With this method, a 10,000 compound library was screened, leading to the identification of a small molecule (RS-1) that enhances hRAD51 binding in a wide range of biochemical conditions. Salt titration experiments showed that RS-1 can enhance filament stability. Ultrastructural analysis of filaments formed on ssDNA showed that RS-1 can increase both protein-DNA complex lengths and the pitch of helical filament turns. RS-1 stimulated hRAD51-mediated homologous strand assimilation (D-loop) activity by at least 5- to 11-fold, depending on the condition. This D-loop stimulation occurred even in the presence of Ca(2+) or adenylyl-imidodiphosphate, indicating that the mechanism of stimulation was distinct from that conferred by Ca(2+) and/or inhibition of ATPase. No D-loop activity was observed in the absence of a nucleotide triphosphate cofactor, indicating that the compound does not substitute for this requirement. These results indicate that RS-1 enhances the homologous recombination activity of hRAD51 by promoting the formation of active presynaptic filaments. Cell survival assays in normal neonatal human dermal fibroblasts demonstrated that RS-1 promotes a dose-dependent resistance to the cross-linking chemotherapeutic drug cisplatin. Given that RAD51-dependent recombination is a major determinant of cisplatin resistance, RS-1 seems to function in vivo to stimulate homologous recombination repair proficiency. RS-1 has many potential applications in both research and medical settings.

  16. Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25{+-}2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% {+-} 1.3% and 10.6% {+-} 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% {+-} 4.5% vs. 6.6% {+-} 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release.

  17. Repetitive transcranial magnetic stimulation of human MT+ reduces apparent motion perception.

    Science.gov (United States)

    Matsuyoshi, Daisuke; Hirose, Nobuyuki; Mima, Tatsuya; Fukuyama, Hidenao; Osaka, Naoyuki

    2007-12-18

    We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) over the human cerebral cortex on apparent motion perception. Previous studies have shown that human extrastriate visual area MT+ (V5) processes not only real but also apparent motion. However, the functional relevance of MT+ on long-range apparent motion perception remains unclear. Here, we show direct evidence for the involvement of MT+ in apparent motion perception using rTMS, which is known to temporarily inhibit a localized region in the cerebral cortex. The results showed that apparent motion perception decreased after applying rTMS over MT+, but not after applying rTMS over the control region (inferior temporal gyrus). The decrease in performance caused by applying rTMS to MT+ suggests that MT+ is a causally responsible region for apparent motion perception, and thus, further supports the idea that MT+ plays a major role in the perception of motion.

  18. Effects of transcranial magnetic stimulation during voluntary and non-voluntary stepping movements in humans.

    Science.gov (United States)

    Solopova, I A; Selionov, V A; Kazennikov, O V; Ivanenko, Y P

    2014-09-05

    Here, we compared motor evoked potentials (MEP) in response to transcranial magnetic stimulation of the motor cortex and the H-reflex during voluntary and vibration-induced air-stepping movements in humans. Both the MEPs (in mm biceps femoris, rectus femoris and tibialis anterior) and H-reflex (in m soleus) were significantly smaller during vibration-induced cyclic leg movements at matched amplitudes of angular motion and muscle activity. These findings highlight differences between voluntary and non-voluntary activation of the spinal pattern generator circuitry in humans, presumably due to an extra facilitatory effect of voluntary control/triggering of stepping on spinal motoneurons and interneurons. The results support the idea of active engagement of supraspinal motor areas in developing central pattern generator-modulating therapies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Homeostatic plasticity in human motor cortex demonstrated by two consecutive sessions of paired associative stimulation.

    Science.gov (United States)

    Müller, J Florian M; Orekhov, Yuriy; Liu, Yali; Ziemann, Ulf

    2007-06-01

    Long-term potentiation (LTP) and long-term depression (LTD) underlie most models of learning and memory, but neural activity would grow or shrink in an uncontrolled manner, if not guarded by stabilizing mechanisms. The Bienenstock-Cooper-Munro (BCM) rule proposes a sliding threshold for LTP/LTD induction: LTP induction becomes more difficult if neural activity was high previously. Here we tested if this form of homeostatic plasticity applies to the human motor cortex (M1) in vivo by examining the interactions between two consecutive sessions of paired associative stimulation (PAS). PAS consisted of repeated pairs of electrical stimulation of the right median nerve followed by transcranial magnetic stimulation of the left M1. The first PAS session employed an interstimulus interval equalling the individual N20-latency of the median nerve somatosensory-evoked cortical potential plus 2 ms, N20-latency minus 5 ms, or a random alternation between these intervals, to induce an LTP-like increase in motor-evoked potential (MEP) amplitudes in the right abductor pollicis brevis muscle (PAS(LTP)), an LTD-like decrease (PAS(LTD)), or no change (PAS(Control)), respectively. The second PAS session 30 min later was always PAS(LTP). It induced an moderate LTP-like effect if conditioned by PAS(Control), which increased if conditioned by PAS(LTD), but decreased if conditioned by PAS(LTP). Effects on MEP amplitude induced by the second PAS session exhibited a negative linear correlation with those in the first PAS session. Because the two PAS sessions activate identical neuronal circuits, we conclude that 'homosynaptic-like' homeostatic mechanisms in accord with the BCM rule contribute to regulating plasticity in human M1.

  20. Effect of serotonin on paired associative stimulation-induced plasticity in the human motor cortex.

    Science.gov (United States)

    Batsikadze, Giorgi; Paulus, Walter; Kuo, Min-Fang; Nitsche, Michael A

    2013-10-01

    Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo-controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory- and excitability-diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation-elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke.

  1. Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation.

    Science.gov (United States)

    Hirt, Marc N; Boeddinghaus, Jasper; Mitchell, Alice; Schaaf, Sebastian; Börnchen, Christian; Müller, Christian; Schulz, Herbert; Hubner, Norbert; Stenzig, Justus; Stoehr, Andrea; Neuber, Christiane; Eder, Alexandra; Luther, Pradeep K; Hansen, Arne; Eschenhagen, Thomas

    2014-09-01

    Spontaneously beating engineered heart tissue (EHT) represents an advanced in vitro model for drug testing and disease modeling, but cardiomyocytes in EHTs are less mature and generate lower forces than in the adult heart. We devised a novel pacing system integrated in a setup for videooptical recording of EHT contractile function over time and investigated whether sustained electrical field stimulation improved EHT properties. EHTs were generated from neonatal rat heart cells (rEHT, n=96) or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hEHT, n=19). Pacing with biphasic pulses was initiated on day 4 of culture. REHT continuously paced for 16-18 days at 0.5Hz developed 2.2× higher forces than nonstimulated rEHT. This was reflected by higher cardiomyocyte density in the center of EHTs, increased connexin-43 abundance as investigated by two-photon microscopy and remarkably improved sarcomere ultrastructure including regular M-bands. Further signs of tissue maturation include a rightward shift (to more physiological values) of the Ca(2+)-response curve, increased force response to isoprenaline and decreased spontaneous beating activity. Human EHTs stimulated at 2Hz in the first week and 1.5Hz thereafter developed 1.5× higher forces than nonstimulated hEHT on day 14, an ameliorated muscular network of longitudinally oriented cardiomyocytes and a higher cytoplasm-to-nucleus ratio. Taken together, continuous pacing improved structural and functional properties of rEHTs and hEHTs to an unprecedented level. Electrical stimulation appears to be an important step toward the generation of fully mature EHT.

  2. Design of Ligands for Affinity Purification of G-CSF Based on Peptide Ligands Derived from a Peptide Library

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Combinatorial peptide libraries have become powerful tools to screen functional ligands by the principle of affinity selection. We screened in a phage peptide library to investigate potential peptide affinity ligands for the purification of human granulocyte colony-stimulation factor(hG-CSF). Peptide ligands will be promising to replace monoclonal antibodies as they have advantages of high stability, efficiency, selectivity and low price.

  3. Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury

    OpenAIRE

    Ming-san Miao; Lin Guo; Rui-qi Li; Xiao Ma

    2016-01-01

    Previous studies have shown that Radix Ilicis Pubescentis total flavonoids have a neuroprotective effect, but it remains unclear whether Radix Ilicis Pubescentis total flavonoids have a synergistic effect with the recombinant human granulocyte colony stimulating factor-mobilized bone marrow stem cell transplantation on cerebral ischemia/reperfusion injury. Rat ischemia models were administered 0.3, 0.15 and 0.075 g/kg Radix Ilicis Pubescentis total flavonoids from 3 days before modeling to 2 ...

  4. Novel SLA-DQ alleles and their recombinant molecules in xenogeneic stimulation of human T cells.

    Science.gov (United States)

    Chen, Fuxiang; Xie, Jin; Li, Ningli; Zhou, Yun; Xin, Lijun; Chou, Kuang-Yen

    2005-06-01

    MHC class II antigens DR and DQ are essential for graft rejection both in allo- and xeno-transplantation. The antigens, especially the DQA and DQB gene-coencoded DQ molecules, are also involved in transplantation tolerance induced by activation of regulatory T cells. Here we report six novel DQ alleles from three properly inbred Chinese pig strains Gz, Bm and Yn. In our study, cDNA of swine leukocyte antigen (SLA)-DQA and -DQB were amplified by RT-PCR and sequenced for each strain. The ORF-containing SLA-DQA and -DQB genes are composed of 768 (or 765) and 786 nucleotides, encoding antigen molecules of 255 (or 254) and 261 amino acid residues, respectively. Sequences of both SLA-DQA and -DQB alleles showed disparities when compared either among the three pig strains or with available SLA data, which allows our novel alleles receiving their accession numbers from GenBank. The sequence analysis further revealed a phylogenic connection of our SLA-DQ alleles with SLA-DQ(c) haplotype. In addition, the homologies of MHC DQ or DQ-like molecules between Chinese pigs (SLA) and human (HLA) are higher than those between pigs and mice (H-2). By co-transfection of Bm pig DQA and DQB genes into L929 cells, the Bm-DQ heterodimer-expressed cells could effectively stimulate the human lymphoproliferation in presence of human APCs with a mean stimulation index (SI) 9.9+/-1.4. This functional assay indicated that our recombinant DQ antigens are capable of initiating human lymphoproliferation in a xeno-MLR.

  5. Heparin-like polymers modulate proinflammatory cytokine production by lipopolysaccharide-stimulated human monocytes.

    Science.gov (United States)

    Anastase-Ravion, Sylvie; Carreno, Marie-Paule; Blondin, Catherine; Ravion, Olivier; Champion, Jacqueline; Chaubet, Frédéric; Haeffner-Cavaillon, Nicole; Letourneur, Didier

    2002-06-05

    The search for heparin-like materials remains an intensive field of research. In this context, we studied the immunomodulatory properties of semisynthetic dextran derivatives and naturally occurring sulfated polysaccharides present in brown seaweed (fucans). In this study, we investigated the functional potencies of fucan and dextran derivatives by analyzing their effects on the release of proinflammatory cytokines by resting or lipopolysaccharide (LPS)-stimulated human monocytes and their interactions on monocyte surfaces. The results showed that fucan, dextran derivatives, and heparin differentially (1) triggered interleukin-1alpha, tumor necrosis factor alpha, interleukin-6, and interleukin-8 production by monocytes in a dose-dependent manner, (2) modulated cytokine production by LPS-stimulated monocytes, and (3) specifically inhibited the binding of biotinylated LPS to monocyte membranes. Taken together, these data indicated that fucan and dextran derivatives displayed interesting immunomodulatory effects on human blood cells that could be relevant as new drugs or biomaterial coatings. Indeed, such polysaccharides, by regulating monocyte activation, could contribute to the improved biocompatibility of implants.

  6. Cyclic mechanical deformation stimulates human lung fibroblast proliferation and autocrine growth factor activity.

    Science.gov (United States)

    Bishop, J E; Mitchell, J J; Absher, P M; Baldor, L; Geller, H A; Woodcock-Mitchell, J; Hamblin, M J; Vacek, P; Low, R B

    1993-08-01

    Cellular hypertrophy and hyperplasia and increased extracellular matrix deposition are features of tissue hypertrophy resulting from increased work load. It is known, for example, that mechanical forces play a critical role in lung development, cardiovascular remodeling following pressure overload, and skeletal muscle growth. The mechanisms involved in these processes, however, remain unclear. Here we examined the effect of mechanical deformation on fibroblast function in vitro. IMR-90 human fetal lung fibroblasts grown on collagen-coated silastic membranes were subjected to cyclical mechanical deformation (10% increase in culture surface area; 1 Hz) for up to 5 days. Cell number was increased by 39% after 2 days of deformation (1.43 +/- .01 x 10(5) cells/membrane compared with control, 1.03 +/- 0.02 x 10(5) cells; mean +/- SEM; P < 0.02) increasing to 163% above control by 4 days (2.16 +/- 0.16 x 10(5) cells compared with 0.82 +/- 0.03 x 10(5) cells; P < 0.001). The medium from mechanically deformed cells was mitogenic for IMR-90 cells, with maximal activity in the medium from cells mechanically deformed for 2 days (stimulating cell replication by 35% compared with media control; P < 0.002). These data suggest that mechanical deformation stimulates human lung fibroblast replication and that this effect is mediated by the release of autocrine growth factors.

  7. G-CSF protects human brain vascular endothelial cells injury induced by high glucose, free fatty acids and hypoxia through MAPK and Akt signaling.

    Directory of Open Access Journals (Sweden)

    Jingjing Su

    Full Text Available Granulocyte-colony stimulating factor (G-CSF has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM-derived endothelial progenitor cells (EPCs, promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A, cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2 and Akt, and deactivation of c-Jun N terminal kinase (JNK and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK and Akt

  8. G-CSF Protects Human Brain Vascular Endothelial Cells Injury Induced by High Glucose, Free Fatty Acids and Hypoxia through MAPK and Akt Signaling

    Science.gov (United States)

    Tao, Yinghong; Guo, Jingchun; Guo, Zhuangli; Zhang, Shuo; Zhang, Yu; Huang, Yanyan; Tang, Yuping; Dong, Qiang; Hu, Renming

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM)-derived endothelial progenitor cells (EPCs), promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs) with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA) and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM) revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A), cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2) and Akt, and deactivation of c-Jun N terminal kinase (JNK) and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK) and Akt signaling

  9. Delivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models human papillomavirus-associated (pre)neoplastic epithelial lesions

    OpenAIRE

    Hubert, Pascale; Evrard, Brigitte; Maillard, Catherine; Franzen-Detrooz, E.; Delattre, Luc; Foidart, Jean-Michel; Noël, Agnès; Boniver, Jacques; Delvenne, Philippe

    2004-01-01

    Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were ev...

  10. A testbed to explore the optimal electrical stimulation parameters for suppressing inter-ictal spikes in human hippocampal slices.

    Science.gov (United States)

    Min-Chi Hsiao; Pen-Ning Yu; Dong Song; Liu, Charles Y; Heck, Christi N; Millett, David; Berger, Theodore W

    2014-01-01

    New interventions using neuromodulatory devices such as vagus nerve stimulation, deep brain stimulation and responsive neurostimulation are available or under study for the treatment of refractory epilepsy. Since the actual mechanisms of the onset and termination of the seizure are still unclear, most researchers or clinicians determine the optimal stimulation parameters through trial-and-error procedures. It is necessary to further explore what types of electrical stimulation parameters (these may include stimulation frequency, amplitude, duration, interval pattern, and location) constitute a set of optimal stimulation paradigms to suppress seizures. In a previous study, we developed an in vitro epilepsy model using hippocampal slices from patients suffering from mesial temporal lobe epilepsy. Using a planar multi-electrode array system, inter-ictal activity from human hippocampal slices was consistently recorded. In this study, we have further transferred this in vitro seizure model to a testbed for exploring the possible neurostimulation paradigms to inhibit inter-ictal spikes. The methodology used to collect the electrophysiological data, the approach to apply different electrical stimulation parameters to the slices are provided in this paper. The results show that this experimental testbed will provide a platform for testing the optimal stimulation parameters of seizure cessation. We expect this testbed will expedite the process for identifying the most effective parameters, and may ultimately be used to guide programming of new stimulating paradigms for neuromodulatory devices.

  11. Substrate specific stimulation of NEIL1 by WRN but not the other human RecQ helicases

    DEFF Research Database (Denmark)

    Popuri, Venkateswarlu; Croteau, Deborah L; Bohr, Vilhelm A

    2010-01-01

    protein (WRN), one of the five human RecQ helicases, stimulates NEIL1 DNA glycosylase activity on oxidative DNA lesions. The goal of this study was to extend this observation and analyze the interaction between NEIL1 and all five human RecQ helicases. The DNA substrate specificity of the interaction...

  12. Elevation of extracellular adenosine enhances haemopoiesis-stimulating effects of G-CSF in normal and gamma-irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Hofer, M.; Pospisil, M.; Netikiva, J.; Hola, J. [Institute of Biophysics, Academy of Sciences of the Czech Republic (Czech Republic)

    1997-03-01

    Effects of combined treatment with drugs elevating extracellular adenosine (dipyridamole /DP/, inhibiting the extracellular uptake of adenosine, and adenosine monophosphate /AMP/, an adenosine pro-drug), and G-CSF (granulocyte colony-stimulating factor) on haemopoiesis of normal and gamma-irradiated mice were ascertained. The agents were administered alone or in combination in a 4-day regimen. In normal, unirradiated animals, the haematological endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, i.e., increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC) and morphologically recognizable granulocyte cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of DP plus AMP administrated 30 minutes before G-CSF. Furthermore, it was found that the stimulatory action of DP plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 {mu}g/d). In experiments with irradiated mice, when the 4-day therapeutic regimen was applied on days 3 to 6 following irradiation with the dose of 4 Gy, analogical stimulation of granulopoiesis was observed in the recovery phase on days 14 and 18 after irradiation. As example, see Fig. 1 for counts of granulocyte cells in femoral bone marrow. (authors)

  13. HIV-1 Vpr induces interferon-stimulated genes in human monocyte-derived macrophages.

    Directory of Open Access Journals (Sweden)

    Muhammad Atif Zahoor

    Full Text Available Macrophages act as reservoirs of human immunodeficiency virus type 1 (HIV-1 and play an important role in its transmission to other cells. HIV-1 Vpr is a multi-functional protein involved in HIV-1 replication and pathogenesis; however, its exact role in HIV-1-infected human macrophages remains poorly understood. In this study, we used a microarray approach to explore the effects of HIV-1 Vpr on the transcriptional profile of human monocyte-derived macrophages (MDMs. More than 500 genes, mainly those involved in the innate immune response, the type I interferon pathway, cytokine production, and signal transduction, were differentially regulated (fold change >2.0 after infection with a recombinant adenovirus expressing HIV-1 Vpr protein. The differential expression profiles of select interferon-stimulated genes (ISGs and genes involved in the innate immune response, including STAT1, IRF7, MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, APOBEC3A, DDX58 (RIG-I, TNFSF10 (TRAIL, and RSAD2 (viperin were confirmed by real-time quantitative PCR and were consistent with the microarray data. In addition, at the post-translational level, HIV-1 Vpr induced the phosphorylation of STAT1 at tyrosine 701 in human MDMs. These results demonstrate that HIV-1 Vpr leads to the induction of ISGs and expand the current understanding of the function of Vpr and its role in HIV-1 immune pathogenesis.

  14. Stimulation of mucin secretion from human bronchial epithelial cells by mast cell chymase

    Institute of Scientific and Technical Information of China (English)

    Shao-heng HE; Jian ZHENG

    2004-01-01

    AIM: To investigate the effect ofchymase on the mucin secretion from human bronchial epithelial cells. METHODS:Primarily-cultured human bronchial epithelial (PCHBE) cells and normal human bronchial epithelial (NHBE) cells were cultured with chymase or other stimulus in a mixture of bronchial epithelial growth medium (BEGM) and Dulbecco's modified Eagle's medium (DMEM), and the quantities of stimulatory mucin release were recorded.MUC5AC mucin was measured with an ELISA and dolichos biflorus agglutinin (DBA) mucin was determined with an enzyme linked DBA assay. RESULTS: A dose-dependent secretion of DBA mucin from PCHBE cells was observed with chymase with a maximum secretion of 98 % above baseline being achieved following 3 h incubation.The action of chymase started from 1 h, peaked at 3 h and dramatically decreased at 20 h following incubation.Chymase was able to also stimulate approximately 38 % increase in MUC5AC mucin release from PCHBE cells, and about 121% increase in DBA mucin release from NHBE cells. A chymase inhibitor soybean trypsin inhibitor (SBTI)was able to inhibit up to 85 % chymase induced mucin release, indicating that the enzymatic activity was essential for the actions of chymase on bronchial epithelial cells. CONCLUSION: Chymase is a potent stimulus of mucin secretion from human bronchial epithelial cells. It can contribute to mucus hypersecretion process in the patients with chronic obstructive pulmonary disease or asthma.

  15. Carbon monoxide stimulates the Ca2(+)-activated big conductance k channels in cultured human endothelial cells.

    Science.gov (United States)

    Dong, De-Li; Zhang, Yan; Lin, Dao-Hong; Chen, Jun; Patschan, Susann; Goligorsky, Michael S; Nasjletti, Alberto; Yang, Bao-Feng; Wang, Wen-Hui

    2007-10-01

    We used the whole-cell patch-clamp technique to study K channels in the human umbilical vein endothelial cells and identified a 201 pS K channel, which was blocked by tetraethylammonium and iberiotoxin but not by TRAM34 and apamin. This suggests that the Ca(2+)-activated big-conductance K channel (BK) is expressed in endothelial cells. Application of carbon monoxide (CO) or tricarbonylchloro(glycinato)ruthenium(II), a water soluble CO donor, stimulated the BK channels. Moreover, application of hemin, a substrate of heme oxygenase, mimicked the effect of CO and increased the BK channel activity. The stimulatory effect of hemin was significantly diminished by tin mesoporphyrin, an inhibitor of heme oxygenase. To determine whether the stimulatory effect of CO on the BK channel was mediated by NO and the cGMP-dependent pathway, we examined the effect of CO on BK channels in cells treated with, N(G)-nitro-l-arginine methyl ester, 1H(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, or KT5823, an inhibitor of protein kinase G. Addition of either diethylamine NONOate or sodium nitroprusside significantly increased BK channel activity. Inhibition of endogenous NO synthesis with N(G)-nitro-l-arginine methyl ester, blocking soluble guanylate cyclase or protein kinase G, delayed but did not prevent the CO-induced activation of BK channels. Finally, application of an antioxidant agent, ebselen, had no effect on CO-mediated stimulation of BK channels in human umbilical vein endothelial cells. We conclude that BK channels are expressed in human umbilical vein endothelial cells and that they are activated by both CO and NO. CO activates BK channels directly, as well as via a mechanism involving NO or the cGMP-dependent pathway.

  16. ALUMINUM STIMULATES UPTAKE OF NON-TRANSFERRIN BOUND IRON AND TRANSFERRIN BOUND IRON IN HUMAN GLIAL CELLS

    OpenAIRE

    Kim, Yongbae; Olivi, Luisa; Cheong, Jae Hoon; Maertens, Alex; Joseph P Bressler

    2007-01-01

    Aluminum and other trivalent metals were shown to stimulate uptake of transferrin bound iron and nontransferrin bound iron in erytholeukemia and hepatoma cells. Because of the association between aluminum and Alzheimer’s Disease, and findings of higher levels of iron in Alzheimer’s disease brains, the effects of aluminum on iron homeostasis were examined in a human glial cell line. Aluminum stimulated dose- and time-dependent uptake of nontransferrin bound iron and iron bound to transferrin. ...

  17. Polarity-specific cortical effects of transcranial direct current stimulation in primary somatosensory cortex of healthy humans

    Directory of Open Access Journals (Sweden)

    Robert eRehmann

    2016-05-01

    Full Text Available Transcranial direct current stimulation (tDCS is a noninvasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1. We measured paired-pulse suppression (PPS of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by paired-pulse suppression. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS.

  18. Prostaglandin E2 regulates macrophage colony stimulating factor secretion by human bone marrow stromal cells.

    Science.gov (United States)

    Besse, A; Trimoreau, F; Faucher, J L; Praloran, V; Denizot, Y

    1999-07-08

    Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth factors such as macrophage colony stimulating factor (M-CSF) that regulates the proliferation, differentiation and several functions of cells of the mononuclear-phagocytic lineage. By using a specific ELISA we found that their constitutive secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The lipid mediator prostaglandin E2 (PGE2) markedly reduces in a time- and dose-dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15-HETE, leukotriene B4, leukotriene C4 and lipoxin A4 have no effect. EP2/EP4 selective agonists (11-deoxy PGE1 and 1-OH PGE1) and EP2 agonist (19-OH PGE2) inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist (sulprostone) has no effect. Stimulation with PGE2 induces an increase of intracellular cAMP levels in bone marrow stromal cells. cAMP elevating agents (forskolin and cholera toxin) mimic the PGE2-induced inhibition of M-CSF production. In conclusion, PGE2 is a potent regulator of M-CSF production by human bone marrow stromal cells, its effects being mediated via cAMP and PGE receptor EP2/EP4 subtypes.

  19. Tissue factor: A potent stimulator of Von Willebrand factor synthesis by human umbilical vein endothelial cells

    Science.gov (United States)

    Meiring, Muriel; Allers, W.; Le Roux, E.

    2016-01-01

    Inflammation and dysfunction of endothelial cells are thought to be triggers for the secretion of Von Willebrand factor. The aim of this study was to examine the effects of the inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-α) and the coagulation factors, tissue factor and thrombin on the release and cleavage potential of ultra-large von Willebrand factor (ULVWF) and its cleavage protease by cultured human umbilical vein endothelial cells (HUVEC). HUVEC were treated with IL-6, IL-8, and TNF-α, tissue factor (TF) and thrombin, and combinations thereof for 24 hours under static conditions. The cells were then exposed to shear stress after which the VWF-propeptide levels and the VWF cleavage protease, ADAMTS13 content were measured. All treatments and their combinations, excluding IL-6, significantly stimulated the secretion of VWF from HUVEC. The VWF secretion from the HUVEC was stimulated most by the combination of TF with TNF-α. Slightly lower levels of ADAMTS13 secretion were found with all treatments. This may explain the thrombogenicity of patients with inflammation where extremely high VWF levels and slightly lower ADAMTS13 levels are present.

  20. Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion

    Science.gov (United States)

    Cataldo, Luis R.; Gutierrez, Juan; Santos, José L.; Casas, Mariana; Contreras-Ferrat, Ariel E.; Moro, Cedric; Bouzakri, Karim

    2017-01-01

    Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle) glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines). We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS). In conditioned media from human myotubes incubated with/without insulin (100 nmol/L) for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets (p < 0.05). Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets. PMID:28286777

  1. Changes in sensory hand representation and pain thresholds induced by motor cortex stimulation in humans.

    Science.gov (United States)

    Houzé, Bérengère; Bradley, Claire; Magnin, Michel; Garcia-Larrea, Luis

    2013-11-01

    Shrinking of deafferented somatosensory regions after neural damage is thought to participate to the emergence of neuropathic pain, and pain-relieving procedures have been reported to induce the normalization of altered cortical maps. While repetitive magnetic stimulation (rTMS) of the motor cortex can lessen neuropathic pain, no evidence has been provided that this is concomitant to changes in sensory maps. Here, we assessed in healthy volunteers the ability of 2 modes of motor cortex rTMS commonly used in pain patients to induce changes in pain thresholds and plastic phenomena in the S1 cortex. Twenty minutes of high-frequency (20 Hz) rTMS significantly increased pain thresholds in the contralateral hand, and this was associated with the expansion of the cortical representation of the hand on high-density electroencephalogram source analysis. Neither of these effects were observed after sham rTMS, nor following intermittent theta-burst stimulation (iTBS). The superiority of 20-Hz rTMS over iTBS to induce sensory plasticity may reflect its better match with intrinsic cortical motor frequencies, which oscillate at around 20 Hz. rTMS-induced changes might partly counterbalance the plasticity induced by a nerve lesion, and thus substantiate the use of rTMS to treat human pain. However, a mechanistic relation between S1 plasticity and pain-relieving effects is far from being established.

  2. Melanocortin agonists stimulate lipolysis in human adipose tissue explants but not in adipocytes.

    Science.gov (United States)

    Møller, Cathrine Laustrup; Pedersen, Steen B; Richelsen, Bjørn; Conde-Frieboes, Kilian W; Raun, Kirsten; Grove, Kevin L; Wulff, Birgitte Schjellerup

    2015-10-12

    The central melanocortin system is broadly involved in the regulation of mammalian nutrient utilization. However, the function of melanocortin receptors (MCRs) expressed directly in peripheral metabolic tissues is still unclear. The objective of this study was to investigate the lipolytic capacity of MC1-5R in differentiated adipocytes versus intact white adipose tissue. Non-selective MCR agonist α-MSH, MC5R-selective agonist PG-901 and MC4R-selective agonist LY2112688 significantly stimulated lipolysis in intact white adipose tissue, whereas stimulation of MCRs in differentiated adipocytes failed to do so. The lipolytic response of MC5R was decreased in intact human white adipose tissue when co-treating with β-adrenergic antagonist propranolol, suggesting that the effect may be dependent on neuronal innervation via noradrenalin release. When developing an anti-obesity therapeutic drug with selective MC4R/MC5R properties, effects on lipolysis in white adipose tissue may be physiologically relevant.

  3. No Effect of Cathodal Transcranial Direct Current Stimulation on Fear Memory in Healthy Human Subjects

    Directory of Open Access Journals (Sweden)

    Aditya Mungee

    2016-11-01

    Full Text Available Background: Studies have demonstrated that fear memories can be modified using non-invasive methods. Recently, we demonstrated that anodal transcranial direct current stimulation (tDCS of the right dorsolateral prefrontal cortex is capable of enhancing fear memories. Here, we examined the effects of cathodal tDCS of the right dorsolateral prefrontal cortex during fear reconsolidation in humans. Methods: Seventeen young, healthy subjects were randomly assigned to two groups, which underwent fear conditioning with mild electric stimuli paired with a visual stimulus. Twenty-four hours later, both groups were shown a reminder of the conditioned fearful stimulus. Shortly thereafter, they received either tDCS (right prefrontal—cathodal, left supraorbital—anodal for 20 min at 1 mA, or sham stimulation. A day later, fear responses of both groups were compared. Results: On Day 3, during fear response assessment, there were no significant differences between the tDCS and sham group (p > 0.05. Conclusion: We conclude that cathodal tDCS of the right dorsolateral prefrontal cortex (right prefrontal—cathodal, left supraorbital—anodal did not influence fear memories.

  4. Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates

    Science.gov (United States)

    Opitz, Alexander; Falchier, Arnaud; Yan, Chao-Gan; Yeagle, Erin M.; Linn, Gary S.