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Sample records for combined granulocyte-colony stimulating

  1. The combination of stem cell factor and granulocyte-colony stimulating factor for chronic stroke treatment in aged animals

    PubMed Central

    2012-01-01

    Background Stroke occurs more frequently in the elderly population and presents the number one leading cause of persistent disability worldwide. Lack of effective treatment to enhance brain repair and improve functional restoration in chronic stroke, the recovery phase of stroke, is a challenging medical problem to be solved in stroke research. Our early study has revealed the therapeutic effects of stem cell factor (SCF) in combination with granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke in young animals. However, whether this treatment is effective and safe to the aged population remains to be determined. Methods Cortical brain ischemia was produced in aged C57BL mice or aged spontaneously hypertensive rats. SCF+G-CSF or equal volume of vehicle solution was subcutaneously injected for 7 days beginning at 3–4 months after induction of cortical brain ischemia. Using the approaches of biochemistry assays, flow cytometry, pathology, and evaluation of functional outcome, several doses of SCF+G-CSF have been examined for their safety and efficiency on chronic stroke in aged animals. Results All tested doses did not show acute or chronic toxicity in the aged animals. Additionally, SCF+G-CSF treatment in chronic stroke of aged animals mobilized bone marrow stem cells and improved functional outcome in a dose-dependent manner. Conclusions SCF+G-CSF treatment is a safe and effective approach to chronic stroke in the aged condition. This study provides important information needed for developing a new therapeutic strategy to improve the health of older adults with chronic stroke. PMID:23254113

  2. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization

    PubMed Central

    Smith, Veronica R.; Popat, Uday; Ciurea, Stefan; Nieto, Yago; Anderlini, Paolo; Rondon, Gabriela; Alousi, Amin; Qazilbash, Muzaffar; Kebriaei, Partow; Khouri, Issa; de Lima, Marcos; Champlin, Richard; Hosing, Chitra

    2014-01-01

    Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin’s and non-Hodgkin’s) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but 1 patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 106/kilogram of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 106/kilogram of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 106/kilogram of body weight. Plerixafor was well tolerated; no grade 2 or higher non- hematologic toxic effects were observed. PMID:23749720

  3. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization.

    PubMed

    Smith, Veronica R; Popat, Uday; Ciurea, Stefan; Nieto, Yago; Anderlini, Paolo; Rondon, Gabriela; Alousi, Amin; Qazilbash, Muzaffar; Kebriaei, Partow; Khouri, Issa; de Lima, Marcos; Champlin, Richard; Hosing, Chitra

    2013-09-01

    Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but one patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 10(6) /kg of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 10(6) /kg of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 10(6) /kg of body weight. Plerixafor was well tolerated; no grade 2 or higher non-hematologic toxic effects were observed.

  4. Case Report: Combination Therapy with Mesenchymal Stem Cells and Granulocyte-Colony Stimulating Factor in a Case of Spinal Cord Injury

    PubMed Central

    Derakhshanrad, Nazi; Saberi, Hooshang; Tayebi Meybodi, Keyvan; Taghvaei, Mohammad; Arjmand, Babak; Aghayan, Hamid Reza; Kohan, Amir Hassan; Haghpanahi, Mohammad; Rahmani, Shahrokh

    2015-01-01

    Introduction: Various neuroregenerative procedures have been recently employed along with neurorehabilitation programs to promote neurological function after Spinal Cord Injury (SCI), and recently most of them have focused on the acute stage of spinal cord injury. In this report, we present a case of acute SCI treated with neuroprotective treatments in conjunction with conventional rehabilitation program. Methods: A case of acute penetrative SCI (gunshot wound), 40 years old, was treated with intrathecal bone marrow derived stem cells and parenteral Granulocyte-Colony Stimulating Factor (G-CSF) along with rehabilitation program. The neurological outcomes as well as safety issues have been reported. Results: Assessment with American Spinal Injury Association (ASIA), showed neurological improvement, meanwhile he reported neuropathic pain, which was amenable to oral medication. Discussion: In the acute setting, combination therapy of G-CSF and intrathecal Mesenchymal Stem Cells (MSCs) was safe in our case as an adjunct to conventional rehabilitation programs. Further controlled studies are needed to find possible side effects, and establish net efficacy. PMID:26649168

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

    PubMed

    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.

  6. Neuroprotective and Angiogenic Effects of Bone Marrow Transplantation Combined With Granulocyte Colony-Stimulating Factor in a Mouse Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Ohta, Yasuyuki; Nagai, Makiko; Miyazaki, Kazunori; Tanaka, Nobuhito; Kawai, Hiromi; Mimoto, Takafumi; Morimoto, Nobutoshi; Kurata, Tomoko; Ikeda, Yoshio; Matsuura, Tohru; Abe, Koji

    2011-01-01

    Bone marrow (BM) cells from amyotrophic lateral sclerosis (ALS) patients show significantly reduced expression of several neurotrophic factors. Monotherapy with either wild-type (WT) BM transplantation (BMT) or granulocyte colony-stimulating factor (GCSF) has only a small clinical therapeutic effect in an ALS mouse model, due to the phenomenon of neuroprotection. In this study, we investigated the clinical benefits of combination therapy using BMT with WT BM cells, plus GCSF after disease onset in ALS mice [transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation]. Combined treatment with BMT and GCSF delayed disease progression and prolonged the survival of G93A mice, whereas BMT or GCSF treatment alone did not. Histological study of the ventral horns of lumbar cords from G93A mice treated with BMT and GCSF showed a reduction in motor neuron loss coupled with induced neuronal precursor cell proliferation, increased expression of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor and angiogenin), and neovascularization compared with controls (vehicle only). Compared with G93A microglial cells, most BM-derived WT cells differentiated into microglial cells and strongly expressed neurotrophic factors, combined BMT and GCSF treatment led to the replacement of G93A microglial cells with BM-derived WT cells. These results indicate combined treatment with BMT and GCSF has potential neuroprotective and angiogenic effects in ALS mice, induced by the replacement of G93A microglial cells with BM-derived WT cells. Furthermore, this is the first report showing the effects of combined BMT and GCSF treatment on blood vessels in ALS. PMID:26998403

  7. Plerixafor on-demand combined with chemotherapy and granulocyte colony-stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs.

    PubMed

    Milone, Giuseppe; Martino, Massimo; Spadaro, Andrea; Leotta, Salvatore; Di Marco, Annalia; Scalzulli, Potito; Cupri, Alessandra; Di Martina, Valentina; Schinocca, Elena; Spina, Eleonora; Tripepi, Giovanni

    2014-01-01

    To date, no prospective study on Plerixafor 'on-demand' in combination with chemotherapy and granulocyte colony-stimulating factor (G-CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on-demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G-CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34(+) cells in peripheral blood was reduced by 'on-demand' strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34(+) cells 2 × 10(6) /kg decreased from 20·9 to 4·0% (P = 0·0001). The on-demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a 'bias-adjusted set of controls'. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G-CSF, the 'on-demand' use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.

  8. Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

    PubMed Central

    Acosta, Sandra A.; Tajiri, Naoki; Shinozuka, Kazutaka; Ishikawa, Hiroto; Sanberg, Paul R.; Sanchez-Ramos, Juan; Song, Shijie; Kaneko, Yuji; Borlongan, Cesar V.

    2014-01-01

    Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function

  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.

    PubMed

    Balseanu, Adrian Tudor; Buga, Ana-Maria; Catalin, Bogdan; Wagner, Daniel-Christoph; Boltze, Johannes; Zagrean, Ana-Maria; Reymann, Klaus; Schaebitz, Wolf; Popa-Wagner, Aurel

    2014-01-01

    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 (10(6) 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 would have to be

  10. Granulocyte colony-stimulating factor in the treatment of acute radiation syndrome: a concise review.

    PubMed

    Hofer, Michal; Pospíšil, Milan; Komůrková, Denisa; Hoferová, Zuzana

    2014-04-16

    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.

  11. 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.

    PubMed

    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.

  12. 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.

    PubMed

    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.

  13. Granulocyte colony-stimulating factor-based stem cell mobilization in patients with sickle cell disease.

    PubMed

    Rosenbaum, Cara; Peace, David; Rich, Elizabeth; Van Besien, Koen

    2008-06-01

    Granulocyte colony-stimulating factor (G-CSF) has been reported to exacerbate vaso-occlusive crises in sickle cell disease. It has been recommended to avoid its use for stem cell mobilization in this population, yet autologous transplant is the standard of care and at times a life-saving treatment for patients with various hematologic malignancies such as relapsed aggressive lymphoma or multiple myeloma. We report 5 cases of patients with sickle cell disease and related hemoglobinopathies who underwent granulocyte-colony stimulating factor (G-CSF)-mobilization of peripheral blood stem cells (PBSC). Three of them developed manageable vaso-occlusive pain symptoms requiring parenteral narcotics alone. The 2 others had no complications. These cases demonstrate that stem cell mobilization using G-CSF, although complicated and not without risk, is feasible in patients with sickle cell syndromes.

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

    PubMed Central

    Vanz, Ana LS; Renard, Gaby; Palma, Mario S; Chies, Jocelei M; Dalmora, Sérgio L; Basso, Luiz A; Santos, Diógenes S

    2008-01-01

    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 even further for large

  15. Increasing aclarubicin dosage of the conventional CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen is more efficacious as a salvage therapy than CAG for relapsed/refractory acute myeloid leukemia.

    PubMed

    Qu, Qi; Liu, Limin; Zhang, Yanming; Li, Xiaoli; Wu, Depei

    2015-12-01

    The efficacy and safety of a modified CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen with an increased aclarubicin dosage [high-dose (HD)-CAG] were observed in 145 patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and compared to the results of 172 patients treated with a conventional CAG regimen. The HD-CAG regimen showed both a higher complete remission (CR) rate (60.7% vs. 46.5%, P=0.013) and overall response (OR) rate (74.5% vs. 63.4%, P=0.039) than CAG. For patients aged <60 years, HD-CAG manifested an efficacy advantage over the CAG regimen (62.6% vs. 47.4%, P=0.015). The 4-year overall survival (OS) rate was 30.3%±13.2% with a median survival time of 19.0±5.4 months for patients re-induced with the HD-CAG regimen, which showed no significant difference compared to the CAG regimen (with a 4-year OS rate of 18.2%±5.3% and a median survival time of 16.0±3.6 months, P=0.485). The main adverse effect was myelosuppression; platelet recovery over 50×10(9)/L was extended by the HD-CAG regimen (15 days vs. 10 days of the CAG regimen, P=0.003), which was tolerable and manageable. HD-CAG can safely improve efficacy compared to the CAG regimen and thus serves as an alternative treatment for R/R AML.

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

    PubMed Central

    Wallner, Stephanie; Peters, Sebastian; Pitzer, Claudia; Resch, Herbert; Bogdahn, Ulrich; Schneider, Armin

    2015-01-01

    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. PMID:26301221

  17. Combination treatment of biomechanical support and targeted intra-arterial infusion of peripheral blood stem cells mobilized by granulocyte-colony stimulating factor for the osteonecrosis of the femoral head: a randomized controlled clinical trial.

    PubMed

    Mao, Qiang; Wang, Weidong; Xu, Taotao; Zhang, Shanxing; Xiao, Luwei; Chen, Di; Jin, Hongting; Tong, Peijian

    2015-04-01

    The objective of this study was to determine the benefits of combination treatment with mechanical support and targeted intra-arterial infusion of peripheral blood stem cells (PBSCs) mobilized by granulocyte-colony stimulating factor (G-CSF) via the medial circumflex femoral artery on the progression of osteonecrosis of the femoral head (ONFH). Fifty-five patients (89 hips) with early and intermediate stage ONFH were recruited and randomly assigned to combination treatment or mechanical support treatment (control group). All hips received mechanical support treatment (porous tantalum rod implantation). Then, hips in the combination treatment group were performed targeted intra-arterial infusion of PBSCs. At each follow-up, Harris hip score (HHS) and Association Research Circulation Osseous (ARCO) classification were used to evaluate the symptoms and progression of osteonecrosis. Total hip arthroplasty (THA) was assessed as an endpoint at each follow-up. At 36 months, 9 of the 41 hips (21.95%) in the control group progressed to clinical failure and underwent THA whereas only 3 of the 48 hips (6.25%) in the combination treatment group required THA (p = 0.031). Kaplan-Meier survival analysis showed a significant difference in the survival time between the two groups (log-rank test; p = 0.025). Compared to the control group, combination treatment significantly improved the HHS at 36 months (p = 0.003). At the final follow-up examination, radiological progression was noted in 13 of 41 hips (31.71%) for the control group, but in only 4 of 48 hips (8.33%) for the combination treatment group (p = 0.005). The overall collapse rates were 15.15% (5/33 hips) and 8.11% (3/37 hips) in the control and combination treatment groups, respectively. Targeted intra-arterial infusion of PBSCs is capable of enhancing the efficacy of biomechanical support in the treatment of ONFH. This clinical trial confirmed that the combination treatment might be a safe and feasible

  18. The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors.

    PubMed Central

    Hill, C P; Osslund, T D; Eisenberg, D

    1993-01-01

    We have determined the three-dimensional structure of recombinant human granulocyte-colony-stimulating factor by x-ray crystallography. Phases were initially obtained at 3.0-A resolution by multiple isomorphous replacement and were refined by solvent flattening and by averaging of the electron density of the three molecules in the asymmetric unit. The current R factor is 21.5% for all data between 6.0- and 2.2-A resolution. The structure is predominantly helical, with 104 of the 175 residues forming a four-alpha-helix bundle. The only other secondary structure is also helical. In the loop between the first two long helices a four-residue 3(10)-helix is immediately followed by a 6-residue alpha-helix. Three residues in the short connection between the second and third bundle helices form almost one turn of left-handed helix. The up-up-down-down connectivity with two long crossover connections has been reported previously for five other proteins, which like granulocyte-colony-stimulating factor are all signaling ligands: growth hormone, granulocyte/macrophage-colony-stimulating factor, interferon beta, interleukin 2, and interleukin 4. Structural similarity among these growth factors occurs despite the absence of similarity in their amino acid sequences. Conservation of this tertiary structure suggests that these different growth factors might all bind to their respective sequence-related receptors in an equivalent manner. Images Fig. 2 PMID:7685117

  19. Effect of thrombopoietin and granulocyte colony-stimulating factor on platelets and polymorphonuclear leukocytes.

    PubMed

    Schattner, M; Pozner, R G; Gorostizaga, A B; Lazzari, M A

    2000-07-15

    Thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) may be administered together in aplastic patients. We evaluated the effect of both cytokines alone or combined on platelets and polymorphonuclear leukocytes (PMN) functional responses. TPO, G-CSF, or the combination of both cytokines, induced neither platelet nor PMN activation. TPO but not G-CSF synergized with threshold ADP concentrations to induce maximal aggregation and ATP release. The synergistic effect of TPO with ADP was not modified by the presence of G-CSF. Flow cytometry studies have shown that thrombin-induced loss of GPIb from platelet surface was significantly increased by pretreatment of platelets with TPO, G-CSF, or both cytokines. P-selectin expression induced by thrombin was augmented by TPO, but not by G-CSF. Coincubation of the cells with TPO and G-CSF did not modify the values obtained with TPO alone. Expression of CD11b on PMN surface was augmented by G-CSF or fMLP. G-CSF-treated PMN increased the effect of fMLP on CD11b expression. TPO did not modify either basal levels of CD11b or the increased expression induced by G-CSF or fMLP. Incubation of PMN with both cytokines showed no differences compared to G-CSF alone. Platelet-PMN aggregates induced by thrombin in whole blood were augmented by TPO. G-CSF alone neither synergized with thrombin nor changed the results observed with TPO. These data show that in vitro functional responses of platelets, or PMN induced by TPO or G-CSF alone, were neither further increased nor inhibited by treatment of the cells with both cytokines.

  20. In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor

    SciTech Connect

    Cohen, A.M.; Zsebo, K.M.; Inoue, H.; Hines, D.; Boone, T.C.; Chazin, V.R.; Tsai, L.; Ritch, T.; Souza, L.M.

    1987-04-01

    Osmotic pumps containing Escherichia coli-derived recombinant human granulocyte colony-stimulating factor (rhG-CSF) were attached to indwelling jugular vein catheters and implanted subcutaneously into Golden Syrian hamsters. Within 3 days, peripheral granulocyte counts had increased > 10-fold with a concomitant 4-fold increase in total leukocytes. Microscopic examination of Wright-Giemsa-stained blood smears from rhG-CSF hamsters showed that only the neutrophil subpopulation of granulocytes had increased. After subcutaneous injection at /sup 35/S-labeled rhG-CSF doses of up to 10 ..mu..g x kg/sup -1/ x day/sup -1/ only granulocyte counts were affected. However, at higher dose levels, a transient thrombocytopenia was noted. Erythrocyte and lymphocyte/monocyte counts remained unaffected by rhG-CSF over the entire dose range studied. Total leukocyte counts increased 3-fold within 12 hr after a single s.c. injection of rhG-CSF. This early effect was associated with an increase in the total number of colony-forming cells and the percent of active cycling cells in the marrow. A sustained elevation of peripheral leukocyte and marrow progenitor counts was observed following seven daily s.c. injections of rhG-CSF. The ability of rhG-CSF to increase the production and release of granulocytes from the marrow may underlie the beneficial effect it produced on the restoration of peripheral leukocyte counts in hamsters made leukopenic by treatment with 5-fluorouracil.

  1. Expression and purification of canine granulocyte colony-stimulating factor (cG-CSF).

    PubMed

    Yamamoto, Akira; Iwata, Akira; Saito, Toshiki; Watanabe, Fumiko; Ueda, Susumu

    2009-08-15

    Canine granulocyte colony-stimulating factor (cG-CSF) with modification of cysteine at position 17 to serine was expressed in Brevibacillus choshinensis HPD31. cG-CSF secreted into the culture medium was purified by ammonium sulfate precipitation and consecutive column chromatography, using butyl sepharose and DEAE sepharose. Biological activity of the recombinant cG-CSF was 8.0 x 10(6) U/mg protein, as determined by its stimulatory effect on NFS-60 cell proliferation. Purified cG-CSF was subcutaneously administered once a day for two successive days to dogs (1, 5, 25, or 125 microg). Neutrophil count increased the following day in all dogs except those administered the lowest dose (1 microg). No severe side effects were observed in dogs after administration of cG-CSF.

  2. Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony-stimulating factor.

    PubMed

    Hayashi, Haruna; Eguchi, Noriaki; Sumimoto, Kyoku; Matsumoto, Kenta; Azakami, Takahiro; Sumida, Tomonori; Tamura, Tadamasa; Sumii, Masaharu; Uraoka, Naohiro; Shimamoto, Fumio

    2016-08-01

    A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G-CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature.

  3. Successful mobilization of peripheral blood stem cells in children with cancer using plerixafor (Mozobil) and granulocyte-colony stimulating factor.

    PubMed

    Avramova, Boryana E; Yordanova, Maya N; Konstantinov, Dobrin N; Bobev, Dragan G

    2011-01-01

    This paper describes the successful mobilization of peripheral blood stem cells for autologous transplantation in three children with malignant diseases by using plerixafor (Mozobil; Genzyme Corporation, Cambridge, MA) and granulocyte-colony stimulating factor (G-CSF) after failed previous mobilizations. A median sixfold increase in the number of circulating CD34+ cells after plerixafor treatment as compared with the baseline level was observed. An optimal CD34+ cell count for transplantation with one or two leukapheresis sessions was achieved. Mobilization using plerixafor was found to be safe with no adverse events. Therefore, the combination of G-CSF and plerixafor in children results in effective increases in peripheral CD34+ cell counts and reduces the risk of mobilization failure.

  4. Successful mobilization of peripheral blood stem cells in children with cancer using plerixafor (Mozobil™) and granulocyte-colony stimulating factor

    PubMed Central

    Avramova, Boryana E; Yordanova, Maya N; Konstantinov, Dobrin N; Bobev, Dragan G

    2011-01-01

    This paper describes the successful mobilization of peripheral blood stem cells for autologous transplantation in three children with malignant diseases by using plerixafor (Mozobil™; Genzyme Corporation, Cambridge, MA) and granulocyte-colony stimulating factor (G-CSF) after failed previous mobilizations. A median sixfold increase in the number of circulating CD34+ cells after plerixafor treatment as compared with the baseline level was observed. An optimal CD34+ cell count for transplantation with one or two leukapheresis sessions was achieved. Mobilization using plerixafor was found to be safe with no adverse events. Therefore, the combination of G-CSF and plerixafor in children results in effective increases in peripheral CD34+ cell counts and reduces the risk of mobilization failure. PMID:21966213

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

    PubMed

    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 < 0.05) in the 28 dogs treated with rcG-CSF compared to disease-matched dogs not treated with rcG-CSF. In addition, the mean duration of hospitalization was reduced (P = 0.01) in rcG-CSF treated dogs compared to untreated dogs. However, survival times were decreased in dogs treated with rcG-CSF compared to untreated dogs. These results suggest that treatment with rcG-CSF was effective in stimulating neutrophil recovery and shortening the duration of hospitalization in dogs with parvovirus infection, but indicate the need for additional studies to evaluate overall safety of the treatment.

  6. Treatment of leg ischemia with biodegradable gelatin hydrogel microspheres incorporating granulocyte colony-stimulating factor.

    PubMed

    Kawamura, Itta; Takemura, Genzou; Tsujimoto, Akiko; Watanabe, Takatomo; Kanamori, Hiromitsu; Esaki, Masayasu; Kobayashi, Hiroyuki; Takeyama, Toshiaki; Kawaguchi, Tomonori; Goto, Kazuko; Maruyama, Rumi; Fujiwara, Takako; Fujiwara, Hisayoshi; Tabata, Yasuhiko; Minatoguchi, Shinya

    2011-04-01

    Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-μg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.

  7. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor.

    PubMed

    Corey, S J; Dombrosky-Ferlan, P M; Zuo, S; Krohn, E; Donnenberg, A D; Zorich, P; Romero, G; Takata, M; Kurosaki, T

    1998-02-06

    Treatment of cells with granulocyte colony-stimulating factor (G-CSF) leads to tyrosine phosphorylation of cellular proteins. G-CSF stimulates both the activation of protein tyrosine kinases Lyn, Jak1, and Jak2 and the association of these enzymes with the G-CSF receptor. Wild-type, lyn-deficient, and syk-deficient chicken B lymphocyte cell lines were transfected with the human G-CSF receptor, and stable transfectants were studied. G-CSF-dependent tyrosyl phosphorylation of Jak1 and Jak2 occurred in all three cell lines. Wild-type and syk-deficient transfectants responded to G-CSF in a dose-responsive fashion with increased thymidine incorporation, but none of the clones of lyn-deficient transfectants did. Ectopic expression of Lyn, but not that of c-Src, in the lyn-deficient cells restored their mitogenic responsiveness to G-CSF. Ectopic expression in wild-type cells of the kinase-inactive form of Lyn, but not of the kinase-inactive form of Jak2, inhibited thymidine incorporation in response to G-CSF. These studies show that the absence of Lyn results in the loss of mitogenic signaling in the G-CSF signaling pathway and that activation of Jak1 or Jak2 is not sufficient to cause mitogenesis.

  8. Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.

    PubMed

    Lennard Richard, Mara L; Brandon, Danielle; Lou, Ning; Sato, Shuzo; Caldwell, Tomika; Nowling, Tamara K; Gilkeson, Gary; Zhang, Xian K

    2016-10-01

    Fli-1 has emerged as a critical regulator of inflammatory mediators, including MCP-1, CCL5, and IL-6. The cytokine, granulocyte colony stimulating factor (G-CSF) regulates neutrophil precursor maturation and survival, and activates mature neutrophils. Previously, a significant decrease in neutrophil infiltration into the kidneys of Fli-1(+/-) lupus-prone mice was observed. In this study, a significant decrease in G-CSF protein expression was detected in stimulated murine and human endothelial cells when expression of Fli-1 was inhibited. The murine G-CSF promoter contains numerous putative Fli-1 binding sites and several regions within the proximal promoter are significantly enriched for Fli-1 binding. Transient transfection assays indicate that Fli-1 drives transcription from the G-CSF promoter and mutation of the Fli-1 DNA binding domain resulted in a 94% loss of transcriptional activation. Mutation of a known acetylation site, led to a significant increase in G-CSF promoter activation. The histone acetyltransferases p300/CBP and p300/CBP associated factor (PCAF) significantly decrease Fli-1 specific activation of the G-CSF promoter. Thus, acetylation appears to be an important mechanism behind Fli-1 driven activation of the G-CSF promoter. These results further support the theory that Fli-1 plays a major role in the regulation of several inflammatory mediators, ultimately affecting inflammatory disease pathogenesis.

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

    PubMed Central

    Bashir, Shaista; Sadaf, Saima; Ahmad, Sajjad; Akhtar, Muhammad Waheed

    2015-01-01

    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. PMID:26881203

  10. Granulocyte colony-stimulating factor increases the platelet volume in peripheral stem cell apheresis donors.

    PubMed

    Ihara, Akihiro; Matsui, Keiko; Minami, Ryouta; Uchida, Shuzou; Ueda, Shuji; Nishiura, Tetsuo

    2008-01-01

    We investigated the short-term influence of granulocyte colony-stimulating factor (G-CSF) administration on platelet counts and platelet indices in 12 donors (8 males and 4 females; median age 34 years, range 16-49) for peripheral stem cell transplantation using an automated blood cell analyzer. On day 3 (D3) compared with D0, 11 donors with normal laboratory and physical findings showed increases in platelet indices (chi(2) = 12.0, p = 0.0025). Furthermore, mean platelet volume (MPV) was significantly increased (p = 0.04). Also, platelet count decreased, and platelet distribution width and platelet-large cell ratio were increased, but these were not significant. On the contrary, 1 donor with abnormal laboratory findings who had large platelets (MPV 11.4 fl) before G-CSF administration showed decreases in platelet indices (MPV 10.3 fl) on D3, although platelet count (18.2 x 10(4)/microl) decreased after G-CSF administration. G-CSF administration induces an inflammatory process with endothelial cell activation. This is probably the reason why platelet volume increases after G-CSF use. This is the first report showing that G-CSF administration immediately induces increases in large platelets in peripheral stem cell transplant donors before harvest.

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

    PubMed

    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.

  12. The use of granulocyte-colony-stimulating factor in volunteer unrelated hemopoietic stem cell donors.

    PubMed

    Pamphilon, Derwood; Nacheva, Elisabeth; Navarrete, Cristina; Madrigal, Alejandro; Goldman, John

    2008-07-01

    Granulocyte-colony-stimulating factor (G-CSF) is used for the mobilization of hemopoietic stem cells in healthy donors. It has a number of common side effects such as bone pain, which resolve rapidly after administration is discontinued. Recent publications have raised concern that it might act as a trigger for the development of hematologic malignancy in susceptible individuals, possibly by causing genomic instability, but to date there is no evidence that healthy volunteer donors who receive G-CSF are at any increased risk. Ongoing studies aim to confirm whether or not G-CSF can cause chromosomal abnormalities in healthy donors. In the UK, the British Bone Marrow Registry and Anthony Nolan Trust give G-CSF to donors who have agreed to donate peripheral blood stem cells. It is recommended by the UK Registries at present that all stem cell donors are given updated information explaining the current uncertainties with regard to the use of G-CSF before they give informed consent to its administration. This information is based on a statement agreed by the World Marrow Donor Association for use by individual donor registries. Further, it is our current practice that all donors who have received G-CSF, as well as marrow donors who do not, should be under regular review for at least 10 years to allow the occurrence of any long-term adverse events to be documented.

  13. Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinson's Disease.

    PubMed

    Tsai, Sheng-Tzung; Chu, Sung-Chao; Liu, Shu-Hsin; Pang, Cheng-Yoong; Hou, Ting-Wen; Lin, Shinn-Zong; Chen, Shin-Yuan

    2017-03-13

    Parkinson's disease (PD) is a slowly progressive neurodegenerative disease. Both medical and surgical choices provide symptomatic treatment. Granulocyte colony-stimulating factor (G-CSF), a conventional treatment for hematological diseases, has demonstrated its effectiveness in acute and chronic neurological diseases through its anti-inflammatory and antiapoptosis mechanisms. Based on previous in vitro and in vivo studies, we administered a lower dose (3.3 μg/kg) G-CSF injection for 5 days and six courses for 1 year in early-stage PD patients as a phase I trial. The four PD patient's mean unified PD rating scale motor scores in medication off status remained stable from 23 before the first G-CSF injection to 22 during the 2-year follow-up. 3,4-Dihydroxy-6-18F-fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) studies also revealed an annual 3.5% decrease in radiotracer uptake over the caudate nucleus and 7% in the putamen, both slower than those of previous reports of PD. Adverse effects included transient muscular-skeletal pain, nausea, vomiting, and elevated liver enzymes. Based on this preliminary report, G-CSF seems to alleviate disease deterioration for early stage PD patients. The effectiveness of G-CSF was possibly due to its amelioration of progressive dopaminergic neuron degeneration.

  14. Biosimilar granulocyte-colony-stimulating factor for healthy donor stem cell mobilization: need we be afraid?

    PubMed

    Bonig, Halvard; Becker, Petra S; Schwebig, Arnd; Turner, Matthew

    2015-02-01

    Biosimilars are approved biologics with comparable quality, safety, and efficacy to a reference product. Unlike generics, which are chemically manufactured copies of small-molecule drugs with relatively simple chemical structures, the biosimilar designation is applied to drugs that are produced by living organisms, implying much more difficult to control manufacturing and purification procedures. To account for these complexities, the European Medicines Agency (EMA), the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and other regulatory authorities have devised and implemented specific, markedly more demanding pathways for the evaluation and approval of biosimilars. To date, several biosimilars have been approved, including versions of somatropin, erythropoietin, and granulocyte-colony-stimulating factor (G-CSF), and several biosimilar monoclonal antibodies are currently in development. The reference G-CSF product (Neupogen, Amgen) has been used for many years for prevention and treatment of neutropenia and also for mobilization of peripheral blood stem cells (PBSCs). However, concerns have been raised about the safety and efficacy of biosimilar G-CSF during PBSC mobilization procedures, especially in healthy donors. This article reviews the available evidence on the use of biosimilar G-CSF in this setting. Aggregate clinical evidence supports the assessment by the EMA of biosimilar and originator G-CSF as highly biologically similar, with respect to desired and undesired effects.

  15. Adjunctive granulocyte colony-stimulating factor for treatment of septic shock due to melioidosis.

    PubMed

    Cheng, Allen C; Stephens, Dianne P; Anstey, Nicholas M; Currie, Bart J

    2004-01-01

    Melioidosis, caused by the intracellular pathogen Burkholderia pseudomallei, is endemic in northern Australia and Southeast Asia. Risk factors for this infection have also been associated with functional neutrophil defects. Because of this, granulocyte colony-stimulating factor (G-CSF) was adopted for use in patients with septic shock due to melioidosis in December 1998. We compared the mortality rates from before and after the introduction of G-CSF therapy at the Royal Darwin Hospital (Darwin, Australia) during the period of 1989-2002. The mortality rate decreased from 95% to 10% after the introduction of G-CSF. Risk factors, the duration of illness before presentation, and the severity of illness were similar in both groups. A smaller decrease in mortality among patients in the intensive care unit who did not have melioidosis was observed, suggesting that other changes in management did not account for the magnitude of the benefit seen. We conclude that G-CSF may have contributed to the reduction in the mortality rate among patients with septic shock due to melioidosis.

  16. Granulocyte colony-stimulating factor in repeated IVF failure, a randomized trial.

    PubMed

    Aleyasin, Ashraf; Abediasl, Zhila; Nazari, Atefeh; Sheikh, Mahdi

    2016-06-01

    Recent studies have revealed key roles for granulocyte colony-stimulating factor (GCSF) in embryo implantation process and maintenance of pregnancy, and some studies showed promising results by using local intrauterine infusion of GCSF in patients undergoing in vitro fertilization (IVF). This multicenter, randomized, controlled trial included 112 infertile women with repeated IVF failure to evaluate the efficacy of systemic single-dose subcutaneous GCSF administration on IVF success in these women. In this study, the Long Protocol of ovarian stimulation was used for all participants. Sealed, numbered envelopes assigned 56 patients to receive subcutaneous 300 µg GCSF before implantation and 56 in the control group. The implantation (number of gestational sacs on the total number of transferred embryos), chemical pregnancy (positive serum β-HCG), and clinical pregnancy (gestational sac and fetal heart) rates were compared between the two groups. This trial is registered at www.irct.ir (IRCT201503119568N11). The successful implantation (18% vs 7.2%, P=0.007), chemical pregnancy (44.6% vs 19.6%, P=0.005), and clinical pregnancy (37.5% vs 14.3%, P=0.005) rates were significantly higher in the intervention group than in the control group. After adjustment for participants' age, endometrial thickness, good-quality oocyte counts, number of transferred embryos, and anti-Mullerian hormone levels, GCSF treatment remained significantly associated with successful implantation (OR=2.63, 95% CI=1.09-6.96), having chemical pregnancy (OR= 2.74, 95% CI=1.11-7.38) and clinical pregnancy (OR=2.94, 95% CI=1.23-8.33). In conclusion, administration of single-dose systemic subcutaneous GCSF before implantation significantly increases the IVF success, implantation, and pregnancy rates in infertile women with repeated IVF failure.

  17. Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Minyoung; Lee, Chang Geun; Jo, Wol Soon; Kim, Sung Dae; Yang, Kwangmo

    2015-07-01

    Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

  18. Granulocyte colony-stimulating factor receptor expression on human transitional cell carcinoma of the bladder.

    PubMed Central

    Tachibana, M.; Miyakawa, A.; Uchida, A.; Murai, M.; Eguchi, K.; Nakamura, K.; Kubo, A.; Hata, J. I.

    1997-01-01

    Receptors for granulocyte colony-stimulating factor (G-CSFRs) have been confirmed on the cell surfaces of several non-haematopoietic cell types, including bladder cancer cells. This observation has naturally led to the hypothesis that the expression of G-CSFR on these cells may enhance their growth by G-CSF. In this study, the expression of G-CSFR was determined in both established human bladder cancer cell lines and primary bladder cancers. We studied five different human bladder cancer cell lines (KU-1, KU-7, T-24, NBT-2 and KK) and 26 newly diagnosed bladder tumours. G-CSFR mRNA expressions on cultured cell lines were determined using the reverse transcriptase polymerase chain reaction (RT-PCR) method. Furthermore, the G-CSFR binding experiments on the cultured cell lines were conducted using the Na(125)I-labelled G-CSF ligand-binding assay method. Moreover, the G-CSFR mRNA expressions on primary bladder tumour specimens were assessed using the in situ RT-PCR method. Three out of the five cultured cell lines (KU-1, NBT-2 and KK) exhibited G-CSFR mRNA signals when the RT-PCR method was used. The G-CSFR binding experiments showed an equilibrium dissociation constant (K[d]) of 490 pM for KU-1, 340 pM for NBT-2 and 103 pM for KK cells. With in situ RT-PCR, the tumour cells of 6 out of 26 primary bladder tumour specimens (23.1%) presented positive G-CSFR mRNA signals. Thus, in this study, G-CSFR expression was frequently observed on bladder cancer cells. Therefore, the clinical use of G-CSF for patients with bladder cancer should be selected with great care. Images Figure 1 Figure 3 Figure 4 PMID:9166942

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

    PubMed

    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.

  20. 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

    PubMed Central

    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

  1. Adrenaline administration promotes the efficiency of granulocyte colony stimulating factor-mediated hematopoietic stem and progenitor cell mobilization in mice.

    PubMed

    Chen, Chong; Cao, Jiang; Song, Xuguang; Zeng, Lingyu; Li, Zhenyu; Li, Yong; Xu, Kailin

    2013-01-01

    A high dose of granulocyte colony stimulating factor (G-CSF) is widely used to mobilize hematopoietic stem and progenitor cells (HSPC), but G-CSF is relatively inefficient and may cause adverse effects. Recently, adrenaline has been found to play important roles in HSPC mobilization. In this study, we explored whether adrenaline combined with G-CSF could induce HSPC mobilization in a mouse model. Mice were treated with adrenaline and either a high or low dose of G-CSF alone or in combination. Peripheral blood HSPC counts were evaluated by flow cytometry. Levels of bone marrow SDF-1 were measured by ELISA, the transcription of CXCR4 and SDF-1 was measured by real-time RT-PCR, and CXCR4 protein was detected by Western blot. Our results showed that adrenaline alone fails to mobilize HSPCs into the peripheral blood; however, when G-CSF and adrenaline are combined, the WBC counts and percentages of HSPCs are significantly higher compared to those in mice that received G-CSF alone. The combined use of adrenaline and G-CSF not only accelerated HSPC mobilization, but also enabled the efficient mobilization of HSPCs into the peripheral blood at lower doses of G-CSF. Adrenaline/G-CSF treatment also extensively downregulated levels of SDF-1 and CXCR4 in mouse bone marrow. These results demonstrated that adrenaline combined with G-CSF can induce HSPC mobilization by down-regulating the CXCR4/SDF-1 axis, indicating that the use of adrenaline may enable the use of reduced dosages or durations of G-CSF treatment, minimizing G-CSF-associated complications.

  2. Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature.

    PubMed

    Vinzens, Sarah; Zindel, Joel; Zweifel, Martin; Rau, Tilman; Gloor, Beat; Wochner, Annette

    2017-01-01

    We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34.

  3. Survival enhancement and hemopoietic regeneration following radiation exposure: Therapeutic approach using glucan and granulocyte colony-stimulating factor

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M. )

    1990-10-01

    C3H/HeN female mice were exposed to whole-body cobalt-60 radiation and administered soluble glucan (5 mg i.v. at 1 h following exposure), recombinant human granulocyte colony-stimulating factor (G-CSF; 2.5 micrograms/day s.c., days 3-12 following exposure), or both agents. Treatments were evaluated for their ability to enhance hemopoietic regeneration, and to increase survival after radiation-induced myelosuppression. Both glucan and G-CSF enhanced hemopoietic regeneration alone; however, greater effects were observed in mice receiving both agents. For example, on day 17 following a sublethal 6.5-Gy radiation exposure, mice treated with saline, G-CSF, glucan, or both agents, respectively, exhibited 36%, 65%, 50%, and 78% of normal bone marrow cellularity, and 84%, 175%, 152%, and 212% of normal splenic cellularity. At this same time, granulocyte-macrophage colony-forming cell (GM-CFC) values in saline, G-CSF, glucan, or combination-treated mice, respectively, were 9%, 46%, 26%, and 57% of normal bone marrow values, and 57%, 937%, 364%, and 1477% of normal splenic values. Endogenous spleen colony formation was also increased in all treatment groups, with combination-treated mice exhibiting the greatest effects. Likewise, although both glucan and G-CSF alone enhanced survival following an 8-Gy radiation exposure, greatest survival was observed in mice treated with both agents. These studies suggest that glucan, a macrophage activator, can synergize with G-CSF to further accelerate hemopoietic regeneration and increase survival following radiation-induced myelosuppression.

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

    PubMed

    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.

  5. Effect of Granulocyte Colony-Stimulating Factor Immobilized by the Electron-Beam Synthesis Nanotechnology on Reparative Regeneration of Spermatogenous Tissue.

    PubMed

    Borovskaya, T G; Dygai, A M; Shchemerova, Yu A; Kamalova, S I; Mashanova, V A; Vychuzhanina, A V; Poluektova, M E; Madonov, P G; Kinsht, D N; Goldberg, V E

    2016-09-01

    Effectiveness of the granulocyte colony-stimulating factor immobilized by using electronbeam synthesis nanotechnology was investigated on the model of experimental testicular failure caused by the toxic effect on stem spermatogonia. Administration of the drug to experimental paclitaxel-treated animals increased the number of sources of the proliferative pool of spermatogenesis and its productivity. The effectiveness of immobilized granulocyte colony-stimulating factor was based on its ability to stimulate reparative regeneration of the spermatogenic tissue, which manifested in a decrease in spermatogenic layer maturity and increase in the number of microenvironment cells. Effectiveness of the immobilized form of the drug was superior to that of non-immobilized form.

  6. Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL.

    PubMed

    Liu, Xiao-Yun; Gonzalez-Toledo, Maria E; Fagan, Austin; Duan, Wei-Ming; Liu, Yanying; Zhang, Siyuan; Li, Bin; Piao, Chun-Shu; Nelson, Lila; Zhao, Li-Ru

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a Notch3 dominant mutation-induced cerebral small vascular disease, is characterized by progressive degeneration of vascular smooth muscle cells (vSMCs) of small arteries in the brain, leading to recurrent ischemic stroke, vascular dementia and death. To date, no treatment can stop or delay the progression of this disease. Herein, we determined the therapeutic effects of stem cell factor (SCF) in combination with granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in a mouse model of CADASIL carrying the human mutant Notch3 gene. SCF+G-CSF was subcutaneously administered for 5 days and repeated 4 times with 1-4 month intervals. We found through water maze testing that SCF+G-CSF treatment improved cognitive function. SCF+G-CSF also attenuated vSMC degeneration in small arteries, increased cerebral blood vascular density, and inhibited apoptosis in CADASIL mice. We also discovered that loss of cerebral capillary endothelial cells and neural stem cells/neural progenitor cells (NSCs/NPCs) occurred in CADASIL mice. SCF+G-CSF treatment inhibited the CADASIL-induced cell loss in the endothelia and NSCs/NPCs and promoted neurogenesis. In an in vitro model of apoptosis, SCF+G-CSF prevented apoptotic cell death in vSMCs through AKT signaling and by inhibiting caspase-3 activity. These data suggest that SCF+G-CSF restricts the pathological progression of CADASIL. This study offers new insights into developing therapeutic strategies for CADASIL.

  7. Granulocyte colony-stimulating factor (G-CSF) transiently suppresses mitogen-stimulated T-cell proliferative response

    PubMed Central

    Reyes, E; García-Castro, I; Esquivel, F; Hornedo, J; Cortes-Funes, H; Solovera, J; Alvarez-Mon, M

    1999-01-01

    Granulocyte colony-stimulation factor (G-CSF) is a cytokine that selectively promotes growth and maturation of neutrophils and may modulate the cytokine response to inflammatory stimuli. The purpose of this study was to examine the effect of G-CSF on ex vivo peripheral blood mononuclear cell (PBMC) functions. Ten patients with breast cancer were included in a clinical trial in which r-metHuG-CSF was administrered daily for 5 days to mobilize peripheral blood stem cells. Ten healthy women were also included as controls. Our data show that G-CSF treatment induces an increase in peripheral blood leucocyte, neutrophil, lymphocyte and monocyte counts. We have found a modulation in the percentages of CD19+, CD45+CD14+, CD4+CD45RA+ and CD4+CD45RO+ cells in PBMC fractions during G-CSF treatment. We have also found a significant reduction in the proliferative response of PBMC to mitogenic stimulation that reverted 14 days after the fifth and the last dose of G-CSF. Furthermore, it was not associated with significant changes in the pattern of cytokine production. The mechanism of this immunoregulatory effect is probably indirect since G-CSF receptor has not been found in T lymphocytes. This mechanism and its potential clinical applications remain to be elucidated. © 1999 Cancer Research Campaign PMID:10390001

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

    PubMed

    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.

  9. Survival enhancement and hemopoietic regeneration following radiation exposure: therapeutic approach using glucan and granulocyte colony-stimulating factor

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M.

    1990-01-01

    C3H/HeN female mice were exposed to whole-body cobalt-60 radiation and administered soluble glucan (5 mg i.v. at 1 h following exposure), recombinant human granulocyte colony-stimulating factor or both agents. Treatments were evaluated for their ability to enhance hemopoietic regeneration, and to increase survival after radiation-induced myelosuppression. Both glucan and G-CSF enhanced hemopoietic regeneration alone; however, greater effects were observed in mice receiving both agents. For example, on day 17 following a sublethal 6.5-Gy radiation exposure, mice treated with saline, G-CSF, glucan, or both agents, respectively, exhibited 36%, 65%, 50%, and 78% of normal bone marrow cellularity, and 84%, 175%, 152%, and 212% of normal splenic cellularity.

  10. Enhanced activation of B cells in a granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft.

    PubMed

    Tayebi, H; Lapierre, V; Saas, P; Lienard, A; Sutton, L; Milpied, N; Attal, M; Cahn, J Y; Kuentz, M; Blaise, D; Hervé, P; Tiberghien, P; Robinet, E

    2001-09-01

    In a randomized study that compared human leucocyte antigen-identical allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) versus bone marrow (BM) transplantation, the expression of activation markers, CD23, CD25 and CD45RO by B cells, was compared in blood before and after G-CSF mobilization and in PBSC versus BM grafts. The fractions of CD23+ and CD25+ B cells were higher in PBSC than in BM grafts. Moreover, we observed a G-CSF-induced increase in B-cell fractions in blood as well as in PBSC grafts when compared with BM grafts. Such an enhanced B-cell activation could contribute to the accelerated kinetics of immuno-haematological reconstitution, the occurrence of acute haemolysis in the ABO minor incompatibility setting, as well as the increased incidence of chronic graft-versus-host disease observed after PBSC transplantation.

  11. Chronic recurrent multifocal osteomyelitis with Crohn's disease exacerbation and vasculitis after granulocyte colony-stimulating factor therapy.

    PubMed

    Manners, P; Robbins, P

    2000-10-01

    Chronic recurrent multifocal osteomyelitis (CRMO), of unknown etiology, is characterized by recurring non-suppurative lesions of bone in multiple sites, and has been considered to be self-limiting. Reported therapies include prolonged antibiotics, corticosteroids and anti-inflammatory medications. This case is presented to illustrate the following: 1) CRMO may be severe, on-going, and unresponsive to treatment; 2) it may be associated with Crohns' disease; 3) the use of granulocyte colony-stimulating factor (G-CSF) may be associated with severe gastrointestinal vasculitis. A male was treated from ages 11-20 years for CRMO (manifesting as multiple bone lesions), with therapies of variable efficacy (anti-inflammatories, antibiotics, corticosteroids, gammaglobulin and methotrexate). With increasing disruption to his life, a 10-day course of granulocyte colony-stimulating factor (G-CSF) was given with benefit seen on magnetic resonance imaging (MRI). With exacerbation of symptoms one month later, G-CSF was re-commenced but ceased after 3 weeks because of abdominal pain, rectal blood loss, and progression of bone lesions with subsequent removal of portions of ileum, colon and appendix, which showed vasculitis. Months later, a colonoscopy revealed perianastomotic ulcers and continuing gastroenterological ulceration not unlike Crohn's disease. With azathioprine, gut and bone symptoms improved. We conclude that 1) CRMO may adversely affect life for years; 2) proven treatments are unavailable; 3) gastroenterological vasculitis/ Crohn's may be associated with CRMO; 4) MRI is useful for monitoring CRMO; 5) In this patient, G-CSF seemed beneficial initially, but later, vasculitis (possibly Crohn's) manifested, leading to bowel resection; 6) Crohn's disease may have been present for years, masked by corticosteroid, and unmasked by reduction of steroids and use of G-CSF.

  12. Porcine granulocyte-colony stimulating factor (G-CSF) delivered via replication-defective adenovirus induces a sustained increase in circulating peripheral blood neutrophils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of immunomodulators is a promising area for biotherapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease, particularly during periods of peak disease incidence. Cytokines, including granulocyte colony-stimulating factor (G-CSF), are one class of compounds that...

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

    PubMed

    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.

  14. Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) for the intracranial hemorrhage in two dogs: a case report

    PubMed Central

    Kang, M. H.; Park, H. M.

    2016-01-01

    Two dogs with generalized seizures were evaluated. The dogs were diagnosed with traumatic intracranial hemorrhages based on the history, neurological examinations, and magnetic resonance imaging (MRI) of the brain. Treatment was started with oxygen, prednisolone and anticonvulsant agents. No further seizure activity was observed after treatment in both dogs, however cushing reflex was detected in case 1 and a left-sided hemi-paresis was detected in case 2. Further supportive treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) was attempted. No abnormal signs were noted in either of the dogs and no recurrence was noted 16 and 14 months later, in case 1 and 2, respectively. These cases indicate that a combination of rhG-CSF treatment with previous therapy could be used in dogs with traumatic brain injury. PMID:27656233

  15. Efficacy of Intrauterine infusion of granulocyte colony stimulating factor on patients with history of implantation failure: A randomized control trial

    PubMed Central

    Eftekhar, Maryam; Miraj, Sepideh; Farid Mojtahedi, Maryam; Neghab, Nosrat

    2016-01-01

    Background: Although pregnancy rate in in vitro fertilization-embryo transfer (IVF-ET) cycles has been increased over the preceding years, but the majority of IVF-ET cycles still fail. Granulocyte colony stimulating factor (GCSF) is a glycoprotein that stimulates cytokine growth factor and induces immune system which may improve pregnancy rate in women with history of implantation failure. Objective: The aim of this study was to evaluate GCSF ability to improve pregnancy rate in women with history of implantation failure Materials and Methods: 0.5 ml (300 µg/ml) GCSF was infused intrauterine in intervention group. Pregnancy outcomes were assessed based on clinical pregnancy. Results: The mean age of participants was 31.95±4.71 years old. There were no significant differences between demographic characteristics in two groups (p>0.05). The pregnancy outcome in GCSF group was improved significantly (p=0.043). Conclusion: GCSF can improve pregnancy outcome in patients with history of implantation failure. PMID:27981253

  16. Simplified Large-Scale Refolding, Purification, and Characterization of Recombinant Human Granulocyte-Colony Stimulating Factor in Escherichia coli

    PubMed Central

    Kim, Chang Kyu; Lee, Chi Ho; Lee, Seung-Bae; Oh, Jae-Wook

    2013-01-01

    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) 2nd 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. PMID:24224041

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

    PubMed Central

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

    2015-01-01

    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 white blood cell (WBC) loss, 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 white blood cell (WBC), specifically neutrophil, loss 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 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. PMID:25909052

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    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

  20. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

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

    PubMed

    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.

  2. Soluble complement receptor 1 is increased in patients with leukemia and after administration of granulocyte colony-stimulating factor.

    PubMed

    Sadallah, S; Lach, E; Schwarz, S; Gratwohl, A; Spertini, O; Schifferli, J A

    1999-01-01

    Complement receptor type 1 is expressed by erythrocytes and most leukocytes. A soluble form is shed from the leukocytes and found in plasma (sCR1). sCR1 is a powerful inhibitor of complement. We report an increased sCR1 in the plasma of leukemia patients, up to levels producing measurable complement inhibition. Half of the 180 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) had sCR1 levels above the normal range. The highest levels were observed in T-ALL (17 patients). The complement function of a T-ALL serum was improved by blocking sCR1 with a specific mAb (3D9). Measurements in 16 peripheral stein cell donors before and after granulocyte colony-stimulating factor (G-CSF) administration showed an increase in sCR1 (before, 43.8+/-15.4; at day 5, 118.3+/-44.7 ng/mL; P < 0.0001). This increase paralleled the increase in total leukocyte counts and was concomitant with de novo leukocyte mRNA CR1 expression in all three individuals tested. Whether pharmacological intervention may be used to up-regulate sCR1 so as to inhibit complement in vivo should be further investigated.

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

    PubMed Central

    Minagawa, Tomohiro; Tabata, Yasuhiko; Oyama, Akihiko; Furukawa, Hiroshi; Yamao, Takeshi; Yamamoto, Yuhei

    2014-01-01

    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. PMID:24829581

  4. Efficient Process Development of Recombinant Human Granulocyte Colony-Stimulating Factor (rh-GCSF) Production in Escherichia coli

    PubMed Central

    Babaeipour, Valiollah; Khanchezar, Sirwan; Mofid, Mohammad Reza; Pesaran Hagi Abbas, Mahdi

    2015-01-01

    Background: The protein hormone granulocyte colony-stimulating factor (GCSF) stimulates the production of white blood cells and plays an important role in medical treatment of cancer patients. Methods: An efficient process was developed for heterologous expression of the human GCSF in E. coli BL21 (DE3). The feeding rate was adjusted to achieve the maximum attainable specific growth rate under critical value. In this method, specific growth rate was maintained at the maximum value of 0.55 h-1 at the beginning of feeding to 0.4 h-1 at the induction time. Recombinant human GCSF (rh-GCSF) was produced as inclusion body. At first, inclusion bodies were released by cell disruption and then washed, solubilized and refolded. Finally, the rh-GCSF was purified by cation exchange chromatography. Results: Obviouly, higher specific growth rate decreases process time and consequently increases productivity. The final concentration of biomass and GCSF was achieved 126 g DCW.l-1 and 32.1 g.l-1. Also, the final specific yield (YP/X) and total productivity of rh-GCSF were obtained 254 mg.g-1 DCW and 1.83 g.l-1.h-1, respectively. According to the available data, this is one of the highest YP/X and productivity that has been reported for any human protein which is expressed in E. coli. Recovery yield of purification process was %40 and purity of recombinant protein was over than 99%. The circular dichroism spectra of purified rh-GCSF, Neupogen® and PD-Grastim showed that all proteins have a similar secondary structure. Conclusion: Modified exponential feeding strategy for fed-batch cultivation of recombinant E. coli, results in minimum fed-batch duration and maximum productivity. PMID:25864815

  5. Identification and characterization of receptors for granulocyte colony-stimulating factor on human placenta and trophoblastic cells

    SciTech Connect

    Uzumaki, Hiroya; Okabe, Tetsuro; Sasaki, Norio; Hagiwara, Koichi; Takaku, Fumimaro; Tobita, Masahito; Yasukawa, Kaoru ); Ito, Seiga ); Umezawa, Yoshimi )

    1989-12-01

    Since radioiodination of human granulocyte colony-stimulating factor (G-CSF) is difficult, the authors synthesized a mutein of human G-CSF that retains full biological activity and receptor-binding capacity for at least 2 weeks after radioiodination. Receptors for human G-CSF were characterized in the plasma membrane fraction from the human term placenta (human placental membranes) and trophoblastic cells by using the {sup 125}I-labeled mutein of human G-CSF (KW-2228). The specific binding of {sup 125}I-labeled KW-2228 to placental membranes was pH-dependent, with maximal specific binding at pH 7.8; it increased linearly with protein to 3.7 mg of protein per ml and was both time- and temperature-dependent, with maximal binding at 4{degree}C after a 24-hr incubation. When the authors examined the ability of hematopoietic growth factors to inhibit {sup 125}I-labeled KW-2228 binding, they found that KW-2228 and intact human G-CSF ihibited {sup 125}I-labeled KW-2228 binding, whereas erythropoietin or granulocyte-macrophage colony-stimulating factor did not. Scatchard analysis revealed a single receptor type. The human G-CSF receptors on human placental membranes were shown to consist of two molecular species that could be specifically cross-linked to {sup 125}I-labeled KW-2228. Human trophoblastic cells, T3M-3, also possessed a single receptor for G-CSF. They have identified the receptor for human G-CSF on human placental membranes and trophoblastic cells.

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

    PubMed

    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.

  7. Granulocyte-Colony Stimulating Factor (G-CSF) for stroke: an individual patient data meta-analysis

    PubMed Central

    England, Timothy J.; Sprigg, Nikola; Alasheev, Andrey M.; Belkin, Andrey A.; Kumar, Amit; Prasad, Kameshwar; Bath, Philip M.

    2016-01-01

    Granulocyte colony stimulating factor (G-CSF) may enhance recovery from stroke through neuroprotective mechanisms if administered early, or neurorepair if given later. Several small trials suggest administration is safe but effects on efficacy are unclear. We searched for randomised controlled trials (RCT) assessing G-CSF in patients with hyperacute, acute, subacute or chronic stroke, and asked Investigators to share individual patient data on baseline characteristics, stroke severity and type, end-of-trial modified Rankin Scale (mRS), Barthel Index, haematological parameters, serious adverse events and death. Multiple variable analyses were adjusted for age, sex, baseline severity and time-to-treatment. Individual patient data were obtained for 6 of 10 RCTs comprising 196 stroke patients (116 G-CSF, 80 placebo), mean age 67.1 (SD 12.9), 92% ischaemic, median NIHSS 10 (IQR 5–15), randomised 11 days (interquartile range IQR 4–238) post ictus; data from three commercial trials were not shared. G-CSF did not improve mRS (ordinal regression), odds ratio OR 1.12 (95% confidence interval 0.64 to 1.96, p = 0.62). There were more patients with a serious adverse event in the G-CSF group (29.6% versus 7.5%, p = 0.07) with no significant difference in all-cause mortality (G-CSF 11.2%, placebo 7.6%, p = 0.4). Overall, G-CSF did not improve stroke outcome in this individual patient data meta-analysis. PMID:27845349

  8. Herbal medicine "sho-saiko-to" induces in vitro granulocyte colony-stimulating factor production on peripheral blood mononuclear cells.

    PubMed

    Yamashiki, M; Asakawa, M; Kayaba, Y; Kosaka, Y; Nishimura, A

    1992-01-01

    The herbal medicine "Sho-saiko-to (Xiao-Chai-Hu-Tang)" has been used in China for about 3000 years for the treatment of pyretic diseases. This medicine is now available as one of the prescribing drugs approved by the Ministry of Health and Welfare of Japan, and has also been widely used for patients with chronic viral liver disease as one of biological response modifiers in the field of Japan's Western Medicine. However, its mode of action has not been fully described. In the present in vitro study, we added "Sho-saiko-to" (TJ-9, Tsumura, Tokyo) to the culture of peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers, and observed a dose-dependent increase in the production of granulocyte colony-stimulating factor (G-CSF). The same experiment was conducted using other herbal medicines "Dai-saiko-to" (TJ-8) and "Saiko-keishi-to" (TJ-10) which showed similar effects, or "Sho-seiryu-to" (TJ-19) which consists of very different compounds and shows different efficacy. The increases of G-CSF production were similar when "Sho-saiko-to" (TJ-9) or one of the 2 reference drugs (TJ-8 and 10) was added, whereas the increase when the control drug "Sho-seiryu-to" (TJ-19) was added, was quite small. This result shows that G-CSF induction is not a common effect of herbal medicines, but a specific effect of TJ-8, 9, and 10. Among these 3 drugs the increase produced by "Sho-saiko-to" was the largest. Based on this result, we conclude that administration of "Sho-saiko-to" may be useful not only for the treatment of chronic liver disease, but also for malignant diseases and acute infectious diseases where G-CSF is efficacious.

  9. Biweekly docetaxel and vinorelbine with granulocyte colony-stimulating factor support for patients with anthracycline-resistant metastatic breast cancer.

    PubMed

    Gómez-Bernal, Amalia; Cruz, Juan Jesús; Olaverri, Amaya; Arizcun, Alberto; Martín, Teresa; Rodríguez, Cesar A; Martín, Germán; Fonseca, Emilio; Sánchez, Pedro

    2005-01-01

    This phase II trial evaluated the efficacy and toxicity of vinorelbine 25 mg/m2 plus docetaxel 60 mg2/m administered on day 1, every 2 weeks with granulocyte colony-stimulating factor support (G-CSF, 5 microg/kg/day, days 3-7) as primary prophylaxis in patients with histologically confirmed metastatic breast cancer (MBC) and previously treated with anthracyclines in the adjuvant or in the first-line setting. A total of 48 patients received 352 cycles (median 8, range 2-10). All patients were included in the efficacy and safety evaluation on an intent-to-treat analysis. Eight patients (17%) showed a complete response and 14 patients (29%) showed a partial response. Overall response rate was 46% [95% confidence interval (CI) 33-60]. The median duration of response was 10.0 months. With a median follow-up of 18.0 months, the median time to progression was 11.9 months and the median overall survival was 27.1 months. The most frequently reported grade 3/4 hematological toxicity was neutropenia (19% of patients, 4% of cycles). Febrile neutropenia was reported in six patients (13%) and 7 cycles (2%), but no toxic deaths were reported. The most common grade 3/4 non-hematological toxicity was asthenia (17% of patients, 6% of cycles) and nail toxicity (15% of patients, 3% of cycles). In conclusion, biweekly docetaxel plus vinorelbine with G-CSF support is active and well tolerated as chemotherapy for patients with MBC resistant to anthracyclines. G-CSF support is recommended for lowering the incidence and severity of neutropenia and febrile neutropenia.

  10. Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

    PubMed

    Shaked, Yuval; Tang, Terence; Woloszynek, Jill; Daenen, Laura G; Man, Shan; Xu, Ping; Cai, Shi-Rong; Arbeit, Jeffrey M; Voest, Emile E; Chaplin, David J; Smythe, Jon; Harris, Adrian; Nathan, Paul; Judson, Ian; Rustin, Gordon; Bertolini, Francesco; Link, Daniel C; Kerbel, Robert S

    2009-10-01

    Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

  11. Granulocyte colony-stimulating factor-producing pancreatic anaplastic carcinoma in ascitic fluid at initial diagnosis: A case report.

    PubMed

    Kubota, Nao; Naito, Yoshiki; Kawahara, Akihiko; Taira, Tomoki; Yamaguchi, Tomohiko; Yoshida, Tomoko; Abe, Hideyuki; Takase, Yorihiko; Fukumitsu, Chihiro; Murata, Kazuya; Ishida, Yusuke; Okabe, Yoshinobu; Kimura, Yoshizo; Tanigawa, Masahiko; Mihara, Yutaro; Nakayama, Masamichi; Yamaguchi, Rin; Akiba, Jun; Yano, Hirohisa

    2017-02-10

    Granulocyte colony-stimulating factor (G-CSF)-producing pancreatic tumors are extremely rare. These tumors have an aggressive clinical course and no established treatment. Here, we report an autopsy case of G-CSF-production in pancreatic anaplastic carcinoma (PAC). A 72-year-old woman presented with a large pancreatic head mass and multiple liver metastases. Laboratory data showed leukocytosis (leukocyte count 113.3 × 10(3) /µL) and high serum G-CSF levels (441 pg/mL; normal range: <39.0 pg/mL). The ascitic fluid was submitted to our pathology laboratory at initial diagnosis. Cytopathology showed that smears from the ascitic fluid were highly cellular and contained numerous malignant cells, mainly in loose groupings. Occasional pseudoglandular formations and giant cells were also present. The malignant cells were round, and no spindle-shaped cells were visible. The nuclei were round to ovoid with coarsely granular chromatin and large prominent nucleoli. Upon immunocytochemistry, tumor cells were positive for G-CSF and vimentin; there was no E-cadherin expression. Histopathological examination of the tumor showed a mixed composition of adenocarcinomatous and sarcomatous regions. Upon immunohistochemistry, both components were positive for G-CSF. Few CD34-positive myeloblasts were observed in the bone marrow. Thus, we diagnosed this as a case of G-CSF production in PAC with leukocytosis. To the best of our knowledge, this is the first report on G-CSF expression immunocytochemically confirmed in PAC. Diagn. Cytopathol. © 2017 Wiley Periodicals, Inc.

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

    PubMed

    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.

  13. Granulocyte-colony stimulating factor improves Parkinson's disease associated with co-morbid depression: An experimental exploratory study

    PubMed Central

    Prakash, Ajay; Chopra, Kanwaljit; Medhi, Bikash

    2013-01-01

    Introduction: The present study was designed to evaluate the effect of granulocyte-colony stimulating factor (G-CSF) in the treatment of Parkinson's disease (PD), the second most common neurodegenerative disease characterized by muscle and movement disorder, often associated with depression. PD is very difficult to treat. Hence, the present study was aimed to evaluate the effect of G-CSF in PD associated with depression. Materials and Methods: Adult Wistar male rats weighing about 180-250 g were selected and divided into five groups in parallel designed method namely; control group (n = 5); sham operated group (n = 5); Vehicle group (n = 5); G-CSF group (70 μg/kg, s.c.) (n = 5) and L-DOPA group (n = 5). The rats were treated with 6-hydroxydopamine (6-OHDA) on day 0 and then treatment was continued for 14 day of L-DOPA/carbidopa, whereas G-CSF (70 μg/kg, s.c.) was given from day 1 to 6. Thereafter, adhesive removal and forced swim tests were conducted to evaluate the behavioral outcome of G-CSF treatment. The finding was correlated and analyzed with Nissl staining findings for the final conclusion. Results: The behavioral parameters were assessed and found to be ameliorate the symptoms of Parkinson's and reduced the depression like behavior in PD. The histological findings were supported the behavioral findings and showed pathological improvement. Conclusion: As a preliminary work, the present study first time suggested that G-CSF have a potential role in PD and associated depression. PMID:24347771

  14. Drugs elevating extracellular adenosine promote regeneration of haematopoietic progenitor cells in severely myelosuppressed mice: their comparison and joint effects with the granulocyte colony-stimulating factor.

    PubMed

    Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Vacek, Antonín; Weiterova, Lenka; Holá, Jirina; Vácha, Jirí

    2002-01-01

    We tested capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF) given alone or in combination to modulate regeneration from severe myelosuppression resulting from combined exposure of mice to ionizing radiation and carboplatin. Elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), serving as an adenosine prodrug. DP+AMP, G-CSF or all these drugs in combination were administered in a 4-d treatment regimen starting on day 3 after induction of myelosuppression. Comparable enhancements of haematopoietic regeneration due to elevation of extracellular adenosine or to action of G-CSF were demonstrated as shown by elevated numbers of haematopoietic progenitor cells for granulocytes/macrophages (GM-CFC) and erythrocytes (BFU-E) in the bone marrow and spleen in early time intervals after termination of the drug treatment, i.e. on days 7 and 10 after induction of myelosuppression. Coadministration of all the drugs further potentiated the restoration of progenitor cell pools in the haematopoietic organs. The effects of the drug treatments on progenitor cells were reflected in the peripheral blood in later time intervals of days 15 and 20 after induction of myelosuppression, especially as significantly elevated numbers of granulocytes and less pronounced elevation of lymphocytes and erythrocytes. The results substantiate the potential of drugs elevating extracellular adenosine for clinical utilization in myelosuppressive states, e.g. those accompanying oncological radio- and chemotherapy.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

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

    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. PMID:16937499

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

    PubMed Central

    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

  19. Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice

    PubMed Central

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

    2014-01-01

    Abstract 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. PMID:25222508

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

    PubMed

    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

  1. Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson's disease.

    PubMed

    Frank, Tobias; Klinker, Florian; Falkenburger, Björn H; Laage, Rico; Lühder, Fred; Göricke, Bettina; Schneider, Armin; Neurath, Hartmud; Desel, Herbert; Liebetanz, David; Bähr, Mathias; Weishaupt, Jochen H

    2012-06-01

    Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.

  2. Lipopolysaccharide-binding protein (LBP) blockade augments the protective effect of granulocyte colony-stimulating factor (G-CSF) in a rat sepsis model.

    PubMed

    Liu, Anding; Weiss, Stefanie; Fang, Haoshu; Claus, Ralf A; Rödel, Jürgen; Dirsch, Olaf; Dahmen, Uta

    2015-05-01

    The effect of granulocyte colony-stimulating factor (G-CSF) on sepsis is discussed controversially in clinical studies. We previously demonstrated that G-CSF treatment induced lipopolysaccharide (LPS) sensitization via up-regulation of LPS-binding protein (LBP). We hypothesized that the futile effect of G-CSF-treatment in sepsis might be due to its ability to up-regulate LBP. Therefore, blockade of LBP may attenuate the G-CSF-induced LPS sensitization and protect animals from polymicrobial sepsis. Endogenous LBP levels were up-regulated by pretreatment with G-CSF, and the LBP protein was blocked by administration of a specific blocking peptide-LBPK95A. Polymicrobial sepsis was induced by intraperitoneal injection of feces slurry. Rats were monitored every 3 up to 72 h to observe the survival rate. Tissue injury, bacterial infiltration, local inflammatory response, and neutrophil infiltration at 0, 2, and 12 h after the septic insult were analyzed. The survival benefit of G-CSF pretreatment was improved when combined with LBPK95A treatment (control vs. G-CSF vs. combi: 36% vs. 56% vs. 93%; P < 0.05). Combined treatment of G-CSF and LBPK95A was associated with the minimal tissue damage. Treatment with LBPK95A significantly inhibited the neutrophil infiltration without interfering with the bacterial clearance. The G-CSF-induced inflammatory sensitization effect was inhibited by LBPK95A, indicated by the decrease of cytokines expression, and the activation of nuclear factor kappa B and signal transducer and activator of transcription 3 signaling pathway. In conclusion, these results suggested that the effect of prophylactic augmentation of the host's response via G-CSF pretreatment was further enhanced by inhibition of the up-regulation of LBP.

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

    PubMed

    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.

  4. Platelet lysate and granulocyte-colony stimulating factor serve safe and accelerated expansion of human bone marrow stromal cells for stroke therapy.

    PubMed

    Yamauchi, Tomohiro; Saito, Hisayasu; Ito, Masaki; Shichinohe, Hideo; Houkin, Kiyohiro; Kuroda, Satoshi

    2014-12-01

    Autologous human bone marrow stromal cells (hBMSCs) should be expanded in the animal serum-free condition within clinically relevant periods in order to secure safe and effective cell therapy for ischemic stroke. This study was aimed to assess whether the hBMSCs enhance their proliferation capacity and provide beneficial effect in the infarct brain when cultured with platelet lysate (PL) and granulocyte-colony stimulating factor (G-CSF). The hBMSCs were cultured in the fetal calf serum (FCS)-, PL-, or PL/G-CSF-containing medium. Cell growth kinetics was analyzed. The hBMSCs-PL, hBMSC-PL/G-CSF, or vehicle was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. As the results, the hBMSCs-PL/G-CSF showed more enhanced proliferation than the hBMSCs-FCS and hBMSCs-PL. Transplantation of hBMSCs expanded with the PL- or PL/G-CSF-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the hBMSCs-PL and hBMSCs-PL/G-CSF. These findings strongly suggest that the combination of PL and G-CSF may accelerate hBMSC expansion and serve safe cell therapy for patients with ischemic stroke at clinically relevant timing.

  5. 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

    PubMed Central

    Eid, Kátia Aparecida de Brito; Miranda, Eliana Cristina Martins; Aguiar, Simone dos Santos

    2015-01-01

    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. PMID:26041417

  6. Granulocyte-Colony-Stimulating Factor Stimulation of Bone Marrow Mesenchymal Stromal Cells Promotes CD34+ Cell Migration Via a Matrix Metalloproteinase-2-Dependent Mechanism

    PubMed Central

    Ponte, Adriana López; Ribeiro-Fleury, Tatiana; Chabot, Valérie; Gouilleux, Fabrice; Langonné, Alain; Hérault, Olivier; Charbord, Pierre

    2012-01-01

    Human hematopoietic stem/progenitor cells (HSPCs) can be mobilized into the circulation using granulocyte-colony stimulating factor (G-CSF), for graft collection in view of hematopoietic transplantation. This process has been related to bone marrow (BM) release of serine proteases and of the matrix metalloproteinase-9 (MMP-9). Yet, the role of these mediators in HSC egress from their niches remains questionable, because they are produced by nonstromal cells (mainly neutrophils and monocytes/macrophages) that are not a part of the niche. We show here that the G-CSF receptor (G-CSFR) is expressed by human BM mesenchymal stromal/stem cells (MSCs), and that G-CSF prestimulation of MSCs enhances the in vitro trans-stromal migration of CD34+ cells. Zymography analysis indicates that pro-MMP-2 (but not pro-MMP-9) is expressed in MSCs, and that G-CSF treatment increases its expression and induces its activation at the cell membrane. We further demonstrate that G-CSF-stimulated migration depends on G-CSFR expression and is mediated by a mechanism that involves MMPs. These results suggest a molecular model whereby G-CSF infusion may drive, by the direct action on MSCs, HSPC egress from BM niches via synthesis and activation of MMPs. In this model, MMP-2 instead of MMP-9 is implicated, which constitutes a major difference with mouse mobilization models. PMID:22651889

  7. Granulocyte colony stimulating factor (G-CSF) can allow treatment with clozapine in a patient with severe benign ethnic neutropaenia (BEN): a case report.

    PubMed

    Spencer, Benjamin W J; Williams, Hugh R J; Gee, Siobhan H; Whiskey, Eromona; Rodrigues, Joseph P; Mijovic, Aleksandar; MacCabe, James H

    2012-09-01

    Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

  8. Dissociation of LPS-induced monocytic ex vivo production of granulocyte colony-stimulating factor (G-CSF) and TNF-alpha in patients with septic shock.

    PubMed

    Weiss, M; Fischer, G; Barth, E; Boneberg, E; Schneider, E M; Georgieff, M; Hartung, T

    2001-01-07

    Over a 6 month period, in 192 patients admitted to the intensive care unit (ICU), a longitudinal analysis of whole blood lipopolysaccharide (LPS)-induced ex vivo cytokine production was performed on a daily basis until discharge from the ICU or death. Twenty-one patients with proven infections were in septic shock for the first time and for at least 3 days' duration. Ex vivo LPS-inducible release of granulocyte colony-stimulating factor (G-CSF) was upregulated and that of TNF-alpha was downregulated in patients with septic shock, regardless whether they survived or died. In conclusion, LPS-induced ex vivo TNF-alpha and G-CSF cytokine release by monocytes is regulated differentially in patients with septic shock. Since upregulation of LPS-induced production of G-CSF occurred earlier in survivors than in non-survivors, rapidly elevated and sustained G-CSF responsiveness may contribute to survival in septic shock.

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

    PubMed

    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.

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

    PubMed

    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

  11. Randomized Prospective Controlled Trial of Recombinant Granulocyte Colony-Stimulating Factor as Adjunctive Therapy for Limb-Threatening Diabetic Foot Infection

    PubMed Central

    de Lalla, Fausto; Pellizzer, Giampietro; Strazzabosco, Marco; Martini, Zeno; Du Jardin, Giovanni; Lora, Luciano; Fabris, Paolo; Benedetti, Paolo; Erle, Giuseppe

    2001-01-01

    Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 μg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had

  12. An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve

    PubMed Central

    Liao, Ming-Feng; Yeh, Shin-Rung; Lo, Ai-Lun; Chao, Po-Kuan; Lee, Yun-Lin; Hung, Yu-Hui; Lu, Kwok-Tung; Ro, Long-Sun

    2016-01-01

    Several studies have shown that the mu opioid receptor (MOR) located in the peripheral nerves can be activated after nerve injury and that it attenuates peripheral nociceptive signals to the spinal dorsal horn. Various cytokines and phosphorylated-p38 (p-p38) activation in the dorsal horn also play an important role in neuropathic pain development. Granulocyte-colony stimulating factor (GCSF) is a growth factor that can stimulate granulocyte formation and has been shown to exert an analgesic effect on neuropathic pain through recruiting opioid-containing leukocytes to the injured nerve. However, the underlying mechanisms are not well understood. Herein, the results of behavior tests in addition to MOR levels in the injured sciatic nerve and the levels of p-p38 and various cytokines in the spinal dorsal horn were studied in vehicle-treated or GCSF-treated chronic constriction injured (CCI) rats at different time points (i.e., 1, 3, and 7 days, respectively) after nerve injury. The results showed that a single early systemic GCSF treatment after nerve injury can up-regulate MORs in the injured nerve, which can decrease peripheral nociceptive signals. Thereafter, those changes suppress the pro-inflammatory cytokine IL-6 but enhance the anti-inflammatory cytokine IL-4, followed by decreases in p-p38 in the dorsal horn, and thus further attenuate neuropathic pain. PMID:27180600

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

    PubMed

    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.

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

    PubMed Central

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    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. PMID:26146654

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

    PubMed

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    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-N(G)-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.

  16. Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization.

    PubMed

    Li, Sidan; Li, Tianshou; Chen, Yongbing; Nie, Yinchao; Li, Changhong; Liu, Lanting; Li, Qiaochuan; Qiu, Lugui

    2015-08-01

    In the bone marrow (BM), hematopoietic stem and progenitor cells (HSPCs) reside in specialized niches near osteoblast cells at the endosteum. HSPCs that egress to peripheral blood are widely used for transplant, and mobilization is most commonly performed with recombinant human granulocyte colony-stimulating factor (G-CSF). However, the cellular targets of G-CSF that initiate the mobilization cascade and bone remodeling are not completely understood. Here, we examined whether T and B lymphocytes modulate the bone niche and influence HSPC mobilization. We used T and B defective mice to show that G-CSF-induced mobilization of HSPCs correlated with B lymphocytes but poorly with T lymphocytes. In addition, we found that defective B lymphocytes prevent G-CSF-mediated osteoblast disruption, and further study showed BM osteoblasts were reduced coincident with mobilization, induced by elevated expression of dickkopf1 of BM B lymphocytes. BM T cells were also involved in G-CSF-induced osteoclast activation by regulating the Receptor Activator of Nuclear Factor-κ B Ligand/Osteoprotegerin (RANKL/OPG) axis. These data provide evidence that BM B and T lymphocytes play a role in G-CSF-induced HSPC mobilization by regulating bone remodeling.

  17. Low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus idarubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia.

    PubMed

    Jin, Jie; Chen, Jian; Suo, Shanshan; Qian, Wenbin; Meng, Haitao; Mai, Wenyuan; Tong, Hongyan; Huang, Jian; Yu, Wenjuan; Wei, Juyin; Lou, Yinjun

    2015-06-01

    With limited data available on the low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) regimen in newly diagnosed older patients with acute myeloid leukemia (AML), this study aimed at comparing the efficacy and toxicity of CAG with idarubicin plus cytarabine (IA) remission induction therapy in these patients. A total of 154 consecutive patients (52 with CAG and 102 with IA) were retrospectively analyzed. The patients in the CAG group had a higher median age (68 vs. 65 years, p = 0.002) and a higher proportion of previous myelodysplastic syndrome (25.0% vs. 2.9%, p < 0.0001) compared to those in the IA group. The complete remission rates with the CAG and IA regimens were 55.8% and 52.9% (p = 0.864). The median overall survival (12.1 vs. 11.7 months, p = 0.650) and 3-year disease-free survival rates (29.6% vs. 48.6%, p = 0.657) were not statistically different in the two groups. The CAG regimen might be an alternative to conventional chemotherapy in older patients with AML.

  18. Granulocyte colony-stimulating factor (G-CSF): A saturated fatty acid-induced myokine with insulin-desensitizing properties in humans

    PubMed Central

    Ordelheide, Anna-Maria; Gommer, Nadja; Böhm, Anja; Hermann, Carina; Thielker, Inga; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

    2016-01-01

    Objective Circulating long-chain free fatty acids (FFAs) are important metabolic signals that acutely enhance fatty acid oxidation, thermogenesis, energy expenditure, and insulin secretion. However, if chronically elevated, they provoke inflammation, insulin resistance, and β-cell failure. Moreover, FFAs act via multiple signaling pathways as very potent regulators of gene expression. In human skeletal muscle cells differentiated in vitro (myotubes), we have shown in previous studies that the expression of CSF3, the gene encoding granulocyte colony-stimulating factor (G-CSF), is markedly induced upon FFA treatment and exercise. Methods and results We now report that CSF3 is induced in human myotubes by saturated, but not unsaturated, FFAs via Toll-like receptor 4-dependent and -independent pathways including activation of Rel-A, AP-1, C/EBPα, Src, and stress kinases. Furthermore, we show that human adipocytes and myotubes treated with G-CSF become insulin-resistant. In line with this, a functional polymorphism in the CSF3 gene affects adipose tissue- and whole-body insulin sensitivity and glucose tolerance in human subjects with elevated plasma FFA concentrations. Conclusion G-CSF emerges as a new player in FFA-induced insulin resistance and thus may be of interest as a target for prevention and treatment of type 2 diabetes. PMID:27069870

  19. Effect of Periodic Granulocyte Colony-Stimulating Factor Administration on Endothelial Progenitor Cells and Different Monocyte Subsets in Pediatric Patients with Muscular Dystrophies

    PubMed Central

    Sienkiewicz, Dorota; Grubczak, Kamil; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Miklasz, Paula; Singh, Paulina; Radzikowska, Urszula; Kulak, Wojciech

    2016-01-01

    Muscular dystrophies (MD) are heterogeneous group of diseases characterized by progressive muscle dysfunction. There is a large body of evidence indicating that angiogenesis is impaired in muscles of MD patients. Therefore, induction of dystrophic muscle revascularization should become a novel approach aimed at diminishing the extent of myocyte damage. Recently, we and others demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) resulted in clinical improvement of patients with neuromuscular disorders. To date, however, the exact mechanisms underlying these beneficial effects of G-CSF have not been fully understood. Here we used flow cytometry to quantitate numbers of CD34+ cells, endothelial progenitor cells, and different monocyte subsets in peripheral blood of pediatric MD patients treated with repetitive courses of G-CSF administration. We showed that repetitive cycles of G-CSF administration induced efficient mobilization of above-mentioned cells including cells with proangiogenic potential. These findings contribute to better understanding the beneficial clinical effects of G-CSF in pediatric MD patients. PMID:26770204

  20. Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M.

    1990-01-01

    The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8 Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF (1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, (2) enhances survival after potentially lethal irradiation and (3) is most effective when initiated 1 h following exposure.

  1. Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Solberg, B.D.; Souza, L.M. )

    1990-03-01

    The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF (2.5 micrograms/day, s.c.) or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity, and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8 Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF (1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, (2) enhances survival after potentially lethal irradiation and (3) is most effective when initiated 1 h following exposure.

  2. Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6.

    PubMed Central

    Rose, T M; Bruce, A G

    1991-01-01

    Oncostatin M (OSM), a glycoprotein of Mr approximately 28,000 produced by activated monocyte and T-lymphocyte cell lines, was previously identified by its ability to inhibit the growth of cells from melanoma and other solid tumors. We have detected significant similarities in the primary amino acid sequences and predicted secondary structures of OSM, leukemia-inhibitory factor (LIF), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). Analysis of the genes encoding these proteins revealed a shared exon organization, suggesting evolutionary descent from a common ancestral gene. Using a panel of DNAs from somatic cell hybrids, we have shown that OSM, like LIF, is located on human chromosome 22. We have also demonstrated that OSM has the ability to inhibit the proliferation of murine M1 myeloid leukemic cells and can induce their differentiation into macrophage-like cells, a function shared by LIF, G-CSF, and IL-6. We propose that OSM, LIF, G-CSF, and IL-6 are structurally related members of a cytokine family that have in common the ability to modulate differentiation of a variety of cell types. Images PMID:1717982

  3. Severe Hypoxemia in a Healthy Donor for Allogeneic Hematopoietic Stem Cell Transplantation after Only the First Administration of Granulocyte-Colony Stimulating Factor

    PubMed Central

    Yamamoto, Keita; Doki, Noriko; Senoo, Yasushi; Najima, Yuho; Kobayashi, Takeshi; Kakihana, Kazuhiko; Haraguchi, Kyoko; Okuyama, Yoshiki; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-01-01

    Background Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) in healthy donors. A few reports have shown that some healthy donors developed acute respiratory distress syndrome or capillary leak syndrome after more than several rounds of G-CSF administration or leukapheresis. Case Report We report the case of a healthy donor for allogeneic stem cell transplantation who developed severe hypoxemia 1 h after only the first administration of G-CSF. The donor was administered 10 μg/kg G-CSF (lenograstim) subcutaneously for PBSC mobilization. 1 h after the first administration of G-CSF, the donor suddenly presented with dry cough and dyspnea. The oxygen saturation by pulse oximetry (SpO2) in the room air was 88%. An electrocardiogram and chest radiography revealed no abnormalities. We excluded other causes of severe hypoxemia and diagnosed the donor with hypoxemia due to G-CSF administration, which was subsequently terminated. The donor was administered 2 l/min oxygen via a nasal cannula and 100 mg hydrocortisone intravenously. He subsequently recovered, and SpO2 in the room air returned to 98% 10 h after hypoxemia. Conclusion These respiratory symptoms might be related to anaphylactoid or hypersensitivity reaction. The donors should be observed for at least 1 h after the first administration of G-CSF. PMID:27994532

  4. Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain--results of the LEARN Study.

    PubMed

    Almenar, D; Mayans, J; Juan, O; Bueno, J M Garcia; Lopez, J I Jalon; Frau, A; Guinot, M; Cerezuela, P; Buscalla, E Garcia; Gasquet, J A; Sanchez, J

    2009-05-01

    Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice.

  5. Immunomodulation of Bu-Zhong-Yi-Qi-Tang on in vitro granulocyte colony-stimulating-factor and tumor necrosis factor-alpha production by peripheral blood mononuclear cells.

    PubMed

    Kao, S T; Yang, S L; Hsieh, C C; Yang, M D; Wang, T F; Lin, J G

    2000-11-01

    Bu-Zhong-Yi-Qi-Tang (BZYQT) is a Chinese medicine, and has been used for the treatment of hepatocellular carcinoma (HCC) patients. At present, we still do not fully understand the effects of BZYQT on the cellular physiology. Present in vitro study demonstrated that BZYQT is capable of increasing granulocyte colony-stimulating-factor (G-CSF) and tumor necrosis factor-alpha (TNF-alpha) production by peripheral blood mononuclear cells (PBMC) in healthy volunteers and patients with HCC. The productions of G-CSF and TNF-alpha by PBMC of volunteers were significantly stimulated by more than 125 microg/ml of BZYQT. G-CSF levels stimulated by PBMC of healthy volunteers were higher than in PBMC of the HCC patients when more than 625 microg/ml of BZYQT was administrated. The reason may be due to the impaired immunologic reactivity of mononuclear cells in HCC patients. However, the production levels of TNF-alpha in HCC patients can be stimulated to levels as high as those in healthy volunteers. When adding high concentration (3.125 mg/ml) of BZYQT to the cultured PBMC, the increments of G-CSF and TNF-alpha production decreased although there were no obvious changes in the number of metabolic active PBMC changed. TNF-alpha andG-CSF are known to play important roles in the biological defensive mechanism. These findings show that BZYQT is a unique formula for the stimulation of PBMC to produce G-CSF and TNF-alpha. Administration of BZYQT may be beneficial for patients with HCC to modulate these cytokines.

  6. Efficacy of LL-37 and granulocyte colony-stimulating factor in a neutropenic murine sepsis due to Pseudomonas aeruginosa.

    PubMed

    Cirioni, Oscar; Ghiselli, Roberto; Tomasinsig, Linda; Orlando, Fiorenza; Silvestri, Carmela; Skerlavaj, Barbara; Riva, Alessandra; Rocchi, Marco; Saba, Vittorio; Zanetti, Margherita; Scalise, Giorgio; Giacometti, Andrea

    2008-10-01

    A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

    Objective 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. Methods 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. Results 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. Conclusion 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. PMID:28090464

  9. Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains

    PubMed Central

    1990-01-01

    We report the isolation from a placental library, of two cDNAs that can encode high affinity receptors for granulocyte colony-stimulating factor (G-CSF) when expressed in COS-7 cells. The cDNAs are predicted to encode integral membrane proteins of 759 and 812 amino acids in length. The predicted extracellular and membrane spanning sequences of the two clones are identical, as are the first 96 amino acids of their respective cytoplasmic regions. Different COOH termini of 34 or 87 residues are predicted for the two cDNAs, due apparently to alternate splicing. The receptor with the longer cytoplasmic domain is the closest human homologue of the murine G-CSF receptor recently described by Fukunaga et al. (Fukunaga, R., E. Ishizaka-Ikeda, Y. Seto, and S. Nagata. 1990. Cell. 61:341). A hybridization probe derived from the placental G-CSF receptor cDNA detects a approximately 3-kb transcript in RNAs isolated from placenta and a number of lymphoid and myeloid cells. The extracellular region of the G-CSF receptors is composed of four distinct types of structural domains, previously recognized in other cell surface proteins. In addition to the two domains of the HP receptor family-defining region (Patthy, L. 1990. Cell. 61:13) it incorporates one NH2-terminal Ig-like domain, and three additional repeats of fibronectin type III-like domains. The presence of both an NH2-terminal Ig-like domain and multiple membrane-proximal FN3-like domains suggests that the G-CSF receptor may be derived from an ancestral NCAM-like molecule and that the G-CSF receptor may function in some adhesion or recognition events at the cell surface in addition to the binding of G-CSF. PMID:2147944

  10. Development of a colon delivery capsule and the pharmacological activity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in beagle dogs.

    PubMed

    Takaya, T; Ikeda, C; Imagawa, N; Niwa, K; Takada, K

    1995-06-01

    A peroral dosage form was examined to deliver recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the colon in beagle dogs. A new gelatin capsule with its inside surface coated with ethylcellulose was prepared for this purpose. RhG-CSF was dissolved with propylene glycol and was filled in the capsule. Several kinds of ethylcellulose-gelatin capsules with an ethylcellulose layer of thickness 46 to 221 mm were used. The capsule was filled with propylene glycol solution containing fluorescein as an absorption marker, castor oil derivative and citric acid. The hardness of the capsule was tested after the gelatin layer was dissolved using a hardness tester and was dependent on the thickness of the ethylcellulose layer of the capsule. The time, Tmax, at which plasma fluorescein level reaches its maximum following oral administration of ethylcellulose capsules was used as a parameter for the in-vivo disintegration time of the ethylcellulose capsule into the colon. Capsules of thickness 84 mm with a Tmax of 4-6 h were filled with rhG-CSF solution containing fluorescein and were administered to dogs. After administration, blood samples were collected for 96 h and the blood total leucocyte (BTL) counts were measured as a pharmacological index of rhG-CSF. The maximum BTL count appeared at 10 h then gradually decreased and returned to its normal level at 48 h. These results suggest the usefulness of ethylcellulose capsules for the delivery of rhG-CSF to the colon and the possibility of a new oral rhG-CSF dosage form has been elucidated.

  11. Crystallization of a 2:2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor

    SciTech Connect

    Honjo, Eijiro; Tamada, Taro; Maeda, Yoshitake; Koshiba, Takumi; Matsukura, Yasuko; Okamoto, Tomoyuki; Ishibashi, Matsujiro; Tokunaga, Masao; Kuroki, Ryota

    2005-08-01

    A 2:2 complex of highly purified GCSF receptor (Ig-CRH) with GCSF was crystallized. The crystal diffracted to 2.8 Å resolution with sufficient quality for further structure determination. The granulocyte-colony stimulating factor (GCSF) receptor receives signals for regulating the maturation, proliferation and differentiation of the precursor cells of neutrophilic granulocytes. The signalling complex composed of two GCSFs (GCSF, 19 kDa) and two GCSF receptors (GCSFR, 34 kDa) consisting of an Ig-like domain and a cytokine-receptor homologous (CRH) domain was crystallized. A crystal of the complex was grown in 1.0 M sodium formate and 0.1 M sodium acetate pH 4.6 and belongs to space group P4{sub 1}2{sub 1}2 (or its enantiomorph P4{sub 3}2{sub 1}2), with unit-cell parameters a = b = 110.1, c = 331.8 Å. Unfortunately, this crystal form did not diffract beyond 5 Å resolution. Since the heterogeneity of GCSF receptor appeared to prevent the growth of good-quality crystals, the GCSF receptor was fractionated by anion-exchange chromatography. Crystals of the GCSF–fractionated GCSF receptor complex were grown as a new crystal form in 0.2 M ammonium phosphate. This new crystal form diffracted to beyond 3.0 Å resolution and belonged to space group P3{sub 1}21 (or its enantiomorph P3{sub 2}21), with unit-cell parameters a = b = 134.8, c = 105.7 Å.

  12. The effect of ammonia on the O-linked glycosylation of granulocyte colony-stimulating factor produced by chinese hamster ovary cells

    SciTech Connect

    Andersen, D.C.; Goochee, C.F.

    1995-07-05

    Ammonium ion concentrations ranging from 0 to 10 mM are shown to significantly reduce the sialylation of granulocyte colony-stimulating factor (G-CSF) produced by recombinant Chinese hamster ovary cells. Specifically, the degree of completion of the final reaction in the O-linked glycosylation pathway, the addition of sialic acid in an {alpha}(2,6) linkage to N-acetylgalactosamine, is reduced by NH{sub 4}{sup +} concentrations of as low as 2 mM. The effect of ammonia on sialylation is rapid, sustained, and does not affect the secretion rate of G-CSF. Additionally, the effect can be mimicked using the weak base chloroquine, suggesting that the effect is related to the weak base characteristics of ammonia. In support of this hypothesis, experiments using brefeldin A suggest that the addition of sialic acid in an {alpha}(2,6) linkage to N-acetylgalactosamine occurs in the trans-Golgi compartment prior to the trans-Golgi network, which would be expected under normal conditions to have a slightly acidic pH in the range from 6.5 to 6.75. Ammonium ion concentrations of 10mM would be expected to reduce significantly the differences in pH between acidic intracellular compartments and the cytoplasm. The pH-activity profile for the CHO O-linked {alpha}(2,6)sialytransferase using monosialylated G-CSF as a substrate reveals a twofold decrease in enzymatic activity across the pH range from 6.75 to 7.0. Mathematical modeling of this sialylation reaction supports the hypothesis that this twofold decrease in sialyltransferase activity resulting from an ammonia-induced increase in trans-Golgi pH could produce the observed decrease in G-CSF sialylation.

  13. Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure

    PubMed Central

    Krivokrysenko, Vadim I.; Shakhov, Alexander N.; Singh, Vijay K.; Bone, Frederick; Kononov, Yevgeniy; Shyshynova, Inna; Cheney, Alec; Maitra, Ratan K.; Purmal, Andrei; Whitnall, Mark H.; Feinstein, Elena

    2012-01-01

    Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure. PMID:22837010

  14. Low-dose granulocyte colony-stimulating factor overcomes neutropenia in the treatment of non-Hodgkin's lymphoma with higher cost-effectiveness.

    PubMed

    Hara, Takeshi; Tsurumi, Hisashi; Kasahara, Senji; Kanemura, Nobuhiro; Yoshikawa, Takeshi; Goto, Naoe; Kojima, Yasushi; Yamada, Toshiki; Sawada, Michio; Takahashi, Takeshi; Oyama, Masami; Tomita, Eiichi; Moriwaki, Hisataka

    2005-12-01

    To facilitate more economical medical care, we carried out a prospective study of whether a THP-COP regimen (cyclophosphamide, pirarubicin, vincristine, and prednisolone) with low-dose granulocyte colony-stimulating factor (G-CSF) would effectively treat non-Hodgkin's lymphoma (NHL). From April 2003 through March 2004, we enrolled 19 consecutive patients with newly diagnosed NHL treated at our hospital. The patients were divided into young and elderly groups. Each patient underwent chemotherapy with 8 courses of a THP-COP regimen with a 50-microg dose of lenograstim. Age- and sex-matched historical control patients (n = 141) received NHL diagnoses between 1998 and 2003. Each patient in the control group underwent the same chemotherapy and received a 100-microg dose of lenograstim. The mean (+/-SD) total amounts of G-CSF per cycle of chemotherapy were 332 +/- 103 microg (young patients) and 345 +/- 128 microg (elderly patients) in the low-dose group and 594 +/- 439 microg (young) and 730 +/- 551 microg (elderly) in the control group. The duration of fever in 1 cycle of chemotherapy was 0.3 +/- 1.0 days (young) and 0.1 +/- 0.8 days (elderly) in the low-dose group and 0.5 +/- 1.3 days (young) and 0.8 +/- 2.0 days (elderly) in the control group. A THP-COP regimen with low-dose G-CSF could be administered to NHL patients with safety. Administration of a 50-microg dose of lenograstim is sufficient and recommended for the treatment of NHL.

  15. G(AnH)MTetra, a naturally occurring 1,6-anhydro muramyl dipeptide, induces granulocyte colony-stimulating factor expression in human monocytes: a molecular analysis.

    PubMed Central

    Dokter, W H; Dijkstra, A J; Koopmans, S B; Mulder, A B; Stulp, B K; Halie, M R; Keck, W; Vellenga, E

    1994-01-01

    N-Acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D-isoglutam yl-m- diaminopimelyl-D-alanine [G (Anh)MTetra], a naturally occurring breakdown product of peptidoglycan from bacterial cell walls, was studied for its ability to induce granulocyte colony-stimulating factor (G-CSF) mRNA and protein expression in human adherent monocytes. Resting monocytes did not express G-CSF mRNA or secrete G-CSF protein. In contrast, monocytes exposed to G(Anh)MTetra showed a dose-dependent increase in G-CSF mRNA accumulation, which correlates with the secretion of G-CSF protein. Maximal levels of G-CSF mRNA were reached within 2 h of activation. Expression of G-CSF was mediated by an increase in the stability of G-CSF transcripts rather than by an increase in the transcription rate of the G-CSF gene. Experiments with the protein synthesis inhibitor cycloheximide revealed that G(Anh)MTetra-induced G-CSF mRNA expression was independent of new protein synthesis. Furthermore, it was shown that the effect of G(Anh)MTetra was regulated by a protein kinase C-dependent pathway, whereas protein kinase A and tyrosine kinases were not involved. Finally, it was shown that G(Anh)MTetra also induced G-CSF mRNA expression in human endothelial cells. The data indicate that, besides lipopolysaccharide, other naturally occurring bacterial cell wall components are able to induce G-CSF expression in different hematopoietic cells. Images PMID:7516314

  16. Attitudes of physicians toward assessing risk and using granulocyte colony-stimulating factor as primary prophylaxis in patients receiving chemotherapy associated with an intermediate risk of febrile neutropenia.

    PubMed

    Freyer, Gilles; Kalinka-Warzocha, Ewa; Syrigos, Konstantinos; Marinca, Mihai; Tonini, Giuseppe; Ng, Say Liang; Wong, Zee Wan; Salar, Antonio; Steger, Guenther; Abdelsalam, Mahmoud; DeCosta, Lucy; Szabo, Zsolt

    2015-10-01

    Febrile neutropenia (FN) is a potentially fatal complication of chemotherapy. This prospective, observational study describes physicians' approaches toward assessing FN risk in patients receiving chemotherapy regimens with an intermediate (10-20 %) FN risk. In the baseline investigator assessment, physicians selected factors considered important when assessing overall FN risk and deciding on granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (PP). Physicians then completed patient assessments using the same lists of factors. The final FN risk scores and whether G-CSF PP was planned were reported. The final analysis included 165 physicians and 944 patients. The most frequently considered factor in both assessments was chemotherapy agents in the backbone (88 % of investigator and 93 % of patient assessments). History of FN (83 %), baseline laboratory values (76 %) and age (73 %) were commonly selected at baseline, whereas tumor type (72 %), guidelines (62 %) and tumor stage (43 %) were selected most during patient assessments. Median investigator-reported FN risk threshold for G-CSF PP was 20 % (range 10-85 %). G-CSF PP was planned in 82 % of patients with an FN risk at or above this threshold; therefore, almost one-fifth of qualifying patients would not receive G-CSF PP. Physicians generally follow guidelines, but also consider individual patient characteristics when assessing FN risk and deciding on G-CSF PP. A standardized FN risk assessment may optimize the use of G-CSF PP, which may minimize the incidence of FN in patients undergoing chemotherapy with an intermediate FN risk. ClinicalTrials.gov Identifier: NCT01813721.

  17. Incidence of chemotherapy-induced neutropenia and current practice of prophylaxis with granulocyte colony-stimulating factors in cancer patients in Spain: a prospective, observational study.

    PubMed

    Jolis, L; Carabantes, F; Pernas, S; Cantos, B; López, A; Torres, P; Funes, C; Caballero, D; Benedit, P; Salar, A

    2013-07-01

    We aimed to describe the incidence of neutropenia in breast cancer and lymphoma patients and granulocyte colony-stimulating factors (G-CSF) use in clinical practice. We conducted a multicentre, prospective, observational study including breast cancer and lymphoma patients initiating chemotherapy (≥ 10% febrile neutropenia risk). We included 734 patients with breast cancer and 291 with lymphoma. Over the first four chemotherapy cycles, patients had an incidence of 11.0% grade 3-4 neutropenia (absolute neutrophil count <1.0 × 10(9) /L) and 4.3% febrile neutropenia (absolute neutrophil count <0.5 × 10(9) /L and fever ≥ 38 °C) in the breast cancer cohort, and 40.5% and 14.8% in the lymphoma cohort. Full dose on schedule (>85% of planned chemotherapy dose and ≤ 3 days delay) was achieved by 85.6% of breast cancer and 68.9% of lymphoma patients. Hospitalisation due to febrile neutropenia was required in 2.0% and 12.0% of breast cancer and lymphoma patients respectively. G-CSF was administered to 70.0% of breast cancer and 83.8% of lymphoma patients, and initiated from the first chemotherapy cycle (primary prophylaxis) in 60.6% and 64.2% of cases. Severe neutropenia affects approximately one in 10 breast cancer patients and one in two lymphoma patients receiving chemotherapy with moderate or greater risk of febrile neutropenia. Most patients received treatment with G-CSF in Spanish clinical practice.

  18. Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

    PubMed Central

    Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

    2015-01-01

    TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

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

    PubMed

    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.

  20. Relationship between native-state solubility and non-native aggregation of recombinant human granulocyte colony stimulating factor: practical implications for protein therapeutic development.

    PubMed

    Banks, Douglas D; Zhang, Jun; Siska, Christine C

    2014-10-06

    Prescreening methods are needed in the biotechnology industry for rapid selection of protein therapeutic candidates and formulations of low aggregation propensity. In recent reports solubility measurements have shown promise as one such method, although the connection between protein solubility and non-native aggregation is not well understood. In the present investigation, recombinant human granulocyte colony stimulating factor (rhGCSF) was used to explore this relationship since it was previously shown to rapidly undergo non-native aggregation/precipitation under physiological conditions in a reaction attenuated by the addition of sucrose [Krishnan, S.; et al. Biochemistry 2002, 41, 6422-6431]. Strong correlations were found between rhGCSF non-native aggregation and both solubility and thermal stability as a function of sucrose concentration. We believe these results make sense in the context of an rhGCSF aggregation mechanism where loss of monomer to insoluble aggregate is limited by association to an observable dimer from a less soluble (and aggregation competent) intermediate species that exists in a temperature sensitive pre-equilibrium with the native monomer. Both solubility and measures of conformational stability report on the position of this equilibrium and therefore the concentration of reactive intermediate. Interestingly, aggregation also correlated with rhGCSF solubility as a function of salting-in concentrations of phosphate since both are dependent on the colloidal stability of the reactive intermediate but not with conformational stability. In lieu of a complete understanding of the aggregation processes that limit protein therapeutic shelf life, these results highlight the potential of using simple solubility measurements as an additional tool in the biotechnology prescreening repertoire.

  1. Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor.

    PubMed

    Ono, Masafumi; Yu, Bi; Hardison, Edith G; Mastrangelo, Mary-Ann A; Tweardy, David J

    2004-06-01

    Chronic ethanol use preceding severe trauma and hemorrhagic shock (HS) is associated with an increased incidence of multiorgan failure (MOF) and death; however, the molecular basis for this increased susceptibility is unknown. We previously demonstrated that production of interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), mediated by nuclear factor-kappa B (NF-kappa B), each make essential contributions to organ injury and inflammation in a rodent model of controlled HS, and we proposed in this study to examine the hypothesis that the increased susceptibility to MOF after shock/trauma in the setting of chronic ethanol use is due to an exaggerated activation of NF-kappa B and production of these proinflammatory cytokines. We observed increased HS-induced liver injury 4 h after resuscitation in rats fed the ethanol-containing Lieber-DeCarli liquid diet for 8 weeks compared with rats fed the control liquid diet (3-fold increase in serum alanine aminotransferase [ALT], P = 0.008, and 2-fold increase in focal liver necrosis, P = 0.005). The increased liver injury in the ethanol-fed HS rats was accompanied by a 70% increase in liver NF-kappa B activation (P < 0.05), a 3- to 5-fold increase in hepatocyte and Kupffer cell production of IL-6 and G-CSF (P < 0.05 for each), and a 2-fold increase in neutrophil infiltration (P < 0.005) compared with the control diet-fed HS rats. Thus, increased susceptibility to HS-induced liver injury in the setting of chronic ethanol use may be mediated, at least in part, by increased NF-kappa B activation resulting in increased local production of IL-6 and G-CSF and increased infiltration of neutrophils, which can damage liver cells directly and contribute to impaired sinusoidal blood flow.

  2. Acute exposure to cadmium induces prolonged neutrophilia along with delayed induction of granulocyte colony-stimulating factor in the livers of mice.

    PubMed

    Horiguchi, Hyogo; Oguma, Etsuko

    2016-12-01

    Acute exposure to cadmium (Cd), a toxic heavy metal, causes systemic inflammation characterized by neutrophilia. To elucidate the mechanism of neutrophilia induced by Cd, we investigated the induction of granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production, in mice with acute Cd toxicity, and compared it with mice injected with lipopolysaccharide (LPS) as an inducer of general inflammatory responses. We injected BALB/c mice with Cd at 2.5 mg/kg i.p. or LPS at 0.5 mg/kg i.p. and sampled the peripheral blood and organs at time points up to 24 h. In Cd-treated mice, the peripheral neutrophil count increased steadily up to 24 h, whereas LPS-treated mice showed a more rapid increase with a peak at 12 h. The serum G-CSF level increased gradually to reach a plateau at 12-18 h in Cd-treated mice, but LPS-treated mice showed a marked increase, reaching a peak at 2-3 h. A gradual elevation of G-CSF mRNA expression up to 24 h was detected by real-time PCR in the livers of Cd-treated mice, but in LPS-treated mice its highest expression was observed in the liver with a rapid increase at 2 h. By in situ hybridization using G-CSF RNA probes, hepatic Kupffer cells were identified as G-CSF-producing cells in the liver. These results indicated that Cd has a characteristic effect of delayed induction of G-CSF in the liver, causing systemic inflammation accompanied by prolonged neutrophilia.

  3. 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.

    PubMed

    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.

  4. Effects of recombinant human granulocyte colony-stimulating factor on central and peripheral T lymphocyte reconstitution after sublethal irradiation in mice

    PubMed Central

    Zhao, Hongxia; Guo, Mei; Sun, Xuedong; Sun, Wanjun; Hu, Hailan; Wei, Li; Ai, Huisheng

    2013-01-01

    Granulocyte colony-stimulating factor (G-CSF) is one of the most critical cytokines used for the treatment of acute radiation syndrome (ARS). In addition to the hematopoietic effects of G-CSF on the differentiation and proliferation of myeloid progenitor cells, G-CSF is also known to have immunomodulatory effects. The aim of the present study was to investigate whether G-CSF could accelerate central and peripheral T lymphocyte recovery after a sublethal dose of irradiation. Female BALB/c mice were subjected to 6 Gy of total body irradiation and then were treated with either 100 μg/kg G-CSF or an equal volume of PBS once daily for 14 days. Percentages of thymocyte subpopulations including CD4 − CD8 − , CD4 + CD8 + , CD4 + CD8− and CD4 − CD8+ T cells, peripheral CD3 + , CD4+ and CD8+ cells were analyzed by flow cytometry. Recent thymic emigrants (RTEs) were assessed by real-time polymerase chain reaction (PCR) using primers specific to the 257-bp T cell receptor rearrangement excision circles (sjTRECs). The proliferative capacity of splenic mononuclear cells upon exposure to ConA was measured by using the Cell Count Kit-8 (CCK-8). G-CSF treatment promoted thymocyte regeneration, accelerated the recovery of CD4 + CD8+ cells and increased the frequency of thymocyte sjTRECs. These effects were more prominent at early time points (Day 28) after irradiation. G-CSF also increased the rate of recovery of peripheral CD3 + , CD4+ and CD8+ cells and shortened the period of severe lymphopenia following irradiation. G-CSF also increased the splenic mononuclear cell mitotic responsiveness to ConA more than control-treated cells. Our results show that G-CSF accelerates T cell recovery through both thymic-dependent and thymic-independent pathways, which could be used to increase the rate of immune reconstitution after sublethal irradiation. PMID:23001765

  5. Increased presence of anti-HLA antibodies early after allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cell transplantation compared with bone marrow transplantation.

    PubMed

    Lapierre, Valérie; Aupérin, Anne; Tayebi, Hakim; Chabod, Jacqueline; Saas, Philippe; Michalet, Mauricette; François, Sylvie; Garban, Frédéric; Giraud, Christine; Tramalloni, Dominique; Oubouzar, Nadia; Blaise, Didier; Kuentz, Matthieu; Robinet, Eric; Tiberghien, Pierre

    2002-08-15

    We have recently shown that the use of allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood hematopoietic stem cell transplantation (PBHSCT), as compared with bone marrow transplantation (BMT), is associated with increased titers of antibodies (Abs) directed against red blood cell ABO antigens. To further evaluate the influence of a G-CSF-mobilized PBHSCT graft on alloimmune Ab responses, we examined the frequency of anti-HLA Abs after transplantation in the setting of the same randomized study, comparing PBHSCT with BMT in adults. Anti-HLA Ab presence was determined by complement-dependent cytotoxicity assay (CDC) and flow cytometry in the recipient before and 30 days after transplantation as well as in the donor before graft donation. The use of PBHSCT was significantly associated with increased detection of anti-HLA immunoglobulin G (IgG) Abs early after transplantation as evidenced by flow cytometry (11 of 24 versus 4 of 27 transplant recipients, P =.03) and, less so, by CDC (5 of 24 versus 1 of 27 transplant recipients, P =.09). The difference between PBHSCT and BMT was further heightened when analysis was restricted to anti-HLA IgG Ab-negative donor/recipient pairs. In such a setting, early anti-HLA Ab was never detected after BMT but was repeatedly detected after PBHSCT (flow cytometry, 6 of 18 versus 0 of 17 transplant recipients, P =.02; CDC, 4 of 23 versus 0 of 26 transplant recipients, P =.04). Importantly, the PBHSCT-associated increase in anti-HLA Ab detection was observed despite a reduction in the median number of platelet-transfusion episodes per patient in PBHSC transplant versus BM transplant recipients (3 platelet-transfusion episodes [range, 1-21] in PBHSCT group vs 6 platelet-transfusion episodes [range, 3-33] in the BMT group; P =.02). In conclusion, this study strongly suggests that G-CSF-mobilized PBHSCT results in an increased incidence of circulating anti-HLA Abs and further confirms that the use of such a

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

    PubMed

    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.

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

    PubMed Central

    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

  8. The pros and cons of split-dose granulocyte colony-stimulating factor alone rather than a single high dose for hematopoietic progenitor cell mobilization in small children (< 15 kg) with solid tumors.

    PubMed

    Merlin, Etienne; Piguet, Christophe; Auvrignon, Anne; Rubie, Hervé; Deméocq, François; Kanold, Justyna

    2006-07-01

    Hematopoietic progenitor cells were mobilized in 34 children with solid tumors weighing < or = 15 kg using granulocyte colony-stimulating factor alone at the doses of 10, 20 or 2 x 12 microg/kg/day. The mobilization with 2 x 12 microg/kg/day was more efficient than that with 10 mg/kg/day. Although the superiority of the split-dose compared to the single, high daily dose (20 microg/kg/day) was not statistically significant, our results suggest that the 2 x 12 microg/kg/day regimen is interesting.

  9. Transfusion-related acute lung injury (TRALI) induced by donor-derived anti-HLA antibodies in aplastic anemia: possible priming effect of granulocyte-colony stimulating factor (G-CSF) on the recipient neutrophils.

    PubMed

    Hishizawa, Masakatsu; Mitsuhashi, Ryuichi; Ohno, Tatsuharu

    2009-01-01

    Transfusion-related acute lung injury (TRALI) is currently the leading cause of transfusion-related death. A 67-year-old man with severe aplastic anemia developed TRALI, consisting of acute respiratory insufficiency with severe hypoxia and diffuse pulmonary infiltration 2 hours after the transfusion of platelet concentrates. Although he required intensive respiratory support, he promptly recovered within 4 days. The presence of anti-HLA antibody (anti-HLA B52) in the donated blood product was demonstrated, and a lymphocytotoxicity test disclosed antibody-mediated cytotoxicity against the patient's cells. Furthermore, administration of granulocyte-colony stimulating factor was suggested to predispose the patient to TRALI by priming the neutrophils.

  10. Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice

    SciTech Connect

    Moore, M.A.S.; Warren, D.J.

    1987-10-01

    The human bladder carcinoma cell line 5637 produces hematopoietic growth factors (granulocyte and granulocyte/macrophage colony-stimulating factors (G-CSF and GM-CSF)) and hemopoietin 1, which synergizes with CSFs to stimulate colony formation by primitive hematopoietic stem cells in 5-fluorouracil-treated mouse bone marrow. Molecular and functional properties of hemopoietin 1 identified it as identical to interleukin 1..cap alpha.. (IL-1..cap alpha..). When bone marrow cells from 5-fluorouracil-treated mice were cultured in suspension for 7 days with recombinant human IL-1..cap alpha.. and/or G-CSF, it was found that the two factors synergized to enhance recovery of myelopoietic cells and colony-forming cells of both high and low proliferative potential. G-CSF alone did not sustain these populations, but the combination had greater-than-additive stimulating capacity. In vivo, 5-fluorouracil (150 mg/kg) produced profound myelosuppression and delayed neutrophil regeneration for up to 2 weeks in C3H/HeJ mice. Daily administration of recombinant human G-CSF or human IL-1..cap alpha.. accelerated recovery of stem cells, progenitor cells, and blood neutrophils by up to 4 days in 5-fluorouracil-treated C3H/HeJ and B6D2F/sub 1/ mice. The combination of IL-1..cap alpha.. and G-CSF acted synergistically, reducing neutropenia and accelerating recovery of normal neutrophil numbers by up to 7 days. These results indicate the possible therapeutic potential of combination therapy with IL-1 and hematopoietic growth factors such as G-CSF in the treatment of chemotherapy- or radiation-induced myelosuppression.

  11. 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.

    PubMed

    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

  12. 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)

    PubMed Central

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

    2016-01-01

    Background 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. Methods 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. Results 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. Conclusions 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

  13. Early measurement of CD34+ cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding “on demand” use of plerixafor

    PubMed Central

    Milone, Giuseppe; Tripepi, Giovanni; Martino, Massimo; Ancora, Flavia; Bartolozzi, Benedetta; Spadaro, Andrea; Nozzoli, Chiara; La Fauci, Alessia; Amico, Irene; Leotta, Salvatore; Poidomani, Massimo; Irrera, Giuseppe; Iacopino, Pasquale; Saccardi, Riccardo; Guidi, Stefano; Bosi, Alberto

    2013-01-01

    Background Early identification of predictive factors of failure to mobilise CD34+ cells could enable rational use of plerixafor during first mobilisation, avoiding the need for a second mobilisation course. However, “on demand” administration of plerixafor needs to be driven by established parameters to avoid inappropriate use. Materials and methods To address this issue, we studied the value of the peripheral blood CD34+ count, measured early (on days +10, +11, +12 and +13), in predicting the mobilisation outcome in the ensuing days. We retrospectively collected data from three Italian centres on 233 patients affected by multiple myeloma or lymphoma who underwent a first or second attempt at mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor. To assess the diagnostic value of peripheral blood white blood cell and CD34+ cell counts with respect to “mobilisation failure”, we considered failed mobilisation as “disease” and the CD34+ cell count in peripheral blood, on a specific day, as a “diagnostic test”. For various thresholds, we measured sensitivity, false positive rate, specificity and positive predictive value (PPV) as well as the area under the receiver-operating characteristic curves (AUC). Results A CD34+ cell count <10×106/L on day 13 had high sensitivity (1.00) and high specificity (1.00) for predicting subsequent mobilisation failure, with an AUC of 1.0. However, good prediction was also obtained using a lower threshold (CD34+ cell count: <6×106/L) at an earlier time (day 12). The PPV of the day 13 threshold was 1.00 while that of the day 12 one was 0.87. Discussion We propose that patients with <6×106/L CD34+ cells in peripheral blood on day 12 and <10×106/L on day 13 following mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor are candidates for “on demand” use of plerixafor, making the administration of this expensive agent more efficient and avoiding its

  14. 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.

    PubMed

    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.

  15. A low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus a daunorubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia: A propensity score analysis.

    PubMed

    Minakata, Daisuke; Fujiwara, Shin-ichiro; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Nakano, Hirofumi; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamasaki, Ryoko; Yamamoto, Chihiro; Ashizawa, Masahiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

    2016-03-01

    This retrospective analysis compared the efficacy of intensive induction therapy consisting of daunorubicin and cytarabine (DNR-AraC) to that of less-intensive therapy including low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming (CAG). Patients aged 60 years or older who were newly diagnosed as acute myeloid leukemia (AML) were analyzed. Sixty-four and 48 patients were treated with DNR-AraC and CAG, respectively. The complete remission rates, 3-year overall survival and event-free survival in the DNR-AraC group were significantly superior to those in the CAG group (65.6% vs. 29.2%, p<0.001, 38.4% vs. 12.3%, p=0.0033, and 20.3% vs. 7.8%, p=0.0030, respectively), although these differences were not statistically significant in multivariate analyses. Next, we calculated a propensity score for selecting the CAG regimen from six factors. The DNR-AraC regimen was associated with better survival than the CAG regimen in a low propensity score group, but there was no difference in survival between regimens in a high propensity score group. Intensive therapy should be performed for patients with sufficient general and comorbid conditions, but less-intensive therapy may be sufficient for patients with higher age, myelodysplasia-related changes, and lower white blood cell counts, which were relevant factors in the propensity score calculation.

  16. 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.

    PubMed

    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.

  17. Succinate ester derivative of δ-tocopherol enhances the protective effects against 60Co γ-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice

    PubMed Central

    Li, Zhong-Tang; Wang, Li-Mei; Yi, Li-Rong; Jia, Chao; Bai, Fan; Peng, Ren-Jun; Yu, Zu-Yin; Xiong, Guo-Lin; Xing, Shuang; Shan, Ya-Jun; Yang, Ri-Fang; Dong, Jun-Xing; Cong, Yu-Wen

    2017-01-01

    α-tocopherol succinate (α-TOS), γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have drawn large attention due to their efficacy as radioprotective agents. α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI). Because α-TOS has been shown to act superior to α-tocopherol (α-TOH) in mice by reducing lethality following total body irradiation (TBI), we hypothesized succinate may be contribute to the radioprotection of α-TOS. To study the contributions of succinate and to identify stronger radioprotective agents, we synthesized α-, γ- and δ-TOS. Then, we evaluated their radioprotective effects and researched further mechanism of δ-TOS on hematological recovery post-irradiation. Our results demonstrated that the chemical group of succinate enhanced the effects of α-, γ- and δ-TOS upon radioprotection and granulocyte colony-stimulating factor (G-CSF) induction, and found δ-TOS a higher radioprotective efficacy at a lower dosage. We further found that treatment with δ-TOS ameliorated radiation-induced pancytopenia, augmenting cellular recovery in bone marrow and the colony forming ability of bone marrow cells in sublethal irradiated mice, thus promoting hematopoietic stem and progenitor cell recovery following irradiation exposure. δ-TOS appears to be an attractive radiation countermeasure without known toxicity, but further exploratory efficacy studies are still required. PMID:28145432

  18. 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.

    PubMed

    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.

  19. G-CSF use in patients receiving first-line chemotherapy for non-Hodgkin's lymphoma (NHL) and granulocyte-colony stimulating factors (G-CSF) as observed in clinical practice in Italy.

    PubMed

    Vitolo, Umberto; Angrili, Francesco; DeCosta, Lucy; Wetten, Sally; Federico, Massimo

    2016-12-01

    Treatment of non-Hodgkin lymphoma (NHL) requires chemotherapy regimens with significant risk of febrile neutropenia (FN). For patients at ≥20% FN risk, guidelines recommend primary prophylaxis (PP) with granulocyte-colony stimulating factor (G-CSF). This study assessed whether G-CSF use in NHL was in line with recommendations in routine practice. This was a retrospective, observational study of adult NHL patients receiving first-line (R)CHOP-like chemotherapy and G-CSF support between June 2010 and 2012, in Italy. The primary outcome was whether G-CSF was provided as PP, which was defined as G-CSF initiation on days 1-3 after chemotherapy, ≥3 days' use for daily G-CSFs and continued prophylaxis from cycle 1 across all cycles. Secondary prophylaxis was defined as continued prophylaxis from cycle 2 or later, and all other use was defined as Suboptimal. The analysis included 199 patients, 61% of whom had diffuse large B cell lymphoma and 21% follicular lymphoma. (R)CHOP-21 was given to 52% of patients and (R)CHOP-14 to 32%. Overall, 29% of patients received PP, while two-thirds received Suboptimal G-CSF. Of patients receiving daily G-CSF, 3% received PP and 94% received Suboptimal use; with pegfilgrastim, 65% received PP and 26% Suboptimal use. FN occurred in 13 patients (7%) and grade 3/4 neutropenia in 43%. Chemotherapy dose delays occurred in 22% and dose reductions in 18% of patients. Delivery of G-CSF, particularly daily G-CSFs, was not in accordance with guideline or product label recommendations in a large proportion of NHL patients receiving chemotherapy in Italy.

  20. 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.

    PubMed

    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.

  1. Proteolytic enzyme levels are increased during granulocyte colony-stimulating factor-induced hematopoietic stem cell mobilization in human donors but do not predict the number of mobilized stem cells.

    PubMed

    van Os, R; van Schie, M L J; Willemze, R; Fibbe, W E

    2002-06-01

    Previous studies from our laboratory indicate that functional, mature neutrophils are essential for interleukin-8 (IL-8)-induced stem cell mobilization. To study a possible role of neutrophils in granulocyte colony-stimulating factor (G-CSF) induced hematopoietic mobilization, we assessed the number of circulating CD34+ cells in healthy allogeneic stem cell donors on days 3, 4, and 5 of mobilization for comparison with the number of peripheral blood neutrophils and the plasma levels of IL-8, Flt3 ligand (FL), matrix metalloproteinase-9 (MMP-9), and human neutrophil elastase (HNE). Thirty-seven of 45 donors required 1 day of apheresis to obtain 5 x 10(6) CD34+/kg recipient body weight (high responders), the remaining 8 donors required 1 extra day of apheresis on day 6 (low responders). On day 5, CD34+ numbers in the blood were significantly highe in high responders (116 x 10(3) +/- 10.4/ml) than in low responders (54.1 x 10(3) +/- 10.3, p < 0.001). In all donors, MMP-9 and HNE levels were increased compared to nonmobilized individuals, but in high responders, plasma MMP-9 levels on days 3-5 of mobilization were substantially higher than in low responders (p < or = 0.02 for MMP-9 and p = 0.89, p = 0.05 and p = 0.52 for HNE on days 3, 4, and 5, respectively). These results are in accordance with the hypothesis that neutrophils play a role in G-CSF-induced mobilization through the release of proteases such as MMP-9 and elastase. No change in plasma levels of IL-8 or Flt3 ligand was observed, suggesting that these cytokines do not play a role in stem cell mobilization. However, because stem cell numbers could not be predicted by proteolytic enzyme levels and/or neutrophil numbers, other undefined factors may be more important.

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

    PubMed Central

    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

  3. Granulocyte colony-stimulating factor (G-CSF) upregulates β1 integrin and increases migration of human trophoblast Swan 71 cells via PI3K and MAPK activation.

    PubMed

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

    2016-03-15

    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.

  4. 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.

    PubMed

    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 < 0.001) in SRC using an RD114-pseudotyped vector. In summary, using an 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).

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

    PubMed

    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.

  6. 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).

    PubMed

    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 (P<0.05). This was compatible with 3.3- and 1.7-fold reductions in ON vascular permeability after G-CSF treatment compared with PBS treatment (P<0.05). Microglial activation was increased by 3.8- and 3.2-fold in the early (beginning treatment at day 0 or 1) G-CSF-treated group compared with the PBS-treated group (P<0.05). Immediate (within 30 mins of infarct) treatment with G-CSF also induced M2 microglia/macrophage activation. The cytokine levels were lower in the group that received immediate G-CSF treatment compared to

  7. 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.

    PubMed

    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 < .01). The cumulative incidences of acute GVHD, chronic GVHD, transplantation-related toxicity, and infectious complications appeared to be equivalent. In total, 53 patients in the rhG-CSF-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 < .01) and 59.6% (95% CI, 49.4% to 69.7%) versus 34.8% (95% CI, 24.9% to 44.7%) (P < .01), respectively. Multivariate analyses indicated that the 2-year probability of LFS of patients who achieved complete remission (CR) before transplantation was better than that of patients who did not achieve CR. The 2-year probability of LFS of patients with no M4/M5/M6 subtype was better than that of patients with the M4/M5/M6 subtype in the G-CSF-priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27

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

    PubMed

    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.

  9. Prognostic factors for re-mobilization using plerixafor and granulocyte colony-stimulating factor (G-CSF) in patients with malignant lymphoma or multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy: the Korean multicenter retrospective study.

    PubMed

    Kim, Jin Seok; Yoon, Dok Hyun; Park, Seonyang; Yoon, Sung-Soo; Cho, Seok-Goo; Min, Chang-Ki; Lee, Je-Jung; Yang, Deok-Hwan; Kwak, Jae-Yong; Eom, Hyeon-Seok; Kim, Won Seog; Kim, Hawk; Do, Young Rok; Moon, Joon Ho; Lee, Jihye; Suh, Cheolwon

    2016-03-01

    Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has been shown to improve the rates of successful peripheral blood stem cell (PBSC) mobilization in patients with malignant lymphoma or multiple myeloma (MM) who experienced prior failure of PBSC mobilization. We evaluated the mobilization results of re-mobilization using plerixafor and G-CSF in insufficiently mobilizing patients. Forty-four patients with lymphoma (n = 29) or MM (n = 15) were included in the study. The median age was 50 (range, 24-64) years. Previous mobilization regimens were chemotherapy with G-CSF (n = 28), including cyclophosphamide with G-CSF (n = 15), and G-CSF only (n = 16). All patients with lymphoma achieved at least partial response (PR) before the mobilization, including 13 complete responses (CRs). Eleven patients with MM achieved at least PR and four patients with MM were in stable disease before mobilization. The median number of apheresis was 3 (range, 1-6). The median yield of PBSC collections was 3.41 (0.13-38.11) × 10(6) CD34(+) cells/kg. Thirty-four (77.3 %) patients had successful collections defined as at least 2 × 10(6) CD34(+) cells/kg. The rate of successful collections was not different between the two underlying diseases (79.3 % in lymphoma and 73.3 % in MM). Of the entire cohort, 38 (86.4 %) of patients went on to receive an autologous transplant. Previous long-term use of high-risk drugs (>4 cycles use of alkylating agents, platinum-containing agents, or thalidomide) (HR 10.8, 95 % CI 1.1-110.0, P = 0.043) and low platelet count (<100 × 10(9)/L) 1 day before the first apheresis (HR 27.9, 95 % CI 2.9-273.7, P = 0.004) were independent prognostic factors for predicting failure of PBSC re-mobilization using plerixafor and G-CSF. In conclusion, re-mobilization using plerixafor and G-CSF showed a success rate of 77.3 % in patients with lymphoma or MM who experienced prior failure of PBSC

  10. The addition of granulocyte-colony stimulating factor shifts the dose limiting toxicity and markedly increases the maximum tolerated dose and activity of the kinesin spindle protein inhibitor SB-743921 in patients with relapsed or refractory lymphoma: results of an international, multicenter phase I/II study.

    PubMed

    O'Connor, Owen A; Gerecitano, John; Van Deventer, Henrik; Hainsworth, John; Zullo, Kelly M; Saikali, Khalil; Seroogy, Joseph; Wolff, Andrew; Escandón, Rafael

    2015-01-01

    This was a phase I study of SB-743921 (SB-921) in patients with relapsed/refractory lymphoma. Previous studies established that neutropenia was the only dose limiting toxicity (DLT). The primary objective was to determine the DLT, maximum tolerated dose (MTD) and efficacy of SB-921 with and without granulocyte-colony stimulating factor (G-CSF). Sixty-eight patients were enrolled, 42 without G-CSF, 26 with G-CSF. In the cohort without G-CSF, SB-921 doses ranged from 2 to 7 mg/m(2), with 6 mg/m(2) being the MTD. In the cohort with G-CSF support, doses of 6-10 mg/m(2) were administered, with 9 mg/m(2) being the MTD, representing a 50% increase in dose density. Fifty-six patients were evaluable for efficacy. Four of 55 patients experienced a partial response (three in Hodgkin lymphoma and one in non-Hodgkin lymphoma, all at doses ≥ 6 mg/m(2)); 19 patients experienced stable disease, 33 patients developed progression of disease. G-CSF shifted the DLT from neutropenia to thrombocytopenia, allowing for a 50% increase in dose density. Responses were seen at higher doses with G-CSF support.

  11. A 3,387 bp 5'-flanking sequence of the goat alpha-S1-casein gene provides correct tissue-specific expression of human granulocyte colony-stimulating factor (hG-CSF) in the mammary gland of transgenic mice.

    PubMed

    Serova, Irina A; Dvoryanchikov, Gennady A; Andreeva, Ludmila E; Burkov, Ivan A; Dias, Luciene P B; Battulin, Nariman R; Smirnov, Alexander V; Serov, Oleg L

    2012-06-01

    A new expression vector containing the 1,944 bp 5'-flanking regulatory region together with exon 1 and intron 1 of the goat alpha-S1-casein gene (CSN1S1), the full-sized human granulocyte colony-stimulating factor gene (hGCSF) and the 3'-flanking sequence of the bovine CSN1S1, was created. The vector DNA was used for generation of four mouse transgenic lines. The transgene was integrated into chromosomes 8 and 12 of two founders as 2 and 5 copies, respectively. Tissue-specific secretion of hG-CSF into the milk of transgenic mice was in the range of 19-40 μg/ml. RT-PCR analysis of various tissues of the transgenic mice demonstrated that expression of hGCSF was detected in only the mammary gland in the progeny of all founders. Moreover, cells were shown to be positive for hG-CSF by immunofluorescent analysis in the mammary glands but not in any other tissues. There were no signs of mosaic expression in the mammary gland. Trace amounts of hG-CSF were detected in the serum of females of two transgenic lines during lactation only. However, no transgenic mice showed any changes in hematopoiesis based on the number of granulocytes in blood. Immunoblotting of hG-CSF in the milk of transgenic mice revealed two forms, presumably the glycosylated and non-glycosylated forms. The hematopoietic activity of hG-CSF in the milk of transgenic females is comparable to that of recombinant G-CSF. In general, the data obtained in this study show that the new expression vector is able to provide correct tissue-specific expression of hG-CSF with high biological activity in transgenic mice.

  12. Functional NF-IL6/CCAAT enhancer-binding protein is required for tumor necrosis factor alpha-inducible expression of the granulocyte colony- stimulating factor (CSF), but not the granulocyte/macrophage CSF or interleukin 6 gene in human fibroblasts [retracted by Adler G. In: J Exp Med 1997 Jul 7;186(1):171

    PubMed Central

    1995-01-01

    Tumor necrosis factor (TNF) alpha participates in the regulation of the acute-phase, immune, and inflammatory responses. Target genes known to be transcriptionally activated by TNF-alpha include the granulocyte (G)- colony-stimulating factor (CSF) gene, the granulocyte/macrophage (GM)- CSF gene, as well as the interleukin (IL) 6 gene. Functional nuclear factor (NF)-IL6 recognition sites have been identified in regulatory regions of these genes by transient transfection studies using deleted promoter constructs. In addition, NF-IL6 is known to form heterodimeric complexes with the NF-kappa B transcription factor, which is also engaged in the transcriptional regulation of these genes. The indispensable importance of NF-IL6 for regulating gene expression of proinflammatory cytokine genes in response to inflammatory stimuli in vivo remains, however, unclear. We here report, by using both antisense (AS) oligodesoxyribonucleotide (ODN) and ribozyme (RZ)-mediated specific elimination of NF-IL6 transcripts in human fibroblasts, that TNF-alpha-induced synthesis of G-CSF, but not of GM-CSF or IL-6, is abolished in the absence of functional NF-IL6 in vivo. Both AS ODN and RZ targeting of the NF-IL6 transcript eliminate NF-IL6 protein, as shown in Western blot analysis and electrophoretic mobility shift assays. Similarly, fibroblasts exposed to either the AS NF-IL6 ODN or the NF-IL6 RZ, but not to the sense or nonsense ODN or a mutated ribozyme, also failed to respond with functional activation of NF-IL6 as assayed in transient transfection studies using heterologous promoter constructs harboring the NF-IL6 recognition site. In contrast, protein synthesis, DNA-binding activity, and transcriptional activation capacity of the NF-kappa B transcription factor is not impaired upon exposure to either ODN or RZ. Fibroblasts that had been cultured in the presence of the AS NF-IL6 ODN or the NF-IL6RZ failed to synthesize G- CSF protein in response to TNF-alpha, while TNF

  13. Reduced salmonella fecal shedding in swine administered porcine granulocyte-colony stimulating factor (G-CSF)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Salmonella colonization of food animals is a concern for animal health, food safety and public health. Key objectives of pre-harvest food safety programs are to detect asymptomatic Salmonella carriage in food animals, reduce colonization, and prevent transmission of Salmonella to other animals and ...

  14. The discovery, development and clinical applications of granulocyte colony-stimulating factor.

    PubMed Central

    Dale, D. C.

    1998-01-01

    The story of the discovery, development and applications of G-CSF illustrates many of the best features of modern laboratory and clinical investigation. The initial discovery of the CSFs was somewhat serendipitous. The pathway to understanding the cellular and molecular base for the action of these substances was long, but fruitful and exciting for those who pursued it tirelessly. The power of modern molecular biology is illustrated by the rapid advances which followed the cloning of the G-CSF gene. Major advances in our understanding of the regulation of neutrophil production and deployment have followed, together with many important clinical observations. To date hundreds of thousands of patients have been treated with G-CSF and some individuals with severe chronic neutropenia have received daily therapy for more than ten years. Results of recent studies suggest that there will be many more interesting and important clinical applications for G-CSF. PMID:9601125

  15. Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans.

    PubMed

    Banks, William A; Dohi, Kenji; Hansen, Kim; Thompson, Hilaire J

    2016-02-01

    Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non-codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h.

  16. Mobilization of hematopoietic progenitor cells with granulocyte colony stimulating factors for autologous transplant in hematologic malignancies: a single center experience

    PubMed Central

    Gabús, Raul; Borelli, Gabriel; Ferrando, Martín; Bódega, Enrique; Citrín, Estela; Jiménez, Constanza Olivera; Álvarez, Ramón

    2011-01-01

    Background In 2006 the Hematology Service of Hospital Maciel published its experience with peripheral blood progenitor cell harvesting for autologous stem cell transplantation using Filgen JP (Clausen Filgrastim). After mobilization with a mean filgrastim dose of 78 mcg/Kg, 4.7 x 106 CD34+ cells/Kg were obtained by apheresis. Age above 50, multiple myeloma as underlying disease and a malignancy that was not in remission were identified as frequent characteristics among patients showing complex mobilization. Objective The aim of this study was to compare stem cell mobilization using different brands of filgrastim. Methods One hundred and fifty-seven mobilizations performed between 1997 and 2006 were analyzed. This retrospective analysis comparative two groups of patients: those mobilized with different brands of filgrastim (Group A) and those who received Filgen JP (Clausen Filgrastim) as mobilizing agent (Group B). A cluster analysis technique was used to identify four clusters of individuals with different behaviors differentiated by age, total dose of filgrastim required, number of apheresis and harvested CD34+ cells. Results The mean total dose of filgrastim administered was 105 mcg/Kg, the median number of apheresis was 2 procedures and the mean number of harvested stem cells was 4.98 x 106 CD34+ cells/Kg. No significant differences were observed between Groups A and B regarding the number of apheresis, harvested CD34+ cells and number of mobilization failures, however the total dose of filgrastim was significantly lower in Group B. Conclusions Among other factors, the origin of the cytokine used as mobilizing agent is an element to be considered when evaluating CD34+ cell mobilization results. PMID:23049356

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

    PubMed

    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.

  18. Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction.

    PubMed

    Bruno, Stefania; Bussolati, Benedetta; Scacciatella, Paolo; Marra, Sebastiano; Sanavio, Fiorella; Tarella, Corrado; Camussi, Giovanni

    2006-04-01

    Mobilization of endothelial progenitor cells has been suggested to contribute to neo-vascularization of ischemic organs. Aim of this study was to investigate whether the combination of granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage (GM)-CSF may influence the expansion of circulating KDR+ cells in patients with acute myocardial infarction (AMI). KDR+ cells significantly increased in peripheral blood of AMI patients treated with G-CSF and GM-CSF compared to untreated patients. This KDR+ cells population was CD14+ but not CD34+ or CD133+. CD14+/KDR+ cells were also obtained in vitro by culturing mononuclear cells from healthy donors in a Rotary Cell Culture System in the presence of G-CSF + GM-CSF, but not of the individual growth factors. CD14+/KDR+ cells, obtained from patients or from in vitro culture, co-expressed hematopoietic (CD45, CD14) and endothelial markers (CD31, CD105, and VE-cadherin). CD14+/KDR+, but not CD14+/KDR- cells, stimulated the organization of human microvascular endothelial cells into capillary-like structures on Matrigel both in vitro and in vivo. The combination of G-CSF and GM-CSF induced a CD14+/KDR+ cell population with potential pro-angiogenic properties.

  19. Case Report. Prevention of Clozapine-Induced Granulocytopenia/Agranulocytosis with Granulocyte-Colony Stimulating Factor (G-CSF) in an Intellectually Disabled Patient with Schizophrenia

    ERIC Educational Resources Information Center

    Rajagopal, G.; Graham, J. G.; Haut, F. F. A.

    2007-01-01

    Background: While clozapine is an effective treatment for refractory schizophrenia, its use is limited by haematological side effects. Treatment options that allow continued prescription of clozapine by tackling these side effects will greatly aid patients for whom this medication is all too often their only hope of recovery. Method: In this case…

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

    PubMed

    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; Löwenberg, Bob

    2012-06-07

    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 cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

  1. Analytical techniques and bioactivity assays to compare the structure and function of filgrastim (granulocyte-colony stimulating factor) therapeutics from different manufacturers.

    PubMed

    Levy, Michaella J; Gucinski, Ashley C; Sommers, Cynthia D; Ghasriani, Houman; Wang, Bo; Keire, David A; Boyne, Michael T

    2014-10-01

    The FDA has approved more than 100 protein and peptide drugs with hundreds more in the pipeline (Lanthier et al. in Nat Rev Drug Discov 7(9):733-737, 2008). Many of these originator biologic products are now coming off patent and are being manufactured by alternate methods than the innovator as follow-on drugs. Because changes to the production method often lead to subtle differences (e.g., degradation products, different posttranslational modifications or impurities) in the therapeutic (Schiestl et al. in Nat Biotechnol 29(4):310-312, 2011), there is a critical need to define techniques to test and insure the quality of these drugs. In addition, the emergence of protein therapeutics manufactured by unapproved methodologies presents an ongoing and growing regulatory challenge. In this work, high-resolution mass spectrometry was used to determine the presence or absence of posttranslational modifications for one FDA-approved and three foreign-sourced, unapproved filgrastim products. Circular dichroism (CD) was used to compare the secondary structure and probe the temperature stability of these products. Native 2D (1)H,(15)N-heteronuclear singular quantum coherence (HSQC) NMR test was applied to these samples to compare the higher-order structure of the four products. Finally, a cell proliferation assay was performed on the filgrastims to compare their bioactivity, and stressed filgrastim was tested in the bioassay to better understand the effects of changes in protein structure on activity. The results showed that orthogonal approaches are capable of characterizing the physiochemical properties of this protein drug and assessing the impact of structural changes on filgrastim purity and potency.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chinese highly pathogenic PRRSV (HP-PRRSV) strain JXwn06 has been shown to produce high fevers, loss of body condition, respiratory distress and death in pigs. Necropsy reveals extensive interstitial pneumonia, multi-systemic pathology and a high occurrence of secondary bacterial infections. The ful...

  4. 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.

    PubMed

    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.

  5. Granulocyte colony-stimulating factor (G-CSF) positive effects on muscle fiber degeneration and gait recovery after nerve lesion in MDX mice

    PubMed Central

    Simões, Gustavo F; Benitez, Suzana U; Oliveira, Alexandre L R

    2014-01-01

    Background G-CSF has been shown to decrease inflammatory processes and to act positively on the process of peripheral nerve regeneration during the course of muscular dystrophy. Aims The aims of this study were to investigate the effects of treatment of G-CSF during sciatic nerve regeneration and histological analysis in the soleus muscle in MDX mice. Methods Six-week-old male MDX mice underwent left sciatic nerve crush and were G-CSF treated at 7 days prior to and 21 days after crush. Ten and twenty-one days after surgery, the mice were euthanized, and the sciatic nerves were processed for immunohistochemistry (anti-p75NTR and anti-neurofilament) and transmission electron microscopy. The soleus muscles were dissected out and processed for H&E staining and subsequent morphologic analysis. Motor function analyses were performed at 7 days prior to and 21 days after sciatic crush using the CatWalk system and the sciatic nerve index. Results Both groups treated with G-CSF showed increased p75NTR and neurofilament expression after sciatic crush. G-CSF treatment decreased the number of degenerated and regenerated muscle fibers, thereby increasing the number of normal muscle fibers. Conclusions The reduction in p75NTR and neurofilament indicates a decreased regenerative capacity in MDX mice following a lesion to a peripheral nerve. The reduction in motor function in the crushed group compared with the control groups may reflect the cycles of muscle degeneration/regeneration that occur postnatally. Thus, G-CSF treatment increases motor function in MDX mice. Nevertheless, the decrease in baseline motor function in these mice is not reversed completely by G-CSF. PMID:25328849

  6. History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in patients with non-Hodgkin lymphoma not receiving granulocyte colony-stimulating factor prophylaxis.

    PubMed

    Chao, Chun; Rodriguez, Roberto; Page, John H; Yang, Su-Jau; Huynh, Julie; Chia, Victoria M

    2015-01-01

    We conducted a cohort study to examine the association between a wide variety of chronic comorbidities and risk of febrile neutropenia (FN) in patients with non-Hodgkin lymphoma (NHL) from 2000 to 2009 treated with chemotherapy at Kaiser Permanente Southern California. History of comorbidities and FN events were identified using electronic medical records. Cox model adjusting for propensity score was used to determine the association between a comorbid condition and FN. Models that additionally adjusted for cancer stage, baseline absolute neutrophil count, chemotherapy regimen and dose reduction were also evaluated. A total of 2480 patients with NHL were included, and 60% received CHOP/R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, with or without rituximab). In total, 236 (9.5%) patients developed FN in the first chemotherapy cycle. Anemia (adjusted hazard ratio [HR] = 1.6, 95% confidence interval [1.2-2.2]), HIV infection (HR = 3.8 [2.0-6.7]) and rheumatoid diseases (HR = 2.4 [1.3-4.0]) were associated with significantly increased risk of FN. These results provide evidence that chronic comorbidity increases the risk of FN.

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

    PubMed

    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.

  8. Severe Agranulocytosis following Simultaneous Administration of Chlorpromazine and Trimethoprim-Sulfamethoxazole in a Patient with Sepsis: A Possible Toxic Combination

    PubMed Central

    Jha, Anil; Ghoz, Hassan

    2016-01-01

    Background. Chlorpromazine and trimethoprim-sulfamethoxazole (TMP/SMX) are two commonly prescribed medications by physicians. Either of those medications could cause fatal drug-induced agranulocytosis, with an unclear underlying mechanism. The likelihood of simultaneous prescription of both medications is high and could hypothetically result in severe agranulocytosis that is resistant to treatment. Case Presentation. We are presenting a case of a patient with psychosis on chlorpromazine who was prescribed TMP/SMX for a urinary tract infection. Consequently, the patient developed severe agranulocytosis and septicemia. Patient was managed by granulocyte colony-stimulating factor; however, the time to neutrophil recovery was delayed when compared to the average reported time published by previous studies. Conclusions. Simultaneous use of chlorpromazine and TMP/SMX is a possible toxic combination that could induce severe agranulocytosis. Further reports are needed to confirm this observation. PMID:27829837

  9. Modulation of colony stimulating factor release and apoptosis in human colon cancer cells by anticancer drugs

    PubMed Central

    Calatayud, S; Warner, T D; Mitchell, J A

    2002-01-01

    Modulation of the immune response against tumour cells is emerging as a valuable approach for cancer treatment. Some experimental studies have shown that secretion of colony stimulating factors by cancer cells reduces their tumorigenicity and increases their immunogenicity probably by promoting the cytolitic and antigen presenting activities of leukocytes. We have observed that human colon cancer cells (HT-29) are able to secrete granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor when stimulated with cytokines (IL-1β and TNF-α). In this study we assessed, for the first time, the effects of several anticancer drugs on colony stimulating factor release or apoptosis in HT-29 cells. Cytokine-induced release of granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor was significantly increased by cisplatin and 6-mercaptopurine. Taxol only increased macrophage-colony stimulating factor release while reduced that of granulocyte-colony stimulating factor. No changes in colony stimulating factor secretion were observed after treatment with methotrexate. Only cisplatin and taxol induced apoptosis in these cells. Secretion of colony stimulating factors by colon cancer cells may contribute to the immune host response against them. Anticancer drugs such as cisplatin and 6-mercaptopurine increase colony stimulating factor secretion by cytokine stimulated cancer cells probably through mechanisms different to those leading to cell apoptosis, an effect that may contribute to their anti-neoplasic action. British Journal of Cancer (2002) 86, 1316–1321. DOI: 10.1038/sj/bjc/6600240 www.bjcancer.com © 2002 Cancer Research UK PMID:11953891

  10. Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients

    PubMed Central

    Shin, Yoon-Kyum; Cho, Sung-Rae

    2016-01-01

    Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. PMID:27043535

  11. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  12. Idarubicin, intermediate-dose cytarabine, etoposide, and granulocyte-colony-stimulating factor are able to recruit CD34+/HLA-DR- cells during early hematopoietic recovery in accelerated and chronic phases of chronic myeloid leukemia.

    PubMed

    Carella, A M; Frassoni, F; Podestá, M; Pungolino, E; Pollicardo, N; Ferrero, R; Soracco, M

    1994-01-01

    A group of 46 patients with chronic myelogenous leukemia (CML) [chronic phase (CP), 24 patients; accelerated phase (AP), 22 patients] ineligible for allogeneic bone marrow transplantation were given an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose cytarabine, and etoposide. All patients had previously received interferon-alpha and only 2 had shown a partial cytogenetic response. During early recovery from chemotherapy-induced aplasia, peripheral blood progenitor cells (PBPC) were harvested by leukapheresis. All metaphases were found to be Philadelphia chromosome (Ph) negative in the collection from 17 of 46 (37%) patients [CP, 12 of 24 (50%); AP, 5 of 22 (23%)], and a decrease to less than 50% Ph-positive metaphases was seen in an additional 6 (CP, 3 patients; AP, 3 patients). The percentage of patients showing complete Ph disappearance was 64% in those receiving this procedure within the first year of diagnosis. In vitro studies were performed to assess the behavior of the Ph-negative PBPC. In clonogenic cultures they responded to stem cell factor and were able to grow as mixed colonies. Moreover, long-term culture initiating cells (LTCIC) were present in many Ph-negative collections but rarely in Ph-positive PBPC. In 4 females, clonality was studied by analyzing X chromosome inactivation and methylation patterns of the DXS255 locus with the probe M27 beta. Hematopoiesis was polyclonal in all 4 patients tested. Thus far, the Ph-negative collections have been used for autografting in 16 patients (CP, 11 patients; PA, 5 patients) after conditioning with total-body irradiation, etoposide, and cyclophosphamide or idarubicin.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. A Combined Anterior Pituitary Stimulation Test: Experience With 285 Individuals

    PubMed Central

    Elias, Alan N.; Valenta, Lubomir J.

    1987-01-01

    A pituitary reserve test was performed in 285 individuals. Eighteen were healthy volunteers without any endocrine disease, 25 suffered from a presumed hypothalamic abnormality, 22 from hypopituitarism, 10 from acromegaly, 65 from the amenorrhea-galactorrhea syndrome, 2 from Nelson's syndrome, 32 from borderline primary hypothyroidism, 15 from borderline hyperthyroidism, 20 were on chronic levothyroxine therapy for primary hypothyroidism, and 15 had severe uncorrected primary hypothyroidism. Sixteen postmenopausal women were also included, as well as 15 patients with idiopathic ovarian failure and six with ovarian dysgenesis. Twelve male patients with hypergonadotropic and 12 with hypogonadotropic hypogonadism were also examined. The pituitary reserve test consisted of intravenous administration of a mixture of the thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and regular insulin. The following tests were obtained prior to the injection only (time 0): serum thyroxine (T4), tri-iodothyronine (T3), T3 resin uptake or thyroxine-binding globulin, total and free testosterone in men, estradiol and progesterone in women, and sex hormone binding globulin. At times 0, 20, 30, and 60 minutes, serum concentrations of the following compounds were obtained: glucose, adrenocorticotropic hormone, cortisol, growth hormone, prolactin, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone. Normal responses were established in a large number of cases. More or less typical patterns were demonstrated in the above-listed disease categories. Poor correlations between basal and stimulated values were observed, which emphasizes the diagnostic importance of the stimulation test. Maximum data were obtained using a combined test that has negligible morbidity, may be performed within an hour in an outpatient setting, and which examines the anterior pituitary function in a comprehensive fashion. PMID:3121862

  14. nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma

    PubMed Central

    Makimoto, Go; Fujiwara, Keiichi; Watanabe, Hiromi; Kameyama, Nobuhisa; Matsushita, Mizuho; Rai, Kammei; Sato, Ken; Yonei, Toshiro; Sato, Toshio; Shibayama, Takuo

    2014-01-01

    We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma. PMID:24575009

  15. Mimicking isovolumic contraction with combined electromechanical stimulation improves the development of engineered cardiac constructs.

    PubMed

    Morgan, Kathy Ye; Black, Lauren Deems

    2014-06-01

    Electrical and mechanical stimulation have both been used extensively to improve the function of cardiac engineered tissue as each of these stimuli is present in the physical environment during normal development in vivo. However, to date, there has been no direct comparison between electrical and mechanical stimulation and current published data are difficult to compare due to the different systems used to create the engineered cardiac tissue and the different measures of functionality studied as outcomes. The goals of this study were twofold. First, we sought to directly compare the effects of mechanical and electrical stimulation on engineered cardiac tissue. Second, we aimed to determine the importance of the timing of the two stimuli in relation to each other in combined electromechanical stimulation. We hypothesized that delaying electrical stimulation after the beginning of mechanical stimulation to mimic the biophysical environment present during isovolumic contraction would improve construct function by improving proteins responsible for cell-cell communication and contractility. To test this hypothesis, we created a bioreactor system that would allow us to electromechanically stimulate engineered tissue created from neonatal rat cardiac cells entrapped in fibrin gel during 2 weeks in culture. Contraction force was higher for all stimulation groups as compared with the static controls, with the delayed combined stimulation constructs having the highest forces. Mechanical stimulation alone displayed increased final cell numbers but there were no other differences between electrical and mechanical stimulation alone. Delayed combined stimulation resulted in an increase in SERCA2a and troponin T expression levels, which did not happen with synchronous combined stimulation, indicating that the timing of combined stimulation is important to maximize the beneficial effect. Increases in Akt protein expression levels suggest that the improvements are at least in

  16. Mimicking Isovolumic Contraction with Combined Electromechanical Stimulation Improves the Development of Engineered Cardiac Constructs

    PubMed Central

    Morgan, Kathy Ye

    2014-01-01

    Electrical and mechanical stimulation have both been used extensively to improve the function of cardiac engineered tissue as each of these stimuli is present in the physical environment during normal development in vivo. However, to date, there has been no direct comparison between electrical and mechanical stimulation and current published data are difficult to compare due to the different systems used to create the engineered cardiac tissue and the different measures of functionality studied as outcomes. The goals of this study were twofold. First, we sought to directly compare the effects of mechanical and electrical stimulation on engineered cardiac tissue. Second, we aimed to determine the importance of the timing of the two stimuli in relation to each other in combined electromechanical stimulation. We hypothesized that delaying electrical stimulation after the beginning of mechanical stimulation to mimic the biophysical environment present during isovolumic contraction would improve construct function by improving proteins responsible for cell–cell communication and contractility. To test this hypothesis, we created a bioreactor system that would allow us to electromechanically stimulate engineered tissue created from neonatal rat cardiac cells entrapped in fibrin gel during 2 weeks in culture. Contraction force was higher for all stimulation groups as compared with the static controls, with the delayed combined stimulation constructs having the highest forces. Mechanical stimulation alone displayed increased final cell numbers but there were no other differences between electrical and mechanical stimulation alone. Delayed combined stimulation resulted in an increase in SERCA2a and troponin T expression levels, which did not happen with synchronous combined stimulation, indicating that the timing of combined stimulation is important to maximize the beneficial effect. Increases in Akt protein expression levels suggest that the improvements are at least in

  17. Combination of endogenous neural stem cell mobilization and lithium chloride treatment for hydrocephalus following intraventricular hemorrhage.

    PubMed

    Yuan, Qiang; Bu, Xing-Yao; Yan, Zhao-Yue; Liu, Xian-Zhi; Wei, Zhen-Yu; Ma, Chun-Xiao; Qu, Ming-Qi

    2016-11-01

    As there are multiple factors causing hydrocephalus subsequent to intraventricular hemorrhage (IVH), it is difficult to achieve the best treatment effect using a single drug alone. In the present study, the protective effect of combination treatment with granulocyte-colony stimulating factor (G-CSF) and lithium chloride against hydrocephalus after IVH was investigated. A total of 130 adult male Sprague-Dawley rats were divided into five groups, including the IVH control, G-CSF treatment, lithium chloride treatment, combination treatment and sham surgery groups. An IVH rat model was established in order to examine the effect of combination treatment on hydrocephalus incidence. A TUNEL assay was performed to detect neuronal apoptosis in the five groups. In addition, the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. The differentiation of nerve cells in the brain tissue obtained from the five rat groups was also determined with double immunofluorescence staining. The results demonstrated that administration of G-CSF or lithium chloride alone was able to only partly relieve the incidence of hydrocephalus after IVH. By contrast, combination treatment with G-CSF and lithium chloride significantly attenuated the development of hydrocephalus following IVH. TUNEL assay showed that neuronal apoptosis was significantly reduced by the combination treatment with G-CSF and lithium chloride. Furthermore, the expression of Bcl-2 was upregulated, whereas Bax expression was downregulated in the combination treatment group. The results also detected the highest expression of BrdU/GFAP, BrdU/NeuN and BrdU/PSA-NCAM in the combination treatment group. In conclusion, the combination of endogenous neural stem cell mobilization (using G-CSF) and lithium chloride treatment resulted in highly reduced incidence of hydrocephalus after IVH by inhibiting neuronal apoptosis.

  18. Combined motor point associative stimulation (MPAS) and transcranial direct current stimulation (tDCS) improves plateaued manual dexterity performance.

    PubMed

    Hoseini, Najmeh; Munoz-Rubke, Felipe; Wan, Hsuan-Yu; Block, Hannah J

    2016-10-28

    Motor point associative stimulation (MPAS) in hand muscles is known to modify motor cortex excitability and improve learning rate, but not plateau of performance, in manual dexterity tasks. Central stimulation of motor cortex, such as transcranial direct current stimulation (tDCS), can have similar effects if accompanied by motor practice, which can be difficult and tiring for patients. Here we asked whether adding tDCS to MPAS could improve manual dexterity in healthy individuals who are already performing at their plateau, with no motor practice during stimulation. We hypothesized that MPAS could provide enough coordinated muscle activity to make motor practice unnecessary, and that this combination of stimulation techniques could yield improvements even in subjects at or near their peak. If so, this approach could have a substantial effect on patients with impaired dexterity, who are far from their peak. MPAS was applied for 30min to two right hand muscles important for manual dexterity. tDCS was simultaneously applied over left sensorimotor cortex. The motor cortex input/output (I/O) curve was assessed with transcranial magnetic stimulation (TMS), and manual dexterity was assessed with the Purdue Pegboard Test. Compared to sham or cathodal tDCS combined with MPAS, anodal tDCS combined with MPAS significantly increased the plateau of manual dexterity. This result suggests that MPAS has the potential to substitute for motor practice in mediating a beneficial effect of tDCS on manual dexterity.

  19. Cochlear dead regions constrain the benefit of combining acoustic stimulation with electric stimulation

    PubMed Central

    Zhang, Ting; Dorman, Michael F.; Gifford, Rene; Moore, Brian C.J.

    2014-01-01

    Objective The aims of this study were to (i) detect the presence and edge frequency (fe) of a cochlear dead region in the ear with residual acoustic hearing for bimodal cochlear implant (CI) users, and (ii) determine whether amplification based on the presence or absence of a dead region would improve speech understanding and sound quality. Design Twenty two listeners with a CI in one ear and residual acoustic hearing in the non-implanted ear were tested. Eleven listeners had a cochlear dead region in the acoustic-hearing ear and eleven did not. Dead regions were assessed with the threshold equalizing noise (TEN) and the sweeping noise, psychophysical tuning curve (SWPTC) tests. Speech understanding was assessed with monosyllabic words and the AzBio sentences at +10 dB signal-to-noise ratio. Speech and music quality judgments were obtained with the Judgment of Sound Quality questionnaire. Results For this population, using shifted tips of the PTCs as a basis for diagnosis, the TEN had high sensitivity (0.91) and poor specificity (0.55). The value of fe was lower when estimated with the SWPTC test than with the TEN test. For the listeners with cochlear dead regions, speech understanding, speech quality and music quality were best when no amplification was applied for frequencies within the dead region. For listeners without dead regions, speech understanding was best with full-bandwidth amplification and was reduced when amplification was not applied when the audiometric threshold exceeded 80 dB HL. Conclusion Our data suggest that, to improve bimodal benefit for listeners who combine electric and acoustic stimulation, audiologists should routinely test for the presence of cochlear dead regions and determine amplification bandwidth accordingly. PMID:24950254

  20. Frequency overlap between electric and acoustic stimulation and speech-perception benefit in patients with combined electric and acoustic stimulation

    PubMed Central

    Zhang, Ting; Spahr, Anthony J.; Dorman, Michael F.

    2010-01-01

    Objectives Our aim was to assess, for patients with a cochlear implant in one ear and low-frequency acoustic hearing in the contralateral ear, whether reducing the overlap in frequencies conveyed in the acoustic signal and those analyzed by the cochlear implant speech processor would improve speech recognition. Design The recognition of monosyllabic words in quiet and sentences in noise was evaluated in three listening configurations: electric stimulation alone, acoustic stimulation alone, and combined electric and acoustic stimulation. The acoustic stimuli were either unfiltered or low-pass (LP) filtered at 250 Hz, 500 Hz, or 750 Hz. The electric stimuli were either unfiltered or high-pass (HP) filtered at 250 Hz, 500 Hz or 750 Hz. In the combined condition the unfiltered acoustic signal was paired with the unfiltered electric signal, the 250 LP acoustic signal was paired with the 250 Hz HP electric signal, the 500 Hz LP acoustic signal was paired with the 500 Hz HP electric signal and the 750 Hz LP acoustic signal was paired with the 750 Hz HP electric signal. Results For both acoustic and electric signals performance increased as the bandwith increased. The highest level of performance in the combined condition was observed in the unfiltered acoustic plus unfiltered electric condition. Conclusions Reducing the overlap in frequency representation between acoustic and electric stimulation does not increase speech understanding scores for patients who have residual hearing in the ear contralateral to the implant. We find that acoustic information below 250 Hz significantly improves performance for patients who combine electric and acoustic stimulation and accounts for the majority of the speech-perception benefit when acoustic stimulation is combined with electric stimulation. PMID:19915474

  1. Combination treatment of flag with non-pegylated liposomal doxorubicin (MYOCET(TM)) in elderly patients with acute myeloid leukemia: a single center experience.

    PubMed

    Melillo, Lorella; Valente, D; D'Arena, G; Dell'Olio, M; Falcone, A; Minervini, M M; Nobile, M; Rossi, G; Sanpaolo, G; Scalzulli, P R; Cascavilla, N

    2011-01-01

    The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

  2. Synergistic combination of near-infrared irradiation and targeted gold nanoheaters for enhanced photothermal neural stimulation

    PubMed Central

    Eom, Kyungsik; Im, Changkyun; Hwang, Seoyoung; Eom, Seyoung; Kim, Tae-Seong; Jeong, Hae Sun; Kim, Kyung Hwan; Byun, Kyung Min; Jun, Sang Beom; Kim, Sung June

    2016-01-01

    Despite a potential of infrared neural stimulation (INS) for modulating neural activities, INS suffers from limited light confinement and bulk tissue heating. Here, a novel methodology for an advanced optical stimulation is proposed by combining near-infrared (NIR) stimulation with gold nanorods (GNRs) targeted to neuronal cell membrane. We confirmed experimentally that in vitro and in vivo neural activation is associated with a local heat generation based on NIR stimulation and GNRs. Compared with the case of NIR stimulation without an aid of GNRs, combination with cell-targeted GNRs allows photothermal stimulation with faster neural response, lower delivered energy, higher stimulation efficiency and stronger behavior change. Since the suggested method can reduce a requisite radiant exposure level and alleviate a concern of tissue damage, it is expected to open up new possibilities for applications to optical neuromodulations for diverse excitable tissues and treatments of neurological disorders. PMID:27446678

  3. Anti-Inflammatory Effect of Combination of Scutellariae Radix and Liriopis Tuber Water Extract

    PubMed Central

    So, Mi-Hye; Choi, You-Kyung

    2015-01-01

    Scutellariae Radix and Liriopis Tuber have been used to treat the inflammatory diseases in traditional Korean medicine and anti-inflammatory effect of each herb has been shown partially in several articles. However, the combined extract of these medicinal herbs (SL) has not been reported for its anti-inflammatory effects. In this study, we investigated the effects of SL on the creation of several proinflammatory mediators in RAW 264.7 cell mouse macrophages induced by Lipopolysaccharide (LPS). SL inhibited significantly the increase of NO, the release of intracellular calcium, the increase of interleukin-6 (IL-6), macrophage inflammatory proteins (MIP-1α, MIP-1β, and MIP-2), and granulocyte colony-stimulating factor (G-CSF) in LPS-induced RAW 264.7 cell at the concentrations of 25, 50, and 100 μg/mL, and SL inhibited significantly the increase of macrophage colony-stimulating factor (M-CSF) at the concentrations of 25 and 50 μg/mL, and tumor necrosis factor (TNF) at the concentration of 25 μg/mL. These results implicate that SL has anti-inflammatory effects by suppressing the production of various inflammatory mediators in macrophages. But SL did not inhibit significantly the increase of granulocyte macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); therefore, further study is demanded for the follow-up research to find out the possibility of SL as a preventive and therapeutic medicine for various inflammatory diseases. PMID:26604969

  4. Combined application of neuromuscular electrical stimulation and voluntary muscular contractions.

    PubMed

    Paillard, Thierry

    2008-01-01

    Electromyostimulation (EMS) and voluntary muscle contraction (VC) constitute different modes of muscle activation and induce different acute physiological effects on the neuromuscular system. Long-term application of each mode of muscle activation can produce different muscle adaptations. It seems theoretically possible to completely or partially cumulate the muscle adaptations induced by each mode of muscle activation applied separately. This work consisted of examining the literature concerning the muscle adaptations induced by long-term application of the combined technique (CT) [i.e. EMS is combined with VC - non-simultaneously] compared with VC and/or EMS alone in healthy subjects and/or athletes and in post-operative knee-injured subjects. In general, CT induced greater muscular adaptations than VC whether in sports training or rehabilitation. This efficiency would be due to the fact that CT can facilitate cumulative effects of training completely or partially induced by VC and EMS practiced alone. CT also provides a greater improvement of the performance of complex dynamic movements than VC. However, EMS cannot improve coordination between different agonistic and antagonistic muscles and thus does not facilitate learning the specific coordination of complex movements. Hence, EMS should be combined with specific sport training to generate neuromuscular adaptations, but also allow the adjustment of motor control during a voluntary movement. Likewise, in a therapeutic context, CT was particularly efficient to accelerate recovery of muscle contractility during a rehabilitation programme. Strength loss and atrophy inherent in a traumatism and/or a surgical operation would be more efficiently compensated with CT than with VC. Furthermore, CT also restored more functional abilities than VC. Finally, in a rehabilitation context, EMS is complementary to voluntary exercise because in the early phase of rehabilitation it elicits a strength increase, which is necessary

  5. Contributions to muscle force and EMG by combined neural excitation and electrical stimulation

    NASA Astrophysics Data System (ADS)

    Crago, Patrick E.; Makowski, Nathaniel S.; Cole, Natalie M.

    2014-10-01

    Objective. Stimulation of muscle for research or clinical interventions is often superimposed on ongoing physiological activity without a quantitative understanding of the impact of the stimulation on the net muscle activity and the physiological response. Experimental studies show that total force during stimulation is less than the sum of the isolated voluntary and stimulated forces, but the occlusion mechanism is not understood. Approach. We develop a model of efferent motor activity elicited by superimposing stimulation during a physiologically activated contraction. The model combines action potential interactions due to collision block, source resetting, and refractory periods with previously published models of physiological motor unit recruitment, rate modulation, force production, and EMG generation in human first dorsal interosseous muscle to investigate the mechanisms and effectiveness of stimulation on the net muscle force and EMG. Main results. Stimulation during a physiological contraction demonstrates partial occlusion of force and the neural component of the EMG, due to action potential interactions in motor units activated by both sources. Depending on neural and stimulation firing rates as well as on force-frequency properties, individual motor unit forces can be greater, smaller, or unchanged by the stimulation. In contrast, voluntary motor unit EMG potentials in simultaneously stimulated motor units show progressive occlusion with increasing stimulus rate. The simulations predict that occlusion would be decreased by a reverse stimulation recruitment order. Significance. The results are consistent with and provide a mechanistic interpretation of previously published experimental evidence of force occlusion. The models also predict two effects that have not been reported previously—voluntary EMG occlusion and the advantages of a proximal stimulation site. This study provides a basis for the rational design of both future experiments and clinical

  6. Mandarin Speech Perception in Combined Electric and Acoustic Stimulation

    PubMed Central

    Li, Yongxin; Zhang, Guoping; Galvin, John J.; Fu, Qian-Jie

    2014-01-01

    For deaf individuals with residual low-frequency acoustic hearing, combined use of a cochlear implant (CI) and hearing aid (HA) typically provides better speech understanding than with either device alone. Because of coarse spectral resolution, CIs do not provide fundamental frequency (F0) information that contributes to understanding of tonal languages such as Mandarin Chinese. The HA can provide good representation of F0 and, depending on the range of aided acoustic hearing, first and second formant (F1 and F2) information. In this study, Mandarin tone, vowel, and consonant recognition in quiet and noise was measured in 12 adult Mandarin-speaking bimodal listeners with the CI-only and with the CI+HA. Tone recognition was significantly better with the CI+HA in noise, but not in quiet. Vowel recognition was significantly better with the CI+HA in quiet, but not in noise. There was no significant difference in consonant recognition between the CI-only and the CI+HA in quiet or in noise. There was a wide range in bimodal benefit, with improvements often greater than 20 percentage points in some tests and conditions. The bimodal benefit was compared to CI subjects’ HA-aided pure-tone average (PTA) thresholds between 250 and 2000 Hz; subjects were divided into two groups: “better” PTA (<50 dB HL) or “poorer” PTA (>50 dB HL). The bimodal benefit differed significantly between groups only for consonant recognition. The bimodal benefit for tone recognition in quiet was significantly correlated with CI experience, suggesting that bimodal CI users learn to better combine low-frequency spectro-temporal information from acoustic hearing with temporal envelope information from electric hearing. Given the small number of subjects in this study (n = 12), further research with Chinese bimodal listeners may provide more information regarding the contribution of acoustic and electric hearing to tonal language perception. PMID:25386962

  7. Combination of Static Magnetic Fields and Peripheral Nerve Stimulation Can Alter Focal Cortical Excitability

    PubMed Central

    Nojima, Ippei; Koganemaru, Satoko; Mima, Tatsuya

    2016-01-01

    For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS±PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect. PMID:27932966

  8. Combination Pharmacotherapies for Stimulant Use Disorder: A Review of Clinical Findings and Recommendations for Future Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2014-01-01

    Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. Innovative strategies are necessary to develop successful pharmacotherapies for stimulant use disorders. This manuscript reviews human laboratory studies and clinical trials to determine whether one such strategy, use of combination pharmacotherapies, holds promise. The extant literature shows that combination pharmacotherapy produced results that were better than placebo treatment, especially with medications shown to have efficacy as monotherapies. However, many studies did not compare individual constituents to the combination treatment, making it impossible to determine whether combination treatment is more effective than monotherapy. Future research should systematically compare combined treatments with individual agents using medications showing some efficacy when tested alone. PMID:24716825

  9. Combined Effects of Acrobatic Exercise and Magnetic Stimulation on the Functional Recovery after Spinal Cord Lesions

    PubMed Central

    Wieraszko, Andrzej

    2008-01-01

    Abstract The objective of the study was to determine whether physical exercise combined with epidural spinal cord magnetic stimulation could improve recovery after injury of the spinal cord. Spinal cord lesioning in mice resulted in reduced locomotor function and negatively affected the muscle strength tested in vitro. Acrobatic exercise attenuated the behavioral effects of spinal cord injury. The exposure to magnetic fields facilitated further this improvement. The progress in behavioral recovery was correlated with reduced muscle degeneration and enhanced muscle contraction. The acrobatic exercise combined with stimulation with magnetic fields significantly facilitates behavioral recovery and muscle physiology in mice following spinal cord injury. PMID:18986227

  10. Time-dependent changes in motor cortical excitability by electrical stimulation combined with voluntary drive.

    PubMed

    Sugawara, Kenichi; Yamaguchi, Tomofumi; Tanabe, Shigeo; Suzuki, Tomotaka; Saito, Kei; Higashi, Toshio

    2014-04-16

    Prolonged changes in primary motor cortex excitability in response to combined neuromuscular electrical stimulation (NMES) and voluntary contraction with motor evoked potentials (MEPs) were investigated by transcranial magnetic stimulation and recorded by mechanomyography. Participants included 22 healthy individuals. NMES was applied to the extensor carpi radialis (ECR) by voluntary ECR contraction with 20% maximum voluntary contraction (MVC) of wrist extension. MEPs were recorded from the flexor carpi radialis (FCR) and ECR at rest with NMES, at 20% MVC with NMES (combined), and at 20% MVC alone. Significant conditional effects were revealed in ECR and FCR. In the combined condition, MEPs showed gradual enhancement, and those in FCR were more inhibited than those in the control condition. Voluntary contraction with NMES increased primary motor cortex excitability in the agonist muscle, whereas the antagonist muscle might affect reciprocal modulation in the combined condition.

  11. Combining acoustic and electric stimulation in the service of speech recognition

    PubMed Central

    Dorman, Michael F.; Gifford, Rene H.

    2010-01-01

    The majority of recently implanted, cochlear implant patients can potentially benefit from a hearing aid in the ear contralateral to the implant. When patients combine electric and acoustic stimulation, word recognition in quiet and sentence recognition in noise increase significantly. Several studies suggest that the acoustic information that leads to the increased level of performance resides mostly in the frequency region of the voice fundamental, e.g. 125 Hz for a male voice. Recent studies suggest that this information aids speech recognition in noise by improving the recognition of lexical boundaries or word onsets. In some noise environments, patients with bilateral implants can achieve similar levels of performance as patients who combine electric and acoustic stimulation. Patients who have undergone hearing preservation surgery, and who have electric stimulation from a cochlear implant and who have low-frequency hearing in both the implanted and not-implanted ears, achieve the best performance in a high noise environment. PMID:20874053

  12. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

    PubMed

    Hidding, U; Gulberti, A; Horn, A; Buhmann, C; Hamel, W; Koeppen, J A; Westphal, M; Engel, A K; Gerloff, C; Weiss, D; Moll, C K E; Pötter-Nerger, M

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

  13. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients

    PubMed Central

    Horn, A.; Hamel, W.; Koeppen, J. A.; Westphal, M.; Engel, A. K.; Gerloff, C.; Moll, C. K. E.

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended. PMID:28246572

  14. Effect of tactile stimulation on primary motor cortex excitability during action observation combined with motor imagery.

    PubMed

    Tanaka, Megumi; Kubota, Shinji; Onmyoji, Yusuke; Hirano, Masato; Uehara, Kazumasa; Morishita, Takuya; Funase, Kozo

    2015-07-23

    We aimed to investigate the effects of the tactile stimulation to an observer's fingertips at the moment that they saw an object being pinched by another person on the excitability of observer's primary motor cortex (M1) using transcranial magnetic stimulation (TMS). In addition, the above effects were also examined during action observation combined with the motor imagery. Motor evoked potentials (MEP) were evoked from the subjects' right first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles. Electrical stimulation (ES) inducing tactile sensation was delivered to the subjects' first and second fingertips at the moment of pinching action performed by another person. Although neither the ES nor action observation alone had significant effects on the MEP amplitude of the FDI or ADM, the FDI MEP amplitude which acts as the prime mover during pinching was reduced when ES and action observation were combined; however, no such changes were seen in the ADM. Conversely, that reduced FDI MEP amplitude was increased during the motor imagery. These results indicated that the M1 excitability during the action observation of pinching action combined with motor imagery could be enhanced by the tactile stimulation delivered to the observer's fingertips at the moment corresponding to the pinching being observed.

  15. Combined pallidal and subthalamic nucleus stimulation in sporadic dystonia-parkinsonism.

    PubMed

    Wöhrle, Johannes C; Blahak, Christian; Capelle, Hans-Holger; Fogel, Wolfgang; Bäzner, Hansjoerg; Krauss, Joachim K

    2012-01-01

    Multifocal deep brain stimulation (DBS) is a new technique that has been introduced recently. A 39-year-old man with dystonia-parkinsonism underwent the simultaneous implantation of subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS electrodes. While bilateral STN DBS controlled the parkinsonian symptoms well and allowed for a reduction in levodopa, the improvement of dystonia was only temporary. Additional GPi DBS also alleviated dystonic symptoms. Formal assessment at the 1-year follow-up showed that both the parkinsonian symptoms and the dystonia were markedly improved via continuous bilateral combined STN and GPi stimulation. Sustained benefit was achieved at 3 years postoperatively.

  16. Multiple Channel Laser Beam Combination and Phasing Using Stimulated Brillouin Scattering in Optical Fibers

    DTIC Science & Technology

    2005-12-01

    Mandel’shtam–Brillouin scattering,” JETP Lett ., 15, 109-112, 1972. 41 . Hellwarth, R. W., “Phase conjugation by stimulated backscattering,” ch. 7, Optical...wavefront-reversing mirrors,” Sov . Phys . JETP , 52, 847-851, 1980. 79. Valley, M., G. Lombardi, and R. Aprahamian, “Beam combination by stimulated...Thomas, and R. Byer, Monolithic, “Unidirectional single-mode Nd:YAG ring laser”, Opt. Lett ., 10, 65-67, 1985 . 56. Imai, M. and E. H. Hara

  17. Multiple Channel Laser Beam Combination and Phasing Using Stimulated Brillouin Scattering in Optical Fibers

    DTIC Science & Technology

    2005-12-22

    Mandel’shtam–Brillouin scattering,” JETP Lett ., 15, 109-112, 1972. 41 . Hellwarth, R. W., “Phase conjugation by stimulated backscattering,” ch. 7, Optical...wavefront-reversing mirrors,” Sov . Phys . JETP , 52, 847-851, 1980. 79. Valley, M., G. Lombardi, and R. Aprahamian, “Beam combination by stimulated...Thomas, and R. Byer, Monolithic, “Unidirectional single-mode Nd:YAG ring laser”, Opt. Lett ., 10, 65-67, 1985 . 56. Imai, M. and E. H. Hara

  18. Combined Fruit and Vegetable Intake Is Correlated with Improved Inflammatory and Oxidant Status from a Cross-Sectional Study in a Community Setting

    PubMed Central

    Root, Martin M.; McGinn, Megan C.; Nieman, David C.; Henson, Dru A.; Heinz, Serena A.; Shanely, R. Andrew; Knab, Amy M.; Jin, Fuxia

    2012-01-01

    Previous studies have examined the relationship between specific nutrient and food intakes with limited markers of either inflammation or oxidant status. The objective of this study was to determine if an increase in combined self-reported fruit and vegetable (F&V) intake in a community setting was associated with improved multiple markers of inflammatory and oxidant status. A community group (N = 1000, age 18–85 years, 61% female) gave two fasted blood samples separated by 12 weeks. Blood inflammatory biomarkers included total leukocytes (WBC), plasma C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1, and granulocyte colony stimulating factor. Measured oxidant status markers were ferric reducing ability of plasma (FRAP), oxygen radical absorbance capacity (ORAC) and plasma F2-isoprostanes. The relation of markers across categories of F&V intake was examined. In analyses controlling for other important dietary and lifestyle factors, IL-6 and TNF-α were significantly lower across categories of increasing F&V intakes (p < 0.008). FRAP and ORAC were significantly higher (p < 0.0001 and p = 0.047 respectively) while F2-isoprostanes was significantly lower (p < 0.0001) across F&V categories. In a community study, several markers of both inflammation and oxidant status were associated in a putatively salutary direction by higher intake of combined F&V, supporting current guidelines suggesting increased F&V consumption for the prevention of chronic diseases. PMID:22347616

  19. Oncofertility: combination of ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval

    PubMed Central

    2013-01-01

    Background New anticancer treatments have increased survival rates for cancer patients, but often at the cost of sterility. Several strategies are currently available for preserving fertility. However, the chances of achieving a pregnancy with one technique are still limited. A combination of methods is therefore recommended in order to maximize women’s chances of future fertility. In this retrospective study, ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval were combined and the quality of the ovarian tissue, the numbers and quality of oocytes, time requirements, and the safety of the strategy were examined. Methods Fourteen female patients suffering from malignant diseases underwent one in vitro fertilization cycle. Different stimulation protocols were used, depending on the menstrual cycle. Transvaginal oocyte retrieval was scheduled 34–36 h after human chorionic gonadotropin administration. Immediately afterwards, ovarian tissue was extracted laparoscopically. Results A mean of 10 oocytes were retrieved per patient, and 67% of the oocytes were successfully fertilized using intracytoplasmic sperm injection. No periprocedural complications and no complications leading to postponement of the start of chemotherapy occurred. The ovarian tissues were of good quality, with a normal age-related follicular distribution and without carcinoma cell invasion. Conclusions An approach using ovarian stimulation first, followed by laparoscopic collection of ovarian tissue, is a useful strategy for increasing the efficacy of fertility preservation techniques. The ovarian tissue is not affected by prior ovarian stimulation. PMID:23510640

  20. Combined effect of motor imagery and peripheral nerve electrical stimulation on the motor cortex.

    PubMed

    Saito, Kei; Yamaguchi, Tomofumi; Yoshida, Naoshin; Tanabe, Shigeo; Kondo, Kunitsugu; Sugawara, Kenichi

    2013-06-01

    Although motor imagery enhances the excitability of the corticospinal tract, there are no peripheral afferent inputs during motor imagery. In contrast, peripheral nerve electrical stimulation (ES) can induce peripheral afferent inputs; thus, a combination of motor imagery and ES may enhance the excitability of the corticospinal tract compared with motor imagery alone. Moreover, the level of stimulation intensity may also be related to the modulation of the excitability of the corticospinal tract during motor imagery. Here, we evaluated whether a combination of motor imagery and peripheral nerve ES influences the excitability of the corticospinal tract and measured the effect of ES intensity on the excitability induced during motor imagery. The imagined task was a movement that involved touching the thumb to the little finger, whereas ES involved simultaneous stimulation of the ulnar and median nerves at the wrist. Two different ES intensities were used, one above the motor threshold and another above the sensory threshold. Further, we evaluated whether actual movement with afferent input induced by ES modulates the excitability of the corticospinal tract as well as motor imagery. We found that a combination of motor imagery and ES enhanced the excitability of the motor cortex in the thenar muscle compared with the other condition. Furthermore, we established that the modulation of the corticospinal tract was related to ES intensity. However, we found that the excitability of the corticospinal tract induced by actual movement was enhanced by peripheral nerve ES above the sensory threshold.

  1. Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy.

    PubMed

    Frauenknecht, Katrin; Diederich, Kai; Leukel, Petra; Bauer, Henrike; Schäbitz, Wolf-Rüdiger; Sommer, Clemens J; Minnerup, Jens

    2016-01-01

    We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 μg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective.

  2. Machine learning approach to optimizing combined stimulation and medication therapies for Parkinson’s disease

    PubMed Central

    Shamir, Reuben R.; Dolber, Trygve; Noecker, Angela M.; Walter, Benjamin L.; McIntyre, Cameron C.

    2015-01-01

    Background Deep brain stimulation (DBS) of the subthalamic region is an established therapy for advanced Parkinson’s disease (PD). However, patients often require time-intensive postoperative management to balance their coupled stimulation and medication treatments. Given the large and complex parameter space associated with this task, we propose that clinical decision support systems (CDSS) based on machine learning algorithms could assist in treatment optimization. Objective Develop a proof-of-concept implementation of a CDSS that incorporates patient-specific details on both stimulation and medication. Methods Clinical data from 10 patients, and 89 post-DBS surgery visits, were used to create a prototype CDSS. The system was designed to provide three key functions: 1) information retrieval; 2) visualization of treatment, and; 3) recommendation on expected effective stimulation and drug dosages, based on three machine learning methods that included support vector machines, Naïve Bayes, and random forest. Results Measures of medication dosages, time factors, and symptom-specific preoperative response to levodopa were significantly correlated with postoperative outcomes (p<0.05) and their effect on outcomes was of similar magnitude to that of DBS. Using those results, the combined machine learning algorithms were able to accurately predict 86% (12/14) of the motor improvement scores at one year after surgery. Conclusions Using patient-specific details, an appropriately parameterized CDSS could help select theoretically optimal DBS parameter settings and medication dosages that have potential to improve the clinical management of PD patients. PMID:26140956

  3. Targeting Neuronal Networks with Combined Drug and Stimulation Paradigms Guided by Neuroimaging to Treat Brain Disorders.

    PubMed

    Faingold, Carl L; Blumenfeld, Hal

    2015-10-01

    Improved therapy of brain disorders can be achieved by focusing on neuronal networks, utilizing combined pharmacological and stimulation paradigms guided by neuroimaging. Neuronal networks that mediate normal brain functions, such as hearing, interact with other networks, which is important but commonly neglected. Network interaction changes often underlie brain disorders, including epilepsy. "Conditional multireceptive" (CMR) brain areas (e.g., brainstem reticular formation and amygdala) are critical in mediating neuroplastic changes that facilitate network interactions. CMR neurons receive multiple inputs but exhibit extensive response variability due to milieu and behavioral state changes and are exquisitely sensitive to agents that increase or inhibit GABA-mediated inhibition. Enhanced CMR neuronal responsiveness leads to expression of emergent properties--nonlinear events--resulting from network self-organization. Determining brain disorder mechanisms requires animals that model behaviors and neuroanatomical substrates of human disorders identified by neuroimaging. However, not all sites activated during network operation are requisite for that operation. Other active sites are ancillary, because their blockade does not alter network function. Requisite network sites exhibit emergent properties that are critical targets for pharmacological and stimulation therapies. Improved treatment of brain disorders should involve combined pharmacological and stimulation therapies, guided by neuroimaging, to correct network malfunctions by targeting specific network neurons.

  4. Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies.

    PubMed

    Leyvraz, S; Herrmann, R; Guillou, L; Honegger, H P; Christinat, A; Fey, M F; Sessa, C; Wernli, M; Cerny, T; Dietrich, D; Pestalozzi, B

    2006-11-20

    Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

  5. A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice

    PubMed Central

    Kalita, Bhargab; Ranjan, Rajiv; Singh, Abhinav; Yashavarddhan, M. H.; Bajaj, Sania; Gupta, Manju Lata

    2016-01-01

    Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application. PMID:28036347

  6. Plasma biomarkers of clinical response during chemotherapy plus combination antiretroviral therapy (cART) in HIV+ patients with advanced Kaposi sarcoma.

    PubMed

    Tedeschi, Rosamaria; Bidoli, Ettore; Bortolin, Maria Teresa; Schioppa, Ornella; Vaccher, Emanuela; De Paoli, Paolo

    2015-10-06

    This study aimed to evaluate plasma concentration of selected cancer-associated inflammatory and immune-modulated cytokines in HIV+ patients with advanced Kaposi sarcoma (KS), and to explore candidate biomarkers capable of predicting clinical outcome in response to chemotherapy (CT) plus combination antiretroviral therapy (cART).Thirty-seven plasma cytokines/chemokines were assessed by Luminex technology in 27 consecutive HIV+ KS patients, followed-up during CT and cART of maintenance (m-cART). Associations between plasma concentration of biomarkers and patient clinical response to m-cART were evaluated by means of Hazard Ratios (HRs) and corresponding 95% Confidence Intervals (CIs).Plasma baseline concentration of Granulocyte colony-stimulating factor (G-CSF), Hepatocyte growth factor (HGF) and endoglin were found to be associated with m-cART clinical response (HR:1.56, 95%CI:1.09-2.22, p = 0.01; HR:0.32, 95% CI:0.10-0.99, p = 0.05; HR:0.72, 95% CI:0.54-0.96, p = 0.03, respectively). The multivariate analysis confirmed the associations of baseline plasma G-CSF and HGF concentration with m-cART clinical complete remission response (HR:1.78, 95% CI:1.15-2.74, p = 0.009; HR:0.19, 95% CI:0.04-0.95, p = 0.04). Our exploratory study suggested that plasma G-CSF, HGF and endoglin may be novel predictors of clinical response during m-cART in HIV+ KS patients. Nonetheless, these findings should be further validated in an independent population study.

  7. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma

    PubMed Central

    Homet Moreno, Blanca; Mok, Stephen; Comin-Anduix, Begonya; Hu-Lieskovan, Siwen; Ribas, Antoni

    2016-01-01

    The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAFV600E mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8+ tumor infiltrating lymphocytes (TILs), as well as CD4+ T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. PMID:27622011

  8. Antitumor protection from the murine T-cell leukemia/lymphoma EL4 by the continuous subcutaneous coadministration of recombinant macrophage-colony stimulating factor and interleukin-2.

    PubMed

    Vallera, D A; Taylor, P A; Aukerman, S L; Blazar, B R

    1993-09-15

    Combined continuous s.c. coadministration of macrophage-colony stimulating factor (M-CSF) plus interleukin-2 (IL-2) by osmotic pump protected mice given i.v. injections of a lethal dose of EL4 T-cell leukemia/lymphoma. Antitumor protection was significantly greater than that afforded by treatment with either cytokine alone. Since neither IL-2 receptors nor M-CSF receptors were expressed on EL4, the antitumor effect was likely attributed to murine effector cells. To determine how M-CSF+IL-2 provided this effect, we performed immunophenotypic and functional analyses as well as in vivo depletion studies of putative antitumor effector cells. Splenic phenotyping experiments revealed that the highest levels of macrophages and natural killer cells were observed in mice given the cytokine combination rather than either M-CSF or IL-2 alone. In vivo depletion of natural killer cells ablated the antitumor protective effect of M-CSF and IL-2. T-cells were also important for M-CSF+IL-2 efficacy, since adult thymectomy/T-cell depletion significantly inhibited the ability of cytokine coadministration to protect against EL4. Coadministration of the 2 cytokines significantly elevated in vivo levels of CD3+CD4+, CD3+CD8+, CD3+NK1.1+ T-cells, and CD3+CD25+ (activated) T-cells, and elevated anti-EL4 cytotoxic T-cell activity measured in vitro. Although WBC counts and fluorescence-activated cell sorter studies showed that M-CSF+IL-2 treatment significantly elevated neutrophils, s.c. delivery of granulocyte-colony stimulating factor at doses sufficient to induce neutrophilia was unable to confer anti-EL4 protection. These studies indicate that macrophages, T-cells, and natural killer cells are all important in the M-CSF+IL-2 anti-EL4 response. The superior antitumor effect of this cytokine combination along with the ability of M-CSF to diminish the toxicity of IL-2 in this model suggests that further investigations into the clinical potential of this combination treatment are warranted.

  9. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators

    PubMed Central

    Wang, Wei; Hong, Jeong S.; Rab, Andras; Sorscher, Eric J.; Kirk, Kevin L.

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3–5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein. PMID:27007499

  10. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.

    PubMed

    Wang, Wei; Hong, Jeong S; Rab, Andras; Sorscher, Eric J; Kirk, Kevin L

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3-5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein.

  11. Combination of transcranial direct current stimulation and methylphenidate in subacute stroke.

    PubMed

    Wang, Qing Mei; Cui, Huashun; Han, Soo Jeong; Black-Schaffer, Randie; Volz, Magdalena Sarah; Lee, Yong-Tae; Herman, Seth; Latif, Lydia Abul; Zafonte, Ross; Fregni, Felipe

    2014-05-21

    Noninvasive transcranial direct current stimulation (tDCS) and methylphenidate (MP) are associated with motor recovery after stroke. Based on the potentially complementary mechanisms of these interventions, we examined whether there is an interactive effect between MP and tDCS. In this preliminary study, we randomized subacute stroke subjects to receive tDCS alone, MP alone or combination of tDCS and MP. A blinded rater measured safety, hand function, and cortical excitability before and after treatment. None of the treatments caused any major or severe adverse effects or induced significant differences in cortical excitability. Analysis of variance of gain score, as measured by Purdue pegboard test, showed a significant between-group difference (F(2,6)=12.167, p=0.008). Post hoc analysis showed that the combination treatment effected greater Purdue pegboard gain scores than tDCS alone (p=0.017) or MP alone (p=0.01). Our preliminary data with nine subjects shows an interesting dissociation between motor function improvement and lack of motor corticospinal plasticity changes as indexed by transcranial magnetic stimulation in subacute stroke subjects.

  12. Combined neuromodulatory interventions in acute experimental pain: assessment of melatonin and non-invasive brain stimulation

    PubMed Central

    da Silva, Nádia Regina Jardim; Laste, Gabriela; Deitos, Alícia; Stefani, Luciana Cadore; Cambraia-Canto, Gustavo; Torres, Iraci L. S.; Brunoni, Andre R.; Fregni, Felipe; Caumo, Wolnei

    2015-01-01

    Transcranial direct current stimulation (tDCS) and melatonin can effectively treat pain. Given their potentially complementary mechanisms of action, their combination could have a synergistic effect. Thus, we tested the hypothesis that compared to the control condition and melatonin alone, tDCS combined with melatonin would have a greater effect on pain modulatory effect, as assessed by quantitative sensory testing (QST) and by the pain level during the Conditioned Pain Modulation (CPM)-task. Furthermore, the combined treatment would have a greater cortical excitability effect as indicated by the transcranial magnetic stimulation (TMS) and on the serum BDNF level. Healthy males (n = 20), (aged 18–40 years), in a blinded, placebo-controlled, crossover, clinical trial, were randomized into three groups: sublingual melatonin (0.25 mg/kg) + a-tDCS, melatonin (0.25 mg/kg) + sham-(s)-tDCS, or sublingual placebo+sham-(s)-tDCS. Anodal stimulation (2 mA, 20 min) was applied over the primary motor cortex. There was a significant difference in the heat pain threshold (°C) for melatonin+a-tDCS vs. placebo+s-tDCS (mean difference: 4.86, 95% confidence interval [CI]: 0.9 to 8.63) and melatonin+s-tDCS vs. placebo+s-tDCS (mean: 5.16, 95% CI: 0.84 to 8.36). There was no difference between melatonin+s-tDCS and melatonin+a-tDCS (mean difference: 0.29, 95% CI: −3.72 to 4.23). The mean change from the baseline on amplitude of motor evocate potential (MEP) was significantly higher in the melatonin+a-tDCS (−19.96% ± 5.2) compared with melatonin+s-tDCS group (−1.36% ± 5.35) and with placebo+s-tDCS group (3.61% ± 10.48), respectively (p < 0.05 for both comparisons). While melatonin alone or combined with a-tDCS did not significantly affect CPM task result, and serum BDNF level. The melatonin effectively reduced pain; however, its association with a-tDCS did not present an additional modulatory effect on acute induced pain. PMID:25873871

  13. The combination of radiotherapy and immunotherapy using glycated chitosan as an immunological stimulant

    NASA Astrophysics Data System (ADS)

    Chang, Chun-Yuan; Leu, Jyh-Der; Wang, Chung-Yi; Chen, Wei R.; Lee, Yi-Jang

    2015-03-01

    Immunotherapy has been reported to effectively treat various cancers. In addition, scientists are dedicated in finding whether the combination of radiotherapy and immunotherapy can efficiently suppress cancer progression and recurrence. Although radiotherapy has been widely used for breast cancer, better strategies to overcome the latestage breast cancer remains explored. The glycated chitosan (GC), a novel immunological stimulant, was demonstrated to trigger local immune response facilitating the enhancement of radiosensitivity. Our previous study also revealed that the cell mortality and invasive ability were decreased under GC treatment, but the underlying mechanism remains unclear. In this study, we used 4T1-3R-L, a derived murine breast cancer cell line from the spontaneous metastasized liver lesion. We combined ionizing radiation with GC to treat 4T1-3R-L and found the expression of DNA damage-related genes such as gamma-H2AX was more than radiation alone In addition, the cell cycle distribution and colony forming assay showed an increased sub-G1 population and decreased cell survival rate after IR combined GC treatment. Taken together, we sought to elucidate the underlying mechanism by the investigation of DNA damage repair process when IR combined with GC, and to explore another advantage of GC to aid other cancer treatments. Based on our most updated results, the GC treatment is able to effectively increase the radiosensitivity through an immune-responsive signaling transduction, indicating that GC could be a valuable therapeutic strategy for treating against advanced breast cancers.

  14. High-dose etoposide plus granulocyte colony-stimulating factor as an effective chemomobilization regimen for autologous stem cell transplantation in patients with non-Hodgkin Lymphoma previously treated with CHOP-based chemotherapy: a study from the Consortium for Improving Survival of Lymphoma.

    PubMed

    Hyun, Shin Young; Cheong, June-Won; Kim, Soo-Jeong; Min, Yoo Hong; Yang, Deok-Hwan; Ahn, Jae-Sook; Lee, Won-Sik; Ryoo, Hun-Mo; Do, Young Rok; Lee, Ho Sup; Lee, Jae Hoon; Oh, Sung Yong; Suh, Cheolwon; Yhim, Ho-Young; Kim, Jin Seok

    2014-01-01

    We conducted a multicenter retrospective study to compare the efficacy and toxicity of various chemomobilization regimens: high-dose (HD) cyclophosphamide, HD etoposide (VP-16), and platinum-based chemotherapies. We reviewed the experiences of 10 institutions with 103 non-Hodgkin lymphoma patients who had previously only been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. The mobilization yields for each regimen were analyzed. HD VP-16 mobilized a significantly higher median number of CD34(+) cells (16.22 × 10(6) cells/kg) than HD cyclophosphamide (4.44 × 10(6) cells/kg) or platinum-based chemotherapies (6.08 × 10(6) cells/kg, P < .001). The rate of successful mobilization (CD34(+) cell count ≥ 5.0 × 10(6) cells/kg) was also significantly higher for HD VP-16 (86%) than for HD cyclophosphamide (45%) or platinum-based chemotherapies (61%, P = .004). The successful mobilization rate on day 1 of 72% for HD VP-16 was significantly higher than the rates for HD cyclophosphamide (13%) and platinum-based chemotherapies (26%, P < .001). In multivariate analysis, HD VP-16 was a significant predictor of successful mobilization (P = .014; odds ratio, 5.25; 95% confidence interval, 1.40 to 19.63). Neutropenic fever occurred in 67% of patients treated with HD VP-16. The incidence was similar for HD cyclophosphamide (58%, P = .454) but was significantly lower for platinum-based chemotherapies (12%, P < .001). However, fatal (grade ≥ 4) infection and treatment-related mortality were not observed in this study. In conclusion, the mobilization yield was significantly influenced by the chemomobilization regimen, and HD VP-16 was a highly effective mobilization regimen in patients with non-Hodgkin lymphoma.

  15. Transcranial Direct Current Stimulation Combined with Treadmill Gait Training in Delayed Neuro-psychomotor Development

    PubMed Central

    Grecco, Luanda André Collange; E Mendonça, Mariana; Duarte, Natália A. C.; Zanon, Nelci; Fregni, Felipe; Oliveira, Claudia Santos

    2014-01-01

    [Purpose] The aim of the present study was to describe the results of transcranial direct current stimulation combined with treadmill training in a child with delayed neuro-psychomotor development. [Subject and Methods] Transcranial direct current stimulation (intensity: 1 mA) was applied over the primary motor cortex for 20 minutes during simultaneous treadmill training (2.5 km/h) in ten sessions. [Results] Clinically significant improvement was found in motor development (fine motor subscale, 23 to 25; gross motor subscale, 32 to 41). Reductions in mean oscillation of the center of pressure were found in the anteroposterior (239.2 to 146.5 mm) and mediolateral (177.4 to 149.2 mm) directions. Increases occurred in cadence (106 to 123 steps/minute), step length (0.16 to 0.23 m), step width (0.09 to 0.14 m) and gait velocity with support (0.3 to 0.7 m/s). [Conclusion] After treatment, the child was able to initiate the standing position for the first time and walk without support. PMID:25013302

  16. Efficacy of Cranial Electrotherapy Stimulation Combined with Biofeedback Therapy in Patients with Functional Constipation

    PubMed Central

    Gong, Bing Yan; Ma, Hong Mei; Zang, Xiao Ying; Wang, Si Yuan; Zhang, Yi; Jiang, Nan; Zhang, Xi Peng; Zhao, Yue

    2016-01-01

    Background/Aims A large number of studies have shown that function constipation (FC) has an extremely high incidence of mental and psychological disorders. Cranial electrotherapy stimulation (CES) was applied to the treatment of psychological disorders such as anxiety and depression. We explored the effects of CES combined with biofeedback therapy (BFT) on the psychological state, clinical symptoms, and anorectal function in patients with FC. Methods A total of 74 patients with FC were randomly divided into 2 groups. The control group received BFT. CES combined with BFT was carried out in the experiment group. All patients were assessed using the self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Wexner constipation score at baseline and the end of each course. Anorectal manometry and balloon expulsion tests were performed before and after treatment. Results After treatment, the participants in the experiment group had significantly lower score SAS, SDS, and Wexner constipation scores than the control group (all P < 0.05). The number of successful expulsion in the experiment group was larger than the control group (P = 0.016). Conclusions CES combined with BFT was effective in improving the psychological status of anxiety, depression, and bowel symptoms in patients with FC. PMID:26932836

  17. Feasibility of Using Lokomat Combined with Functional Electrical Stimulation for the Rehabilitation of Foot Drop

    PubMed Central

    Laursen, Christian B.; Nielsen, Jørgen F.; Andersen, Ole K.; Spaich, Erika G.

    2016-01-01

    This study investigated the clinical feasibility of combining the electromechanical gait trainer Lokomat with functional electrical therapy (LokoFET), stimulating the common peroneal nerve during the swing phase of the gait cycle to correct foot drop as an integrated part of gait therapy. Five patients with different acquired brain injuries trained with LokoFET 2-3 times a week for 3-4 weeks. Pre- and post-intervention evaluations were performed to quantify neurophysiological changes related to the patients’ foot drop impairment during the swing phase of the gait cycle. A semi-structured interview was used to investigate the therapists’ acceptance of LokoFET in clinical practice. The patients showed a significant increase in the level of activation of the tibialis anterior muscle and the maximal dorsiflexion during the swing phase, when comparing the pre- and post-intervention evaluations. This showed an improvement of function related to the foot drop impairment. The interview revealed that the therapists perceived the combined system as a useful tool in the rehabilitation of gait. However, lack of muscle selectivity relating to the FES element of LokoFET was assessed to be critical for acceptance in clinical practice. PMID:27990246

  18. Best of both worlds: promise of combining brain stimulation and brain connectome

    PubMed Central

    Luft, Caroline Di Bernardi; Pereda, Ernesto; Banissy, Michael J.; Bhattacharya, Joydeep

    2014-01-01

    Transcranial current brain stimulation (tCS) is becoming increasingly popular as a non-pharmacological non-invasive neuromodulatory method that alters cortical excitability by applying weak electrical currents to the scalp via a pair of electrodes. Most applications of this technique have focused on enhancing motor and learning skills, as well as a therapeutic agent in neurological and psychiatric disorders. In these applications, similarly to lesion studies, tCS was used to provide a causal link between a function or behavior and a specific brain region (e.g., primary motor cortex). Nonetheless, complex cognitive functions are known to rely on functionally connected multitude of brain regions with dynamically changing patterns of information flow rather than on isolated areas, which are most commonly targeted in typical tCS experiments. In this review article, we argue in favor of combining tCS method with other neuroimaging techniques (e.g., fMRI, EEG) and by employing state-of-the-art connectivity data analysis techniques (e.g., graph theory) to obtain a deeper understanding of the underlying spatiotemporal dynamics of functional connectivity patterns and cognitive performance. Finally, we discuss the possibilities of using these combined techniques to investigate the neural correlates of human creativity and to enhance creativity. PMID:25126060

  19. Combined effects of fast treadmill walking and functional electrical stimulation on post-stroke gait.

    PubMed

    Kesar, Trisha M; Reisman, Darcy S; Perumal, Ramu; Jancosko, Angela M; Higginson, Jill S; Rudolph, Katherine S; Binder-Macleod, Stuart A

    2011-02-01

    Gait dysfunctions are highly prevalent in individuals post-stroke and affect multiple lower extremity joints. Recent evidence suggests that treadmill walking at faster than self-selected speeds can help improve post-stroke gait impairments. Also, the combination of functional electrical stimulation (FES) and treadmill training has emerged as a promising post-stroke gait rehabilitation intervention. However, the differential effects of combining FES with treadmill walking at the fast versus a slower, self-selected speed have not been compared previously. In this study, we compared the immediate effects on gait while post-stroke individuals walked on a treadmill at their self-selected speed without FES (SS), at the SS speed with FES (SS-FES), at the fastest speed they are capable of attaining (FAST), and at the FAST speed with FES (FAST-FES). During SS-FES and FAST-FES, FES was delivered to paretic ankle plantarflexors during terminal stance and to paretic dorsiflexors during swing phase. Our results showed improvements in peak anterior ground reaction force (AGRF) and trailing limb angle during walking at FAST versus SS. FAST-FES versus SS-FES resulted in greater peak AGRF, trailing limb angle, and swing phase knee flexion. FAST-FES resulted in further increase in peak AGRF compared to FAST. We posit that the enhancement of multiple aspects of post-stroke gait during FAST-FES suggest that FAST-FES may have potential as a post-stroke gait rehabilitation intervention.

  20. The combined effects of transcutaneous electrical nerve stimulation (TENS) and stretching on muscle hardness and pressure pain threshold.

    PubMed

    Karasuno, Hiroshi; Ogihara, Hisayoshi; Morishita, Katsuyuki; Yokoi, Yuka; Fujiwara, Takayuki; Ogoma, Yoshiro; Abe, Koji

    2016-04-01

    [Purpose] This study aimed to clarify the immediate effects of a combined transcutaneous electrical nerve stimulation and stretching protocol. [Subjects] Fifteen healthy young males volunteered to participate in this study. The inclusion criterion was a straight leg raising range of motion of less than 70 degrees. [Methods] Subjects performed two protocols: 1) stretching (S group) of the medial hamstrings, and 2) tanscutaneous electrical nerve stimulation (100 Hz) with stretching (TS group). The TS group included a 20-minute electrical stimulation period followed by 10 minutes of stretching. The S group performed 10 minutes of stretching. Muscle hardness, pressure pain threshold, and straight leg raising range of motion were analyzed to evaluate the effects. The data were collected before transcutaneous electrical nerve stimulation (T1), before stretching (T2), immediately after stretching (T3), and 10 minutes after stretching (T4). [Results] Combined transcutaneous electrical nerve stimulation and stretching had significantly beneficial effects on muscle hardness, pressure pain threshold, and straight leg raising range of motion at T2, T3, and T4 compared with T1. [Conclusion] These results support the belief that transcutaneous electrical nerve stimulation combined with stretching is effective in reducing pain and decreasing muscle hardness, thus increasing range of motion.

  1. The combined effects of transcutaneous electrical nerve stimulation (TENS) and stretching on muscle hardness and pressure pain threshold

    PubMed Central

    Karasuno, Hiroshi; Ogihara, Hisayoshi; Morishita, Katsuyuki; Yokoi, Yuka; Fujiwara, Takayuki; Ogoma, Yoshiro; Abe, Koji

    2016-01-01

    [Purpose] This study aimed to clarify the immediate effects of a combined transcutaneous electrical nerve stimulation and stretching protocol. [Subjects] Fifteen healthy young males volunteered to participate in this study. The inclusion criterion was a straight leg raising range of motion of less than 70 degrees. [Methods] Subjects performed two protocols: 1) stretching (S group) of the medial hamstrings, and 2) tanscutaneous electrical nerve stimulation (100 Hz) with stretching (TS group). The TS group included a 20-minute electrical stimulation period followed by 10 minutes of stretching. The S group performed 10 minutes of stretching. Muscle hardness, pressure pain threshold, and straight leg raising range of motion were analyzed to evaluate the effects. The data were collected before transcutaneous electrical nerve stimulation (T1), before stretching (T2), immediately after stretching (T3), and 10 minutes after stretching (T4). [Results] Combined transcutaneous electrical nerve stimulation and stretching had significantly beneficial effects on muscle hardness, pressure pain threshold, and straight leg raising range of motion at T2, T3, and T4 compared with T1. [Conclusion] These results support the belief that transcutaneous electrical nerve stimulation combined with stretching is effective in reducing pain and decreasing muscle hardness, thus increasing range of motion. PMID:27190439

  2. Bioreactor for modulation of cardiac microtissue phenotype by combined static stretch and electrical stimulation

    PubMed Central

    Miklas, Jason W; Nunes, Sara S; Sofla, Aarash; Reis, Lewis A; Pahnke, Aric; Xiao, Yun; Laschinger, Carol; Radisic, Milica

    2014-01-01

    We describe here a bioreactor capable of simultaneously applying mechanical and electrical field stimulation in conjunction with static strain and on-line force of contraction measurements. It consisted of a polydimethylsiloxane (PDMS) tissue chamber and a pneumatically driven stretch platform. The chamber contained eight tissue microwells (8.05 mm in length and 2.5 mm in width) with a pair of posts (2.78 mm in height and 0.8 mm in diameter) in each well to serve as fixation points and for measurements of contraction force. Carbon rods, stimulating electrodes, were placed into the PDMS chamber such that one pair stimulated four microwells. For feasibility studies, neonatal rat cardiomyocytes were seeded in collagen gels into the microwells. Following three days of gel compaction, electrical field stimulation at 3–4 V/cm and 1Hz, mechanical stimulation of 5% static strain or electromechanical stimulation (field stimulation at 3–4 V/cm, 1Hz and 5% static strain) were applied for 3 days. Cardiac microtissues subjected to electromechanical stimulation exhibited elevated amplitude of contraction and improved sarcomere structure as evidenced by sarcomeric α-actinin, actin and troponin T staining compared to microtissues subjected to electrical or mechanical stimulation alone or non-stimulated controls. The expression of atrial natriuretic factor and brain natriuretic peptide was also elevated in the electromechanically stimulated group. PMID:24876342

  3. E-ring 8-isoprostanes are agonists at EP2- and EP4-prostanoid receptors on human airway smooth muscle cells and regulate the release of colony-stimulating factors by activating cAMP-dependent protein kinase.

    PubMed

    Clarke, Deborah L; Belvisi, Maria G; Hardaker, Elizabeth; Newton, Robert; Giembycz, Mark A

    2005-02-01

    8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and Falpha-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1beta (IL-1beta). The elaboration of GM-CSF and G-CSF by IL-1beta was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E(1) and 8-iso-PGE(2), but not by 8-iso-PGF(1alpha), 8-iso-PGF(2alpha), and 8-iso-PGF(3)alpha. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP(1)-/EP(2)-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE(1) and 8-iso-PGE(2) on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP(2)-subtype. In contrast, the facilitation by 8-iso-PGE(1) and 8-iso-PGE(2) of G-CSF release was unaffected by AH 6809 and the selective EP(4)-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing (1)effect of E-ring (2)8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE(1) and 8-iso-PGE(2

  4. Combination of Eccentric Exercise and Neuromuscular Electrical Stimulation to Improve Quadriceps Function Post-ACL Reconstruction

    PubMed Central

    Lepley, Lindsey K.; Wojtys, Edward M.; Palmieri-Smith, Riann M.

    2014-01-01

    Background Neuromuscular electrical stimulation (NMES) has been shown to reduce quadriceps activation failure (QAF), and eccentric exercise has been shown lessen muscle atrophy post-ACL reconstruction. Given that these are two critical components of quadriceps strength, intervention combining these therapies may be effective at reinstituting quadriceps function post-anterior cruciate ligament (ACL) reconstruction. Objectives To evaluate the effectiveness of a combined NMES and eccentric exercise intervention to improve the recovery of quadriceps activation and strength post-reconstruction. Design Parallel longitudinal design. Setting Laboratory. Participants Thirty-six individuals post-injury were placed into four treatment groups (N&E, NMES and eccentrics; E-only, eccentrics only; N-only, NMES-only; STND, standard of care) and ten healthy controls participated. Intervention N&E and N-only received the NMES protocol 2x per week for the first six weeks post-reconstruction. N&E and E-only received the eccentric exercise protocol 2x per week beginning six weeks post-reconstruction. Main outcome measure Quadriceps activation was assessed via the superimposed burst technique and quantified via the central activation ratio. Quadriceps strength was assessed via maximal voluntary isomeric contractions (Nm/kg). Data was gathered on three occasions: pre-operative, 12-weeks-post-surgery and at return-to-play. Results No differences in pre-operative measures existed (P>0.05). E-only recovered quadriceps activation better than N-only or STND (P<0.05). N&E and E-only recovered strength better than N-only or the STND (P<0.05) and had strength values that were similar to healthy individuals at return-to-play (P>0.05). Conclusion Eccentric exercise was capable of restoring levels of quadriceps activation and strength that were similar to those of healthy adults and better than NMES alone. PMID:25819154

  5. Iron 'ElectriRx' man: Overground stepping in an exoskeleton combined with noninvasive spinal cord stimulation after paralysis.

    PubMed

    Gad, Parag N; Gerasimenko, Yury P; Zdunowski, Sharon; Sayenko, Dimitry; Haakana, Piia; Turner, Amanda; Lu, Daniel; Roy, Roland R; Edgerton, V Reggie

    2015-08-01

    We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 yr) and completely absent of vision (>15 yr) using a novel strategy - transcutaneous spinal cord stimulation at selected sites over the spinal vertebrae with just one week of training. We also asked whether this stimulation strategy could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton. These stepping sessions in the presence of stimulation were accompanied by greater cardiac responses and sweating than could be attained without the stimulation. Based on the data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the overground stepping in an exoskeleton, a novel transcutaneous spinal cord stimulation paradigm, and daily training.

  6. Characterizing and Modulating Brain Circuitry through Transcranial Magnetic Stimulation Combined with Electroencephalography

    PubMed Central

    Farzan, Faranak; Vernet, Marine; Shafi, Mouhsin M. D.; Rotenberg, Alexander; Daskalakis, Zafiris J.; Pascual-Leone, Alvaro

    2016-01-01

    The concurrent combination of transcranial magnetic stimulation (TMS) with electroencephalography (TMS-EEG) is a powerful technology for characterizing and modulating brain networks across developmental, behavioral, and disease states. Given the global initiatives in mapping the human brain, recognition of the utility of this technique is growing across neuroscience disciplines. Importantly, TMS-EEG offers translational biomarkers that can be applied in health and disease, across the lifespan, and in humans and animals, bridging the gap between animal models and human studies. However, to utilize the full potential of TMS-EEG methodology, standardization of TMS-EEG study protocols is needed. In this article, we review the principles of TMS-EEG methodology, factors impacting TMS-EEG outcome measures, and the techniques for preventing and correcting artifacts in TMS-EEG data. To promote the standardization of this technique, we provide comprehensive guides for designing TMS-EEG studies and conducting TMS-EEG experiments. We conclude by reviewing the application of TMS-EEG in basic, cognitive and clinical neurosciences, and evaluate the potential of this emerging technology in brain research. PMID:27713691

  7. Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease.

    PubMed

    Rowland, Nathan C; Starr, Philip A; Larson, Paul S; Ostrem, Jill L; Marks, William J; Lim, Daniel A

    2015-02-01

    Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.

  8. Combined effect of relativistic and ponderomotive filamentation on coexisting stimulated Raman and Brillouin scattering

    SciTech Connect

    Vyas, Ashish Singh, Ram Kishor; Sharma, R. P.

    2014-11-15

    This paper presents a model to study the interplay between the stimulated Raman (SRS) and Brillouin scattering (SBS) along with the combined effect of relativistic and ponderomotive nonlinearities, at relativistic laser power. As the intense non-uniform laser beam propagates through the plasma, both the non-linearities are operative and modify the plasma refractive index in such a manner that one enhances the self-focusing (of the pump beam) caused by the other non-linearity. The interplay between the scattering processes (SRS and SBS) affects the pump filamentation process because of pump depletion and at the same time these scattering processes get modified due to this filamentation process. An impact of the filamentation process and coexistence of the scattering processes (SRS and SBS) on the back-reflectivity of scattered beams (SRS and SBS) has been explored and found that the back-reflectivity gets modified significantly. Results are also compared with the three wave interaction case (isolated SRS or SBS case)

  9. Combining simulation, instructor-produced videos, and online discussions to stimulate critical thinking in nursing students.

    PubMed

    Guhde, Jacqueline

    2010-01-01

    Combining the use of several different types of technology enables an instructor to develop teaching methods to address a specific problem area that students encounter and can greatly affect student learning. This article discusses a program that was developed that utilized SimMan, instructor-produced videos, and online discussion to stimulate critical thinking in beginning-level nursing students. The goal was to make the student aware of the importance of an initial thorough assessment of a client. This is especially difficult since new students are focused on learning the skills and have not had enough clinical experience to appreciate the importance of assessment. The first two videos show a nurse who makes a very incomplete assessment of the client and misses important observations. This leads to the patient (SimMan) going into respiratory distress. The third video demonstrates a complete assessment. The students viewed and discussed the first two videos online. After the third video, students posted their own reflections of this activity including what they learned and how this would change their behavior. The outcome showed an increased awareness of the importance of assessment. Instructors observed a change in behavior, which included early assessment of the client.

  10. Combining near-infrared spectroscopy with electroencephalography and repetitive transcranial magnetic stimulation

    NASA Astrophysics Data System (ADS)

    Näsi, Tiina; Kotilahti, Kalle; Mäki, Hanna; Nissilä, Ilkka; Meriläinen, Pekka

    2009-07-01

    The objective of the study was to assess the usability of a near-infrared spectroscopy (NIRS) device in multimodal measurements. We combined NIRS with electroencephalography (EEG) to record hemodynamic responses and evoked potentials simultaneously, and with transcranial magnetic stimulation (TMS) to investigate hemodynamic responses to repetitive TMS (rTMS). Hemodynamic responses and visual evoked potentials (VEPs) to 3, 6, and 12 s stimuli consisting of pattern-reversing checkerboards were successfully recorded in the NIRS/EEG measurement, and ipsi- and contralateral hemodynamic responses to 0.5, 1, and 2 Hz rTMS in the NIRS/TMS measurement. In the NIRS/EEG measurements, the amplitudes of the hemodynamic responses increased from 3- to 6-s stimulus, but not from 6- to 12-s stimulus, and the VEPs showed peaks N75, P100, and N135. In the NIRS/TMS measurements, the 2-Hz stimulus produced the strongest hemodynamic responses compared to the 0.5- and 1-Hz stimuli. In two subjects oxyhemoglobin concentration decreased and in one increased as a consequence of the 2-Hz rTMS. To locate the origin of the measured NIRS responses, methods have to be developed to investigate TMS-induced scalp muscle contractions. In the future, multimodal measurements may prove useful in monitoring or treating diseases such as stroke or Alzheimer's disease.

  11. Assessing consciousness in coma and related states using transcranial magnetic stimulation combined with electroencephalography.

    PubMed

    Gosseries, O; Thibaut, A; Boly, M; Rosanova, M; Massimini, M; Laureys, S

    2014-02-01

    Thanks to advances in medical care, an increased number of patients recover from coma. However, some remain in vegetative/unresponsive wakefulness syndrome or in a minimally conscious state. Detection of awareness in severely brain-injured patients is challenging because it relies on behavioral assessments, which can be affected by motor, sensory and cognitive impairments of the patients. Other means of evaluation are needed to improve the accuracy of the diagnosis in this challenging population. We will here review the different altered states of consciousness occurring after severe brain damage, and explain the difficulties associated with behavioral assessment of consciousness. We will then describe a non-invasive technique, transcranial magnetic stimulation combined with high-density electroencephalography (TMS-EEG), which has allowed us to detect the presence or absence of consciousness in different physiological, pathological and pharmacological states. Some potential underlying mechanisms of the loss of consciousness will then be discussed. In conclusion, TMS-EEG is highly promising in identifying markers of consciousness at the individual level and might be of great value for clinicians in the assessment of consciousness.

  12. Characterizing and Modulating Brain Circuitry through Transcranial Magnetic Stimulation Combined with Electroencephalography.

    PubMed

    Farzan, Faranak; Vernet, Marine; Shafi, Mouhsin M D; Rotenberg, Alexander; Daskalakis, Zafiris J; Pascual-Leone, Alvaro

    2016-01-01

    The concurrent combination of transcranial magnetic stimulation (TMS) with electroencephalography (TMS-EEG) is a powerful technology for characterizing and modulating brain networks across developmental, behavioral, and disease states. Given the global initiatives in mapping the human brain, recognition of the utility of this technique is growing across neuroscience disciplines. Importantly, TMS-EEG offers translational biomarkers that can be applied in health and disease, across the lifespan, and in humans and animals, bridging the gap between animal models and human studies. However, to utilize the full potential of TMS-EEG methodology, standardization of TMS-EEG study protocols is needed. In this article, we review the principles of TMS-EEG methodology, factors impacting TMS-EEG outcome measures, and the techniques for preventing and correcting artifacts in TMS-EEG data. To promote the standardization of this technique, we provide comprehensive guides for designing TMS-EEG studies and conducting TMS-EEG experiments. We conclude by reviewing the application of TMS-EEG in basic, cognitive and clinical neurosciences, and evaluate the potential of this emerging technology in brain research.

  13. Comparison of the effects of auditory subliminal stimulation and rational-emotive therapy, separately and combined, on self-concept.

    PubMed

    Möller, A T; Kotzé, H F; Sieberhagen, K J

    1993-02-01

    The present study investigated the effects on self-concept of Rational-Emotive Therapy and auditory subliminal stimulation (separately and in combination) on 141 undergraduate students with self-concept problems. They were randomly assigned to one of four groups receiving either Rational-Emotive Therapy, subliminal stimulation, both, or a placebo treatment. Rational-Emotive Therapy significantly improved scores on all the dependent measures (cognition, self-concept, self-esteem, anxiety), except for behavior. Results for the subliminal stimulation group were similar to those of the placebo treatment except for a significant self-concept improvement and a decline in self-concept related irrational cognitions. The combined treatment yielded results similar to those of Rational-Emotive Therapy, with tentative indications of continued improvement in irrational cognitions and self-concept from posttest to follow-up.

  14. Ultrafiltered pig leukocyte extract (IMUNOR) decreases nitric oxide formation and hematopoiesis-stimulating cytokine production in lipopolysaccharide-stimulated RAW 264.7 macrophages.

    PubMed

    Hofer, Michal; Vacek, Antonín; Lojek, Antonín; Holá, Jirina; Streitová, Denisa

    2007-10-01

    A low-molecular-weight (<12 kDa) ultrafiltered pig leukocyte extract, IMUNOR, was tested in experiments in vitro on non-stimulated and lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages in order to assess modulation of nitric oxide (NO) production (measured indirectly as the concentration of nitrites), hematopoiesis-stimulating activity of the supernatant of the macrophage cells (ascertained by counting cell colonies growing from progenitor cells for granulocytes and macrophages (GM-CFC) in vitro), and the release of hematopoiesis-stimulating cytokines. No hematopoiesis-stimulating activity and cytokine or NO production were found in the supernatant of non-stimulated macrophages. It was found that IMUNOR does not influence this status. Supernatant of LPS-stimulated macrophages was characterized by hematopoiesis-stimulating activity, as well as by the presence of nitrites, interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF). A key role in the hematopoiesis-stimulating activity of the supernatant of LPS-stimulated macrophages could be ascribed to G-CSF since the formation of the colonies could be abrogated nearly completely by monoclonal antibodies against G-CSF. IMUNOR was found to suppress all the mentioned manifestations of the LPS-activated macrophages. When considering these results together with those from our previous in vivo study revealing stimulatory effects of IMUNOR on radiation-suppressed hematopoiesis, a hypothesis may be formulated which postulates a homeostatic role of IMUNOR, consisting in stimulation of impaired immune and hematopoietic systems but also in cutting back the production of proinflammatory mediators in cases of overstimulation which threats with undesirable consequences.

  15. The Combined Use of Hypnosis and Sensory and Motor Stimulation in Assisting Children with Developmental Learning Problems.

    ERIC Educational Resources Information Center

    Jampolsky, Gerald G.

    Hypnosis was combined with sensory and motor stimulation to remediate reversal problems in five children (6 1/2- 9-years-old). Under hypnosis Ss were given the suggestion that they learn their numbers through feel and then given 1 hour of structured instruction daily for 10 days. Instruction stressed conditioning, vibratory memory, touch memory,…

  16. Effect of Digital Frequency Compression (DFC) on Speech Recognition in Candidates for Combined Electric and Acoustic Stimulation (EAS)

    ERIC Educational Resources Information Center

    Gifford, Rene H.; Dorman, Michael F.; Spahr, Anthony J.; McKarns, Sharon A.

    2007-01-01

    Purpose: To compare the effects of conventional amplification (CA) and digital frequency compression (DFC) amplification on the speech recognition abilities of candidates for a partial-insertion cochlear implant, that is, candidates for combined electric and acoustic stimulation (EAS). Method: The participants were 6 patients whose audiometric…

  17. Detection of dead regions in the cochlea: relevance for combined electric and acoustic stimulation.

    PubMed

    Moore, Brian C J; Glasberg, Brian; Schlueter, Anne

    2010-01-01

    A dead region is a region in the cochlea where the inner hair cells and/or the auditory neurones are functioning very poorly, if at all. People who are being considered for a combination of a cochlear implant and a hearing aid typically have a dead region in the parts of the cochlea that normally respond to medium and high frequencies, but have some functional hearing at lower frequencies. For such people, it may be useful to determine the edge frequency, f(e), of any dead region. This may be relevant to choosing the most appropriate insertion depth of the electrode array, and to the way that frequencies in the input signal are mapped to acoustic and electric stimulation. It may also be helpful in interpreting the results of research studies. This paper reviews methods for diagnosing dead regions and defining the value of f(e). It is argued that the value of f(e) cannot be determined reliably from the audiogram, although a dead region is likely to be present at a given frequency when the hearing loss at that frequency is 70 dB or more. When a sinusoidal signal is reported as sounding highly distorted or noise-like, a dead region may be present at the signal frequency, but again this is not a reliable indicator. The TEN test is a simple clinical method for diagnosis of dead regions. Where this test gives a positive diagnosis, it is recommended that psychophysical tuning curves be measured to define the value of f(e) more precisely.

  18. Enhanced chondrocyte densities on carbon nanotube composites: the combined role of nanosurface roughness and electrical stimulation.

    PubMed

    Khang, Dongwoo; Park, Grace E; Webster, Thomas J

    2008-07-01

    Simultaneous incorporation of intrinsic nanosurface roughness and external electrical stimulation may maximize the regeneration of articular cartilage tissue more than on nanosmooth, electrically nonstimulated biomaterials. Here, we report enhanced functions of chondrocytes (cartilage synthesizing cells) on electrically and nonelectrically stimulated highly dispersed carbon nanotubes (CNT) in polycarbonate urethane (PCU) compared to, respectively, stimulated pure PCU. Specifically, compared to conventional longitudinal (or vertical) electrical stimulation of chondrocytes on conducting surfaces which require high voltage, we developed a lateral electrical stimulation across CNT/PCU composite films of low voltage that enhanced chondrocyte functions. Chondrocyte adhesion and long-term cell densities (up to 2 days) were enhanced (more than 50%) on CNT/PCU composites compared to PCU alone without electrical stimulation. This study further explained why by measuring greater amounts of initial fibronectin adsorption (a key protein that mediates chondrocyte adhesion) on CNT/PCU composites which were more hydrophilic (than pure PCU) due to greater nanometer roughness. Importantly, the same trend was observed and was even significantly enhanced when chondrocytes were subjected to electrical stimulation (more than 200%) compared to nonstimulated CNT/PCU. For this reason, this study provided direct evidence of the positive role that conductive CNT/PCU films can play in promoting functions of chondrocytes for cartilage regeneration.

  19. Effects of combining mental practice with electromyogram-triggered electrical stimulation for stroke patients with unilateral neglect

    PubMed Central

    Park, Ji-Su; Choi, Jong-Bae; Kim, Won-Jin; Jung, Nam-Hae; Chang, Moonyoung

    2015-01-01

    [Purpose] The aim of this study was to investigate the effect of mental practice combined with electromyogram-triggered electrical stimulation on neglect and activities of daily living in stroke patients with unilateral neglect. [Subjects and Methods] Thirty-three stroke patients with unilateral neglect were recruited from a local university hospital, and were divided into two groups. The experimental group received an intervention consisting of mental practice combined with electromyogram-triggered electrical stimulation on the neglected side, while the control group received cyclic electrical stimulation at the same site. In addition, both groups received an identical intervention of conventional occupational and physical therapy. [Results] After the intervention, the experimental group showed a statistically significant improvement in the line bisection test result, star cancellation test result, and Catherine Bergego Scale scores. The control group showed a significant improvement only in the line bisection test result. [Conclusion] These data suggest that mental practice combined with electromyogram-triggered electrical stimulation is an effective, novel treatment for reducing unilateral neglect in stroke patients. PMID:26696725

  20. Effects of Practice Combined with Somatosensory or Motor Stimulation on Hand Function in Persons with Spinal Cord Injury

    PubMed Central

    2013-01-01

    Background: Individuals with chronic tetraplegia prioritize recovery of hand function as an important factor in improving their quality of life. Interventions that may improve hand function and increase corticomotor excitability are functional electrical stimulation (FES), somatosensory stimulation (SS), and task-oriented training. Objective: We compared functional and corticomotor outcomes in a control condition to changes associated with FES (triggered via electromygraphic signals) and with SS (constant trains), each combined with either unimanual or bimanual training. Methods: Using a randomized, clinical trial design, comparisons were made to a delayed intervention control group. Participants (n = 24) had chronic tetraplegia, with the ability to activate thenar muscles, and were randomly assigned to either the immediate intervention (intervention) or control/ delayed intervention groups. Primary analyses compared intervention (FES or SS) to control/delayed intervention. Secondary analyses compared subgroups of FES versus SS (regardless of uni- or bilateral training) and uni- versus bimanual training (regardless of stimulation type). Outcomes were assessed before and after the control and the intervention period. Results: Compared to control/delayed intervention, the intervention group had greater changes in unimanual function and corticomotor area, regardless of whether practice was combined with FES or with SS. Irrespective of stimulation type, the bimanual subgroups improved to a greater extent than the unimanual subgroups on the bimanual hand function test. Conclusions: Hand training combined with either SS or FES was associated with improved hand use and corticomotor activity in persons with chronic tetraplegia. Both interventions appear to be equally effective. PMID:24244094

  1. Effect of Combination of Non-Invasive Spinal Cord Electrical Stimulation and Serotonin Receptor Activation in Patients with Chronic Spinal Cord Lesion.

    PubMed

    Moshonkina, T R; Shapkova, E Yu; Sukhotina, I A; Emeljannikov, D V; Gerasimenko, Yu P

    2016-10-01

    We analyzed the efficiency of percutaneous electrical stimulation of the spinal cord and serotonin receptor activation in rehabilitation of paralyzed patients. Four-week course of spinal cord electrical stimulation combined with mechanotherapy produced positive shifts in the status of chronically paralyzed patients. Serotonin receptor activation potentiated the effect of spinal cord stimulation and can be regarded as an additional neurorehabilitation option.

  2. Granulocyte, granulocyte–macrophage, and macrophage colony-stimulating factors can stimulate the invasive capacity of human lung cancer cells

    PubMed Central

    Pei, X-H; Nakanishi, Y; Takayama, K; Bai, F; Hara, N

    1999-01-01

    We and other researchers have previously found that colony-stimulating factors (CSFs), which generally include granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), promote invasion by lung cancer cells. In the present study, we studied the effects of these CSFs on gelatinase production, urokinase plasminogen activator (uPA) production and their activity in human lung cancer cells. Gelatin zymographs of conditioned media derived from human lung adenocarcinoma cell lines revealed two major bands of gelatinase activity at 68 and 92 kDa, which were characterized as matrix metalloproteinase (MMP)-2 and MMP-9 respectively. Treatment with CSFs increased the 68- and 92-kDa activity and converted some of a 92-kDa proenzyme to an 82-kDa enzyme that was consistent with an active form of the MMP-9. Plasminogen activator zymographs of the conditioned media from the cancer cells showed that CSF treatment resulted in an increase in a 48–55 kDa plasminogen-dependent gelatinolytic activity that was characterized as human uPA. The conditioned medium from the cancer cells treated with CSFs stimulated the conversion of plasminogen to plasmin, providing a direct demonstration of the ability of enhanced uPA to increase plasmin-dependent proteolysis. The enhanced invasive behaviour of the cancer cells stimulated by CSFs was well correlated with the increase in MMPs and uPA activities. These data suggest that the enhanced production of extracellular matrix-degrading proteinases by the cancer cells in response to CSF treatment may represent a biochemical mechanism which promotes the invasive behaviour of the cancer cells. © 1999 Cancer Research Campaign PMID:10408691

  3. Multiple Channel Laser Beam Combination and Phasing Using Stimulated Brillouin Scattering in Optical Fibers

    DTIC Science & Technology

    2005-12-01

    light in stimulated Mandel’shtam–Brillouin scattering,” JETP Lett ., 15, 109-112, 1972. 41 . Hellwarth, R. W., “Phase conjugation by stimulated...interferometry with wavefront-reversing mirrors,” Sov . Phys . JETP , 52, 847-851, 1980. 79. Valley, M., G. Lombardi, and R. Aprahamian, “Beam...discharge,” Appl. Phys . Lett ., 86, 111104, 2005. 13. Lange, Mathew A., “Kinetics of the electric discharge pumped oxygen-iodine laser,” Sixth

  4. Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury.

    PubMed

    Miao, Ming-San; Guo, Lin; Li, Rui-Qi; Ma, Xiao

    2016-02-01

    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 days after injury. Results showed that Radix Ilicis Pubescentis total flavonoids could reduce pathological injury in rats with cerebral ischemia/reperfusion injury. The number of Nissl bodies increased, Bax protein expression decreased, Bcl-2 protein expression increased and the number of CD34-positive cells increased. Therefore, Radix Ilicis Pubescentis total flavonoids can improve the bone marrow stem cell mobilization effect, enhance the anti-apoptotic ability of nerve cells, and have a neuroprotective effect on cerebral ischemia/reperfusion injury in rats.

  5. Effects of withholding feed on thyrotropin-releasing hormone stimulation test results and effects of combined testing on oral sugar test and thyrotropin-releasing hormone stimulation test results in horses.

    PubMed

    Restifo, Melissa M; Frank, Nicholas; Hermida, Pilar; Sanchez-Londoño, Alfredo

    2016-07-01

    OBJECTIVE To assess effects of withholding feed on thyrotropin-releasing hormone (TRH) stimulation test results used in diagnosis of pituitary pars intermedia dysfunction in horses and determine effects of combined testing on results of the TRH stimulation test and the oral sugar test (OST) used in diagnosis of equine metabolic syndrome. ANIMALS 30 adult horses. PROCEDURES All horses underwent TRH stimulation tests under fed and nonfed conditions, an OST alone, and an OST combined with TRH stimulation testing. For TRH stimulation tests, plasma ACTH concentrations were measured before (baseline) and 10 minutes after (poststimulation) IV TRH administration. For the OST, plasma glucose and insulin concentrations were measured before (baseline) and 60 and 90 minutes after oral corn syrup administration. For combined testing, the TRH stimulation test was initiated immediately after 60-minute posttreatment sample collection for the OST. Results were compared among methods by Wilcoxon matched-pairs, signed rank tests, paired t tests, and Bland-Altman analysis. RESULTS Feeding conditions did not affect median ACTH concentrations when TRH stimulation tests were performed alone. Median baseline ACTH concentration did not differ between TRH stimulation tests performed alone (under fed or nonfed conditions) and those combined with OSTs. Median poststimulation ACTH concentration was significantly lower for combined tests than for solitary TRH stimulation tests. Mean 60-minute plasma glucose concentration was significantly lower for solitary OSTs than for combined tests, but this difference could not be attributed to TRH administration. CONCLUSIONS AND CLINICAL RELEVANCE Combined testing in the manner described impacted ACTH concentrations during TRH stimulation tests and is not recommended at this time.

  6. Hybrid Neuroprosthesis for the Upper Limb: Combining Brain-Controlled Neuromuscular Stimulation with a Multi-Joint Arm Exoskeleton.

    PubMed

    Grimm, Florian; Walter, Armin; Spüler, Martin; Naros, Georgios; Rosenstiel, Wolfgang; Gharabaghi, Alireza

    2016-01-01

    Brain-machine interface-controlled (BMI) neurofeedback training aims to modulate cortical physiology and is applied during neurorehabilitation to increase the responsiveness of the brain to subsequent physiotherapy. In a parallel line of research, robotic exoskeletons are used in goal-oriented rehabilitation exercises for patients with severe motor impairment to extend their range of motion (ROM) and the intensity of training. Furthermore, neuromuscular electrical stimulation (NMES) is applied in neurologically impaired patients to restore muscle strength by closing the sensorimotor loop. In this proof-of-principle study, we explored an integrated approach for providing assistance as needed to amplify the task-related ROM and the movement-related brain modulation during rehabilitation exercises of severely impaired patients. For this purpose, we combined these three approaches (BMI, NMES, and exoskeleton) in an integrated neuroprosthesis and studied the feasibility of this device in seven severely affected chronic stroke patients who performed wrist flexion and extension exercises while receiving feedback via a virtual environment. They were assisted by a gravity-compensating, seven degree-of-freedom exoskeleton which was attached to the paretic arm. NMES was applied to the wrist extensor and flexor muscles during the exercises and was controlled by a hybrid BMI based on both sensorimotor cortical desynchronization (ERD) and electromyography (EMG) activity. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. The hybrid BMI controlled the stimulation significantly better than the offline analyzed ERD (p = 0.028) or EMG (p = 0.021) modality alone. Neuromuscular stimulation could be well integrated into the exoskeleton-based training and amplified both the task-related ROM (p = 0.009) and the movement-related brain modulation (p = 0.019). Combining a hybrid BMI with neuromuscular stimulation

  7. Hybrid Neuroprosthesis for the Upper Limb: Combining Brain-Controlled Neuromuscular Stimulation with a Multi-Joint Arm Exoskeleton

    PubMed Central

    Grimm, Florian; Walter, Armin; Spüler, Martin; Naros, Georgios; Rosenstiel, Wolfgang; Gharabaghi, Alireza

    2016-01-01

    Brain-machine interface-controlled (BMI) neurofeedback training aims to modulate cortical physiology and is applied during neurorehabilitation to increase the responsiveness of the brain to subsequent physiotherapy. In a parallel line of research, robotic exoskeletons are used in goal-oriented rehabilitation exercises for patients with severe motor impairment to extend their range of motion (ROM) and the intensity of training. Furthermore, neuromuscular electrical stimulation (NMES) is applied in neurologically impaired patients to restore muscle strength by closing the sensorimotor loop. In this proof-of-principle study, we explored an integrated approach for providing assistance as needed to amplify the task-related ROM and the movement-related brain modulation during rehabilitation exercises of severely impaired patients. For this purpose, we combined these three approaches (BMI, NMES, and exoskeleton) in an integrated neuroprosthesis and studied the feasibility of this device in seven severely affected chronic stroke patients who performed wrist flexion and extension exercises while receiving feedback via a virtual environment. They were assisted by a gravity-compensating, seven degree-of-freedom exoskeleton which was attached to the paretic arm. NMES was applied to the wrist extensor and flexor muscles during the exercises and was controlled by a hybrid BMI based on both sensorimotor cortical desynchronization (ERD) and electromyography (EMG) activity. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. The hybrid BMI controlled the stimulation significantly better than the offline analyzed ERD (p = 0.028) or EMG (p = 0.021) modality alone. Neuromuscular stimulation could be well integrated into the exoskeleton-based training and amplified both the task-related ROM (p = 0.009) and the movement-related brain modulation (p = 0.019). Combining a hybrid BMI with neuromuscular stimulation

  8. Effects of combined carotid chemoreceptor and atrial receptor stimulation on renal blood flow in anaesthetized dogs.

    PubMed Central

    Kappagoda, C T; Karim, F; Mackay, D

    1983-01-01

    In dogs anaesthetized with chloralose and artificially ventilated, carotid chemoreceptors were stimulated by changing the perfusate of the vascularly isolated carotid bifurcations from arterial to venous blood. Left atrial receptors were stimulated by distending balloons in two pulmonary vein-left atrial junctions and in this left atrial appendage. The left renal blood flow was measured by an electromagnetic flow meter at a constant systemic (renal) arterial pressure in preparations in which heart rate changes were prevented by administration of propranolol hydrochloride (0.5 mg kg-1) and atropine sulphate (0.4 mg kg-1). Muscular movement was prevented by gallamine triethiodide (0.2 mg kg-1). Stimulation of left atrial receptors resulted in a significant increase (P less than 0.001) in renal blood flow of 5.6 +/- 0.88 ml min-1 100 g-1 renal mass from a control of 223 ml min-1 100 g-1 renal mass. The responses were abolished by cooling the cervical vagus nerves to 6-8 degrees C. Stimulation of carotid chemoreceptors, by perfusion of the carotid bifurcations by venous blood, caused a decrease in renal blood flow of 20 +/- 6.9 ml min-1 100 g-1 renal mass from 224 ml min-1 100 g-1 renal mass. Stimulation of left atrial receptors during venous perfusion of carotid chemoreceptors resulted in an increase in renal blood flow of 10.9 +/- 1.82 ml min-1 100 g-1 renal mass from 208 ml min-1 100 g-1 renal mass. These results show that atrial receptors and chemoreceptors can interact in their effects on renal blood flow. PMID:6410054

  9. Strong stimulation of recombinant protein production in Escherichia coli by combining stimulatory control elements in an expression cassette

    PubMed Central

    2012-01-01

    Background The XylS/Pm expression system has been used to produce recombinant proteins at industrial levels in Escherichia coli. Activation of transcription from the Pm promoter takes place in the presence of benzoic acid or derivatives of it. Previous mutagenesis studies resulted in identification of several variants of the expression control elements xylS (X), Pm (P) and the 5'-untranslated region (U) that individually gave rise to strongly stimulated expression. The goal of this study was to test if combination of such stimulatory mutations in the same expression vectors would lead to further increase of expression levels. Results We combined X, P and U variants that were originally identified due to their ability to strongly stimulate expression of the reporter gene bla (resistance to penicillin). Combination of optimized elements stimulated bla expression up to 75-fold (X, P and U combined) relative to the wild-type system, while accumulated transcript levels increased about 50-fold. This is much more than for the elements individually. We also tested combination of the variant elements on two other and unrelated genes, celB (encoding phosphoglucomutase) and the human growth factor gene gm-csf. Protein production from these genes is much more efficient than from bla in the wild-type system, but expression was still significantly stimulated by the combination of X, P and U variants, although not to the same extent as for bla. We also integrated a single copy of the expression cassette with each gene into the E. coli chromosome and found that the expression level from this single copy was higher for bla than for the wild-type plasmid system, while it was lower for celB and gm-csf. Conclusion Our results show that combination of stimulatory expression control elements can be used to further increase production of different proteins in E. coli. For one reporter gene (bla) this allowed for more protein production from a single gene copy integrated on the chromosome

  10. A method for predicting the outcomes of combined pharmacologic and deep brain stimulation therapy for Parkinson's disease.

    PubMed

    Shamir, Reuben R; Dolbert, Trygve; Noecker, Angela M; Frankemolle, Anneke M; Walter, Benjamin L; McIntyre, Cameron C

    2014-01-01

    Deep brain stimulation (DBS) is an established therapy for the management of advanced Parkinson's disease (PD). However, the coupled adjustment of pharmacologic therapy and stimulation parameter settings is a time-consuming process and treatment outcomes are not always optimal. In this study, we develop a linear function that relates the DBS parameters, the levodopa dosage, and patient-specific preoperative clinical data with the actual treatment motor outcomes. To this end, we incorporate image-based patient-specific computer models of the volume of tissue activated by DBS in a multilinear regression analysis (6 PD patients; 60 follow up visits). The resulting predictor function was highly correlated with the actual motor outcomes (r = 0.76; p < 0.05). These results demonstrate that the outcomes of a combined pharmacologic-DBS therapy can be predicted and may facilitate patient-specific treatment optimization for maximal benefits and minimal adverse effects.

  11. Beam Clean-Up and Combining via Stimulated Scattering in Liquid Crystals

    DTIC Science & Technology

    2007-11-02

    3 High-power CW solid-state and fiber lasers are here ! They have the power more...Experiment.) d kα 14 Observation of Stimulated Grating Orientational Scattering in NLC λ = 1.08 mkm, Yb-doped IPG fiber laser , output power 100 W...1.08 mkm, Yb-doped IPG fiber laser , output power 100 W, power to the cell 3.2 W. Lens F = 20 cm, beam ∅ = 5 mm (FWe-2M) at the lens. Cell

  12. Combining statistical and physics-based methods for predicting induced seismic hazard during reservoir stimulation

    NASA Astrophysics Data System (ADS)

    Gischig, V. S.; Mena Cabrera, B.; Goertz-Allmann, B.; Wiemer, S.

    2012-12-01

    Improving the management of risk associated with induced seismicity during reservoir stimulation depends on real-time analysis and forecasting of time-dependent seismic hazard during a stimulation experiment. We present a forward-model based on a semi-stochastic approach that can be used in a probabilistic seismic hazard analysis (PSHA) framework, and calibrate it against observations of induced seismicity during the Basel EGS stimulation in 2006. The modeling strategy is based on two components: a non-linear fluid pressure diffusion model, and a stochastic seed model that includes basic geo-mechanical principles. The transient fluid pressure field is computed with a numerical continuum flow model, in which permeability can increase irreversibly above a certain pressure threshold. The flow model thus mimics permeability enhancement through shear-induced fracture dilation, and is capable of reproducing the wellhead pressure behavior during stimulation. The pressure field is used to trigger events at so-called seed points, locations of potential seismic events that are randomly distributed around an injection well. They are assigned principal stress magnitudes drawn from a normal distribution representative of the ambient stress field. Once the effective stress at a seed point meets a pre-defined Mohr-Coulomb failure criterion due to a fluid pressure increase a seismic event is induced. Inspired by observed event statistics of both tectonic earthquakes and acoustic emissions in laboratory experiments, we assume a negative linear relationship between b-values and differential stress. Thus, for each event a magnitude can be drawn from a frequency-magnitude distribution with a b-value corresponding to the differential stress at failure. The result is a synthetic event catalogue of a seismic cloud evolving in time and space. Computing a large number (several hundred) of such random synthetic catalogues allows a statistically sound comparison between model results and

  13. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression.

    PubMed

    Thomas, Samantha J; Shin, Mirae; McInnis, Melvin G; Bostwick, Jolene R

    2015-04-01

    Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of

  14. Vestibular contributions to a right-hemisphere network for bodily awareness: combining galvanic vestibular stimulation and the "Rubber Hand Illusion".

    PubMed

    Ferrè, Elisa Raffaella; Berlot, Eva; Haggard, Patrick

    2015-03-01

    An altered sense of one's own body is a common consequence of vestibular damage, and also of damage to vestibular networks in the right hemisphere. However, few experimental studies have investigated whether vestibular signals contribute to bodily awareness. We addressed this issue by combining an established experimental model of bodily awareness (Rubber Hand Illusion -RHI) with galvanic vestibular stimulation (GVS) in healthy participants. Brief left anodal and right cathodal GVS (which predominantly activates vestibular networks in the right hemisphere), or right anodal and left cathodal GVS, or sham stimulation were delivered at random, while participants experienced either synchronous or asynchronous visuo-tactile stimulation of a rubber hand and their own hand. The drift in the perceived position of the participant's hand towards the rubber hand was used as a proxy measure of the resulting multisensory illusion of body ownership. GVS induced strong polarity-dependent effects on this measure of RHI: left anodal and right cathodal GVS produced significantly lower proprioceptive drift than right anodal and left cathodal GVS. We suggest that vestibular inputs influence the multisensory weighting functions that underlie bodily awareness: the right hemisphere vestibular projections activated by the left anodal and right cathodal GVS increased the weight of intrinsic proprioceptive signals about hand position, and decreased the weight of visual information responsible for visual capture during the RHI.

  15. Modulating the Behaviors of Mesenchymal Stem Cells Via the Combination of High-Frequency Vibratory Stimulations and Fibrous Scaffolds

    PubMed Central

    Tong, Zhixiang; Duncan, Randall L.

    2013-01-01

    We are interested in the in vitro engineering of artificial vocal fold tissues via the strategic combination of multipotent mesenchymal stem cells (MSCs), physiologically relevant mechanical stimulations, and biomimetic artificial matrices. We have constructed a vocal fold bioreactor that is capable of imposing vibratory stimulations on the cultured cells at human phonation frequencies. Separately, fibrous poly (ɛ-caprolactone) (PCL) scaffolds emulating the ligamentous structure of the vocal fold were prepared by electrospinning, were incorporated in the vocal fold bioreactor, and were driven into a wave-like motion in an axisymmetrical fashion by the oscillating air. MSC-laden PCL scaffolds were subjected to vibrations at 200 Hz with a normal center displacement of ∼40 μm for a total of 7 days. A continuous (CT) or a 1 h-on-1 h-off (OF) regime with a total dynamic culture time of 12 h per day was applied. The dynamic loading did not cause any physiological trauma to the cells. Immunohistotochemical staining revealed the reinforcement of the actin filament and the enhancement of α5β1 integrin expression under selected dynamic culture conditions. Cellular expression of essential vocal fold extracellular matrix components, such as elastin, hyaluronic acid, and matrix metalloproteinase-1, was significantly elevated as compared with the static controls, and the OF regime is more conducive to matrix production than the CT vibration mode. Analyses of genes of typical fibroblast hallmarks (tenascin-C, collagen III, and procollagen I) as well as markers for MSC differentiation into nonfibroblastic lineages confirmed MSCs' adaptation of fibroblastic behaviors. Overall, the high-frequency vibratory stimulation, when combined with a synthetic fibrous scaffold, serves as a potent modulator of MSC functions. The novel bioreactor system presented here, as a versatile, yet well-controlled model, offers an in vitro platform for understanding vibration

  16. Targeted near infrared hyperthermia combined with immune stimulation for optimized therapeutic efficacy in thyroid cancer treatment

    PubMed Central

    Zhou, Le; Zhang, Mengchao; Fu, Qingfeng; Li, Jingting; Sun, Hui

    2016-01-01

    Treatment of thyroid cancer has incurred much focus because of its high prevalency. As a new strategy treating thyroid cancer, hyperthermia takes several advantages compared with surgery or chemotherapy, including minimal invasion, low systematic toxicity and the ability to enhance the immunogenicity of cancer cells with the expression Hsp70 which serves as Toll-like receptors-4 (TLR-4 agonist). However, Hsp70 as a molecular chaperone can protect cells from heat induced apoptosis and therefore compromise the tumor killing effect of hyperthermia. In this study, to solve this problem, a combined hyperthermia therapy was employed to treat thyroid cancer. We prepared a probe with the tumor targeting agent AG to monitor thyroid tumor issue and generate heat to kill tumor cells in vivo. At the same time Quercetin (inhibitor of HSP70) and lipopolysaccharide (LPS) (agonist of TLR-4) were used for the combined hyperthermia therapy. The results showed that compared with free IR820, AG modification facilitated much enhanced cellular uptake and greatly pronounced tumor targeting ability. The combined therapy exhibited the most remarkable tumor inhibition compared with the single treatments both in vitro and in vivo. These findings verified that the new therapeutic combination could significantly improve the effect of hyperthermia and shed light on a novel clinical strategy in thyroid cancer treatment. PMID:26769848

  17. Combined nitrogen limitation and cadmium stress stimulate total carbohydrates, lipids, protein and amino acid accumulation in Chlorella vulgaris (Trebouxiophyceae).

    PubMed

    Chia, Mathias Ahii; Lombardi, Ana Teresa; da Graça Gama Melão, Maria; Parrish, Christopher C

    2015-03-01

    Metals have interactive effects on the uptake and metabolism of nutrients in microalgae. However, the effect of trace metal toxicity on amino acid composition of Chlorella vulgaris as a function of varying nitrogen concentrations is not known. In this research, C. vulgaris was used to investigate the influence of cadmium (10(-7) and 2.0×10(-8)molL(-1) Cd) under varying nitrogen (2.9×10(-6), 1.1×10(-5) and 1.1×10(-3)molL(-1)N) concentrations on its growth rate, biomass and biochemical composition. Total carbohydrates, total proteins, total lipids, as well as individual amino acid proportions were determined. The combination of Cd stress and N limitation significantly inhibited growth rate and cell density of C. vulgaris. However, increasing N limitation and Cd stress stimulated higher dry weight and chlorophyll a production per cell. Furthermore, biomolecules like total proteins, carbohydrates and lipids increased with increasing N limitation and Cd stress. Ketogenic and glucogenic amino acids were accumulated under the stress conditions investigated in the present study. Amino acids involved in metal chelation like proline, histidine and glutamine were significantly increased after exposure to combined Cd stress and N limitation. We conclude that N limitation and Cd stress affects the physiology of C. vulgaris by not only decreasing its growth but also stimulating biomolecule production.

  18. Testosterone Combined with Electrical Stimulation and Standing: Effect on Muscle and Bone

    DTIC Science & Technology

    2015-10-01

    and placebo, with an appropriate dispensing system in place, was an onerous task, and our main difficulty with initiating this study to date. A...of exoskeleton-assisted walking over ground for persons with chronic SCI will positively affect the musculoskeletal system . In addition we will...Co-PI) 10/01/2011 – 9/31/17 NIDRR Models Systems Primary Research Project Restoring Lost Functions after Spinal Cord Injury: Combination

  19. Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages.

    PubMed

    Rajan, Thangavelu Soundara; Giacoppo, Sabrina; Iori, Renato; De Nicola, Gina Rosalinda; Grassi, Gianpaolo; Pollastro, Federica; Bramanti, Placido; Mazzon, Emanuela

    2016-07-01

    Inflammatory response plays an important role in the activation and progress of many debilitating diseases. Natural products, like cannabidiol, a constituent of Cannabis sativa, and moringin, an isothiocyanate obtained from myrosinase-mediated hydrolysis of the glucosinolate precursor glucomoringin present in Moringa oleifera seeds, are well known antioxidants also endowed with anti-inflammatory activity. This is due to a covalent-based mechanism for ITC, while non-covalent interactions underlie the activity of CBD. Since these two mechanisms are distinct, and the molecular endpoints are potentially complementary, we investigated in a comparative way the protective effect of these compounds alone or in combination on lipopolysaccharide-stimulated murine macrophages. Our results show that the cannabidiol (5μM) and moringin (5μM) combination outperformed the single constituents that, at this dosage had only a moderate efficacy on inflammatory (Tumor necrosis factor-α, Interleukin-10) and oxidative markers (inducible nitric oxide synthase, nuclear factor erythroid 2-related factor 2, nitrotyrosine). Significant upregulation of Bcl-2 and downregulation of Bax and cleaved caspase-3 was observed in cells treated with cannabidiol-moringin combination. Treatment with the transient receptor potential vanilloid receptor 1 antagonist was detrimental for the efficacy of cannabidiol, while no effect was elicited by cannabinoid receptor 1 and cannabinoid receptor 2 antagonists. None of these receptors was involved in the activity of moringin. Taken together, our in vitro results testify the anti-inflammatory, antioxidative, and anti-apoptotic effects of the combination of cannabidiol and moringin.

  20. Nerve conduction block using combined thermoelectric cooling and high frequency electrical stimulation.

    PubMed

    Ackermann, D Michael; Foldes, Emily L; Bhadra, Niloy; Kilgore, Kevin L

    2010-10-30

    Conduction block of peripheral nerves is an important technique for many basic and applied neurophysiology studies. To date, there has not been a technique which provides a quickly initiated and reversible "on-demand" conduction block which is both sustainable for long periods of time and does not generate activity in the nerve at the onset of the conduction block. In this study we evaluated the feasibility of a combined method of nerve block which utilizes two well established nerve blocking techniques in a rat and cat model: nerve cooling and electrical block using high frequency alternating currents (HFAC). This combined method effectively makes use of the contrasting features of both nerve cooling and electrical block using HFAC. The conduction block was initiated using nerve cooling, a technique which does not produce nerve "onset response" firing, a prohibitive drawback of HFAC electrical block. The conduction block was then readily transitioned into an electrical block. A long-term electrical block is likely preferential to a long-term nerve cooling block because nerve cooling block generates large amounts of exhaust heat, does not allow for fiber diameter selectivity and is known to be unsafe for prolonged delivery.

  1. Program and Abstracts of the National Meeting of the Society for Leukocyte Biology (25th) Held in Washington, DC on October 27-30, 1988. Journal of Leukocyte Biology. Volume 44, Number 4

    DTIC Science & Technology

    1988-10-01

    RADIATION EXPOSURE: THERAPEUTIC APPROACH USING GLUCAN , A MACROPHAGE-ACTIVATOR, IN COMBINATION WITH GRANULOCYTE-COLONY STIMULATING FACTOR. M.L. Patchen...Emeryville, CA 94608. 5:00 PM 128. EFFECT OF TRANSFORMING GROWTH FACTOR (TGF) TYPE BETA ON MURINE INFLAMMATORY MONONUCLEAR PHAGOCYTES: INCREASED FIBRONECTIN...20850. 5:15 PM 129. TRANSFORMING GROWTH FACTOR BETA INDUCES LEUKOCYTE INFILTRATION AND INFLAMMATION IN THE SYNOVIAL JOINT. Janice B. Allen, Larry

  2. Analyses of chondrogenic induction of adipose mesenchymal stem cells by combined co-stimulation mediated by adenoviral gene transfer

    PubMed Central

    2013-01-01

    Introduction Adipose-derived stem cells (ASCs) have the potential to differentiate into cartilage under stimulation with some reported growth and transcriptional factors, which may constitute an alternative for cartilage replacement approaches. In this study, we analyzed the in vitro chondrogenesis of ASCs transduced with adenoviral vectors encoding insulin-like growth factor-1 (IGF-1), transforming growth factor beta-1 (TGF-β1), fibroblast growth factor-2 (FGF-2), and sex-determining region Y-box 9 (SOX9) either alone or in combinations. Methods Aggregate cultures of characterized ovine ASCs were transduced with 100 multiplicity of infections of Ad.IGF-1, Ad.TGF-β1, Ad.FGF-2, and Ad.SOX9 alone or in combination. These were harvested at various time points for detection of cartilage-specific genes expression by quantitative real-time PCR or after 14 and 28 days for histologic and biochemical analyses detecting proteoglycans, collagens (II, I and X), and total sulfated glycosaminoglycan and collagen content, respectively. Results Expression analyses showed that co-expression of IGF-1 and FGF-2 resulted in higher significant expression levels of aggrecan, biglycan, cartilage matrix, proteoglycan, and collagen II (all P ≤0.001 at 28 days). Aggregates co-transduced with Ad.IGF-1/Ad.FGF-2 showed a selective expression of proteoglycans and collagen II, with limited expression of collagens I and × demonstrated by histological analyses, and had significantly greater glycosaminoglycan and collagen production than the positive control (P ≤0.001). Western blot analyses for this combination also demonstrated increased expression of collagen II, while expression of collagens I and × was undetectable and limited, respectively. Conclusion Combined overexpression of IGF-1/FGF-2 within ASCs enhances their chondrogenic differentiation inducing the expression of chondrogenic markers, suggesting that this combination is more beneficial than the other factors tested for the

  3. 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

    SciTech Connect

    Moroni, Maria; Ngudiankama, Barbara F.; Christensen, Christine; Olsen, Cara H.; Owens, Rossitsa; Lombardini, Eric D.; Holt, Rebecca K.; Whitnall, Mark H.

    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.

  4. A combined cICA-EEMD analysis of EEG recordings from depressed or schizophrenic patients during olfactory stimulation

    NASA Astrophysics Data System (ADS)

    Götz, Th; Stadler, L.; Fraunhofer, G.; Tomé, A. M.; Hausner, H.; Lang, E. W.

    2017-02-01

    Objective. We propose a combination of a constrained independent component analysis (cICA) with an ensemble empirical mode decomposition (EEMD) to analyze electroencephalographic recordings from depressed or schizophrenic subjects during olfactory stimulation. Approach. EEMD serves to extract intrinsic modes (IMFs) underlying the recorded EEG time. The latter then serve as reference signals to extract the most similar underlying independent component within a constrained ICA. The extracted modes are further analyzed considering their power spectra. Main results. The analysis of the extracted modes reveals clear differences in the related power spectra between the disease characteristics of depressed and schizophrenic patients. Such differences appear in the high frequency γ-band in the intrinsic modes, but also in much more detail in the low frequency range in the α-, θ- and δ-bands. Significance. The proposed method provides various means to discriminate both disease pictures in a clinical environment.

  5. Combining brain stimulation and video game to promote long-term transfer of learning and cognitive enhancement

    PubMed Central

    Looi, Chung Yen; Duta, Mihaela; Brem, Anna-Katharine; Huber, Stefan; Nuerk, Hans-Christoph; Cohen Kadosh, Roi

    2016-01-01

    Cognitive training offers the potential for individualised learning, prevention of cognitive decline, and rehabilitation. However, key research challenges include ecological validity (training design), transfer of learning and long-term effects. Given that cognitive training and neuromodulation affect neuroplasticity, their combination could promote greater, synergistic effects. We investigated whether combining transcranial direct current stimulation (tDCS) with cognitive training could further enhance cognitive performance compared to training alone, and promote transfer within a short period of time. Healthy adults received real or sham tDCS over their dorsolateral prefrontal cortices during two 30-minute mathematics training sessions involving body movements. To examine the role of training, an active control group received tDCS during a non-mathematical task. Those who received real tDCS performed significantly better in the game than the sham group, and showed transfer effects to working memory, a related but non-numerical cognitive domain. This transfer effect was absent in active and sham control groups. Furthermore, training gains were more pronounced amongst those with lower baseline cognitive abilities, suggesting the potential for reducing cognitive inequalities. All effects associated with real tDCS remained 2 months post-training. Our study demonstrates the potential benefit of this approach for long-term enhancement of human learning and cognition. PMID:26902664

  6. A combined therapeutic approach in stroke rehabilitation: A review on non-invasive brain stimulation plus pharmacotherapy

    PubMed Central

    Perez, Carolina; Morales-Quezada, Leon; Fregni, Felipe

    2015-01-01

    Stroke is a leading cause of disability in the United States. Available treatments for stroke have only a modest effect on motor rehabilitation and about 50-60% of stroke patients remain with some degree of motor impairment after standard treatment. Non-invasive brain stimulation (NIBS) techniques have been proposed as adjuvant treatments to physical therapy for motor recovery after stroke. High frequency rTMS and anodal tDCS can be delivered over the affected motor cortex in order to increase cortical excitability and induce brain plasticity with the intention to enhance motor learning and achieve functional goals in stroke patients. Similarly, low frequency rTMS and cathodal tDCS can be delivered to the unaffected motor cortex to reduce interhemispheric inhibition and hinder maladaptive plasticity. The use of several drugs such as amphetamines, selective serotonin reuptake inhibitors (SSRIs), levodopa and cholinergic agents have been also proposed to enhance the motor function. Given that both NIBS and pharmacotherapy might provide some treatment effect independently for motor rehabilitation in stroke and with the rationale that they could work in a synergistic fashion, we believe that a combined therapy- NIBS plus pharmacotherapy- canlead to better outcomes than one or the other alone. In this paper we review the literature that support the potential use of a combined approach in stroke recovery and present the studies that have already investigated this idea.

  7. Bilateral Repetitive Transcranial Magnetic Stimulation Combined with Intensive Swallowing Rehabilitation for Chronic Stroke Dysphagia: A Case Series Study

    PubMed Central

    Momosaki, Ryo; Abo, Masahiro; Kakuda, Wataru

    2014-01-01

    The purpose of this study was to clarify the safety and feasibility of a 6-day protocol of bilateral repetitive transcranial magnetic stimulation (rTMS) combined with intensive swallowing rehabilitation for chronic poststroke dysphagia. In-hospital treatment was provided to 4 poststroke patients (age at treatment: 56–80 years; interval between onset of stroke and treatment: 24–37 months) with dysphagia. Over 6 consecutive days, each patient received 10 sessions of rTMS at 3 Hz applied to the pharyngeal motor cortex bilaterally, followed by 20 min of intensive swallowing rehabilitation exercise. The swallowing function was evaluated by the Penetration Aspiration Scale (PAS), Modified Mann Assessment of Swallowing Ability (MMASA), Functional Oral Intake Scale (FOIS), laryngeal elevation delay time (LEDT) and Repetitive Saliva-Swallowing Test (RSST) on admission and at discharge. All patients completed the 6-day treatment protocol and none showed any adverse reactions throughout the treatment. The combination treatment improved laryngeal elevation delay time in all patients. Our proposed protocol of rTMS plus swallowing rehabilitation exercise seems to be safe and feasible for chronic stroke dysphagia, although its efficacy needs to be confirmed in a large number of patients. PMID:24803904

  8. Combining brain stimulation and video game to promote long-term transfer of learning and cognitive enhancement.

    PubMed

    Looi, Chung Yen; Duta, Mihaela; Brem, Anna-Katharine; Huber, Stefan; Nuerk, Hans-Christoph; Cohen Kadosh, Roi

    2016-02-23

    Cognitive training offers the potential for individualised learning, prevention of cognitive decline, and rehabilitation. However, key research challenges include ecological validity (training design), transfer of learning and long-term effects. Given that cognitive training and neuromodulation affect neuroplasticity, their combination could promote greater, synergistic effects. We investigated whether combining transcranial direct current stimulation (tDCS) with cognitive training could further enhance cognitive performance compared to training alone, and promote transfer within a short period of time. Healthy adults received real or sham tDCS over their dorsolateral prefrontal cortices during two 30-minute mathematics training sessions involving body movements. To examine the role of training, an active control group received tDCS during a non-mathematical task. Those who received real tDCS performed significantly better in the game than the sham group, and showed transfer effects to working memory, a related but non-numerical cognitive domain. This transfer effect was absent in active and sham control groups. Furthermore, training gains were more pronounced amongst those with lower baseline cognitive abilities, suggesting the potential for reducing cognitive inequalities. All effects associated with real tDCS remained 2 months post-training. Our study demonstrates the potential benefit of this approach for long-term enhancement of human learning and cognition.

  9. Interaction between endometrial epithelial cells and blood leucocytes promotes cytokine release and epithelial barrier function in response to Chlamydia trachomatis lipopolysaccharide stimulation.

    PubMed

    Sze Ho, Lok; He, Qiong; Chen, Jie; Xu, Penghui; Ling Tsang, Lai; Yu, Sidney; Wa Chung, Yiu; Chang Chan, Hsiao

    2010-09-01

    Chlamydia trachomatis infection is currently the most common cause of infection-related sterility in women. However, it remains largely unknown how uterine epithelial cells interact with recruited leucocytes in response to C. trachomatis infection in the female genital tract. To study the defence mechanism of the endometrium against C. trachomatis infection, we established an in vitro co-culture of EEC (endometrial epithelial cells) and PBL (peripheral blood leucocytes) isolated from mice and investigated the immune response of these cells upon C. trachomatis LPS (lipopolysaccharide) challenge using a cytokine antibody array and RT-PCR (reverse transcription-PCR). Our results showed that upon C. trachomatis LPS stimulation, proinflammatory cytokines/chemokines, such as TNF-alpha, IL-1beta, MIPs (macrophage inflammatory proteins), IL-12p40p70, KC, GCSFs (granulocyte colony stimulating factors), IL-6 and TIMPs (tissue inhibition metalloproteinases) are up-regulated and/or released from EEC-PBL co-culture. Further, the TER (transepithelial resistance), measured by the Isc (short-circuit current) technique was significantly increased in EEC/PBL co-cultured cells and also when stimulated with C. trachomatis LPS compared with EEC alone. These changes appear to be mediated by the change in cytokine-induced expression of tight junction-related protein ZO-1. The present results demonstrated that the epithelial-immune cross-talk could promote the release of proinflammatory cytokines and enhance the barrier function of the endometrium against C. trachomatis infection in the female reproductive tract.

  10. Growth of human hemopoietic colonies in response to recombinant gibbon interleukin 3: comparison with human recombinant granulocyte and granulocyte-macrophage colony-stimulating factor

    SciTech Connect

    Messner, H.A.; Yamasaki, K.; Jamal, N.; Minden, M.M.; Yang, Y.C.; Wong, G.G.; Clark, S.C.

    1987-10-01

    Supernatants of COS-1 cells transfected with gibbon cDNA encoding interleukin 3 (IL-3) with homology to sequences for human IL-3 were tested for ability to promote growth of various human hemopoietic progenitors. The effect of these supernatants as a source of recombinant IL-3 was compared to that of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) as well as to that of medium conditioned by phytohemagglutinin-stimulated leukocytes. The frequency of multilineage colonies, erythroid bursts, and megakaryocyte colonies in cultures containing the COS-1 cell supernatant was equivalent to the frequency observed in the controls and significantly higher than found in cultures plated with recombinant GM-CSF. G-CSF did not support the formation of multilineage colonies, erythroid bursts, and megakaryocyte colonies. In contrast, growth of granulocyte-macrophage colonies was best supported with GM-CSF, while recombinant IL-3 yielded colonies at lower or at best equivalent frequency. The simultaneous addition of higher concentrations of GM-CSF to cultures containing IL-3 in optimal amounts did not enhance the formation of multilineage colonies, erythroid bursts, and megakaryocyte colonies. However, the frequency of such colonies and bursts increased with GM-CSF when cultures were plated with suboptimal concentrations of IL-3. Growth of colonies within the granulocyte-macrophage lineage is optimally supported by GM-CSF and does not increase with further addition of IL-3.

  11. Spinal electro-magnetic stimulation combined with transgene delivery of neurotrophin NT-3 and exercise: novel combination therapy for spinal contusion injury.

    PubMed

    Petrosyan, Hayk A; Alessi, Valentina; Hunanyan, Arsen S; Sisto, Sue A; Arvanian, Victor L

    2015-11-01

    Our recent terminal experiments revealed that administration of a single train of repetitive spinal electromagnetic stimulation (sEMS; 35 min) enhanced synaptic plasticity in spinal circuitry following lateral hemisection spinal cord injury. In the current study, we have examined effects of repetitive sEMS applied as a single train and chronically (5 wk, every other day) following thoracic T10 contusion. Chronic studies involved examination of systematic sEMS administration alone and combined with exercise training and transgene delivery of neurotrophin [adeno-associated virus 10-neurotrophin 3 (AAV10-NT3)]. Electrophysiological intracellular/extracellular recordings, immunohistochemistry, behavioral testing, and anatomical tracing were performed to assess effects of treatments. We found that administration of a single sEMS train induced transient facilitation of transmission through preserved lateral white matter to motoneurons and hindlimb muscles in chronically contused rats with effects lasting for at least 2 h. These physiological changes associated with increased immunoreactivity of GluR1 and GluR2/3 glutamate receptors in lumbar neurons. Systematic administration of sEMS alone for 5 wk, however, was unable to induce cumulative improvements of transmission in spinomuscular circuitry or improve impaired motor function following thoracic contusion. Encouragingly, chronic administration of sEMS, followed by exercise training (running in an exercise ball and swimming), induced the following: 1) sustained strengthening of transmission to lumbar motoneurons and hindlimb muscles, 2) better retrograde transport of anatomical tracer, and 3) improved locomotor function. Greatest improvements were seen in the group that received exercise combined with sEMS and AAV-NT3.

  12. Influence of extremely low frequency, low energy electromagnetic fields and combined mechanical stimulation on chondrocytes in 3-D constructs for cartilage tissue engineering.

    PubMed

    Hilz, Florian M; Ahrens, Philipp; Grad, Sibylle; Stoddart, Martin J; Dahmani, Chiheb; Wilken, Frauke L; Sauerschnig, Martin; Niemeyer, Philipp; Zwingmann, Jörn; Burgkart, Rainer; von Eisenhart-Rothe, Rüdiger; Südkamp, Norbert P; Weyh, Thomas; Imhoff, Andreas B; Alini, Mauro; Salzmann, Gian M

    2014-02-01

    Articular cartilage, once damaged, has very low regenerative potential. Various experimental approaches have been conducted to enhance chondrogenesis and cartilage maturation. Among those, non-invasive electromagnetic fields have shown their beneficial influence for cartilage regeneration and are widely used for the treatment of non-unions, fractures, avascular necrosis and osteoarthritis. One very well accepted way to promote cartilage maturation is physical stimulation through bioreactors. The aim of this study was the investigation of combined mechanical and electromagnetic stress affecting cartilage cells in vitro. Primary articular chondrocytes from bovine fetlock joints were seeded into three-dimensional (3-D) polyurethane scaffolds and distributed into seven stimulated experimental groups. They either underwent mechanical or electromagnetic stimulation (sinusoidal electromagnetic field of 1 mT, 2 mT, or 3 mT; 60 Hz) or both within a joint-specific bioreactor and a coil system. The scaffold-cell constructs were analyzed for glycosaminoglycan (GAG) and DNA content, histology, and gene expression of collagen-1, collagen-2, aggrecan, cartilage oligomeric matrix protein (COMP), Sox9, proteoglycan-4 (PRG-4), and matrix metalloproteinases (MMP-3 and -13). There were statistically significant differences in GAG/DNA content between the stimulated versus the control group with highest levels in the combined stimulation group. Gene expression was significantly higher for combined stimulation groups versus static control for collagen 2/collagen 1 ratio and lower for MMP-13. Amongst other genes, a more chondrogenic phenotype was noticed in expression patterns for the stimulated groups. To conclude, there is an effect of electromagnetic and mechanical stimulation on chondrocytes seeded in a 3-D scaffold, resulting in improved extracellular matrix production.

  13. Long-term results of a clinical trial comparing isolated vaginal stimulation with combined treatment for women with stress incontinence

    PubMed Central

    Fürst, Maria Cláudia Bicudo; de Mendonça, Rafaela Rosalba; Rodrigues, Alexandre Oliveira; de Matos, Leandro Luongo; Pompeo, Antônio Carlos Lima; Bezerra, Carlos Alberto

    2014-01-01

    ABSTRACT Objective To determine the efficacy of stress urinary incontinence treatments adding pelvic floor muscle training to vaginal electrical stimulation. Methods Forty-eight women with stress urinary incontinence were randomized into 2 groups: 24 underwent isolated vaginal electrical stimulation, and 24 vaginal electrical stimulation plus pelvic floor muscle training. History, physical examination, voiding diary, perineum strength test, and urodynamic study were assessed. Comparisons were made for adherence to treatment, muscle strength improvement, urinary symptoms, and degree of satisfaction immediately, 12 and 96 months after treatment. Results Patients' degree of satisfaction on vaginal electrical stimulation, and on vaginal electrical stimulation plus pelvic floor muscle training immediately, 12 and 96 months post treatment, were, respectively: 88.2% versus 88.9% 64.7% versus 61.1% and 42.9% versus 28.6% (p>0.05). Conclusion Vaginal electrical stimulation associated to pelvic floor muscle training did not show better results than vaginal electrical stimulation alone. PMID:25003921

  14. Mechanisms for independent and combined effects of calorie restriction and acute exercise on insulin-stimulated glucose uptake by skeletal muscle of old rats.

    PubMed

    Sharma, Naveen; Wang, Haiyan; Arias, Edward B; Castorena, Carlos M; Cartee, Gregory D

    2015-04-01

    Either calorie restriction [CR; consuming 60-65% of ad libitum (AL) intake] or acute exercise can independently improve insulin sensitivity in old age, but their combined effects on muscle insulin signaling and glucose uptake have previously been unknown. Accordingly, we assessed the independent and combined effects of CR (beginning at 14 wk old) and acute exercise (3-4 h postexercise) on insulin signaling and glucose uptake in insulin-stimulated epitrochlearis muscles from 30-mo-old rats. Either CR alone or exercise alone vs. AL sedentary controls induced greater insulin-stimulated glucose uptake. Combined CR and exercise vs. either treatment alone caused an additional increase in insulin-stimulated glucose uptake. Either CR or exercise alone vs. AL sedentary controls increased Akt Ser(473) and Akt Thr(308) phosphorylation. Combined CR and exercise further elevated Akt phosphorylation on both sites. CR alone, but not exercise alone, vs. AL sedentary controls significantly increased Akt substrate of 160 kDa (AS160) Ser(588) and Thr(642) phosphorylation. Combined CR and exercise did not further enhance AS160 phosphorylation. Exercise alone, but not CR alone, modestly increased GLUT4 abundance. Combined CR and exercise did not further elevate GLUT4 content. These results suggest that CR or acute exercise independently increases insulin-stimulated glucose uptake via overlapping (greater Akt phosphorylation) and distinct (greater AS160 phosphorylation for CR, greater GLUT4 for exercise) mechanisms. Our working hypothesis is that greater insulin-stimulated glucose uptake in the combined CR and exercise group vs. CR or exercise alone relies on greater Akt activation, leading to greater phosphorylation of one or more Akt substrates other than AS160.

  15. Pain Reduction in Myofascial Pain Syndrome by Anodal Transcranial Direct Current Stimulation Combined with Standard Treatment: A Randomized Controlled Study

    PubMed Central

    Sakrajai, Piyaraid; Janyacharoen, Taweesak; Jensen, Mark P.; Sawanyawisuth, Kittisak; Auvichayapat, Narong; Tunkamnerdthai, Orathai; Keeratitanont, Keattichai; Auvichayapat, Paradee

    2014-01-01

    Background Myofascial pain syndrome (MPS) in the shoulder is among the most prevalent pain problems in the middle-aged population worldwide. Evidence suggests that peripheral and central sensitization may play an important role in the development and maintenance of shoulder MPS. Given previous research supporting the potential efficacy of anodal transcranial direct current stimulation (tDCS) for modulating pain-related brain activity in individuals with refractory central pain, we hypothesized that anodal tDCS when applied over the primary motor cortex (M1) combined with standard treatment will be more effective for reducing pain in patients with MPS than standard treatment alone. Method Study participants were randomized to receive either (1) standard treatment with 5-consecutive days of 1 mA anodal tDCS over M1 for 20 min or (2) standard treatment plus sham tDCS. Measures of pain intensity, shoulder passive range of motion, analgesic medication use, and self-reported physical functioning were administered before treatment and again at post-treatment and 1-, 2-, 3-and 4-week follow-up. Results Thirty-one patients with MPS were enrolled. Participants assigned to the active tDCS condition reported significantly more pre- to post-treatment reductions in pain intensity that were maintained at 1-week post-treatment, and significant improvement in shoulder adduction PROM at 1-week follow-up than participants assigned to the sham tDCS condition. Conclusion 5 consecutive days of anodal tDCS over M1 combined with standard treatment appears to reduce pain intensity, and may improve PROM, faster than standard treatment alone. Further tests of the efficacy and duration of effects of tDCS in the treatment of MPS are warranted. PMID:25373724

  16. Combination of Eccentric Exercise and Neuromuscular Electrical Stimulation to Improve Biomechanical Limb Symmetry After Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Lepley, Lindsey K.; Wojtys, Edward M.; Palmieri-Smith, Riann M.

    2015-01-01

    Background We have previously reported that an eccentrically-based rehabilitation protocol post-ACLr induced greater quadriceps activation and strength than a neuromuscular electrical stimulation (NMES) intervention and was just as effective as a combined NMES and eccentric intervention. However, the effect an eccentrically-based intervention has on restoring normal knee mechanics during a single-legged landing task remains unknown. Methods Thirty-six individuals post-injury were placed into four treatment groups: NMES and eccentrics, eccentrics-only, NMES-only, standard of care, and Healthy controls participated. NMES and eccentrics received a combined NMES and eccentric protocol post-reconstruction (each treatment 2x per week for 6 wks), whereas groups NMES-only and eccentric-only received only the NMES or eccentric therapy, respectively. To evaluate knee mechanics limb symmetry, the area under the curve for knee flexion angle and extension moment was derived and then normalized to the contralateral limb. Quadriceps strength was evaluated using the quadriceps index. Findings Compared to Healthy, reduced sagittal plane knee limb symmetry was found for groups NMES-only, ECC-only and standard of care for knee extension moment (P<0.05). No difference was detected between Healthy and NMES and eccentrics (P>0.06). No difference between groups was detected for knee flexion angle limb symmetry (P>0.05). Greater knee flexion angles and moments over stance were related to quadriceps strength. Interpretation The NMES and eccentrics group was found to restore biomechanical limb symmetry that was most closely related to Healthy individuals following ACL reconstruction. Greater knee flexion angles and moments over stance were related to quadriceps strength. PMID:25953255

  17. Studies for improved understanding of lipid distributions in human skin by combining stimulated and spontaneous Raman microscopy.

    PubMed

    Klossek, A; Thierbach, S; Rancan, F; Vogt, A; Blume-Peytavi, U; Rühl, E

    2016-11-15

    Advanced Raman techniques, such as stimulated Raman spectroscopy (SRS), have become a valuable tool for investigations of distributions of substances in biological samples. However, these techniques lack spectral information and are therefore highly affected by cross-sensitivities, which are due to blended Raman bands. One typical example is the symmetric CH2 stretching vibration of lipids, which is blended with the more intense Raman band of proteins. We report in this work an approach to reduce such cross-sensitivities by a factor of 8 in human skin samples. This is accomplished by careful spectral deconvolutions revealing the neat spectra of skin lipids. Extensive Raman studies combining the complementary advantages of fast mapping and scanning, i.e. SRS, as well as spectral information provided by spontaneous Raman spectroscopy, were performed on the same skin regions. In addition, an approach for correcting artifacts is reported, which are due to transmission and reflection geometries in Raman microscopy as well as scattering of radiation from rough and highly structured skin samples. As a result, these developments offer improved results obtained from label-free spectromicroscopy provided by Raman techniques. These yield substance specific information from spectral regimes in which blended bands dominate. This improvement is illustrated by studies on the asymmetric CH2 stretching vibration of lipids, which was previously difficult to identify due to the strong background signal from proteins. The advantage of the correction procedures is demonstrated by higher spatial resolution permitting to perform more detailed investigations on lipids and their composition in skin.

  18. Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD–severe combined immunodeficiency (SCID) mice

    PubMed Central

    Levitt, H. E.; Cyphert, T. J.; Pascoe, J. L.; Hollern, D. A.; Abraham, N.; Lundell, R. J.; Rosa, T.; Romano, L. C.; Zou, B.; O’Donnell, C. P.; Stewart, A. F.; Garcia-Ocaña, A.; Alonso, L. C.

    2011-01-01

    Aims/hypothesis We determined whether hyperglycaemia stimulates human beta cell replication in vivo in an islet transplant model Methods Human islets were transplanted into streptozotocin-induced diabetic NOD–severe combined immunodeficiency mice. Blood glucose was measured serially during a 2 week graft revascularisation period. Engrafted mice were then catheterised in the femoral artery and vein, and infused intravenously with BrdU for 4 days to label replicating beta cells. Mice with restored normoglycaemia were co-infused with either 0.9% (wt/vol.) saline or 50% (wt/vol.) glucose to generate glycaemic differences among grafts from the same donors. During infusions, blood glucose was measured daily. After infusion, human beta cell replication and apoptosis were measured in graft sections using immunofluorescence for insulin, and BrdU or TUNEL. Results Human islet grafts corrected diabetes in the majority of cases. Among grafts from the same donor, human beta cell proliferation doubled in those exposed to higher glucose relative to lower glucose. Across the entire cohort of grafts, higher blood glucose was strongly correlated with increased beta cell replication. Beta cell replication rates were unrelated to circulating human insulin levels or donor age, but tended to correlate with donor BMI. Beta cell TUNEL reactivity was not measurably increased in grafts exposed to elevated blood glucose. Conclusions/interpretation Glucose is a mitogenic stimulus for transplanted human beta cells in vivo. Investigating the underlying pathways may point to mechanisms capable of expanding human beta cell mass in vivo. PMID:20936253

  19. Paired-Pulse Parietal-Motor Stimulation Differentially Modulates Corticospinal Excitability across Hemispheres When Combined with Prism Adaptation

    PubMed Central

    Martín-Arévalo, Elisa; Salemme, Romeo; Pisella, Laure; Farnè, Alessandro

    2016-01-01

    Rightward prism adaptation ameliorates neglect symptoms while leftward prism adaptation (LPA) induces neglect-like biases in healthy individuals. Similarly, inhibitory repetitive transcranial magnetic stimulation (rTMS) on the right posterior parietal cortex (PPC) induces neglect-like behavior, whereas on the left PPC it ameliorates neglect symptoms and normalizes hyperexcitability of left hemisphere parietal-motor (PPC-M1) connectivity. Based on this analogy we hypothesized that LPA increases PPC-M1 excitability in the left hemisphere and decreases it in the right one. In an attempt to shed some light on the mechanisms underlying LPA's effects on cognition, we investigated this hypothesis in healthy individuals measuring PPC-M1 excitability with dual-site paired-pulse TMS (ppTMS). We found a left hemisphere increase and a right hemisphere decrease in the amplitude of motor evoked potentials elicited by paired as well as single pulses on M1. While this could indicate that LPA biases interhemispheric connectivity, it contradicts previous evidence that M1-only MEPs are unchanged after LPA. A control experiment showed that input-output curves were not affected by LPA per se. We conclude that LPA combined with ppTMS on PPC-M1 differentially alters the excitability of the left and right M1. PMID:27418979

  20. Effect of Digital Frequency Compression (DFC) on Speech Recognition in Candidates for Combined Electric and Acoustic Stimulation (EAS)

    PubMed Central

    Gifford, René H.; Dorman, Michael F.; Spahr, Anthony J.; McKarns, Sharon A.

    2008-01-01

    Purpose To compare the effects of conventional amplification (CA) and digital frequency compression (DFC) amplification on the speech recognition abilities of candidates for a partial-insertion cochlear implant, that is, candidates for combined electric and acoustic stimulation (EAS). Method The participants were 6 patients whose audiometric thresholds at 500 Hz and below were ≤60 dB HL and whose thresholds at 2000 Hz and above were ≥80 dB HL. Six tests of speech understanding were administered with CA and DFC. The Abbreviated Profile of Hearing Aid Benefit (APHAB) was also administered following use of CA and DFC. Results Group mean scores were not statistically different in the CA and DFC conditions. However, 2 patients received substantial benefit in DFC conditions. APHAB scores suggested increased ease of communication, but also increased aversive sound quality. Conclusion Results suggest that a relatively small proportion of individuals who meet EAS candidacy will receive substantial benefit from a DFC hearing aid and that a larger proportion will receive at least a small benefit when speech is presented against a background of noise. This benefit, however, comes at a cost—aversive sound quality. PMID:17905905

  1. Combined Transcriptomic–1H NMR Metabonomic Study Reveals That Monoethylhexyl Phthalate Stimulates Adipogenesis and Glyceroneogenesis in Human Adipocytes

    PubMed Central

    2011-01-01

    Adipose tissue is a major storage site for lipophilic environmental contaminants. The environmental metabolic disruptor hypothesis postulates that some pollutants can promote obesity or metabolic disorders by activating nuclear receptors involved in the control of energetic homeostasis. In this context, monoethylhexyl phthalate (MEHP) is of particular concern since it was shown to activate the peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 murine preadipocytes. In the present work, we used an untargeted, combined transcriptomic-1H NMR-based metabonomic approach to describe the overall effect of MEHP on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP stimulated rapidly and selectively the expression of genes involved in glyceroneogenesis, enhanced the expression of the cytosolic phosphoenolpyruvate carboxykinase, and reduced fatty acid release. These results demonstrate that MEHP increased glyceroneogenesis and fatty acid reesterification in human adipocytes. A longer treatment with MEHP induced the expression of genes involved in triglycerides uptake, synthesis, and storage; decreased intracellular lactate, glutamine, and other amino acids; increased aspartate and NAD, and resulted in a global increase in triglycerides. Altogether, these results indicate that MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to the suspected obesogenic effect of MEHP. PMID:22017230

  2. Shifts in connectivity during procedural learning after motor cortex stimulation: A combined transcranial magnetic stimulation/functional magnetic resonance imaging study.

    PubMed

    Steel, Adam; Song, Sunbin; Bageac, Devin; Knutson, Kristine M; Keisler, Aysha; Saad, Ziad S; Gotts, Stephen J; Wassermann, Eric M; Wilkinson, Leonora

    2016-01-01

    Inhibitory transcranial magnetic stimulation (TMS), of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory TMS affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area "offline".

  3. A simulation study of the combined thermoelectric extracellular stimulation of the sciatic nerve of the Xenopus laevis: the localized transient heat block.

    PubMed

    Mou, Zongxia; Triantis, Iasonas F; Woods, Virginia M; Toumazou, Christofer; Nikolic, Konstantin

    2012-06-01

    The electrical behavior of the Xenopus laevis nerve fibers was studied when combined electrical (cuff electrodes) and optical (infrared laser, low power sub-5 mW) stimulations are applied. Assuming that the main effect of the laser irradiation on the nerve tissue is the localized temperature increase, this paper analyzes and gives new insights into the function of the combined thermoelectric stimulation on both excitation and blocking of the nerve action potentials (AP). The calculations involve a finite-element model (COMSOL) to represent the electrical properties of the nerve and cuff. Electric-field distribution along the nerve was computed for the given stimulation current profile and imported into a NEURON model, which was built to simulate the electrical behavior of myelinated nerve fiber under extracellular stimulation. The main result of this study of combined thermoelectric stimulation showed that local temperature increase, for the given electric field, can create a transient block of both the generation and propagation of the APs. Some preliminary experimental data in support of this conclusion are also shown.

  4. Combined CpG and poly I:C stimulation of monocytes results in unique signaling activation not observed with the individual ligands

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toll-like receptors (TLRs) bind to components of microbes, activate cellular signal transduction pathways, and stimulate innate immune responses. Previously, we have shown in chicken monocytes that the combination of CpG, the ligand for TLR21 (the chicken equivalent of TLR9), and poly I:C, the liga...

  5. Combination of Transcranial Direct Current Stimulation and Neuromuscular Electrical Stimulation Improves Gait Ability in a Patient in Chronic Stage of Stroke

    PubMed Central

    Satow, Takeshi; Kawase, Tomotaka; Kitamura, Atsushi; Kajitani, Yuki; Yamaguchi, Takuya; Tanabe, Nobuhiko; Otoi, Reiko; Komuro, Taro; Kobayashi, Akira; Nagata, Hirokazu; Mima, Tatsuya

    2016-01-01

    Background Walking ability is important in stroke patients to maintain daily life. Nevertheless, its improvement is limited with conventional physical therapy in chronic stage. We report the case of a chronic stroke patient showing a remarkable improvement in gait function after a new neurorehabilitation protocol using transcranial direct current stimulation (tDCS) and neuromuscular electrical stimulation (NMES). Case Presentation A 62-year-old male with left putaminal hemorrhage suffered from severe right hemiparesis. He could move by himself with a wheelchair 1 year after the ictus. Anodal tDCS at the vertex (2 mA, 20 min) with NMES at the anterior tibialis muscle had been applied for 3 weeks. The Timed Up and Go test and 10-meter walk test improved after the intervention, which had been maintained for at least 1 month. Conclusion This single case suggests the possibility that tDCS with NMES could be a new rehabilitation approach to improve the gait ability in chronic stroke patients. PMID:27293403

  6. The role of G-CSF and IL-6 in the granulopoiesis-stimulating activity of murine blood serum induced by perorally administered ultrafiltered pig leukocyte extract, IMUNOR.

    PubMed

    Vacek, Antonín; Hofer, Michal; Holá, Jirina; Weiterová, Lenka; Streitová, Denisa; Svoboda, Jaroslav

    2007-05-01

    IMUNOR, a low-molecular weight (< 12 kD) ultrafiltered pig leukocyte extract, has been previously found to have significant stimulatory effects on murine hematopoiesis supressed by ionizing radiation or cytotoxic drugs. This communication shows data on the mechanisms of these effects. Using ELISA assay, significantly increased levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed. On the contrary, no detectable levels of granulocyte-macrophage colony-stimulating factor (GM-CFC) and interleukin-3 (IL-3) have been found in blood serum of IMUNOR-treated mice. Incubation of the serum from IMUNOR-treated mice with antibodies against G-CSF caused abrogation of the ability of the sera to stimulate in vitro growth of colonies originating from granulocyte-macrophage progenitor cells (GM-CFC). In contrast, incubation of the serum with antibodies against IL-6 did not change its colony-stimulating activity. It may be inferred from these findings that G-CSF is probably the main cytokine responsible for the granulopoiesis-stimulating effects of IMUNOR. When the serum from IMUNOR-treated mice with G-CSF inactivated by anti-G-CSF antibodies (but with elevated IL-6) was added to cultures of bone marrow cells together with a suboptimum concentration of IL-3, a significant increase in the numbers of GM-CFC colonies was found. Moreover, conjoint inactivation of G-CSF and IL-6 significantly decreased the numbers of GM-CFC colonies in comparison with those observed when only G-CSF was inactivated. This observation strongly suggests that though IMUNOR-induced IL-6 is not able to induce the growth of GM-CFC colonies alone, it is able to potentiate the hematopoiesis-stimulating effect of IL-3. These findings represent a new knowledge concerning the hematopoiesis-stimulating action of IMUNOR, a promising immunomodulatory agent.

  7. A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder, Including Patient Characteristics, Treatment Strategies, Effectiveness, and Tolerability

    PubMed Central

    Gau, Susan Shur-Fen; Méndez, Luis; Montgomery, William; Monk, Julie A.; Altin, Murat; Wu, Shenghu; Lin, Chaucer C.H.; Dueñas, Héctor J.

    2013-01-01

    Abstract Objective The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability. Methods Literature databases (MEDLINE®, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms. Results Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events. Conclusions Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing

  8. Closed-Loop Neuroprosthesis for Reach-to-Grasp Assistance: Combining Adaptive Multi-channel Neuromuscular Stimulation with a Multi-joint Arm Exoskeleton.

    PubMed

    Grimm, Florian; Gharabaghi, Alireza

    2016-01-01

    Stroke patients with severe motor deficits cannot execute task-oriented rehabilitation exercises with their affected upper extremity. Advanced rehabilitation technology may support them in performing such reach-to-grasp movements. The challenge is, however, to provide assistance as needed, while maintaining the participants' commitment during the exercises. In this feasibility study, we introduced a closed-loop neuroprosthesis for reach-to-grasp assistance which combines adaptive multi-channel neuromuscular stimulation with a multi-joint arm exoskeleton. Eighteen severely affected chronic stroke patients were assisted by a gravity-compensating, seven-degree-of-freedom exoskeleton which was attached to the paretic arm for performing reach-to-grasp exercises resembling activities of daily living in a virtual environment. During the exercises, adaptive electrical stimulation was applied to seven different muscles of the upper extremity in a performance-dependent way to enhance the task-oriented movement trajectory. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. Closed-loop neuromuscular stimulation could be well integrated into the exoskeleton-based training, and increased the task-related range of motion (p = 0.0004) and movement velocity (p = 0.015), while preserving accuracy. The highest relative stimulation intensity was required to facilitate the grasping function. The facilitated range of motion correlated with the upper extremity Fugl-Meyer Assessment score of the patients (p = 0.028). Combining adaptive multi-channel neuromuscular stimulation with antigravity assistance amplifies the residual motor capabilities of severely affected stroke patients during rehabilitation exercises and may thus provide a customized training environment for patient-tailored support while preserving the participants' engagement.

  9. Closed-Loop Neuroprosthesis for Reach-to-Grasp Assistance: Combining Adaptive Multi-channel Neuromuscular Stimulation with a Multi-joint Arm Exoskeleton

    PubMed Central

    Grimm, Florian; Gharabaghi, Alireza

    2016-01-01

    Stroke patients with severe motor deficits cannot execute task-oriented rehabilitation exercises with their affected upper extremity. Advanced rehabilitation technology may support them in performing such reach-to-grasp movements. The challenge is, however, to provide assistance as needed, while maintaining the participants' commitment during the exercises. In this feasibility study, we introduced a closed-loop neuroprosthesis for reach-to-grasp assistance which combines adaptive multi-channel neuromuscular stimulation with a multi-joint arm exoskeleton. Eighteen severely affected chronic stroke patients were assisted by a gravity-compensating, seven-degree-of-freedom exoskeleton which was attached to the paretic arm for performing reach-to-grasp exercises resembling activities of daily living in a virtual environment. During the exercises, adaptive electrical stimulation was applied to seven different muscles of the upper extremity in a performance-dependent way to enhance the task-oriented movement trajectory. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. Closed-loop neuromuscular stimulation could be well integrated into the exoskeleton-based training, and increased the task-related range of motion (p = 0.0004) and movement velocity (p = 0.015), while preserving accuracy. The highest relative stimulation intensity was required to facilitate the grasping function. The facilitated range of motion correlated with the upper extremity Fugl-Meyer Assessment score of the patients (p = 0.028). Combining adaptive multi-channel neuromuscular stimulation with antigravity assistance amplifies the residual motor capabilities of severely affected stroke patients during rehabilitation exercises and may thus provide a customized training environment for patient-tailored support while preserving the participants' engagement. PMID:27445658

  10. Dynamic changes following combined treatment with gentamicin and ethacrynic acid with and without acoustic stimulation. Cellular uptake and functional correlates.

    PubMed

    Hayashida, T; Hiel, H; Dulon, D; Erre, J P; Guilhaume, A; Aran, J M

    1989-01-01

    Regional selectivity of gentamicin (GM) ototoxicity was studied in guinea pigs (GPs) using electrophysiological, morphological, autoradiographic and immunohistological observations following combined treatment with GM (150 mg/kg i.m.) and ethacrynic acid (EA) (30 mg/kg i.c. or i.v., 1.5 h after GM injection). The GPs were either continuously stimulated every 5 min with a series of 256 clicks (70 dB peSPL, 10/s) during 3 h for monitoring fast changes in VIII nerve compound action potential (CAP) after the EA injection, and thereafter kept in the animal quarters (background noise of 60 dB SPL) (group I), or similarly monitored for only 10 min after the EA injection and thereafter kept in a soundproof room (around 0 dB SPL) (group II). Whenever GM labelling was observed it was localized only in the sensory hair cells. From 3 h after EA injection, the GPs in group I presented threshold elevations in the high-frequency region, which progressed to 60-80 dB at all frequencies at and after 48 h. Parallel to the threshold pattern, GM uptake in outer hair cells (OHCs) was seen with an increasing concentration from apex toward base from 3 to 24 h, while after 48 h almost all OHCs were destroyed and inner hair cells (IHCs) were marked by GM. In group II no changes in CAP thresholds were observed until more than 24 h, although GM was detected in the hair cells from 6 h on. At this early stage, the distribution of GM lacked a clear pattern, particularly without a clear apex-base gradient, and GM deposits were found only around the basal body. However in both groups, in late stage (greater than 24 h), the base-apex gradient was more pronounced and GM was found throughout the cell body, with a marked concentration below the cuticular plate. These results suggest that GM may penetrate hair cells around the basal body and that activating the cells by sound potentiates both GM uptake and its intracellular toxicity.

  11. Combined exercise and transcranial direct current stimulation intervention for knee osteoarthritis: protocol for a pilot randomised controlled trial

    PubMed Central

    Chang, Wei-Ju; Bennell, Kim L; Hodges, Paul W; Hinman, Rana S; Liston, Matthew B; Schabrun, Siobhan M

    2015-01-01

    Introduction Osteoarthritis (OA) is a major health problem and a leading cause of disability. The knee joint is commonly affected, resulting in pain and physical dysfunction. Exercise is considered the cornerstone of conservative management, yet meta-analyses indicate, at best, moderate effect sizes. Treatments that bolster the effects of exercise, such as transcranial direct current stimulation (tDCS), may improve outcomes in knee OA. The aims of this pilot study are to (1) determine the feasibility, safety and perceived patient response to a combined tDCS and exercise intervention in knee OA, and (2) provide data to support a sample size calculation for a fully-powered trial should trends of effectiveness be present. Methods and analysis A pilot randomised, assessor-blind and participant-blind, sham-controlled trial. 20 individuals with knee OA who report a pain score of 40 or more on a 100 mm visual analogue scale on walking, and meet a priori selection criteria will be randomly allocated to receive either: (1) active tDCS plus exercise, or (2) sham tDCS plus exercise. All participants will receive 20 min of either active or sham tDCS immediately prior to 30 min of supervised muscle strengthening exercise twice a week for 8 weeks. Participants in both groups will also complete unsupervised home exercises twice per week. Outcome measures of feasibility, safety, pain, disability and pain system function will be assessed immediately before and after the 8-week intervention. Analyses of feasibility and safety will be performed using descriptive statistics. Statistical analyses will be used to determine trends of effectiveness and will be based on intention-to-treat as well as per protocol. Ethics and dissemination This study was approved by the institutional ethics committee (H10184). Written informed consent will be obtained from all participants. The results of this study will be submitted for peer-reviewed publication. Trial registration number ANZCTR

  12. Left-hand somatosensory stimulation combined with visual scanning training in rehabilitation for post-stroke hemineglect: a randomised, double-blind study.

    PubMed

    Polanowska, Katarzyna; Seniów, Joanna; Paprot, Ewa; Leśniak, Marcin; Członkowska, Anna

    2009-06-01

    The aim of this randomised, double-blind study was to investigate the therapeutic effectiveness of left-hand electrical stimulation for patients with post-stroke left visuo-spatial neglect. This approach was hypothesised to enhance activation of the right hemisphere attention system and to improve visual exploration of extrapersonal space. Participants (n = 40) in the study were in a relatively early stage of recovery from their first right hemisphere stroke, and were randomly assigned to the experimental (E) or control (C) group. Group E received conventional visual scanning training combined with electrostimulation of the left hand, while Group C received scanning training with sham stimulation. Their visuo-spatial neglect was assessed twice, prior to the rehabilitation programme and on its completion, using cancellation tests and a letter-reading task. The effect of electrostimulation on hemineglect was assessed following a single administration and after a month-long rehabilitation programme. Although the immediate effect of stimulation was poor, after a month-long rehabilitation period we found significantly greater improvement in Group E patients than in Group C patients. Interestingly, the presence of hemisensory loss did not weaken the observed effect. Therefore, we claim that contralesional hand stimulation combined with visual scanning was a more effective treatment for hemineglect rehabilitation than scanning training alone.

  13. Effects of combined application of progressive resistance training and Russian electrical stimulation on quadriceps femoris muscle strength in elderly women with knee osteoarthritis.

    PubMed

    Park, Seong Hoon; Hwangbo, Gak

    2015-03-01

    [Purpose] The aim of this study was to investigate the effects of combined application of progressive resistance training and Russian electrical stimulation on quadriceps femoris muscle strength in elderly women with osteoarthritis of the knee. [Subjects] Thirty women over 65 years of age diagnosed with knee osteoarthritis participated in the present study. The subjects were randomly assigned to a control group (n=10), a progressive resistance training group (n=10), or a Russian electrical stimulation group (n=10). [Methods] Each group was treated 3 times weekly for 8 weeks, and each session lasted 45 minutes. Muscle strength was assessed by measuring the peak torque of the quadriceps femoris muscle. Outcome measurements were performed at baseline and at the fourth and eighth weeks of the treatment period. [Results] All groups showed significant intragroup differences in the quadriceps femoris muscle peak torque after the treatment intervention. There were significant intergroup differences between the Russian electrical stimulation group and the other groups. [Conclusion] The results of this study suggest that combined application of progressive resistance training and Russian electrical stimulation can be effective in strengthening the quadriceps femoris muscle in elderly women with knee osteoarthritis.

  14. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production.

    PubMed

    Chafe, Shawn C; Lou, Yuanmei; Sceneay, Jaclyn; Vallejo, Marylou; Hamilton, Melisa J; McDonald, Paul C; Bennewith, Kevin L; Möller, Andreas; Dedhar, Shoukat

    2015-03-15

    The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-κB in hypoxic breast cancer cells and constitutive activation of the NF-κB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-κB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche.

  15. The Observation of Manual Grasp Actions Affects the Control of Speech: A Combined Behavioral and Transcranial Magnetic Stimulation Study

    ERIC Educational Resources Information Center

    Gentilucci, Maurizio; Campione, Giovanna Cristina; Volta, Riccardo Dalla; Bernardis, Paolo

    2009-01-01

    Does the mirror system affect the control of speech? This issue was addressed in behavioral and Transcranial Magnetic Stimulation (TMS) experiments. In behavioral experiment 1, participants pronounced the syllable /da/ while observing (1) a hand grasping large and small objects with power and precision grasps, respectively, (2) a foot interacting…

  16. Polymerizing Pyrrole Coated Poly (l-lactic acid-co-ε-caprolactone) (PLCL) Conductive Nanofibrous Conduit Combined with Electric Stimulation for Long-Range Peripheral Nerve Regeneration

    PubMed Central

    Song, Jialin; Sun, Binbin; Liu, Shen; Chen, Wei; Zhang, Yuanzheng; Wang, Chunyang; Mo, Xiumei; Che, Junyi; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

    2016-01-01

    Electrospinning and electric stimulation (ES) are both promising methods to support neuron adhesion and guide extension of neurons for nerve regeneration. Concurrently, all studies focus on either electrospinning for conduits material or ES in vitro study to accelerate nerve regeneration; few work on the combined use of these two strategies or ES in vivo study. Therefore, this study aimed to investigate the abilities of direct current ES through electrospinning conductive polymer composites composed of polypyrrole and Poly (l-lactic acid-co-ε-caprolactone) (PPY/PLCL) in peripheral nerve regeneration. PPY/PLCL composite conduits were synthesized by polymerizing pyrrole coated electrospun PLCL scaffolds. Morphologies and chemical compositions were characterized by scanning electron microscope and attenuated total reflection fourier transform infrared (ATR-FTIR) microscope. Rat pheochromocytoma 12 (PC12) cells and dorsal root ganglia (DRG) cells cultured on PPY/PLCL scaffolds were stimulated with 100 mV/cm for 4 h per day. The median neurite length and cell viability were measured in PC-12 cells. The levels of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) were analyzed in DRG cells. In rats, 15 mm gaps of sciatic nerves were bridged using an autograft, non-stimulated PPY/PLCL conduit and PPY/PLCL conduit stimulated with 100 mV potential, respectively. A 100 mV potential direct current ES was applied for 1 h per day at 1, 3, 5 and 7 days post-implantation. The PPY/PLCL conduits with ES showed a similar performance compared with the autograft group, and significantly better than the non-stimulated PPY/PLCL conduit group. These promising results show that the PPY/PLCL conductive conduits’ combined use with ES has great potential for peripheral nerve regeneration. PMID:27877111

  17. Effects of combined electrical stimulation of the dorsal column and dorsal roots on wide-dynamic range neuronal activity in nerve-injured rats

    PubMed Central

    Yang, Fei; Zhang, Tong; Tiwari, Vinod; Shu, Bin; Zhang, Chen; Wang, Yun; Vera-Portocarrero, Louis P.; Raja, Srinivasa N.; Guan, Yun

    2015-01-01

    Objectives Electrical stimulation at the dorsal column (DC) and dorsal root (DR) may inhibit spinal wide-dynamic-range (WDR) neuronal activity in nerve-injured rats. The objective of this study was to determine if applying electrical conditioning stimulation (CS) at both sites provides additive or synergistic benefits. Materials and Methods By conducting in vivo extracellular recordings of WDR neurons in rats that had undergone L5 spinal nerve ligation, we tested whether combining 50 Hz CS at the two sites in either a concurrent (2.5 minutes) or alternate (5 minutes) pattern inhibits WDR neuronal activity better than CS at DC alone (5 minutes). The intensities of CS were determined by recording antidromic compound action potentials to graded stimulation at the DC and DR. We measured the current thresholds that resulted in the first detectable Aα/β waveform (Ab0) and the peak Aα/β waveform (Ab1) to select CS intensity at each site. The same number of electrical pulses and amount of current were delivered in different patterns to allow comparison. Results At a moderate intensity of 50%(Ab0+Ab1), different patterns of CS all attenuated the C-component of WDR neurons in response to graded intracutaneous electrical stimuli (0.1-10 mA, 2 ms), and inhibited windup in response to repetitive noxious stimuli (0.5 Hz). However, the inhibitory effects did not differ significantly between different patterns. At the lower intensity (Ab0), no CS inhibited WDR neurons. Conclusions These findings suggest that combined stimulation of DC and DR may not be superior to DC stimulation alone for inhibition of WDR neurons. PMID:26307526

  18. Polymerizing Pyrrole Coated Poly (l-lactic acid-co-ε-caprolactone) (PLCL) Conductive Nanofibrous Conduit Combined with Electric Stimulation for Long-Range Peripheral Nerve Regeneration.

    PubMed

    Song, Jialin; Sun, Binbin; Liu, Shen; Chen, Wei; Zhang, Yuanzheng; Wang, Chunyang; Mo, Xiumei; Che, Junyi; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

    2016-01-01

    Electrospinning and electric stimulation (ES) are both promising methods to support neuron adhesion and guide extension of neurons for nerve regeneration. Concurrently, all studies focus on either electrospinning for conduits material or ES in vitro study to accelerate nerve regeneration; few work on the combined use of these two strategies or ES in vivo study. Therefore, this study aimed to investigate the abilities of direct current ES through electrospinning conductive polymer composites composed of polypyrrole and Poly (l-lactic acid-co-ε-caprolactone) (PPY/PLCL) in peripheral nerve regeneration. PPY/PLCL composite conduits were synthesized by polymerizing pyrrole coated electrospun PLCL scaffolds. Morphologies and chemical compositions were characterized by scanning electron microscope and attenuated total reflection fourier transform infrared (ATR-FTIR) microscope. Rat pheochromocytoma 12 (PC12) cells and dorsal root ganglia (DRG) cells cultured on PPY/PLCL scaffolds were stimulated with 100 mV/cm for 4 h per day. The median neurite length and cell viability were measured in PC-12 cells. The levels of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) were analyzed in DRG cells. In rats, 15 mm gaps of sciatic nerves were bridged using an autograft, non-stimulated PPY/PLCL conduit and PPY/PLCL conduit stimulated with 100 mV potential, respectively. A 100 mV potential direct current ES was applied for 1 h per day at 1, 3, 5 and 7 days post-implantation. The PPY/PLCL conduits with ES showed a similar performance compared with the autograft group, and significantly better than the non-stimulated PPY/PLCL conduit group. These promising results show that the PPY/PLCL conductive conduits' combined use with ES has great potential for peripheral nerve regeneration.

  19. Brain Activity during Mental Imagery of Gait Versus Gait-Like Plantar Stimulation: A Novel Combined Functional MRI Paradigm to Better Understand Cerebral Gait Control.

    PubMed

    Labriffe, Matthieu; Annweiler, Cédric; Amirova, Liubov E; Gauquelin-Koch, Guillemette; Ter Minassian, Aram; Leiber, Louis-Marie; Beauchet, Olivier; Custaud, Marc-Antoine; Dinomais, Mickaël

    2017-01-01

    Human locomotion is a complex sensorimotor behavior whose central control remains difficult to explore using neuroimaging method due to technical constraints, notably the impossibility to walk with a scanner on the head and/or to walk for real inside current scanners. The aim of this functional Magnetic Resonance Imaging (fMRI) study was to analyze interactions between two paradigms to investigate the brain gait control network: (1) mental imagery of gait, and (2) passive mechanical stimulation of the plantar surface of the foot with the Korvit boots. The Korvit stimulator was used through two different modes, namely an organized ("gait like") sequence and a destructured (chaotic) pattern. Eighteen right-handed young healthy volunteers were recruited (mean age, 27 ± 4.7 years). Mental imagery activated a broad neuronal network including the supplementary motor area-proper (SMA-proper), pre-SMA, the dorsal premotor cortex, ventrolateral prefrontal cortex, anterior insula, and precuneus/superior parietal areas. The mechanical plantar stimulation activated the primary sensorimotor cortex and secondary somatosensory cortex bilaterally. The paradigms generated statistically common areas of activity, notably bilateral SMA-proper and right pre-SMA, highlighting the potential key role of SMA in gait control. There was no difference between the organized and chaotic Korvit sequences, highlighting the difficulty of developing a walking-specific plantar stimulation paradigm. In conclusion, this combined-fMRI paradigm combining mental imagery and gait-like plantar stimulation provides complementary information regarding gait-related brain activity and appears useful for the assessment of high-level gait control.

  20. Brain Activity during Mental Imagery of Gait Versus Gait-Like Plantar Stimulation: A Novel Combined Functional MRI Paradigm to Better Understand Cerebral Gait Control

    PubMed Central

    Labriffe, Matthieu; Annweiler, Cédric; Amirova, Liubov E.; Gauquelin-Koch, Guillemette; Ter Minassian, Aram; Leiber, Louis-Marie; Beauchet, Olivier; Custaud, Marc-Antoine; Dinomais, Mickaël

    2017-01-01

    Human locomotion is a complex sensorimotor behavior whose central control remains difficult to explore using neuroimaging method due to technical constraints, notably the impossibility to walk with a scanner on the head and/or to walk for real inside current scanners. The aim of this functional Magnetic Resonance Imaging (fMRI) study was to analyze interactions between two paradigms to investigate the brain gait control network: (1) mental imagery of gait, and (2) passive mechanical stimulation of the plantar surface of the foot with the Korvit boots. The Korvit stimulator was used through two different modes, namely an organized (“gait like”) sequence and a destructured (chaotic) pattern. Eighteen right-handed young healthy volunteers were recruited (mean age, 27 ± 4.7 years). Mental imagery activated a broad neuronal network including the supplementary motor area-proper (SMA-proper), pre-SMA, the dorsal premotor cortex, ventrolateral prefrontal cortex, anterior insula, and precuneus/superior parietal areas. The mechanical plantar stimulation activated the primary sensorimotor cortex and secondary somatosensory cortex bilaterally. The paradigms generated statistically common areas of activity, notably bilateral SMA-proper and right pre-SMA, highlighting the potential key role of SMA in gait control. There was no difference between the organized and chaotic Korvit sequences, highlighting the difficulty of developing a walking-specific plantar stimulation paradigm. In conclusion, this combined-fMRI paradigm combining mental imagery and gait-like plantar stimulation provides complementary information regarding gait-related brain activity and appears useful for the assessment of high-level gait control. PMID:28321186

  1. [Electrical stimulation therapy and its effects on the general activity of motor impaired cerebral palsied children; a comparative study of the Bobath physiotherapy and its combination with the Hufschmidt electrical stimulation therapy (author's transl)].

    PubMed

    Leyendecker, C

    1975-08-01

    The purpose of this study was to answer the following questions: (1) Is it more effective to treat spastic cerebral palsy with the Hufschmidt electrical stimulation therapy combined with the Bobath neuro-development treatment or only with the Bobath therapy? (2) Can a general increase in activity be obtained by the electrotherapeutic muscle stimulation? A test group (combined Hufschmidt/Bobath therapy) and a control group (Bobath), both consisting of 10 subjects, were observed for four months. The duration of observation was divided into two four months treatment periods with a rest interval of two months in between. At the start of therapeutic measures, motor activity and psychic condition were tested with corresponding motormetric and psychodiagnostic techniques; three check-up examinations were carried out at the end of the first, and at the beginning and end of the second period of treatment. The motor-metric control examination showed that at the end of the first period the test group had achieved by far the better results, but at the end of the second therapeutic period, both groups were equally successful. The combined electrophysiotherapy hence reached in a relatively shorter time - as it were by leaps and bounds - the optimal obtainable state of functional improvements which, with the Bobath therapy alone, can be effected more slowly but with more continuity. The psychodiagnostic controls clearly indicate that the electrical stimulation produced an unspecified increase in activity, especially after the first phase of treatment, whereas in the second phase this could only be proven in a graded form. The report closes with an examination of the results and their consequences for the implementation of the treatment for cerebral palsied children.

  2. Transcranial Direct Current Stimulation Combined with Aerobic Exercise to Optimize Analgesic Responses in Fibromyalgia: A Randomized Placebo-Controlled Clinical Trial

    PubMed Central

    Mendonca, Mariana E.; Simis, Marcel; Grecco, Luanda C.; Battistella, Linamara R.; Baptista, Abrahão F.; Fregni, Felipe

    2016-01-01

    Fibromyalgia is a chronic pain syndrome that is associated with maladaptive plasticity in neural central circuits. One of the neural circuits that are involved in pain in fibromyalgia is the primary motor cortex. We tested a combination intervention that aimed to modulate the motor system: transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) and aerobic exercise (AE). In this phase II, sham-controlled randomized clinical trial, 45 subjects were assigned to 1 of 3 groups: tDCS + AE, AE only, and tDCS only. The following outcomes were assessed: intensity of pain, level of anxiety, quality of life, mood, pressure pain threshold, and cortical plasticity, as indexed by transcranial magnetic stimulation. There was a significant effect for the group-time interaction for intensity of pain, demonstrating that tDCS/AE was superior to AE [F(13, 364) = 2.25, p = 0.007] and tDCS [F(13, 364) = 2.33, p = 0.0056] alone. Post-hoc adjusted analysis showed a difference between tDCS/AE and tDCS group after the first week of stimulation and after 1 month intervention period (p = 0.02 and p = 0.03, respectively). Further, after treatment there was a significant difference between groups in anxiety and mood levels. The combination treatment effected the greatest response. The three groups had no differences regarding responses in motor cortex plasticity, as assessed by TMS. The combination of tDCS with aerobic exercise is superior compared with each individual intervention (cohen's d effect sizes > 0.55). The combination intervention had a significant effect on pain, anxiety and mood. Based on the similar effects on cortical plasticity outcomes, the combination intervention might have affected other neural circuits, such as those that control the affective-emotional aspects of pain. Trial registration: (www.ClinicalTrials.gov), identifier NTC02358902. PMID:27014012

  3. Hochuekkito, a Kampo (Traditional Japanese Herbal) Medicine, and its Polysaccharide Portion Stimulate G-CSF Secretion from Intestinal Epithelial Cells.

    PubMed

    Matsumoto, Tsukasa; Moriya, Michiyo; Kiyohara, Hiroaki; Tabuchi, Yoshiaki; Yamada, Haruki

    2010-09-01

    Kampo (traditional Japanese herbal) medicines are taken orally due to which the gastric mucosal immune system may act as one of the major targets for the expression of pharmacological activity. The inner surface of the intestinal tract possesses a large area of mucosal membranes, and the intestinal epithelial cells sit at the interface between a lumen and a lymphocyte-rich lamina propria. The cross talk that occurs between these compartments serves to maintain intestinal homeostasis, and the cytokine network plays an important role in the cross talk. In this study, the effect of Hochuekkito (HET), one of Kampo medicines, on cytokine secretion of intestinal epithelial cells was investigated. When murine normal colonic epithelial cell-line MCE301 cells were stimulated with HET, the contents of granulocyte colony-stimulating factor (G-CSF) in the conditioned medium were significantly increased in dose- and time-dependent manners. The enhanced G-CSF gene transcription in MCE301 cells by the stimulation of HET was observed by RT-PCR. The enhanced G-CSF secretion by HET was also observed in C3H/HeJ mice-derived primary cultured colonic epithelial cells. When the HET was fractionated, only the polysaccharide fraction (F-5) enhanced the G-CSF secretion of MCE301 cells, and the activity of F-5 lost after the treatment of periodate that can degrade the carbohydrate moiety. These results suggest that HET enhances secretion of G-CSF from colonic epithelial cells and the polysaccharide is one of the active ingredients of HET. The enhanced G-CSF secretion by HET may partly contribute to the clinically observed various pharmacological activities of HET including immunomodulating activity.

  4. Constraint-Induced Movement Therapy Combined with Transcranial Direct Current Stimulation over Premotor Cortex Improves Motor Function in Severe Stroke: A Pilot Randomized Controlled Trial

    PubMed Central

    Batista, Larissa M.; Nogueira, Lídia L. R. F.; de Oliveira, Eliane A.; de Carvalho, Antonio G. C.; Lima, Soriano S.; Santana, Jordânia R. M.; de Lima, Emerson C. C.; Fernández-Calvo, Bernardino

    2017-01-01

    Objective. We compared the effects of transcranial direct current stimulation at different cortical sites (premotor and motor primary cortex) combined with constraint-induced movement therapy for treatment of stroke patients. Design. Sixty patients were randomly distributed into 3 groups: Group A, anodal stimulation on premotor cortex and constraint-induced movement therapy; Group B, anodal stimulation on primary motor cortex and constraint-induced movement therapy; Group C, sham stimulation and constraint-induced movement therapy. Evaluations involved analysis of functional independence, motor recovery, spasticity, gross motor function, and muscle strength. Results. A significant improvement in primary outcome (functional independence) after treatment in the premotor group followed by primary motor group and sham group was observed. The same pattern of improvement was highlighted among all secondary outcome measures regarding the superior performance of the premotor group over primary motor and sham groups. Conclusions. Premotor cortex can contribute to motor function in patients with severe functional disabilities in early stages of stroke. This study was registered in ClinicalTrials.gov database (NCT 02628561). PMID:28250992

  5. Constraint-Induced Movement Therapy Combined with Transcranial Direct Current Stimulation over Premotor Cortex Improves Motor Function in Severe Stroke: A Pilot Randomized Controlled Trial.

    PubMed

    Andrade, Suellen M; Batista, Larissa M; Nogueira, Lídia L R F; de Oliveira, Eliane A; de Carvalho, Antonio G C; Lima, Soriano S; Santana, Jordânia R M; de Lima, Emerson C C; Fernández-Calvo, Bernardino

    2017-01-01

    Objective. We compared the effects of transcranial direct current stimulation at different cortical sites (premotor and motor primary cortex) combined with constraint-induced movement therapy for treatment of stroke patients. Design. Sixty patients were randomly distributed into 3 groups: Group A, anodal stimulation on premotor cortex and constraint-induced movement therapy; Group B, anodal stimulation on primary motor cortex and constraint-induced movement therapy; Group C, sham stimulation and constraint-induced movement therapy. Evaluations involved analysis of functional independence, motor recovery, spasticity, gross motor function, and muscle strength. Results. A significant improvement in primary outcome (functional independence) after treatment in the premotor group followed by primary motor group and sham group was observed. The same pattern of improvement was highlighted among all secondary outcome measures regarding the superior performance of the premotor group over primary motor and sham groups. Conclusions. Premotor cortex can contribute to motor function in patients with severe functional disabilities in early stages of stroke. This study was registered in ClinicalTrials.gov database (NCT 02628561).

  6. Muscular Strength Gains and Sensory Perception Changes: A Comparison of Electrical and Combined Electrical/Magnetic Stimulation.

    DTIC Science & Technology

    1992-04-10

    Trentin and Visentin applied low-amplitude (200 to 600 gauss) magnetic stimulation to patients suffering from rheumatoid and osteoarthritis with mixed...results. The osteoarthritis group had pain and range of motion changes they classified as "good", but were limited to only four months. 64 Binder and co...muscle. Physiotherapy Canada. 1979;31:265-267. 5. Johnson DH, ThurstonP, Ashcroft PJ. The Russian techique of faradism in the treatment of chondromalacia

  7. Combined roles of contact stimulant and deterrents in assessment of host-plant quality by ovipositing zebra swallowtail butterflies.

    PubMed

    Haribal, Meena; Feeny, Paul

    2003-03-01

    Zebra swallowtail (Eurytides marcellus) butterflies are stimulated to oviposit by a single compound, 3-caffeoyl-muco-quinic acid (1). Analysis of the aqueous extracts of the leaves of the host. Asimina triloba, showed that they contained stimulant 1, its isomer (2), and the flavonoids rutin (3) and nicotiflorine (4) as major components. We compared the concentrations of compounds 1-4 in terminal leaves (TL) and expanded leaves (EL) of the host plants at four different times throughout the growing season. In spring, the concentration of 1 was highest in TLs, and flavonoids were not detectable or present at low levels. As the season progressed, however, the concentrations of flavonoids increased, reached maxima by late summer, and then decreased as the plants started senescing. There were also significant differences in the concentrations of these compounds between TLs and ELs. In a choice assay with model leaves, we tested equivalent amounts of post-dichloromethane aqueous extracts made in spring (May) and in fall (September). September extracts received significantly fewer approaches and eggs. In greenhouse experiments with potted A. triloba plants, the butterflies chose some leaves to lay eggs, while others were rejected or ignored. Analyses showed that the concentrations of compound 1 were not significantly different in the three kinds of leaves. The flavonoids (3 and 4), however, were significantly higher in the leaves that were ignored. Multiple-choice tests using model plants suggested that concentrations of both flavonoids and stimulant were important in assessing host suitability. There was a gradual decrease in approaches as the concentration of 1 decreased. Higher amounts of flavonoids deterred egg laying even in the presence of high concentrations of stimulant 1. At lower concentrations of 1, the addition of low doses of flavonoids deterred egg laying. Thus, the results suggest that the butterflies use both qualitative and quantitative information about

  8. Effect of Transcranial Direct-Current Stimulation Combined with Treadmill Training on Balance and Functional Performance in Children with Cerebral Palsy: A Double-Blind Randomized Controlled Trial

    PubMed Central

    Duarte, Natália de Almeida Carvalho; Grecco, Luanda André Collange; Galli, Manuela; Fregni, Felipe; Oliveira, Cláudia Santos

    2014-01-01

    Background Cerebral palsy refers to permanent, mutable motor development disorders stemming from a primary brain lesion, causing secondary musculoskeletal problems and limitations in activities of daily living. The aim of the present study was to determine the effects of gait training combined with transcranial direct-current stimulation over the primary motor cortex on balance and functional performance in children with cerebral palsy. Methods A double-blind randomized controlled study was carried out with 24 children aged five to 12 years with cerebral palsy randomly allocated to two intervention groups (blocks of six and stratified based on GMFCS level (levels I-II or level III).The experimental group (12 children) was submitted to treadmill training and anodal stimulation of the primary motor cortex. The control group (12 children) was submitted to treadmill training and placebo transcranial direct-current stimulation. Training was performed in five weekly sessions for 2 weeks. Evaluations consisted of stabilometric analysis as well as the administration of the Pediatric Balance Scale and Pediatric Evaluation of Disability Inventory one week before the intervention, one week after the completion of the intervention and one month after the completion of the intervention. All patients and two examiners were blinded to the allocation of the children to the different groups. Results The experimental group exhibited better results in comparison to the control group with regard to anteroposterior sway (eyes open and closed; p<0.05), mediolateral sway (eyes closed; p<0.05) and the Pediatric Balance Scale both one week and one month after the completion of the protocol. Conclusion Gait training on a treadmill combined with anodal stimulation of the primary motor cortex led to improvements in static balance and functional performance in children with cerebral palsy. Trial Registration Ensaiosclinicos.gov.br/RBR-9B5DH7 PMID:25171216

  9. Effects of Amphetamine-CNS Depressant Combinations and of Other CNS Stimulants in Four-Choice Drug Discriminations

    ERIC Educational Resources Information Center

    Li, Mi; Wessinger, William D.; McMillan, D. E.

    2005-01-01

    Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine--pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs…

  10. The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

    NASA Technical Reports Server (NTRS)

    Goldspink, G.; Goldspink, D.; Loughna, P.

    1984-01-01

    The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

  11. A proof of concept study investigating the feasibility of combining iPAM robot assisted rehabilitation with functional electrical stimulation to deliver whole arm exercise in stroke survivors.

    PubMed

    O'Connor, Rory J; Jackson, Andrew; Makower, Sophie G; Cozens, Alastair; Levesley, Martin

    2014-01-01

    Rehabilitation robots can provide exercise for stroke survivors with weakness at the shoulder and elbow, but most do not facilitate hand movements. The aim was to combine robotics and functional electrical stimulation to facilitate exercise in stroke survivors with upper limb impairment. iPAM Mk II was used to assist active reaching in combination with an Odstock Pace stimulator to assist hand opening. The ABILHAND, Action Research Arm Test (ARAT) and the Stroke Impact Scale (SIS) were recorded at baseline and completion. Nine participants (eight males and one female; mean age = 58 years) were recruited; mean time since stroke was 16 months (range = 6-64). The ABILHAND at baseline was -2.73, improving to -1.45 at follow-up (p = 0.038). The ARAT changed from 4.1 to 2.6 (p = 0.180), and the SIS from 49 to 60 (p = 0.019). This study demonstrates that it is possible to combine two technologies in stroke rehabilitation.

  12. Low-frequency electrical stimulation combined with a cooling vest improves recovery of elite kayakers following a simulated 1000-m race in a hot environment.

    PubMed

    Borne, R; Hausswirth, C; Costello, J T; Bieuzen, F

    2015-06-01

    This study compared the effects of a low-frequency electrical stimulation (LFES; Veinoplus(®) Sport, Ad Rem Technology, Paris, France), a low-frequency electrical stimulation combined with a cooling vest (LFESCR ) and an active recovery combined with a cooling vest (ACTCR ) as recovery strategies on performance (racing time and pacing strategies), physiologic and perceptual responses between two sprint kayak simulated races, in a hot environment (∼32 wet-bulb-globe temperature). Eight elite male kayakers performed two successive 1000-m kayak time trials (TT1 and TT2), separated by a short-term recovery period, including a 30-min of the respective recovery intervention protocol, in a randomized crossover design. Racing time, power output, and stroke rate were recorded for each time trial. Blood lactate concentration, pH, core, skin and body temperatures were measured before and after both TT1 and TT2 and at mid- and post-recovery intervention. Perceptual ratings of thermal sensation were also collected. LFESCR was associated with a very likely effect in performance restoration compared with ACTCR (99/0/1%) and LFES conditions (98/0/2%). LFESCR induced a significant decrease in body temperature and thermal sensation at post-recovery intervention, which is not observed in ACTCR condition. In conclusion, the combination of LFES and wearing a cooling vest (LFESCR ) improves performance restoration between two 1000-m kayak time trials achieved by elite athletes, in the heat.

  13. Effects of electrical stimulation combined with dysphagia therapy in elderly individual with oropharyngeal dysphagia: a case study

    PubMed Central

    Lee, Doo-Ho; Park, Ji-Su; Lee, Seung-Woong; Choi, Jong-Bae

    2017-01-01

    [Purpose] The purpose of the present study was to investigate the effects of dysphagia therapy in an old man with difficulty swallowing in the oral and pharyngeal phases. [Subjects and Methods] The subject was a 72-year-old man with no history of neurological disorders. He was admitted to local hospital because of the complaint of swallowing difficulty. The interventions performed were electrical stimulation and conventional dysphagia therapy. We assessed the tongue and lip muscle strengths. Swallowing function was evaluated by using the videofluoroscopic dysphagia and penetration-aspiration scales. [Results] After the intervention, the tongue and lip muscle strengths increased from 35 to 39 kPa and from 18 to 23 kPa, respectively. Moreover, the oral and pharyngeal phases of the videofluoroscopic dysphagia scale were improved. Furthermore, aspiration decreased from 4 to 2 points in the penetration-aspiration scale. [Conclusion] Our results suggest that electrical stimulation and conventional dysphagia therapy were effective in improving the swallowing function in an elderly individual with dysphagia. PMID:28356653

  14. The observation of manual grasp actions affects the control of speech: a combined behavioral and Transcranial Magnetic Stimulation study.

    PubMed

    Gentilucci, Maurizio; Campione, Giovanna Cristina; Dalla Volta, Riccardo; Bernardis, Paolo

    2009-12-01

    Does the mirror system affect the control of speech? This issue was addressed in behavioral and Transcranial Magnetic Stimulation (TMS) experiments. In behavioral experiment 1, participants pronounced the syllable /da/ while observing (1) a hand grasping large and small objects with power and precision grasps, respectively, (2) a foot interacting with large and small objects and (3) differently sized objects presented alone. Voice formant 1 was higher when observing power as compared to precision grasp, whereas it remained unaffected by observation of the different types of foot interaction and objects alone. In TMS experiment 2, we stimulated hand motor cortex, while participants observed the two types of grasp. Motor Evoked Potentials (MEPs) of hand muscles active during the two types of grasp were greater when observing power than precision grasp. In experiments 3-5, TMS was applied to tongue motor cortex of participants silently pronouncing the syllable /da/ and simultaneously observing power and precision grasps, pantomimes of the two types of grasps, and differently sized objects presented alone. Tongue MEPs were greater when observing power than precision grasp either executed or pantomimed. Finally, in TMS experiment 6, the observation of foot interaction with large and small objects did not modulate tongue MEPs. We hypothesized that grasp observation activated motor commands to the mouth as well as to the hand that were congruent with the hand kinematics implemented in the observed type of grasp. The commands to the mouth selectively affected postures of phonation organs and consequently basic features of phonological units.

  15. The advantage of combining MEG and EEG: comparison to fMRI in focally-stimulated visual cortex

    PubMed Central

    Sharon, Dahlia; Hämäläinen, Matti S; Tootell, Roger BH; Halgren, Eric; Belliveau, John W

    2009-01-01

    To exploit the high (millisecond) temporal resolution of magnetoencephalography (MEG) and electroencephalography (EEG) for measuring neuronal dynamics within well-defined brain regions, it is important to quantitatively assess their localizing ability. Previous modeling studies and empirical data suggest that a combination of MEG and EEG signals should yield the most accurate localization, due to their complementary sensitivities. However, these two modalities have rarely been explicitly combined for source estimation in studies of recorded brain activity, and a quantitative empirical assessment of their abilities, combined and separate, is currently lacking. Here we studied early visual responses to focal Gabor patches flashed during subject fixation. MEG and EEG data were collected simultaneously, and compared with the functional MRI (fMRI) localization produced by identical stimuli, in the same subjects. This allowed direct evaluation of the localization accuracy of separate and combined MEG/EEG inverse solutions. We found that the localization accuracy of the combined MEG+EEG solution was consistently better than that of either modality alone, using three different source estimation approaches. Further analysis suggests that this improved localization is due to the different properties of the two imaging modalities, rather than simply due to increased total channel number. Thus, combining MEG and EEG data is important for high-resolution spatiotemporal studies of the human brain. PMID:17532230

  16. Encouraging overweight students with intellectual disability to actively perform walking activity using an air mouse combined with preferred stimulation.

    PubMed

    Chang, Chia-Jui; Chang, Man-Ling; Shih, Ching-Hsiang

    2016-08-01

    This study continues the research on using an air mouse as a physical activity detector. An air mouse is embedded with a MEMS (Micro Electro Mechanical Systems) gyro sensor, which can measure even the slightest movement in the air. The air mouse was strapped to one of each participant's calves to detect walking activity. This study was conducted to evaluate whether four students with intellectual disability who were overweight and disliked exercising could be motivated to engage in walking actively by linking the target response with preferred stimulation. Single-subject research with ABAB design was adopted in this study. The experimental data showed substantial increases in the participants' target responses (i.e. the performance of the activity of walking) during the intervention phases compared to the baseline phases. The practical and developmental implications of the findings are discussed.

  17. Combined Scopolamine and Ethanol Treatment Results in a Locomotor Stimulant Response Suggestive of Synergism That is Not Blocked by Dopamine Receptor Antagonists

    PubMed Central

    Scibelli, Angela C.; Phillips, Tamara J.

    2010-01-01

    Background Muscarinic acetylcholine receptors (mAChRs) are well positioned to mediate ethanol’s stimulant effects. To investigate this possibility, we examined the effects of scopolamine, a receptor subtype nonselective mAChR antagonist, on ethanol-induced stimulation in genotypes highly sensitive to this effect of ethanol. We also investigated whether the dopamine D1-like receptor antagonist, SCH-23390 or the dopamine D2-like receptor antagonist, haloperidol, could block the extreme stimulant response found following co-administration of scopolamine and ethanol. Methods Scopolamine (0, 0.0625, 0.125, 0.25, or 0.5 mg/kg) was given 10 minutes prior to saline or ethanol (0.75 to 2 g/kg) to female FAST (Experiment I) or DBA/2J (Experiment II) mice that were then tested for locomotion for 30 minutes. In Experiments III and IV, respectively, SCH-23390 (0, 0.015, or 0.03 mg/kg) was given 10 minutes prior, and haloperidol (0, 0.08, or 0.16 mg/kg) was given 2 minutes prior, to scopolamine (0 or 0.5 mg/kg), followed 10 minutes later by saline or ethanol (1.5 g/kg) and female DBA/2J mice were tested for locomotion for 30 minutes. Results FAST and DBA/2J mice displayed a robust enhancement of the locomotor effects of ethanol following pretreatment with scopolamine that was suggestive of synergism. SCH-23390 had no effect on the response to the scopolamine + ethanol drug combination, nor did it attenuate ethanol- or scopolamine-induced locomotor activity. Haloperidol, while attenuating the effects of ethanol, was not able to block the effects of scopolamine or the robust response to the scopolamine-ethanol drug combination. Conclusions These results suggest that while muscarinic receptor antagonism robustly enhances acute locomotor stimulation to ethanol, dopamine receptors are not involved in the super-additive interaction of scopolamine and ethanol treatment. They also suggest that in addition to cautions regarding the use of alcohol when scopolamine is clinically

  18. Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis?

    PubMed Central

    Hara, Takatoshi; Abo, Masahiro; Kakita, Kiyohito; Masuda, Takeshi; Yamazaki, Ryunosuke

    2016-01-01

    Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) to the contralesional hemisphere and intensive occupational therapy (iOT) have been shown to contribute to a significant improvement in upper limb hemiparesis in patients with chronic stroke. However, the effect of the combined intervention program of LF-rTMS and iOT on cognitive function is unknown. We retrospectively investigated whether the combined treatment influence patient's Trail-Making Test part B (TMT-B) performance, which is a group of easy and inexpensive neuropsychological tests that evaluate several cognitive functions. Twenty-five patients received 11 sessions of LF-rTMS to the contralesional hemisphere and 2 sessions of iOT per day over 15 successive days. Patients with right- and left-sided hemiparesis demonstrated significant improvements in upper limb motor function following the combined intervention program. Only patients with right-sided hemiparesis exhibited improved TMT-B performance following the combined intervention program, and there was a significant negative correlation between Fugl-Meyer Assessment scale total score change and TMT-B performance. The results indicate the possibility that LF-rTMS to the contralesional hemisphere combined with iOT improves the upper limb motor function and cognitive function of patients with right-sided hemiparesis. However, further studies are necessary to elucidate the mechanism of improved cognitive function. PMID:28197189

  19. Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis?

    PubMed

    Hara, Takatoshi; Abo, Masahiro; Kakita, Kiyohito; Masuda, Takeshi; Yamazaki, Ryunosuke

    2016-12-01

    Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) to the contralesional hemisphere and intensive occupational therapy (iOT) have been shown to contribute to a significant improvement in upper limb hemiparesis in patients with chronic stroke. However, the effect of the combined intervention program of LF-rTMS and iOT on cognitive function is unknown. We retrospectively investigated whether the combined treatment influence patient's Trail-Making Test part B (TMT-B) performance, which is a group of easy and inexpensive neuropsychological tests that evaluate several cognitive functions. Twenty-five patients received 11 sessions of LF-rTMS to the contralesional hemisphere and 2 sessions of iOT per day over 15 successive days. Patients with right- and left-sided hemiparesis demonstrated significant improvements in upper limb motor function following the combined intervention program. Only patients with right-sided hemiparesis exhibited improved TMT-B performance following the combined intervention program, and there was a significant negative correlation between Fugl-Meyer Assessment scale total score change and TMT-B performance. The results indicate the possibility that LF-rTMS to the contralesional hemisphere combined with iOT improves the upper limb motor function and cognitive function of patients with right-sided hemiparesis. However, further studies are necessary to elucidate the mechanism of improved cognitive function.

  20. Single-chain bifunctional vascular endothelial growth factor (VEGF)-follicle-stimulating hormone (FSH)-C-terminal peptide (CTP) is superior to the combination therapy of recombinant VEGF plus FSH-CTP in stimulating angiogenesis during ovarian folliculogenesis.

    PubMed

    Trousdale, Rhonda K; Pollak, Susan V; Klein, Jeffrey; Lobel, Leslie; Funahashi, Yasuhiro; Feirt, Nikki; Lustbader, Joyce W

    2007-03-01

    Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.

  1. Motor training and the combination of action observation and peripheral nerve stimulation reciprocally interfere with the plastic changes induced in primary motor cortex excitability.

    PubMed

    Bisio, Ambra; Avanzino, Laura; Biggio, Monica; Ruggeri, Piero; Bove, Marco

    2017-04-21

    AO-PNS is a stimulation protocol combining action observation (AO) and peripheral nerve stimulation (PNS) to induce plasticity in the primary motor cortex (M1) (increased excitability). Another method to increase M1 excitability is motor training. The combination of two protocols, which individually induce long-term potentiation (LTP)-like plasticity in overlapping neural circuits, results in a transitory occlusion or reverse of this phenomenon. This study aimed to understand the neurophysiological mechanisms underlying AO-PNS by testing whether AO-PNS and motor training induced LTP-like plasticity in, at least partially, overlapping neural networks. One group of participants practiced a motor training (finger opposition movements) followed by AO-PNS, whereas another group performed the two protocols in reverse order. Motor performance was evaluated by means of a sensor-engineered glove and transcranial magnetic stimulation was used to assess M1 excitability before and after each conditioning protocol. Motor training increased movement frequency, suggesting the occurrence of motor learning in both groups. When applied on first, both motor training and AO-PNS significantly increased the motor-evoked potential (MEP), but occluded the increase of cortical excitability expected after the following protocol, leading to a significant decrease of MEP amplitude. These results suggest that motor training and AO-PNS act on partially overlapping neuronal networks, which include M1, and that AO-PNS might be able to induce LTP-like plasticity in a similar way to overt movement execution. This candidates AO-PNS as methodology potentially useful when planning rehabilitative interventions on patients who cannot voluntarily move.

  2. Combined Oral and Intravenous Immunization Stimulates Strong IgA Responses in Both Systemic and Mucosal Compartments

    PubMed Central

    Yang, Zhe; Zhao, Qing; Gao, Yun-An; Zhang, Wei

    2016-01-01

    To investigate the influence of immunization routes onIgG, IgA and IgM production in systemic and mucosal compartments, we immunized mice with keyhole limpet hemocyanin (KLH) via oral, intranasal (i.n.) or subcutaneous (s.c.) routes alone or combined with the intravenous (i.v.) route. We found that administering antigen intravenously could affect antibody production and formation of antibody secreting cells (ASCs) depending on the immunization route previously used. Combined oral/i.v. immunization but not s.c./i.v. immunization caused a great increase of IgA ASCs in the spleen and enhanced IgA production in the small intestine and serum. Combined i.n./i.v. immunization could also increase IgA ASCs in the spleen and enhance IgA production in serum but had no effect on IgA production in the small intestine. Oral/i.v. immunization caused increase of IgG ASCs in both the spleen and bone marrow. In comparison, combined i.n./i.v. and s.c./i.v. immunization could increase IgG ASCs in the spleen but not in bone marrow. Intravenous administration of KLH in mice that had been immunized via oral, i.n. or s.c. routes caused some increase of IgM ASCs in the spleen but not in bone marrow. In conclusion, combined oral and i.v. administration of an antigen can induce fast and strong immune responses, especially for IgA, in both systemic and mucosal compartments. PMID:27936222

  3. Combined Oral and Intravenous Immunization Stimulates Strong IgA Responses in Both Systemic and Mucosal Compartments.

    PubMed

    Yang, Zhe; Zhao, Qing; Gao, Yun-An; Zhang, Wei

    2016-01-01

    To investigate the influence of immunization routes onIgG, IgA and IgM production in systemic and mucosal compartments, we immunized mice with keyhole limpet hemocyanin (KLH) via oral, intranasal (i.n.) or subcutaneous (s.c.) routes alone or combined with the intravenous (i.v.) route. We found that administering antigen intravenously could affect antibody production and formation of antibody secreting cells (ASCs) depending on the immunization route previously used. Combined oral/i.v. immunization but not s.c./i.v. immunization caused a great increase of IgA ASCs in the spleen and enhanced IgA production in the small intestine and serum. Combined i.n./i.v. immunization could also increase IgA ASCs in the spleen and enhance IgA production in serum but had no effect on IgA production in the small intestine. Oral/i.v. immunization caused increase of IgG ASCs in both the spleen and bone marrow. In comparison, combined i.n./i.v. and s.c./i.v. immunization could increase IgG ASCs in the spleen but not in bone marrow. Intravenous administration of KLH in mice that had been immunized via oral, i.n. or s.c. routes caused some increase of IgM ASCs in the spleen but not in bone marrow. In conclusion, combined oral and i.v. administration of an antigen can induce fast and strong immune responses, especially for IgA, in both systemic and mucosal compartments.

  4. Galvanic vestibular stimulation combines with Earth-horizontal rotation in roll to induce the illusion of translation.

    PubMed

    Schneider, Erich; Bartl, Klaus; Glasauer, Stefan

    2009-05-01

    Human head rotation in roll around an earth-horizontal axis constitutes a vestibular stimulus that, by its rotational component, acts on the semicircular canals (SCC) and that, by its tilt of the gravity vector, also acts on the otoliths. Galvanic vestibular stimulation (GVS) is thought to resemble mainly a rotation in roll. A superposition of sinusoidal GVS with a natural earth-horizontal roll movement was therefore applied in order to cancel the rotation effects and to isolate the otolith activation. By self-adjusting the amplitude and phase of GVS, subjects were able to minimize their sensation of rotation and to generate the perception of a linear translation. The final adjustments are in the range of a model that predicts SCC activation during natural rotations and GVS. This indicates that the tilt-translation ambiguity of the otoliths is resolved by SCC-otolith interaction. It is concluded that GVS might be able to cancel rotations in roll and that the residual tilt of the gravitoinertial force is possibly interpreted as a linear translation.

  5. Combined Peptidomic and Proteomic Analysis of Electrically Stimulated and Manually Dissected Venom from the South American Bullet Ant Paraponera clavata.

    PubMed

    Aili, Samira R; Touchard, Axel; Petitclerc, Frédéric; Dejean, Alain; Orivel, Jérôme; Padula, Matthew P; Escoubas, Pierre; Nicholson, Graham M

    2017-03-03

    Ants have evolved venoms rich in peptides and proteins used for predation, defense, and communication. However, they remain extremely understudied due to the minimal amount of venom secreted by each ant. The present study investigated the differences in the proteome and peptidome of the venom from the bullet ant, Paraponera clavata. Venom samples were collected from a single colony either by manual venom gland dissection or by electrical stimulation and were compared using proteomic methods. Venom proteins were separated by 2D-PAGE and identified by nanoLC-ESI-QTOF MS/MS. Venom peptides were initially separated using C18 reversed-phase high-performance liquid chromatography, then analyzed by MALDI-TOF MS. The proteomic analysis revealed numerous proteins that could be assigned a biological function (total 94), mainly as toxins, or roles in cell regulation and transport. This investigation found that ca. 73% of the proteins were common to venoms collected by the two methods. The peptidomic analysis revealed a large number of peptides (total 309) but with <20% shared by the two collection methods. There was also a marked difference between venoms obtained by venom gland dissection from different ant colonies. These findings demonstrate the rich composition and variability of P. clavata venom.

  6. Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy

    PubMed Central

    Merlini, Esther; Tincati, Camilla; Biasin, Mara; Saulle, Irma; Cazzaniga, Federico Angelo; d’Arminio Monforte, Antonella; Cappione, Amedeo J.; Snyder-Cappione, Jennifer; Clerici, Mario; Marchetti, Giulia Carla

    2016-01-01

    In HIV-infected, combination antiretroviral therapy (cART)-treated patients, immune activation and microbial translocation persist and associate with inadequate CD4 recovery and morbidity/mortality. We analyzed whether alterations in the toll-like receptor (TLR) pathway could be responsible for the immune hyperactivation seen in these patients. PBMC/monocyte-derived macrophages (MDMs) of 28 HIV+ untreated and 35 cART-treated patients with HIV-RNA < 40 cp/mL [20 Full Responders (FRs): CD4 ≥ 350; 15 Immunological Non-Responders (INRs): CD4 < 350], as well as of 16 healthy controls were stimulated with a panel of TLR agonists. We measured: CD4/CD8/CD14/CD38/HLA-DR/Ki67/AnnexinV/CD69/TLR4/8 (Flow Cytometry); PBMC expression of 84 TLR pathway genes (qPCR); PBMC/MDM cytokine release (Multiplex); and plasma lipopolysaccharide (LPS)/sCD14 (LAL/ELISA). PBMC/MDM from cART patients responded weakly to LPS stimulation but released high amounts of pro-inflammatory cytokines. MDM from these patients were characterized by a reduced expression of HLA-DR+ MDM and failed to expand activated HLA-DR+ CD38+ T-lymphocytes. PBMC/MDM from cART patients responded more robustly to ssRNA stimulation; this resulted in a significant expansion of activated CD38 + CD8 and the release of amounts of pro-inflammatory cytokines comparable to those seen in untreated viremic patients. Despite greater constitutive TLR pathway gene expression, PBMC from INRs seemed to upregulate only type I IFN genes following TLR stimulation, whereas PBMC from full responders showed a broader response. Systemic exposure to microbial antigens drives immune activation during cART by triggering TLRs. Bacterial stimulation modifies MDM function/pro-inflammatory profile in cART patients without affecting T-lymphocytes; this suggests translocating bacteria as selective stimulus to chronic innate activation during cART. High constitutive TLR activation is seen in patients lacking CD4 recovery, suggesting

  7. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB.

    PubMed

    Sahai, Michelle A; Davidson, Colin; Khelashvili, George; Barrese, Vincenzo; Dutta, Neelakshi; Weinstein, Harel; Opacka-Juffry, Jolanta

    2017-04-03

    Novel psychoactive substances (NPS) are increasingly prevalent world-wide although their pharmacological characteristics are largely unknown; those with stimulant properties, due to interactions with the dopamine transporter (DAT), have addictive potential which their users may not realise. We evaluated the binding of 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) to rat striatal DAT by means of quantitative autoradiography with [(125)I]RTI-121, and the effects of 5-MAPB on electrically-evoked dopamine efflux by fast-cyclic voltammetry in rat brain slices. 5-MAPB displaced [(125)I]RTI-121 in a concentration-dependent manner, with significant effects at 10 and 30μM. The voltammetry data suggest that 5-MAPB reduces the rate of dopamine reuptake; while the peak dopamine efflux was not increased, the area under the curve was augmented. 5-MAPB can also cause reverse dopamine transport consistent with stimulant properties, more similar to amphetamine than cocaine. Molecular modelling and docking studies compared the binding site of DAT in complex with 5-MAPB to dopamine, amphetamine, 5-APB, MDMA, cocaine and RTI-121. This structural comparison reveals a binding mode for 5-MAPB found in the primary binding (S1) site, central to transmembrane domains 1, 3, 6 and 8, which overlaps with the binding modes of dopamine, cocaine and its analogues. Atomistic molecular dynamics simulations further show that, when in complex with 5-MAPB, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into inward-facing state, similarly to that observed in dopamine-bound DAT. These novel insights, offered by the combination of computational methods of biophysics with neurobiological procedures, provide structural context for NPS at DAT and relate them with their functional properties at DAT as the molecular target of stimulants.

  8. Keratinocyte Antiviral Response to Poly(dA:dT) Stimulation and Papillomavirus Infection in a Canine Model of X-Linked Severe Combined Immunodeficiency

    PubMed Central

    Luff, Jennifer A.; Yuan, Hang; Kennedy, Douglas; Schlegel, Richard; Felsburg, Peter; Moore, Peter F.

    2014-01-01

    X-linked severe combined immunodeficiency (XSCID) is caused by a genetic mutation within the common gamma chain (γc), an essential component of the cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT) to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV) infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT) and canine papillomavirus-2 (CPV-2) upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG) on poly(dA:dT) stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT) as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients. PMID:25025687

  9. Effect of Transcranial Direct Current Stimulation Combined With Virtual Reality Training on Balance in Children With Cerebral Palsy: A Randomized, Controlled, Double-Blind, Clinical Trial.

    PubMed

    Lazzari, Roberta Delasta; Politti, Fabiano; Belina, Stefany Ferreira; Collange Grecco, Luanda André; Santos, Cibele Almeida; Dumont, Arislander Jonathan Lopes; Lopes, Jamile Benite Palma; Cimolin, Veronica; Galli, Manuela; Santos Oliveira, Cláudia

    2016-09-20

    The authors' aim was to investigate the effects of continuous transcranial direct current stimulation (tDCS) combined with virtual reality training on static and functional balance in children with cerebral palsy (CP). Twenty children with CP (6 girls and 14 boys; M age = 7 years 6 months ± 2 years) were randomly allocated to two groups. The experimental group received active tDCS and the control group received sham stimulation during the 10 sessions of virtual reality mobility training protocols. The children were evaluated on 3 occasions (preintervention, postintervention, and 1-month follow-up). Static balance was evaluated using a force plate under 4 conditions: feet on force plate with (a) eyes open and (b) with eyes closed, and feet on foam mat with (c) eyes open and (d) with eyes closed. Functional balance was evaluated using the Pediatric Balance Scale and the Timed Up and Go Test. The analyses demonstrated statistically significant postintervention and follow-up effects favoring the experimental group over the control group with regard to the Pediatric Balance Scale, Timed Up and Go Test, and area of oscillation of the center of pressure when standing on the force plate with eyes open. The present findings suggest that tDCS can potentiate the effects of virtual reality training on static and functional balance among children with CP.

  10. Developing patient-centered treatment protocols in brain stimulation: a rationale for combining quantitative and qualitative approaches in persons with HIV.

    PubMed

    Rosedale, Mary; Malaspina, Dolores; Malamud, Daniel; Strauss, Shiela M; Horne, Jaclyn D; Abouzied, Salman; Cruciani, Ricardo A; Knotkova, Helena

    2012-01-01

    This article reports and discusses how quantitative (physiological and behavioral) and qualitative methods are being combined in an open-label pilot feasibility study. The study evaluates safety, tolerability, and acceptability of a protocol to treat depression in HIV-infected individuals, using a 2-week block of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex. Major depressive disorder (MDD) is the second most prevalent psychiatric disorder after substance abuse among HIV-positive adults, and novel antidepressant treatments are needed for this vulnerable population. The authors describe the challenges and contributions derived from different research perspectives and methodological approaches and provide a philosophical framework for combining quantitative and qualitative measurements for a fuller examination of the disorder. Four methodological points are presented: (1) the value of combining quantitative and qualitative approaches; (2) the need for context-specific measures when studying patients with medical and psychiatric comorbidities; (3) the importance of research designs that integrate physiological, behavioral, and qualitative approaches when evaluating novel treatments; and (4) the need to explore the relationships between biomarkers, clinical symptom assessments, patient self-evaluations, and patient experiences when developing new, patient-centered protocols. The authors conclude that the complexity of studying novel treatments in complex and new patient populations requires complex research designs to capture the richness of data that inform translational research.

  11. Immunotherapy against metastatic bladder cancer by combined administration of granulocyte macrophage-colony stimulating factor and interleukin-2 surface modified MB49 bladder cancer stem cells vaccine.

    PubMed

    Wang, Chun-Yan; Hua, Rui; Liu, Li; Zhan, Xiaomin; Chen, Simei; Quan, Song; Chu, Qing-Jun; Zhu, Yong-Tong

    2017-02-16

    In previous studies, it has been shown that the granulocyte macrophage-colony stimulating factor (GM-CSF) or interleukin-2 (IL-2) surface modified MB49 bladder cancer stem cells (MCSCs) vaccine could induce a specific antitumor immunity and against bladder cancer in mice model respectively. However, whether combined administration of GM-CSF and IL-2 could produce specific immune responses to cancer stem cells (CSCs) was uncertain. MCSCs were established and characterized. GM-CSF and IL-2 MCSCs vaccines were prepared and bioactivity was evaluated. The therapeutic, protective, specific, and memorial immune response animal experiments were designed. Tumor-specific cytotoxic T lymphocytes assay, enzyme linked immunosorbent assay, flow cytometry assay were performed to indentify whether vaccine caused an antitumor immunity. Streptavidin (SA)-GM-CSF and SA-IL-2 MCSCs vaccines were prepared successfully. Such vaccines inhibited the volume of tumor and prolonged the survival of the mice in animal experiments. The express of IgG or IFN-c, the portion of dendritic cells, CD8(+) and CD4(+) T cells were highest in the combined vaccines group than the SA-GM-CSF vaccine group, the SA-IL-2 vaccine group, the MCSCs group and the PBS group. The combined of GM-CSF and IL-2 vaccines could induce better antitumor immunity than a vaccine alone.

  12. The effects of electrical stimulation combined with continuous passive motion versus isometric exercise on symptoms, functional capacity, quality of life and balance in knee osteoarthritis: randomized clinical trial.

    PubMed

    Tok, Fatih; Aydemir, Koray; Peker, Fatma; Safaz, Ismail; Taşkaynatan, Mehmet Ali; Ozgül, Ahmet

    2011-02-01

    The aim of this study was to evaluate effects of electrical stimulation combined with continuous passive motion (CPM-ES) versus isometric exercise on symptoms, functional capacity, quality of life, muscle strength, knee and thigh circle measurements, and balance in knee osteoarthritis (OA). This is a randomized clinical trial. The study was done in Gulhane Military Medical Academy (GMMA) Rehabilitation Center. Forty patients with knee OA were included in this study. Participants were randomly assigned to two groups: 20 patients placed in Group 1 were treated with conventional physical therapy and CPM-ES combination; 20 patients in Group 2 were treated with conventional physical therapy and isometric exercise. Therapies were applied 3 weeks, 5 days per week. The following main outcome measures were done: values of pain (VAS was used), WOMAC, SF-36, knee and thigh circle measurements, isokinetic tests, dynamic and static balance tests were determined at baseline and after the treatment. There were no statistically significant differences in the tested variables between the groups for post-treatment values. Dynamic and static balance test improved statistically strongly significantly in both groups. The findings of this study demonstrate that knee OA patients could improve their balance function in both static and dynamic conditions after CPM-ES combination or isometric exercise therapy. The improvement might prevent knee OA patients from falling down and increase their sense of security during physical activities.

  13. The effect of mechanical extension stimulation combined with epithelial cell sorting on outcomes of implanted tissue-engineered muscular urethras.

    PubMed

    Fu, Qiang; Deng, Chen-Liang; Zhao, Ren-Yan; Wang, Ying; Cao, Yilin

    2014-01-01

    Urethral defects are common and frequent disorders and are difficult to treat. Simple natural or synthetic materials do not provide a satisfactory curative solution for long urethral defects, and urethroplasty with large areas of autologous tissues is limited and might interfere with wound healing. In this study, adipose-derived stem cells were used. These cells can be derived from a wide range of sources, have extensive expansion capability, and were combined with oral mucosal epithelial cells to solve the problem of finding seeding cell sources for producing the tissue-engineered urethras. We also used the synthetic biodegradable polymer poly-glycolic acid (PGA) as a scaffold material to overcome issues such as potential pathogen infections derived from natural materials (such as de-vascular stents or animal-derived collagen) and differing diameters. Furthermore, we used a bioreactor to construct a tissue-engineered epithelial-muscular lumen with a double-layer structure (the epithelial lining and the muscle layer). Through these steps, we used an epithelial-muscular lumen built in vitro to repair defects in a canine urethral defect model (1 cm). Canine urethral reconstruction was successfully achieved based on image analysis and histological techniques at different time points. This study provides a basis for the clinical application of tissue engineering of an epithelial-muscular lumen.

  14. Combining natural language processing and network analysis to examine how advocacy organizations stimulate conversation on social media.

    PubMed

    Bail, Christopher Andrew

    2016-10-18

    Social media sites are rapidly becoming one of the most important forums for public deliberation about advocacy issues. However, social scientists have not explained why some advocacy organizations produce social media messages that inspire far-ranging conversation among social media users, whereas the vast majority of them receive little or no attention. I argue that advocacy organizations are more likely to inspire comments from new social media audiences if they create "cultural bridges," or produce messages that combine conversational themes within an advocacy field that are seldom discussed together. I use natural language processing, network analysis, and a social media application to analyze how cultural bridges shaped public discourse about autism spectrum disorders on Facebook over the course of 1.5 years, controlling for various characteristics of advocacy organizations, their social media audiences, and the broader social context in which they interact. I show that organizations that create substantial cultural bridges provoke 2.52 times more comments about their messages from new social media users than those that do not, controlling for these factors. This study thus offers a theory of cultural messaging and public deliberation and computational techniques for text analysis and application-based survey research.

  15. Combining natural language processing and network analysis to examine how advocacy organizations stimulate conversation on social media

    PubMed Central

    Bail, Christopher Andrew

    2016-01-01

    Social media sites are rapidly becoming one of the most important forums for public deliberation about advocacy issues. However, social scientists have not explained why some advocacy organizations produce social media messages that inspire far-ranging conversation among social media users, whereas the vast majority of them receive little or no attention. I argue that advocacy organizations are more likely to inspire comments from new social media audiences if they create “cultural bridges,” or produce messages that combine conversational themes within an advocacy field that are seldom discussed together. I use natural language processing, network analysis, and a social media application to analyze how cultural bridges shaped public discourse about autism spectrum disorders on Facebook over the course of 1.5 years, controlling for various characteristics of advocacy organizations, their social media audiences, and the broader social context in which they interact. I show that organizations that create substantial cultural bridges provoke 2.52 times more comments about their messages from new social media users than those that do not, controlling for these factors. This study thus offers a theory of cultural messaging and public deliberation and computational techniques for text analysis and application-based survey research. PMID:27694580

  16. Evaluation of the Effects of Neuromuscular Electrical Stimulation of The Lower Limbs Combined with Pulmonary Rehabilitation on Exercise Tolerance in Patients with Chronic Obstructive Pulmonary Disease.

    PubMed

    Kucio, Cezary; Niesporek, Justyna; Kucio, Ewa; Narloch, Dominika; Węgrzyn, Bartosz

    2016-12-01

    Chronic obstructive pulmonary disease (COPD) is a systemic disease with multiple extrapulmonary manifestations including impeded skeletal muscle function, leading to decreased muscular strength and endurance in patients with COPD. Pulmonary rehabilitation eases the symptoms of the condition and produces increased muscular endurance. Neuromuscular electrical stimulation (NMES) may serve as a treatment alternative to traditional pulmonary rehabilitation. The aim of the study was to assess the effects of NMES combined with pulmonary rehabilitation on exercise tolerance in patients in comparison with pulmonary rehabilitation alone. The subjects included 30 patients with COPD randomly assigned to one of the two groups. The first group consisted of 15 patients who were treated with neuromuscular electrical stimulation at frequency of 35Hz and pulmonary rehabilitation (NMES+RP). The second group comprised 15 patients treated with pulmonary rehabilitation only (RP). Pre- and poststudy assessments were performed. The retrospective evaluation including an exercise tolerance test (i.e. six minute walk test (6MWT)), spirometry and blood gasometry was carried out after 3 weeks. Twenty-eight patients in total completed the study. In the NMES+RP group, an increase in exercise tolerance manifested by a longer distance walked in the 6MWT was observed in comparison to the pulmonary rehabilitation group. No effects of NMES combined with pulmonary rehabilitation on selected spirometric and gasometric parameters in patients with COPD were observed in comparison with traditional pulmonary rehabilitation. The acquired results suggest that NMES of the lower limbs may be applied as an additional form of pulmonary rehabilitation in patients with COPD.

  17. Evaluation of the Effects of Neuromuscular Electrical Stimulation of The Lower Limbs Combined with Pulmonary Rehabilitation on Exercise Tolerance in Patients with Chronic Obstructive Pulmonary Disease

    PubMed Central

    Niesporek, Justyna; Kucio, Ewa; Narloch, Dominika; Węgrzyn, Bartosz

    2016-01-01

    Abstract Chronic obstructive pulmonary disease (COPD) is a systemic disease with multiple extrapulmonary manifestations including impeded skeletal muscle function, leading to decreased muscular strength and endurance in patients with COPD. Pulmonary rehabilitation eases the symptoms of the condition and produces increased muscular endurance. Neuromuscular electrical stimulation (NMES) may serve as a treatment alternative to traditional pulmonary rehabilitation. The aim of the study was to assess the effects of NMES combined with pulmonary rehabilitation on exercise tolerance in patients in comparison with pulmonary rehabilitation alone. The subjects included 30 patients with COPD randomly assigned to one of the two groups. The first group consisted of 15 patients who were treated with neuromuscular electrical stimulation at frequency of 35Hz and pulmonary rehabilitation (NMES+RP). The second group comprised 15 patients treated with pulmonary rehabilitation only (RP). Pre- and poststudy assessments were performed. The retrospective evaluation including an exercise tolerance test (i.e. six minute walk test (6MWT)), spirometry and blood gasometry was carried out after 3 weeks. Twenty-eight patients in total completed the study. In the NMES+RP group, an increase in exercise tolerance manifested by a longer distance walked in the 6MWT was observed in comparison to the pulmonary rehabilitation group. No effects of NMES combined with pulmonary rehabilitation on selected spirometric and gasometric parameters in patients with COPD were observed in comparison with traditional pulmonary rehabilitation. The acquired results suggest that NMES of the lower limbs may be applied as an additional form of pulmonary rehabilitation in patients with COPD. PMID:28031759

  18. Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma.

    PubMed

    Chachoua, A; Oratz, R; Liebes, L; Alter, R S; Felice, A; Peace, D; Vilcek, J; Blum, R H

    1994-08-01

    R24, a murine monoclonal antibody, has been shown to mediate complement- and antibody-dependent cellular cytotoxicity (ADCC) of melanoma tumor targets. We conducted a Phase Ib clinical trial using granulocyte-macrophage colony-stimulating factor (GM-CSF) and R24 in 20 patients with metastatic melanoma. The purpose of this study was to test the hypothesis that treatment with GM-CSF could up-regulate monocyte and granulocyte ADCC and that the combination of GM-CSF plus R24, which mediates ADCC, would lead to enhanced anti-tumor activity in patients with melanoma. GM-CSF was administered by subcutaneous injection daily for 21 days at a dose of 150 micrograms/m2/day. R24 was administered by continuous intravenous infusion on days 8-15 at three dose levels: 0, 10, and 50 mg/m2/day. All 20 patients received one cycle of treatment only. Immune parameters measured were monocyte and granulocyte direct cytotoxicity and ADCC. All patients were evaluable for toxicity. Fifteen patients were evaluable for immune response. Treatment with GM-CSF alone was well tolerated. Toxicity from the combination of GM-CSF plus R24 included diffuse urticaria, nausea and vomiting, hypertension, and hypotension. Hypotension was the dose-limiting toxicity. Two patients on the 50-mg/m2/day dose level of R24 achieved a partial response lasting 2+ and 5+ months. Treatment with GM-CSF led to a statistically significant enhancement of monocyte and granulocyte direct cytotoxicity and ADCC. The maximally tolerated dose of R24 given at this schedule combined with GM-CSF is < 50 mg/m2/day. We conclude that GM-CSF given by subcutaneous injection at 150 micrograms/m2 x 21 days can enhance effector cell ADCC and direct cytotoxicity and that the combination of GM-CSF and R24 can be therapeutic.

  19. Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): a review.

    PubMed

    Singh, Vijay K; Newman, Victoria L; Seed, Thomas M

    2015-01-01

    One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event. Direct medical interventions would be necessary for all those individuals who had received substantial radiation exposures (e.g., >1 Gy). Although no drugs or products have yet been specifically approved by the United States Food and Drug Administration (US FDA) to treat the effects of acute radiation syndrome (ARS), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and pegylated G-CSF have been used off label for treating radiation accident victims. Recent threats of terrorist attacks using nuclear or radiologic devices makes it imperative that the medical community have up-to-date information and a clear understanding of treatment protocols using therapeutically effective recombinant growth factors and cytokines such as G-CSF and GM-CSF for patients exposed to injurious doses of ionizing radiation. Based on limited human studies with underlying biology, we see that the recombinants, G-CSF and GM-CSF appear to have modest, but significant medicinal value in treating radiation accident victims. In the near future, the US FDA may approve G-CSF and GM-CSF as ‘Emergency Use Authorization’ (EUA) for managing radiation-induced aplasia, an ARS-related pathology. In this article, we review the status of growth factors for the treatment of radiological/nuclear accident victims.

  20. Do two different stem cell grafts: G-CSF stimulated and unstimulated bone marrow differ according to hematopoietic colony forming capacity?

    PubMed

    Özgüner, Meltem; Azık, Mehmet Fatih; Tavil, Betül; Bozkaya, Ikbal; Köksal, Yasin; Canal, Elif; Uçkan, Duygu; Tunç, Bahattin

    2014-06-01

    The study was designed to compare colony forming capacity of granulocyte-colony stimulating factor (G-CSF) stimulated bone marrow (G-BM) with standard unstimulated bone marrow (U-BM) of healthy donors of pediatric patients. CFU-Assay results of 26 healthy donors of pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) were analyzed retrospectively. 13 of donors received 10 μg/kg per day of G-CSF as a single injection for 3 consecutive days and other 13 of donors had unstimulated BM. Colony forming capacity of hematopoietic stem cells evaluated with Colony Forming Unit-Assay (CFU-Assay) with in semi-solid agar culture medium after 14-18 days of culture period. CFU-Assay results of G-BM and U-BM (expressed as means) were; Burst Forming Unit-Erythroid (BFU-E): 15.20 × 10(4)/kg and 8.38 × 10(4)/kg, Colony Forming Unit-Granulocyte Macrophage (CFU-GM): 10.35 × 10(4)/kg and 5.67 × 10(4)/kg, Colony Forming Unit-Erythroid (CFU-E): 0.59 × 10(4)/kg and 0.33 × 10(4)/kg, CFU-Granulocyte Erythroid Macrophage Megakaryocyte (CFU-GEMM): 0.52 × 10(4)/kg and 0.53 × 10(4)/kg respectively. BFU-E and CFU-GM capacity of G-BM was increased and statistically significantly different than standard U-BM (p ⩽ 0.01). In conclusion, increased colony forming capacity of hematopoietic stem cells of G-BM when compared with standard unstimulated BM could be a major advantage for transplantation.

  1. Quinidine-induced neutropenia: report of a case with drug-dependent inhibition of granulocyte colony generation.

    PubMed

    Ascensao, J L; Flynn, P J; Slungaard, A; Wachsman, W; Zanjani, E D; Jacob, H S

    1984-01-01

    We describe a case of quinidine-induced agranulocytosis in which in vitro marrow culture studies suggested immune inhibition of committed human granulocyte-macrophage progenitors (CFU-GM). Autologous, but not allogeneic, inhibition of CFU-GM was seen with 'acute' serum from the patient in the presence of quinidine but not other drugs. Cytotoxic antibodies to mature granulocytes were not found. These studies provide a novel mechanism for drug-induced neutropenia and suggest that a battery of in vitro assays of progenitor and of mature granulocyte cytotoxicity might identify offending agents in suspected drug-induced neutropenias.

  2. Does combining infant stimulation with emergency feeding improve psychosocial outcomes for displaced mothers and babies? A controlled evaluation from northern Uganda.

    PubMed

    Morris, Jodi; Jones, Lynne; Berrino, Annamaria; Jordans, Mark J D; Okema, Leonard; Crow, Carmen

    2012-07-01

    Combined psychosocial and nutrition interventions improve the development of infants. However, there is a paucity of studies examining the effectiveness of such interventions in humanitarian settings. This article examines the impact of combining a group-based psychosocial intervention with an existing emergency feeding program for internally displaced mothers in Northern Uganda. The intervention consisted of mother and baby group sessions and home visits for mothers attending 3 emergency feeding centers. Psychosocial outcomes were compared with a contrast group of mothers who received nutritional support alone. The outcomes investigated were infant stimulation and maternal mood. After controlling for the effects of interview site and baseline scores, mothers in the intervention group (n = 70) showed greater involvement with their babies, more availability of play materials, and less sadness and worry at follow-up in comparison to the contrast group (n = 77). The intervention was acceptable to the mothers and easily taught. A proportion of the mothers chose to continue the intervention spontaneously with other mothers in their neighbourhoods. Further research needs to be done to validate these preliminary findings and explore the longer term impact on child growth and intellectual development as well as maternal mood.

  3. Role of percutaneous posterior tibial nerve stimulation either alone or combined with an anticholinergic agent in treating patients with overactive bladder

    PubMed Central

    Kızılyel, Sadık; Karakeçi, Ahmet; Ozan, Tunç; Ünüş, İhsan; Barut, Osman; Onur, Rahmi

    2015-01-01

    Objective To evaluate the efficacy of percutaneous tibial nerve stimulation (PTNS), either alone or combined with an anticholinergic agent, in treating patients with an overactive bladder (OAB) in whom previous conservative treatment failed. Material and methods In this study, we included a total of 30 female patients with OAB in whom all conventional therapies failed between January 2010 and April 2011. Patients were randomly divided into three groups: Group 1, PTNS group; Group 2, patients receiving an anticholinergic agent; and Group 3, patients receiving both PTNS and anticholinergic agent. PTNS treatment continued for 12 weeks with each session lasting 30 min. Results All parameters of the bladder diary significantly improved in all groups (p<0.05). Similarly, all scores measured by questionnaires (UDI-6, IIQ-7, and OABSS) revealed significant improvements in all groups. When the improvements in symptoms were compared among the groups, there was a statistically significantly higher improvement in groups 1 and 3 than in Group 2. Conclusion PTNS is a safe, simple, and minimally invasive treatment modality in patients with OAB, and it may be suggested either alone or in combination with anticholinergics when conventional treatments fail. PMID:26623150

  4. The evaluation of clinical therapy effects of oral western medicine combined with magnetic pulse acupoint stimulation in treating elderly patients with coronary heart disease

    PubMed Central

    Fu, Xin; Guo, Li; Jiang, Zheng-Ming; Xu, Ai-Guo

    2015-01-01

    Objective: Treat the patients suffered from coronary heart disease with oral western medicine, combining with magnetic pulse acupoint stimulation, and observe the therapeutic effects of such combination therapy method. Methods: 56 old people with coronary heart disease are randomly divided into a treatment group and a control group. Both groups of patients are treated by the routine drugs, in addition, the patients of the treatment group are treated by magnetic pulse therapy additionally. Compare clinical symptoms, blood lipid and blood rheological indexes of the patients in the two groups when they are selected and after 30 days’ treatment. Results: after 30 days’ treatment, it is found that clinical symptoms, blood lipid and blood rheological indexes of the patients in the treatment group are significantly improved compared with those when they are selected and those of the control group (P<0.05). Conclusion: patients with coronary heart disease, treated by pulsed magnetic therapy and the conventional drug intervention, had relieved synptom, improve blood lipid and heart blood supply function. PMID:26309664

  5. Mirror therapy combined with biofeedback functional electrical stimulation for motor recovery of upper extremities after stroke: a pilot randomized controlled trial.

    PubMed

    Kim, Jung Hee; Lee, Byoung-Hee

    2015-06-01

    The objective of this study was to evaluate the effects of mirror therapy in combination with biofeedback functional electrical stimulation (BF-FES) on motor recovery of the upper extremities after stroke. Twenty-nine patients who suffered a stroke > 6 months prior participated in this study and were randomly allocated to three groups. The BF-FES + mirror therapy and FES + mirror therapy groups practiced training for 5 × 30 min sessions over a 4-week period. The control group received a conventional physical therapy program. The following clinical tools were used to assess motor recovery of the upper extremities: electrical muscle tester, electrogoniometer, dual-inclinometer, electrodynamometer, the Box and Block Test (BBT) and Jabsen Taylor Hand Function Test (JHFT), the Functional Independence Measure, the Modified Ashworth Scale, and the Stroke Specific Quality of Life (SSQOL) assessment. The BF-FES + mirror therapy group showed significant improvement in wrist extension as revealed by the Manual Muscle Test and Range of Motion (p < 0.05). The BF-FES + mirror therapy group showed significant improvement in the BBT, JTHT, and SSQOL compared with the FES + mirror therapy group and control group (p < 0.05). We found that BF-FES + mirror therapy induced motor recovery and improved quality of life. These results suggest that mirror therapy, in combination with BF-FES, is feasible and effective for motor recovery of the upper extremities after stroke.

  6. Conditioning with targeted busulfan for autologous peripheral blood stem cells transplantation for acute myelogenous leukemia in an XYY male.

    PubMed

    Sada, Eriko; Henzan, Hideho; Ohtani, Ryoko; Takase, Ken; Miyamoto, Toshihiro; Fukuda, Takahiro; Nagafuji, Koji; Yamauchi, Keita; Takamatsu, Yasushi; Inaba, Shoichi; Harada, Mine

    2005-01-01

    We report herein a 19-year-old Japanese male with XYY syndrome who developed acute myelogenous leukemia. During three courses of cytotoxic chemotherapy, he suffered repeated hepatic and renal insufficiencies, possibly related to latent dysfunction from the XYY syndrome. The patient was treated with granulocyte colony-stimulating factor combined with etoposide, cytarabine, and busulfan (the latter adjusted to a targeting dose) followed by autologous peripheral blood stem cell transplantation. He had no severe regimen-related toxicities and is now free of leukemia.

  7. Combined neuromuscular electrical stimulation (NMES) with fiberoptic endoscopic evaluation of swallowing (FEES) and traditional swallowing rehabilitation in the treatment of stroke-related dysphagia.

    PubMed

    Sun, Shu-Fen; Hsu, Chien-Wei; Lin, Huey-Shyan; Sun, Hsien-Pin; Chang, Ping-Hsin; Hsieh, Wan-Ling; Wang, Jue-Long

    2013-12-01

    Dysphagia is common after stroke. Neuromuscular electrical stimulation (NMES) and fiberoptic endoscopic evaluation of swallowing (FEES) for the treatment of dysphagia have gained in popularity, but the combined application of these promising modalities has rarely been studied. We aimed to evaluate whether combined NMES, FEES, and traditional swallowing rehabilitation can improve swallowing functions in stroke patients with moderate to severe dysphagia. Thirty-two patients with moderate to severe dysphagia poststroke (≥3 weeks) were recruited. Patients received 12 sessions of NMES for 1 h/day, 5 days/week within a period of 2-3 weeks. FEES was done before and after NMES for evaluation and to guide dysphagic therapy. All patients subsequently received 12 sessions of traditional swallowing rehabilitation (50 min/day, 3 days/week) for 4 weeks. Primary outcome measure was the Functional Oral Intake Scale (FOIS). Secondary outcome measures included clinical degree of dysphagia, the patient's self-perception of swallowing ability, and the patient's global satisfaction with therapy. Patients were assessed at baseline, after NMES, at 6-month follow-up, and at 2-year follow-up. Twenty-nine patients completed the study. FOIS, degree of dysphagia, and patient's self-perception of swallowing improved significantly after NMES, at the 6-month follow-up, and at the 2-year follow-up (p < 0.001, each compared with baseline). Most patients reported considerable satisfaction with no serious adverse events. Twenty-three of the 29 (79.3 %) patients maintained oral diet with no pulmonary complications at 2-year follow-up. This preliminary case series demonstrated that combined NMES, FEES, and traditional swallowing rehabilitation showed promise for improving swallowing functions in stroke patients with moderate-to-severe dysphagia. The benefits were maintained for up to 2 years. The results are promising enough to justify further studies.

  8. Effect of Transcutaneous Electrical Nerve Stimulation, Cold, and a Combination Treatment on Pain, Decreased Range of Motion, and Strength Loss Associated with Delayed Onset Muscle Soreness

    PubMed Central

    Denegar, Craig R.; Perrin, David H.

    1992-01-01

    Athletic trainers have a variety of therapeutic agents at their disposal to treat musculoskeletal pain, but little objective evidence exists of the efficacy of the modalities they use. In this study, delayed onset muscle soreness (DOMS) served as a model for musculoskeletal injury in order to: (1) compare the changes in perceived pain, elbow extension range of motion, and strength loss in subjects experiencing DOMS in the elbow flexor muscle group following a single treatment with either transcutaneous electrical nerve stimulation (TENS), cold, a combination of TENS and cold, sham TENS, or 20 minutes of rest; (2) compare the effects of combining static stretching with these treatments; and (3) determine if decreased pain is accompanied by a restoration of strength. DOMS was induced in the non-dominant elbow flexor muscle group in 40 females (age = 22.0 ± 4.3 yr) with repeated eccentric contractions. Forty-eight hours following exercise, all subjects presented with pain, decreased elbow extension range of motion, and decreased strength consistent with DOMS. Subjects were randomly assigned to 20-minute treatments followed by static stretching. Cold, TENS, and the combined treatment resulted in significant decreases in perceived pain. Treatments with cold resulted in a significant increase in elbow extension range of motion. Static stretching also significantly reduced perceived pain. Only small, nonsignificant changes in muscle strength were observed following treatment or stretching, regardless of the treatment group. These results suggest that the muscle weakness associated with DOMS is not the result of inhibition caused by pain. The results suggest that these modalities are effective in treating the pain and muscle spasm associated with DOMS, and that decreased pain may not be an accurate indicator of the recovery of muscle strength. PMID:16558162

  9. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

    PubMed Central

    Grace, Marcy B.; Singh, Vijay K.; Rhee, Juong G.; Jackson, William E.; Kao, Tzu-Cheg; Whitnall, Mark H.

    2012-01-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID:22843381

  10. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.

    PubMed

    Grace, Marcy B; Singh, Vijay K; Rhee, Juong G; Jackson, William E; Kao, Tzu-Cheg; Whitnall, Mark H

    2012-11-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.

  11. Effect of combined low-frequency repetitive transcranial magnetic stimulation and virtual reality training on upper limb function in subacute stroke: a double-blind randomized controlled trail.

    PubMed

    Zheng, Chan-juan; Liao, Wei-jing; Xia, Wen-guang

    2015-04-01

    The effect of combined low-frequency repetitive transcranial magnetic stimulation (LF rTMS) and virtual reality (VR) training in patients after stroke was assessed. In a double-blind randomized controlled trial, 112 patients with hemiplegia after stroke were randomly divided into two groups: experimental and control. In experimental group, the patients received LF rTMS and VR training treatment, and those in control group received sham rTMS and VR training treatment. Participants in both groups received therapy of 6 days per week for 4 weeks. The primary endpoint including the upper limb motor function test of Fugl-meyer assessment (U-FMA) and wolf motor function test (WMFT), and the secondary endpoint including modified Barthel index (MBI) and 36-item Short Form Health Survey Questionnaire (SF-36) were assessed before and 4 weeks after treatment. Totally, 108 subjects completed the study (55 in experimental group and 53 in control group respectively). After 4-week treatment, the U-FMA scores [mean difference of 13.2, 95% confidence interval (CI) 3.6 to 22.7, P<0.01], WMFT scores (mean difference of 2.9, 95% CI 2.7 to 12.3, P<0.01), and MBI scores (mean difference 16.1, 95% CI 3.8 to 9.4, P<0.05) were significantly increased in the experimental group as compared with the control group. The results suggested the combined use of LF rTMS with VR training could effectively improve the upper limb function, the living activity, and the quality of life in patients with hemiplegia following subacute stroke, which may provide a better rehabilitation treatment for subacute stroke.

  12. Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model.

    PubMed

    Kurimoto, Shigeru; Kato, Shuichi; Nakano, Tomonori; Yamamoto, Michiro; Takanobu, Nishizuka; Hirata, Hitoshi

    2016-10-01

    Reinnervation of denervated muscle by motor neurons transplanted into the peripheral nerve may provide the potential to excite muscles artificially with functional electrical stimulation (FES). Here we investigated whether transplantation of embryonic motor neurons into peripheral nerve combined with FES restored functional muscle activity in adult Fischer 344 rats after transection of the sciatic nerve. One week after sciatic nerve transection, cell culture medium containing (cell transplantation group, n = 6) or lacking (surgical control group, n = 6) dissociated embryonic spinal neurons was injected into the distal stump of the tibial and peroneal nerves. Electrophysiological and tissue analyses were performed in the cell transplantation and surgical control groups 12 weeks after transplantation, as well as a in naïve control group (n = 6) that received no surgery. In the cell transplantation group, ankle angle was measured during gait, with and without FES of the peroneal nerve. Ankle angle at mid-swing was more flexed during gait with FES (26.6 ± 8.7°) than gait without FES (51.4 ± 12.8°, p = 0.011), indicating that transplantated motor neurons in conjunction with FES restored ankle flexion in gait, even though no neural connection between central nervous system and muscle was present. These results indicate that transplantation of embryonic motor neurons into peripheral nerve combined with FES can provide a novel treatment strategy for paralysed muscles. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Anti-tumor effects of recombinant human macrophage colony-stimulating factor, alone or in combination with local irradiation, in mice inoculated with Lewis lung carcinoma cells.

    PubMed

    Lu, L; Shen, R N; Lin, Z H; Aukerman, S L; Ralph, P; Broxmeyer, H E

    1991-01-02

    Recombinant human (rhu) macrophage colony-stimulating factor (M-CSF) was evaluated for efficacy, either alone or in combination with local X-irradiation (LR), in mice inoculated subcutaneously (s.c.) with Lewis lung carcinoma (LLC) cells. The size of the primary tumor and numbers of lung metastases, 21 days after tumor inoculation and 15 days after the start of treatment, were reduced by 87% in tumor-bearing mice treated with 20 micrograms/dose M-CSF s.c. twice a day for 5 days. LR (800 cGy) to the tumor once a week for 2 weeks had a moderate anti-tumor effect and enhanced the anti-tumor effect of M-CSF. Hematological parameters, including nucleated cellularity in peripheral blood, femoral marrow, spleen and peritoneal exudate, as well as marrow and splenic granulocyte-macrophage progenitor cells, and numbers of splenic Thy 1.2+ cell and peritoneal mast cells, were perturbed in LLC-bearing mice, and were influenced by treatment with M-CSF and LR. Treatment with M-CSF plus LR, but not with either agent alone, was associated with a significant, although slight, enhancement in survival time for LLC-bearing mice. Inability to obtain a better survival-enhancing effect appeared to be related to the limited treatment, since the anti-tumor effects of M-CSF were more notable early on in disease progression and were related to the dose of M-CSF used. The effects of M-CSF were most probably indirect ones on the host immune system. M-CSF, in combination with LR, may be of benefit in the treatment of human tumors that have metastatic potential.

  14. SBD.4 stimulates regenerative processes in vitro, and wound healing in genetically diabetic mice and in human skin/severe-combined immunodeficiency mouse chimera.

    PubMed

    Zhao, Hui; Mortezaei, Reza; Wang, Yanrong; Sheng, Xinsheng; Aria, Fariba; Bojanowski, Krzysztof

    2006-01-01

    In search of novel angiostimulators, we performed a high-throughput screening of medicinal plants beneficial for blood circulation. From the panel of positive hits, Angelica sinensis was selected for further investigation. Purified down to a low-molecular-weight fraction and characterized by high-performance liquid chromatography-mass spectrometry, the material, named SBD.4A, revealed a particularly strong wound healing activity in the diabetic mouse wound-healing model, and in the human/severe combined immunodeficiency mouse chimera wound-healing model. In both models, SBD.4A compared favorably with the Food and Drug Administration-approved wound-healing drug becaplermin, suggesting that this botanical product could be a valuable treatment for difficult-to-heal wounds. Further high-performance liquid chromatography fractionation of SBD.4A yielded a hydrophilic fraction, which strongly stimulated endothelial cell proliferation, tridimensional endothelial cell network formation, as well as the proliferation of human dermal fibroblasts and type I collagen secretion. Because angiogenesis and fibroblast proliferation are essential for wound healing, we propose that this liquid chromatography-mass spectrometry-defined hydrophilic fraction is at least partially responsible for the wound-healing activity of SBD.4A.

  15. Mononuclear cells from the cord blood and granulocytecolony stimulating factor-mobilized peripheral blood: is there a potential for treatment of cerebral palsy?

    PubMed

    Koh, Hani; Hwang, Kyoujung; Lim, Hae-Young; Kim, Yong-Joo; Lee, Young-Ho

    2015-12-01

    To investigate a possible therapeutic mechanism of cell therapy in the field of cerebral palsy using granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (mPBMCs), we compared the expression of inflammatory cytokines and neurotrophic factors in PBMCs and mPBMCs from children with cerebral palsy to those from healthy adult donors and to cord blood mononuclear cells donated from healthy newborns. No significant differences in expression of neurotrophic factors were found between PBMCs and mPBMCs. However, in cerebral palsy children, the expression of interleukin-6 was significantly increased in mPBMCs as compared to PBMCs, and the expression of interleukin-3 was significantly decreased in mPBMCs as compared to PBMCs. In healthy adults, the expression levels of both interleukin-1β and interleukin-6 were significantly increased in mPBMCs as compared to PBMCs. The expression of brain-derived neurotrophic factors in mPBMC from cerebral palsy children was significantly higher than that in the cord blood or mPBMCs from healthy adults. The expression of G-CSF in mPBMCs from cerebral palsy children was comparable to that in the cord blood but significantly higher than that in mPBMCs from healthy adults. Lower expression of pro-inflammatory cytokines (interleukin-1β, interleukin-3, and -6) and higher expression of anti-inflammatory cytokines (interleukin-8 and interleukin-9) were observed from the cord blood and mPBMCs from cerebral palsy children rather than from healthy adults. These findings indicate that mPBMCs from cerebral palsy and cord blood mononuclear cells from healthy newborns have the potential to become seed cells for treatment of cerebral palsy.

  16. Effect of a single session of transcranial direct-current stimulation combined with virtual reality training on the balance of children with cerebral palsy: a randomized, controlled, double-blind trial.

    PubMed

    Lazzari, Roberta Delasta; Politti, Fabiano; Santos, Cibele Alimedia; Dumont, Arislander Jonathan Lopes; Rezende, Fernanda Lobo; Grecco, Luanda André Collange; Braun Ferreira, Luiz Alfredo; Oliveira, Claudia Santos

    2015-03-01

    [Purpose] The aim of the present study was to investigate the effects of a single session of transcranial direct current stimulation combined with virtual reality training on the balance of children with cerebral palsy. [Subjetcs and Methods] Children with cerebral palsy between four and 12 years of age were randomly allocated to two groups: an experimental group which performed a single session of mobility training with virtual reality combined with active transcranial direct current stimulation; and a control group which performed a single session of mobility training with virtual reality combined with placebo transcranial direct current stimulation. The children were evaluated before and after the training protocols. Static balance (sway area, displacement, velocity and frequency of oscillations of the center of pressure on the anteroposterior and mediolateral axes) was evaluated using a force plate under four conditions (30-second measurements for each condition): feet on the force plate with the eyes open, and with the eyes closed; feet on a foam mat with the eyes open, and with the eyes closed. [Results] An increase in sway velocity was the only significant difference found. [Conclusion] A single session of anodal transcranial direct current stimulation combined with mobility training elicited to lead to an increase in the body sway velocity of children with cerebral palsy.

  17. Effect of a single session of transcranial direct-current stimulation combined with virtual reality training on the balance of children with cerebral palsy: a randomized, controlled, double-blind trial

    PubMed Central

    Lazzari, Roberta Delasta; Politti, Fabiano; Santos, Cibele Alimedia; Dumont, Arislander Jonathan Lopes; Rezende, Fernanda Lobo; Grecco, Luanda André Collange; Braun Ferreira, Luiz Alfredo; Oliveira, Claudia Santos

    2015-01-01

    [Purpose] The aim of the present study was to investigate the effects of a single session of transcranial direct current stimulation combined with virtual reality training on the balance of children with cerebral palsy. [Subjetcs and Methods] Children with cerebral palsy between four and 12 years of age were randomly allocated to two groups: an experimental group which performed a single session of mobility training with virtual reality combined with active transcranial direct current stimulation; and a control group which performed a single session of mobility training with virtual reality combined with placebo transcranial direct current stimulation. The children were evaluated before and after the training protocols. Static balance (sway area, displacement, velocity and frequency of oscillations of the center of pressure on the anteroposterior and mediolateral axes) was evaluated using a force plate under four conditions (30-second measurements for each condition): feet on the force plate with the eyes open, and with the eyes closed; feet on a foam mat with the eyes open, and with the eyes closed. [Results] An increase in sway velocity was the only significant difference found. [Conclusion] A single session of anodal transcranial direct current stimulation combined with mobility training elicited to lead to an increase in the body sway velocity of children with cerebral palsy. PMID:25931726

  18. Enhancement of brain plasticity and recovery of locomotive function after lumbar spinal cord stimulation in combination with gait training with partial weight support in rats with cerebral ischemia.

    PubMed

    Choi, Yoon-Hee; Lee, Shi-Uk

    2017-02-22

    Lumbar spinal cord stimulation (LSCS) is reportedly effective for the recovery of locomotive intraspinal neural network, motor cortex and basal ganglia in animals with complete spinal cord injury and parkinsonism. We evaluated the effect of LSCS in combination with gait training on the recovery of locomotive function and brain plasticity using a rat model of brain ischemia. Adult male Sprague Dawley rats with ischemia were randomly assigned into one of four groups: sham treatment (group 1), LSCS only (group 2), LSCS with gait training and 50% (group 3) and 80% (group 4) of body weight support. Evaluations before randomization and 4 weeks after intervention included motor scoring index, real-time PCR and Western blot. Motor scoring index was significantly improved after the intervention in groups 2 and 3. The ratio of phospho-Protein Kinase C (PKC) to PKC measured in the infarcted area tended to be higher in groups 3 and 4. Protein expression of mGluR2 and mRNA expression of mGluR1 measured in the contralateral cortex were lower in groups 3 and 4. The ratio of phospho-Akt to Akt and mRNA expression of vascular endothelial growth factor measured in the ischemic border zone were higher in group 2. The mRNA expression of MAP1b measured in the infarcted area was significantly higher in group 2. The findings suggest that LSCS and gait training with an adequate amount of body weight support may promote brain plasticity and facilitate the functional recovery.

  19. Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: clinical experience.

    PubMed

    Rabey, Jose Martin; Dobronevsky, Evgenia

    2016-12-01

    Alzheimer's disease (AD) is the most common type of dementia among the elderly. Common treatments available and non-pharmacological interventions have their limitations, and new therapeutic approaches are critically needed. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current-inducing modulation in cortical excitability. The previous clinical trials showed that combinations of rTMS and cognitive training (rTMS-COG), as provided by the NeuroAD medical device system, offer a novel, safe, and effective method improving mild-to-moderate AD patients. In this article, we present our experience with rTMS-COG treatment, in clinical settings, of 30 mild-to-moderate AD patients that received rTMS-COG commercial treatments in two clinics for 1-h daily sessions, 5 days per week, for 6 weeks (30 sessions). Five patients returned for a second treatment. ADAS-Cog and MMSE scores were measured pre- and post-treatments. The main analyses were conducted on patients who received 1 treatment (n = 30). Data received from the five returning patients were analyzed separately. The effect of rTMS-COG treatment was statistically significant regarding both ADAS-Cog (-2.4 point improvement, PV <0.001) and MMSE (+1.7 points improvement, PV <0.001) scores. About 80 % of patients gained some cognitive improvement following NeuroAD treatment, with more than 60 % improving by more than two points, for a minimum of 9 months. The Neuronix NeuroAD System was shown to be a safe and effective non-invasive modality for cognitive improvement of Alzheimer patients, with measurable outcomes lasting, in some of them, for up to 1 year, following completion of the 6-week daily intervention course (a carryover effect).

  20. Comparison of outcomes after transplantation of G-CSF-stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia.

    PubMed

    Chu, Roland; Brazauskas, Ruta; Kan, Fangyu; Bashey, Asad; Bredeson, Christopher; Camitta, Bruce; Chiang, Kuang-Yueh; Frangoul, Haydar; Gale, Robert Peter; Gee, Adrian; George, Biju; Goldman, Frederick D; Gross, Thomas G; Gupta, Vikas; Hale, Gregory A; Isola, Luis; Ispizua, Alvaro Urbano; Lazarus, Hillard; Marsh, Judith; Russell, James; Sabloff, Mitchell; Waller, Edmund K; Eapen, Mary

    2011-07-01

    We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.

  1. Clinical effects of a chimeric anti-EpCAM monoclonal antibody in combination with granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma.

    PubMed

    Liljefors, Maria; Nilsson, Bo; Fagerberg, Jan; Ragnhammar, Peter; Mellstedt, Håkan; Frödin, Jan-Erik

    2005-06-01

    The EpCAM antigen is highly expressed on colorectal carcinoma (CRC) cells. Murine anti-EpCAM MAb (anti-EpCAM mMAb) alone or in combination with cytokines may induce clinical responses including long-lasting complete remissions (CR) in patients with metastatic disease. The chimeric variant of anti-EpCAM MAb (anti-EpCAM cMAb) interacts more efficiently with human effector cells (ADCC) than the murine counterpart in the killing of colorectal carcinoma cells in vitro, an important mechanism of action for antibody in vivo. Granulocyte-macrophage colony-stimulating factor (GM-CSF) augments immune effector cell functions in vivo and may enhance the therapeutic effect of MAbs. In this study, the therapeutic efficacy of the combination of anti-EpCAM cMAb and GM-CSF was evaluated in 24 patients with metastatic CRC. GM-CSF was given s.c. once daily for 10 consecutive days and on day 3, anti-EpCAM cMAb was given i.v. A treatment cycle was repeated every 4th week. Five patients achieved stable disease > 3 months (overall response rate 21%). Responding patients survived significantly longer than non-responding patients (p = 0.030). The frequency of patients with an immediate-type allergic reaction (ITAR) against anti-EpCAM cMAb at the 1st, 2nd, 3rd and 4th treatment cycles was as 13%, 29%, 25% and 19% respectively. Compared to a previous study where anti-EpCAM mMAb was used in a similar treatment regimen, the present protocol did not augment the overall or progression-free survival. The overall response rate was also similar to anti-EpCAM mMAb treated patients (6/22, 27%), but the anti-EpCAM mMAb treatment protocol induced two CR, one MR and three SD. Further studies are warranted to establish the role of EpCAM as a target for antibody therapy, specifically the significance of chimeric or humanized anti-EpCAM MAbs.

  2. Effects of low-frequency repetitive transcranial magnetic stimulation combined with intensive speech therapy on cerebral blood flow in post-stroke aphasia.

    PubMed

    Hara, Takatoshi; Abo, Masahiro; Kobayashi, Kentaro; Watanabe, Motoi; Kakuda, Wataru; Senoo, Atushi

    2015-10-01

    We provided an intervention to chronic post-stroke aphasic patients using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) guided by a functional magnetic resonance imaging (fMRI) evaluation of language laterality, combined with intensive speech therapy (ST). We performed a single photon emission-computed tomography (SPECT) scan pre- and post-intervention and investigated the relationship between cerebral blood flow (CBF) and language function. Fifty right-handed chronic post-stroke aphasic patients were enrolled in the study. During their 11-day hospital admission, the patients received a 40-min session of 1-Hz LF-rTMS on the left or right hemisphere, according to language localization identified by the fMRI evaluation, and intensive ST daily for 10 days, except for Sunday. A SPECT scan and language evaluation by the Standard Language Test of Aphasia (SLTA) were performed at the time of admission and at 3 months following discharge. We calculated laterality indices (LIs) of regional CBF (rCBF) in 13 language-related Brodmann area (BA) regions of interest. In patients who received LF-rTMS to the intact right hemisphere (RH-LF-rTMS), the improvement in the total SLTA score was significantly correlated with the pre- and post-intervention change of LI (ΔLI) in BA44. In patients who received LF-rTMS to the lesional left hemisphere (LH-LF-rTMS), this association was not observed. Analyses of the SLTA subscales and rCBF ΔLI demonstrated that in the RH-LF-rTMS group, the SLTA Speaking subscale scores were significantly correlated with ΔLIs in BA11, 20, and 21, and the SLTA Writing subscale scores were significantly correlated with ΔLIs in BA6 and 39. Conversely, in the LH-LF-rTMS group, the SLTA Speaking subscale scores were correlated with ΔLI in BA10, and the SLTA Reading subscale scores were significantly correlated with ΔLIs in BA13, 20, 22, and 44. Our results suggest the possibility that fMRI-guided LF-rTMS combined with intensive ST may

  3. Effect of low-frequency repetitive transcranial magnetic stimulation combined with physical therapy on L-dopa-induced painful off-period dystonia in Parkinson's disease.

    PubMed

    Kodama, Mitsuhiko; Kasahara, Takashi; Hyodo, Masaki; Aono, Koji; Sugaya, Mutsumi; Koyama, Yuji; Hanayama, Kozo; Masakado, Yoshihisa

    2011-02-01

    Previous research has shown that low-frequency repetitive transcranial magnetic stimulation over the primary motor area and supplementary motor area can reduce L-dopa-induced dyskinesias in Parkinson's disease; however, it involved only patients with peak-dose or diphasic dyskinesia. We report a case of a patient with severely painful off-period dystonia in the unilateral lower limb who underwent 0.9-Hz subthreshold repetitive transcranial magnetic stimulation over contralateral primary motor area and supplementary motor area. Repetitive transcranial magnetic stimulation over the primary motor area significantly reduced the painful dystonia and walking disturbances but repetitive transcranial magnetic stimulation over the supplementary motor area did not. The cortical silent period also prolonged after repetitive transcranial magnetic stimulation over the primary motor area. At 5 mos of approximately once a week repetitive transcranial magnetic stimulation over the primary motor area, the Unified Parkinson's Disease Rating Scale motor score also improved. This report shows that repetitive transcranial magnetic stimulation over the inhibitory primary motor area can be useful for rehabilitating patients with Parkinson's disease with off-period dystonia and suggests that this treatment should be further verified in such patients.

  4. Lack of Effect of Stimulant Combination with Second-Generation Antipsychotics on Weight Gain, Metabolic Changes, Prolactin Levels, and Sedation in Youth with Clinically Relevant Aggression or Oppositionality

    PubMed Central

    Penzner, Julie B.; Dudas, Melissa; Saito, Ema; Olshanskiy, Vladimir; Parikh, Umesh H.; Kapoor, Sandeep; Chekuri, Raja; Gadaleta, Dominick; Avedon, Jennifer; Sheridan, Eva M.; Randell, Jane; Malhotra, Anil K.; Kane, John M.

    2009-01-01

    Abstract Background Second-generation antipsychotics (SGAs) are associated with weight gain, metabolic abnormalities, sedation/sleep disturbance, and prolactin abnormalities, especially in youths. Although stimulants have opposing dopamine receptor and adverse effects, it is unclear whether stimulant co-treatment counteracts the therapeutic or side effects of antipsychotics. Methods This was a naturalistic cohort study including 153 antipsychotic trials in youths aged 4–19 (mean, 11.3 ± 3.0) years, started on an SGA for clinically significant aggression or oppositionality associated with oppositional defiant disorder, conduct disorder, disruptive behavior disorder not otherwise specified (NOS), impulse control disorder NOS, intermittent explosive disorder, Tourette's disorder, autistic disorder, and pervasive developmental disorder NOS. Patients underwent fasting assessments of body composition, lipids, glucose, insulin, prolactin, sedation, and general efficacy at baseline, weeks 4, 8, and 12, comparing patients co-prescribed stimulants (n = 71) with those not co-prescribed stimulants (n = 82). Results Patients received risperidone (33.3%), aripiprazole (29.4%), quetiapine (18.4%), olanzapine (11.8%), ziprasidone (5.9%), or clozapine (0.7%). With and without adjustment for differences in baseline variables (sex, prior stimulant use, primary Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] disorders, co-morbid attention-deficit/hyperactivity disorder [ADHD], present in 46.3% of youths not receiving stimulants, and some body composition parameters), patients on versus off stimulants did not differ on any of the assessed outcomes (all p values ≥ 0.1). Conclusions In contrast to guidelines, stimulant use did not precede or accompany antipsychotic use during the current episode of aggression/oppositionality in almost half of those youths who had aggressive/oppositional behavior and a DSM-IV diagnosis of ADHD. At the

  5. A novel combinational approach of microstimulation and bioluminescence imaging to study the mechanisms of action of cerebral electrical stimulation in mice

    PubMed Central

    Arsenault, Dany; Drouin-Ouellet, Janelle; Saint-Pierre, Martine; Petrou, Petros; Dubois, Marilyn; Kriz, Jasna; Barker, Roger A; Cicchetti, Antonio; Cicchetti, Francesca

    2015-01-01

    Key points We have developed a unique prototype to perform brain stimulation in mice. This system presents a number of advantages and new developments: 1) all stimulation parameters can be adjusted, 2) both positive and negative current pulses can be generated, guaranteeing electrically balanced stimulation regimen, 3) which can be produced with both low and high impedance electrodes, 4) the developed electrodes ensure localized stimulation and 5) can be used to stimulate and/or record brain potential and 6) in vivo recording of electric pulses allows the detection of defective electrodes (wire breakage or short circuits). This new micro-stimulator device further allows simultaneous live bioluminescence imaging of the mouse brain, enabling real time assessment of the impact of stimulation on cerebral tissue. The use of this novel tool in various transgenic mouse models of disease opens up a whole new range of possibilities in better understanding brain stimulation. Abstract Deep brain stimulation (DBS) is used to treat a number of neurological conditions and is currently being tested to intervene in neuropsychiatric conditions. However, a better understanding of how it works would ensure that side effects could be minimized and benefits optimized. We have thus developed a unique device to perform brain stimulation (BS) in mice and to address fundamental issues related to this methodology in the pre-clinical setting. This new microstimulator prototype was specifically designed to allow simultaneous live bioluminescence imaging of the mouse brain, allowing real time assessment of the impact of stimulation on cerebral tissue. We validated the authenticity of this tool in vivo by analysing the expression of toll-like receptor 2 (TLR2), corresponding to the microglial response, in the stimulated brain regions of TLR2-fluc-GFP transgenic mice, which we further corroborated with post-mortem analyses in these animals as well as in human brains of patients who underwent DBS

  6. Trastuzumab (Herceptin®): overcoming resistance in HER2-overexpressing breast cancer models.

    PubMed

    Albrecht, Huguette

    2010-11-01

    Evaluation of: Fujimoto-Ouchi K, Sekiguchi F, Yamamoto K et al.: Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy. Cancer Chemother. Pharmacol. 66, 269-276 (2010). Trastuzumab, a humanized antibody targeted against human epidermal receptor (HER)2, is used in combination with chemotherapy to treat patients with breast cancers overexpressing HER2. Despite initial clinical responses, disease progresses in a significant proportion of patients treated with trastuzumab and chemotherapy. Evidence of resistance to trastuzumab has not deterred a widespread clinical practice in the treatment of metastatic breast cancer - at least before lapatinib entered the clinic - which consists of continued administration of trastuzumab in combination with another chemotherapeutic drug. At present, it is not known if patients benefit from this practice. The present preclinical study demonstrates that, in the MDA-MB-361 and KPL-4 HER2(+) breast cancer models, induced resistance to trastuzumab monotherapy can be overcome by a combination of trastuzumab and granulocyte colony stimulating factor or chemotherapy. The response to trastuzumab and granulocyte colony stimulating factor appears to involve the host's immune system and antibody-dependent cellular cytotoxicity. The mechanisms underlying the response to trastuzumab and chemotherapy remain unclear.

  7. Immunogenicity of granulocyte-macrophage colony-stimulating factor (GM-CSF) products in patients undergoing combination therapy with GM-CSF.

    PubMed

    Wadhwa, M; Skog, A L; Bird, C; Ragnhammar, P; Lilljefors, M; Gaines-Das, R; Mellstedt, H; Thorpe, R

    1999-06-01

    In this study, we have assessed the development of neutralizing and nonneutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in two groups of patients with metastatic colorectal carcinoma receiving two different GM-CSF products. Three clinical trials were carried out, and a combination of GM-CSF and a colon carcinoma-reactive antibody was used in the absence of any concomitant chemotherapy. Two different GM-CSF products, both rDNA-derived and produced in Escherichia coli, were used. Patients in Trial 1 received product X, and those in Trials 2 and 3 received product Y. Patients in Trial 2 also received interleukin 2 in an attempt to potentiate immune responses. After the first cycle of treatment, no GM-CSF antibodies were detected, but on subsequent therapy, 28 of the 38 patients tested receiving product Y (Trials 2 and 3) developed antibodies that bound to the GM-CSF product used for therapy. However, none of the patients developed antibodies that neutralized the biological activity of GM-CSF, as assessed using an in vitro bioassay. Furthermore, there was no in vivo impairment in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in the patients. In contrast, 19 of the 20 patients given product X (Trial 1) developed GM-CSF binding antibodies, and 9 of these patients were shown to develop antibodies that neutralized the biological activity of GM-CSF. The presence of the latter was associated with a significant reduction in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in patients. Therefore, product X appears to be more immunogenic than product Y. Immunochemical characterization confirmed that the specificity of the antibody responses varied depending on the product used for therapy. Whereas sera from Trial 1 patients treated with product X showed the presence of antibodies with strong recognition of GM-CSF proteins, sera from patients treated with product Y showed varied recognition of GM

  8. A method for the study of the effects of combining multiple pseudorandom fusimotor stimulation on the responses of muscle-spindle primary-ending afferents.

    PubMed

    Hulliger, Manuel; Banks, Robert W

    2009-03-30

    We describe a new method of investigation of the integrative action of fusimotor inputs in mammalian muscle spindles by stimulation of multiple fusimotor axons using independent pseudorandom pulse trains, each of low mean rate with pseudorandomly distributed stimulus intervals. Technically it was feasible only because of the development of (1) a novel, highly efficient approach to functional isolation of fusimotor efferents in ventral-root filaments, which we have called the isodyne strategy; (2) a real-time, microprocessor-based stimulus artefact cancellation device (SACAD); and (3) a highly adjustable, multi-branch stimulation electrode array. The general approach of using multiple, independent, pseudorandom stimulation of several input channels has wider applications in controlled-activation paradigms.

  9. Effect of transcranial direct current stimulation combined with gait and mobility training on functionality in children with cerebral palsy: study protocol for a double-blind randomized controlled clinical trial

    PubMed Central

    2013-01-01

    Background The project proposes three innovative intervention techniques (treadmill training, mobility training with virtual reality and transcranial direct current stimulation that can be safely administered to children with cerebral palsy. The combination of transcranial stimulation and physical therapy resources will provide the training of a specific task with multiple rhythmic repetitions of the phases of the gait cycle, providing rich sensory stimuli with a modified excitability threshold of the primary motor cortex to enhance local synaptic efficacy and potentiate motor learning. Methods/design A prospective, double-blind, randomized, controlled, analytical, clinical trial will be carried out.Eligible participants will be children with cerebral palsy classified on levels I, II and III of the Gross Motor Function Classification System between four and ten years of age. The participants will be randomly allocated to four groups: 1) gait training on a treadmill with placebo transcranial stimulation; 2) gait training on a treadmill with active transcranial stimulation; 3) mobility training with virtual reality and placebo transcranial stimulation; 4) mobility training with virtual reality and active transcranial stimulation. Transcranial direct current stimulation will be applied with the anodal electrode positioned in the region of the dominant hemisphere over C3, corresponding to the primary motor cortex, and the cathode positioned in the supraorbital region contralateral to the anode. A 1 mA current will be applied for 20 minutes. Treadmill training and mobility training with virtual reality will be performed in 30-minute sessions five times a week for two weeks (total of 10 sessions). Evaluations will be performed on four occasions: one week prior to the intervention; one week following the intervention; one month after the end of the intervention;and 3 months after the end of the intervention. The evaluations will involve three-dimensional gait analysis

  10. A novel combinational approach of microstimulation and bioluminescence imaging to study the mechanisms of action of cerebral electrical stimulation in mice.

    PubMed

    Arsenault, Dany; Drouin-Ouellet, Janelle; Saint-Pierre, Martine; Petrou, Petros; Dubois, Marilyn; Kriz, Jasna; Barker, Roger A; Cicchetti, Antonio; Cicchetti, Francesca

    2015-05-15

    Deep brain stimulation (DBS) is used to treat a number of neurological conditions and is currently being tested to intervene in neuropsychiatric conditions. However, a better understanding of how it works would ensure that side effects could be minimized and benefits optimized. We have thus developed a unique device to perform brain stimulation (BS) in mice and to address fundamental issues related to this methodology in the pre-clinical setting. This new microstimulator prototype was specifically designed to allow simultaneous live bioluminescence imaging of the mouse brain, allowing real time assessment of the impact of stimulation on cerebral tissue. We validated the authenticity of this tool in vivo by analysing the expression of toll-like receptor 2 (TLR2), corresponding to the microglial response, in the stimulated brain regions of TLR2-fluc-GFP transgenic mice, which we further corroborated with post-mortem analyses in these animals as well as in human brains of patients who underwent DBS to treat their Parkinson's disease. In the present study, we report on the development of the first BS device that allows for simultaneous live in vivo imaging in mice. This tool opens up a whole new range of possibilities that allow a better understanding of BS and how to optimize its effects through its use in murine models of disease.

  11. Effect of a combined continuous and intermittent transcutaneous electrical nerve stimulation on pain perception of burn patients evaluated by visual analog scale: a pilot study

    PubMed Central

    Pérez-Ruvalcaba, Irma; Sánchez-Hernández, Viridiana; Mercado-Sesma, Arieh R

    2015-01-01

    Aim The aim of this study was to assess the effect of continuous and intermittent electrical transcutaneous nerve stimulation on the perception of pain in patients with burns of different types. Materials and methods A pilot study was conducted in 14 patients (age 30.9±7.5 years) with second- and third-degree burns of different types. The burn types included electrical, fire/flame, and chemical. All patients received continuous and intermittent electrical transcutaneous nerve stimulation sessions three times per week for 4 weeks. Each session had a duration of 30 minutes. A pair of electrodes were placed around the burn. The primary efficacy endpoint was the perception of pain assessed by a visual analog scale at baseline and at the 30th day. Results A significant reduction of pain perception was reported (8.0±1.7 vs 1.0±0.5; P=0.027) by all patients after electrical stimulation therapy. There were no reports of adverse events during the intervention period. Conclusion Electrical stimulation could be a potential nonpharmacological therapeutic option for pain management in burn patients. PMID:26719723

  12. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation.

    PubMed

    Spivak, Jerry L

    2010-03-02

    The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.

  13. The effects of p38 MAPK inhibition combined with G-CSF administration on the hematoimmune system in mice with irradiation injury.

    PubMed

    Li, Deguan; Wang, Yueying; Wu, Hongying; Lu, Lu; Wang, Xiaochun; Zhang, Junling; Zhang, Heng; Fan, Saijun; Fan, Feiyue; Zhou, Daohong; Meng, Aimin

    2013-01-01

    The acute and residual (or long-term) bone marrow (BM) injury induced by ionizing radiation (IR) is a major clinic concern for patients receiving conventional radiotherapy and victims accidentally exposed to a moderate-to-high dose of IR. In this study, we investigated the effects of the treatment with the p38 inhibitor SB203580 (SB) and/or granulocyte colony-stimulating factor (G-CSF) on the hematoimmune damage induced by IR in a mouse model. Specifically, C57BL/6 mice were exposed to a sublethal dose (6 Gy) of total body irradiation (TBI) and then treated with vehicle, G-CSF, SB, and G-CSF plus SB. G-CSF (1 µg/mouse) was administrated to mice by intraperitoneal (ip) injection twice a day for six successive days; SB (15 mg/kg) by ip injection every other day for 10 days. It was found that the treatment with SB and/or G-CSF significantly enhanced the recovery of various peripheral blood cell counts and the number of BM mononuclear cells 10 and 30 days after the mice were exposed to TBI compared with vehicle treatment. Moreover, SB and/or G-CSF treatment also increased the clonogenic function of BM hematopoietic progenitor cells (HPCs) and the frequency of BM lineage -Sca1+c-kit+ cells (LSK cells) and short-term and long term hematopoietic stem cells (HSCs) 30 days after TBI, in comparison with vehicle treated controls. However, the recovery of peripheral blood B cells and CD4+ and CD8+ T cells was not significantly affected by SB and/or G-CSF treatment. These results suggest that the treatment with SB and/or G-CSF can reduce IR-induced BM injury probably in part via promoting HSC and HPC regeneration.

  14. Darbepoetin alfa for anemia with myelodysplastic syndrome.

    PubMed

    Seastone, David J; Gerds, Aaron T

    2015-04-01

    The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two decades, the use of darbepoetin and other erythropoietin stimulating agents to treat symptomatic anemia in lower-risk myelodysplastic syndromes has been a standard of care. This practice is supported by numerous Phase I/II studies and one Phase III study demonstrating the benefit of using erythropoietin stimulating agents alone, or in combination with granulocyte colony stimulating factor, for treatment of symptomatic anemia with the goal of decreasing red blood cell transfusion requirements. This review summarizes the published experience regarding the use of erythropoietin stimulating agents, with a special focus on darbepoetin, in patients with myelodysplastic syndrome and symptomatic anemia.

  15. Human mesenchymal stem cells stimulate EaHy926 endothelial cell migration: combined proteomic and in vitro analysis of the influence of donor-donor variability

    PubMed Central

    Walter, Merlin N.M.; Kohli, Nupur; Khan, Neelam; Major, Triin; Fuller, Heidi; Wright, Karina T.; Kuiper, Jan-Herman; Johnson, William E.B.

    2015-01-01

    Mesenchymal stem cells (MSCs) stimulate angiogenesis within a wound environment and this effect is mediated through paracrine interactions with the endothelial cells present. Here we report that human MSC-conditioned medium (n=3 donors) significantly increased EaHy-926 endothelial cell adhesion and cell migration, but that this stimulatory effect was markedly donor-dependent. MALDI-TOF/TOF mass spectrometry demonstrated that whilst collagen type I and fibronectin were secreted by all of the MSC cultures, the small leucine rich proteoglycan, decorin was secreted only by the MSC culture that was least effective upon EaHy-926 cells. These individual extracellular matrix components were then tested as culture substrata. EaHy-926 cell adherence was greatest on fibronectin-coated surfaces with least adherence on decorin-coated surfaces. Scratch wound assays were used to examine cell migration. EaHy-926 cell scratch wound closure was quickest on substrates of fibronectin and slowest on decorin. However, EaHy-926 cell migration was stimulated by the addition of MSC-conditioned medium irrespective of the types of culture substrates. These data suggest that whilst the MSC secretome may generally be considered angiogenic, the composition of the secretome is variable and this variation probably contributes to donor-donor differences in activity. Hence, screening and optimizing MSC secretomes will improve the clinical effectiveness of pro-angiogenic MSC-based therapies. PMID:26195891

  16. Associations between clinical outcome and navigated transcranial magnetic stimulation characteristics in patients with motor-eloquent brain lesions: a combined navigated transcranial magnetic stimulation-diffusion tensor imaging fiber tracking approach.

    PubMed

    Sollmann, Nico; Wildschuetz, Noémie; Kelm, Anna; Conway, Neal; Moser, Tobias; Bulubas, Lucia; Kirschke, Jan S; Meyer, Bernhard; Krieg, Sandro M

    2017-03-31

    OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking (DTI FT) based on nTMS data are increasingly used for preoperative planning and resection guidance in patients suffering from motor-eloquent brain tumors. The present study explores whether nTMS-based DTI FT can also be used for individual preoperative risk assessment regarding surgery-related motor impairment. METHODS Data derived from preoperative nTMS motor mapping and subsequent nTMS-based tractography in 86 patients were analyzed. All patients suffered from high-grade glioma (HGG), low-grade glioma (LGG), or intracranial metastasis (MET). In this context, nTMS-based DTI FT of the corticospinal tract (CST) was performed at a range of fractional anisotropy (FA) levels based on an individualized FA threshold ([FAT]; tracking with 50%, 75%, and 100% FAT), which was defined as the highest FA value allowing for visualization of fibers (100% FAT). Minimum lesion-to-CST distances were measured, and fiber numbers of the reconstructed CST were assessed. These data were then correlated with the preoperative, postoperative, and follow-up status of motor function and the resting motor threshold (rMT). RESULTS At certain FA levels, a statistically significant difference in lesion-to-CST distances was observed between patients with HGG who had no impairment and those who developed surgery-related transient or permanent motor deficits (75% FAT: p = 0.0149; 100% FAT: p = 0.0233). In this context, no patient with a lesion-to-CST distance ≥ 12 mm suffered from any new surgery-related permanent paresis (50% FAT and 75% FAT). Furthermore, comparatively strong negative correlations were observed between the rMT and lesion-to-CST distances of patients with surgery-related transient paresis (Spearman correlation coefficient [rs]; 50% FAT: rs = -0.8660; 75% FAT: rs = -0.8660) or surgery-related permanent paresis (50% FAT: rs = -0.7656; 75% FAT: rs = -0.6763). CONCLUSIONS This is

  17. Development of a modified artificial insemination technique combining penile vibration stimulation and the swim-up method in the common marmoset.

    PubMed

    Takabayashi, Shuji; Suzuki, Yuiko; Katoh, Hideki

    2015-05-01

    The common marmoset, Callithrix jacchus, is used as a New World monkey species in biomedical studies because of its small body size and good reproduction in captivity. A modified artificial insemination technique was developed in this species to encourage breeding of lines carrying interesting genes and traits. Fresh semen was collected by penile vibratory stimulation. Medium containing highly motile sperm was inseminated into the uterus using a catheter. Seven females were inseminated using freshly prepared sperm from different males every day for 3 days including the expected ovulation day. As a result, four females conceived, and three females delivered six offspring in total (two singletons and one quadruplet). The paternity of the newborns was determined using microsatellite markers to accurately pinpoint the timing of insemination and ovulation. It is expected that our artificial insemination protocol can be effectively used to establish marmoset lines and genetically manage marmoset colonies.

  18. Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment.

    PubMed

    Köbe, Theresa; Witte, A Veronica; Schnelle, Ariane; Lesemann, Anne; Fabian, Sonja; Tesky, Valentina A; Pantel, Johannes; Flöel, Agnes

    2016-05-01

    Previous studies in older adults suggested beneficial effects of omega-3 fatty acid (FA) supplementation, aerobic exercise, or cognitive stimulation on brain structure and function. However, combined effects of these interventions in patients suffering from mild cognitive impairment (MCI) are unknown. Using a randomized interventional design, we evaluated the effect of combined omega-3 FA supplementation, aerobic exercise and cognitive stimulation (target intervention) versus omega-3 FA supplementation and non-aerobic exercise (control intervention) on cognitive function and gray matter volume in patients with MCI. Moreover, we analyzed potential vascular, metabolic or inflammatory mechanisms underlying these effects. Twenty-two MCI patients (8 females; 60-80years) successfully completed six months of omega-3 FA intake, aerobic cycling training and cognitive stimulation (n=13) or omega-3 FA intake and non-aerobic stretching and toning (n=9). Before and after the interventions, cognitive performance, magnetic resonance imaging of the brain at 3T (n=20), intima-media thickness of the internal carotid artery and serum markers of glucose control, lipid and B-vitamin metabolism, and inflammation were assessed. Intervention-related changes in gray matter volume of Alzheimer's disease (AD)-related brain regions, i.e., frontal, parietal, temporal and cingulate cortex were examined using voxel-based morphometry of high resolution T1-weighted images. After the intervention period, significant differences emerged in brain structure between groups: Gray matter volume decreased in the frontal, parietal and cingulate cortex of patients in the control intervention, while gray matter volume in these areas was preserved or even increased after the target intervention. Decreases in homocysteine levels in the target intervention group were associated with increases in gray matter volume in the middle frontal cortex (p=0.010). No significant differences in cognitive performance or

  19. Combined Stimulation with the T Helper Cell Type 2 Cytokines Interleukin (Il)-4 and IL-10 Induces Mouse Mast Cell Apoptosis

    PubMed Central

    Yeatman, C. Fitzhugh; Jacobs-Helber, Sarah M.; Mirmonsef, Paria; Gillespie, Sheila R.; Bouton, Lawrence Andrew; Collins, Henrietta A.; Sawyer, Stephen T.; Shelburne, Christopher P.; Ryan, John J.

    2000-01-01

    Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)–antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3–dependent bone marrow–derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-xL and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3–independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine–mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival. PMID:11034599

  20. Feedback control of arm movements using Neuro-Muscular Electrical Stimulation (NMES) combined with a lockable, passive exoskeleton for gravity compensation

    PubMed Central

    Klauer, Christian; Schauer, Thomas; Reichenfelser, Werner; Karner, Jakob; Zwicker, Sven; Gandolla, Marta; Ambrosini, Emilia; Ferrante, Simona; Hack, Marco; Jedlitschka, Andreas; Duschau-Wicke, Alexander; Gföhler, Margit; Pedrocchi, Alessandra

    2014-01-01

    Within the European project MUNDUS, an assistive framework was developed for the support of arm and hand functions during daily life activities in severely impaired people. This contribution aims at designing a feedback control system for Neuro-Muscular Electrical Stimulation (NMES) to enable reaching functions in people with no residual voluntary control of the arm and shoulder due to high level spinal cord injury. NMES is applied to the deltoids and the biceps muscles and integrated with a three degrees of freedom (DoFs) passive exoskeleton, which partially compensates gravitational forces and allows to lock each DOF. The user is able to choose the target hand position and to trigger actions using an eyetracker system. The target position is selected by using the eyetracker and determined by a marker-based tracking system using Microsoft Kinect. A central controller, i.e., a finite state machine, issues a sequence of basic movement commands to the real-time arm controller. The NMES control algorithm sequentially controls each joint angle while locking the other DoFs. Daily activities, such as drinking, brushing hair, pushing an alarm button, etc., can be supported by the system. The robust and easily tunable control approach was evaluated with five healthy subjects during a drinking task. Subjects were asked to remain passive and to allow NMES to induce the movements. In all of them, the controller was able to perform the task, and a mean hand positioning error of less than five centimeters was achieved. The average total time duration for moving the hand from a rest position to a drinking cup, for moving the cup to the mouth and back, and for finally returning the arm to the rest position was 71 s. PMID:25228853

  1. Feedback control of arm movements using Neuro-Muscular Electrical Stimulation (NMES) combined with a lockable, passive exoskeleton for gravity compensation.

    PubMed

    Klauer, Christian; Schauer, Thomas; Reichenfelser, Werner; Karner, Jakob; Zwicker, Sven; Gandolla, Marta; Ambrosini, Emilia; Ferrante, Simona; Hack, Marco; Jedlitschka, Andreas; Duschau-Wicke, Alexander; Gföhler, Margit; Pedrocchi, Alessandra

    2014-01-01

    Within the European project MUNDUS, an assistive framework was developed for the support of arm and hand functions during daily life activities in severely impaired people. This contribution aims at designing a feedback control system for Neuro-Muscular Electrical Stimulation (NMES) to enable reaching functions in people with no residual voluntary control of the arm and shoulder due to high level spinal cord injury. NMES is applied to the deltoids and the biceps muscles and integrated with a three degrees of freedom (DoFs) passive exoskeleton, which partially compensates gravitational forces and allows to lock each DOF. The user is able to choose the target hand position and to trigger actions using an eyetracker system. The target position is selected by using the eyetracker and determined by a marker-based tracking system using Microsoft Kinect. A central controller, i.e., a finite state machine, issues a sequence of basic movement commands to the real-time arm controller. The NMES control algorithm sequentially controls each joint angle while locking the other DoFs. Daily activities, such as drinking, brushing hair, pushing an alarm button, etc., can be supported by the system. The robust and easily tunable control approach was evaluated with five healthy subjects during a drinking task. Subjects were asked to remain passive and to allow NMES to induce the movements. In all of them, the controller was able to perform the task, and a mean hand positioning error of less than five centimeters was achieved. The average total time duration for moving the hand from a rest position to a drinking cup, for moving the cup to the mouth and back, and for finally returning the arm to the rest position was 71 s.

  2. Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial

    PubMed Central

    Schröder, L.; Rack, B.; Sommer, H.; Koch, J. G.; Weissenbacher, T.; Janni, W.; Schneeweiss, A.; Rezai, M.; Lorenz, R.; Jäger, B.; Schramm, A.; Häberle, L.; Fasching, P. A.; Friedl, T. W. P.; Beckmann, M. W.; Scholz, C.

    2016-01-01

    Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3–4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles. PMID:27239063

  3. Combinational Immunotherapy with Allo-DRibble Vaccines and Anti-OX40 Co-Stimulation Leads to Generation of Cross-Reactive Effector T Cells and Tumor Regression

    PubMed Central

    Yu, Guangjie; Li, Yuhuan; Cui, Zhihua; Morris, Nicholas P.; Weinberg, Andrew D.; Fox, Bernard A.; Urba, Walter J.; Wang, Lixin; Hu, Hong-Ming

    2016-01-01

    It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+ T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic “off-the-shelf” DRibble vaccines together with antibodies against co-stimulatory molecules. PMID:27874054

  4. Brain Stimulation Therapies

    MedlinePlus

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  5. Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice.

    PubMed

    Sundaresan, Arjunan; Radhiga, Thangaiyan; Pugalendi, Kodukkur Viswanathan

    2016-06-01

    The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance.

  6. Hybrid use of combined and sequential delivery of growth factors and ultrasound stimulation in porous multilayer composite scaffolds to promote both vascularization and bone formation in bone tissue engineering.

    PubMed

    Yan, Haoran; Liu, Xia; Zhu, Minghua; Luo, Guilin; Sun, Tao; Peng, Qiang; Zeng, Yi; Chen, Taijun; Wang, Yingying; Liu, Keliang; Feng, Bo; Weng, Jie; Wang, Jianxin

    2016-01-01

    In this study, a multilayer coating technology would be adopted to prepare a porous composite scaffold and the growth factor release and ultrasound techniques were introduced into bone tissue engineering to finally solve the problems of vascularization and bone formation in the scaffold whilst the designed multilayer composite with gradient degradation characteristics in the space was used to match the new bone growth process better. The results of animal experiments showed that the use of low intensity pulsed ultrasound (LIPUS) combined with growth factors demonstrated excellent capabilities and advantages in both vascularization and new bone formation in bone tissue engineering. The degradation of the used scaffold materials could match new bone formation very well. The results also showed that only RGD-promoted cell adhesion was insufficient to satisfy the needs of new bone formation while growth factors and LIPUS stimulation were the key factors in new bone formation.

  7. Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy.

    PubMed

    Wadhwa, M; Bird, C; Fagerberg, J; Gaines-Das, R; Ragnhammar, P; Mellstedt, H; Thorpe, R

    1996-05-01

    In this study, the development of neutralizing and non-neutralizing GM-CSF antibodies and the clinical consequences related to the induction of these antibodies were analysed in 20 patients with metastatic colorectal carcinoma receiving a combination therapy of Escherichia coli-derived GM-CSF and a colon carcinoma-reactive MoAb in the absence of any concomitant chemotherapy. The recombinant human GM-CSF was administered subcutaneously for 10 days every month for 4 months. Following the first cycle of treatment, no GM-CSF antibodies were detected, but during subsequent therapy, 19 of the 20 patients studied developed GM-CSF binding antibodies. However, only a proportion (40%) of the 19 antibody-positive patients developed antibodies that neutralized the biological activity of GM-CSF in an in vitro bioassay. The presence of GM-CSF neutralizing antibodies was associated with a significant reduction in GM-CSF-induced expansion of leucocytes, neutrophils and eosinophils. Such clinical effects were not apparent in patients with non-neutralizing antibodies. Further characterization of sera from patients with neutralizing antibodies showed that, in most cases, the antibodies neutralized the biological activity of GM-CSF preparations derived using different expression systems (Chinese hamster ovary cells and yeast), suggesting that these antibodies may have the potential to cross-react with endogenously produced GM-CSF. These effects should be considered before therapeutic use of cytokines, particularly in patients who are not immunosuppressed, and therefore capable of mounting an effective immune response. Our results indicate that assessment of production of neutralizing antibodies induced during cytokine therapy can be used to predict diminished clinical response to further therapy.

  8. Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory.

    PubMed

    Choy, Kwok Ho Christopher; de Visser, Yvonne; Nichols, Nancy R; van den Buuse, Maarten

    2008-01-01

    Epidemiological studies suggest that multiple developmental disruptions are involved in the etiology of psychiatric illnesses including schizophrenia. In addition, altered expression of brain-derived neurotrophic factor (BDNF) has been implicated in these illnesses. In the present study, we examined the combined long-term effect of an early stress, in the form of maternal deprivation, and a later stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone, on BDNF expression in the hippocampus of rats. To assess whether there were behavioral effects, which may correlate with the BDNF changes, learning and memory was tested in the Y-maze test for short term spatial memory, the Morris water maze for long-term spatial memory, and the T-maze test for working memory. Four groups of rats received either no stress, maternal deprivation, corticosterone treatment, or both. Dorsal hippocampus sections obtained from parallel groups were used for BDNF mRNA in situ hybridization. Rats which had undergone both maternal deprivation and corticosterone treatment displayed a unique and significant 25-35% reduction of BDNF expression in the dentate gyrus (DG), and similar trends in the CA1 and CA3 regions of the hippocampus. These "two-hit" animals exhibited a learning delay in the Morris water maze test, a marked deficit in the Y-maze, but little change in the T-maze test. However, some aspects of cognition were also altered in rats with either maternal deprivation or corticosterone treatment. This study demonstrates a persistent effect of two developmental disruptions on BDNF expression in the hippocampus, with parallel, but not completely correlative changes in learning and memory.

  9. STRENGTH EXERCISES COMBINED WITH DRY NEEDLING WITH ELECTRICAL STIMULATION IMPROVE PAIN AND FUNCTION IN PATIENTS WITH CHRONIC ROTATOR CUFF TENDINOPATHY: A RETROSPECTIVE CASE SERIES

    PubMed Central

    2016-01-01

    noted with the intervention protocol. All subjects responded positively to the intervention and reported quality of life was improved for each subject. The results of this case series show promising outcomes for the combination of SE and DN in the treatment of chronic RTCT. Level of Evidence Level 4 PMID:27274427

  10. The case for aromatase inhibitors use in oncofertility patients. Should aromatase inhibitors be combined with gonadotropin treatment in breast cancer patients undergoing ovarian stimulation for fertility preservation prior to chemotherapy? A debate.

    PubMed

    Fatum, Muhammad; McVeigh, Enda; Child, Tim

    2013-12-01

    Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers. Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer. A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients. As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised

  11. Utility of the clinical practice of administering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors treated with G-CSF for mobilization of peripheral blood stem cells.

    PubMed

    Martino, Massimo; Luise, Francesca; Oriana, Vincenzo; Console, Giuseppe; Moscato, Tiziana; Mammì, Corrado; Messina, Giuseppe; Massara, Elisabetta; Irrera, Giuseppe; Piromalli, Angela; Lombardo, Vincenzo Trapani; Laganà, Carmelo; Iacopino, Pasquale

    2007-01-01

    The aim of the study was to verify the utility of the clinical practice of administering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors receiving granulocyte colony-stimulating factor to mobilize peripheral blood stem cells. Thrombophilia screening comprised of testing for factor V Leiden G1691A, prothrombin G20210A, the thermolabile variant (C677T) of the methylene tetrahydrofolate reductase gene, protein C, protein S, factor VIII and homocysteine plasmatic levels, antithrombin III activity, and acquired activated protein C resistance. We investigated prospectively 72 white Italian healthy donors, 39 men and 33 women, with a median age of 42 years (range, 18-65). Five donors (6.9%) were heterozygous carriers of Factor V Leiden G1691A; two healthy donors had the heterozygous prothrombin G20210A gene mutation; C677T mutation in the methylene tetrahydrofolate reductase gene was present in 34 (47.2%) donors in heterozygous and in 7 donors (9.7%) in homozygous. Acquired activated protein C resistance was revealed in 8 donors of the study (11.1%). The protein C plasmatic level was decreased in 3 donors (4.2%); the protein S level was decreased in 7 donors (9.7%). An elevated factor VIII dosage was shown in 10 donors (13.9%) and hyperhomocysteinemia in 9 donors (12.5%). Concentration of antithrombin III was in the normal range for all study group donors. The factor V Leiden mutation was combined with the heterozygous prothrombin G20210A in 2 cases and with protein S deficiency in one case; 2 healthy donors presented an associated deficiency of protein C and protein S. Although none of these healthy subjects had a previous history of thrombosis, low-molecular-weight heparin was administered to all donors during granulocyte colony-stimulating factor administration to prevent thrombotic events. No donor experienced short or long-term thrombotic diseases after a median follow-up of 29.2 months. Our data do not

  12. Stimulated Raman photoacoustic imaging

    PubMed Central

    Yakovlev, Vladislav V.; Zhang, Hao F.; Noojin, Gary D.; Denton, Michael L.; Thomas, Robert J.; Scully, Marlan O.

    2010-01-01

    Achieving label-free, molecular-specific imaging with high spatial resolution in deep tissue is often considered the grand challenge of optical imaging. To accomplish this goal, significant optical scattering in tissues has to be overcome while achieving molecular specificity without resorting to extrinsic labeling. We demonstrate the feasibility of developing such an optical imaging modality by combining the molecularly specific stimulated Raman excitation with the photoacoustic detection. By employing two ultrashort excitation laser pulses, separated in frequency by the vibrational frequency of a targeted molecule, only the specific vibrational level of the target molecules in the illuminated tissue volume is excited. This targeted optical absorption generates ultrasonic waves (referred to as stimulated Raman photoacoustic waves) which are detected using a traditional ultrasonic transducer to form an image following the design of the established photoacoustic microscopy. PMID:21059930

  13. Biochemical assays on plasminogen activators and hormones from kidney sources

    NASA Technical Reports Server (NTRS)

    Barlow, Grant H.; Lewis, Marian L.; Morrison, Dennis R.

    1988-01-01

    Investigations were established for the purpose of analyzing the conditioned media from human embryonic kidney cell subpopulations separated in space by electrophoresis. This data is based on the experiments performed on STS-8 on the continuous flow electrophoresis system. The primary biological activity that was analyzed was plasminogen activator activity, but some assays for erythropoeitin and human granulocyte colony stimulating activity were also performed. It is concluded that a battery of assays are required to completely define the plasminogen activator profile of a conditioned media from cell culture. Each type of assay measures different parts of the mixture and are influenced by different parameters. The functional role of each assay is given along with an indication of which combination of assays are required to answer specific questions. With this type of information it is possible by combinations of assays with mathematical analysis to pinpoint a specific component of the system.

  14. Establishment of a retinoic acid-resistant human acute promyelocytic leukaemia (APL) model in human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgenic severe combined immunodeficiency (SCID) mice.

    PubMed Central

    Fukuchi, Y.; Kizaki, M.; Kinjo, K.; Awaya, N.; Muto, A.; Ito, M.; Kawai, Y.; Umezawa, A.; Hata, J.; Ueyama, Y.; Ikeda, Y.

    1998-01-01

    To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9764578

  15. Biochemical Assays of Cultured Cells

    NASA Technical Reports Server (NTRS)

    Barlow, G. H.

    1985-01-01

    Subpopulations of human embryonic kidney cells isolated from continuous flow electrophoresis experiments performed at McDonnell Douglas and on STS-8 have been analyzed. These analyses have included plasminogen activator assays involving indirect methodology on fibrin plated and direct methodology using chromogenic substrates. Immunological studies were performed and the conditioned media for erythropoietin activity and human granulocyte colony stimulating (HGCSF) activity was analyzed.

  16. Department of Clinical Investigation Annual Progress Report: Fiscal Year 1989

    DTIC Science & Technology

    1989-01-01

    Bacterially Synthetized b Human Granulocyte Colony Stimulating Factor (hg-CSF) Against Pseudomonas aeruginosa Infection DEPARTMENT OF MEDICINE Allergy ...C-01) A Clinical Trial to Evaluate Postoperative 30 Immunotherapy and Postoperative Systemic Chemotherapy in the Management of Resectable Colon...Publications/Presentations: None to date. -6- Annual Progress Report DEPARTMENT OF MEDICINE Allergy and Immunology Service Date: 1 October 1989 Protocol

  17. Hematopoietic progenitor cell mobilization for autologous transplantation – a literature review

    PubMed Central

    Salvino, Marco Aurélio; Ruiz, Jefferson

    2015-01-01

    The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4) inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34+ cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone. PMID:26969772

  18. Felty syndrome

    MedlinePlus

    ... at risk for infection because they have a low white blood cell count. Symptoms Symptoms include: General feeling of discomfort ( malaise ) ... activity of their RA. Methotrexate may improve the low white blood cell count. Granulocyte-colony stimulating factor (G-CSF) may raise ...

  19. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia....

  20. Potential use of G-CSF for protection against Streptococcus suis infection in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of immunomodulators is a promising alternative to the use of antibiotics for therapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease. We developed a replication-defective adenovirus vector that expresses porcine granulocyte colony-stimulating factor (G-CSF) ...

  1. G-CSF Analogue Treatment Increases Peripheral Neutrophil Numbers in Pigs - a Potential Alternative for In-Feed Antibiotics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Immunomodulators is a promising area for therapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease during periods of peak disease incidence. Granulocyte colony-stimulating factor (G-CSF) enhances neutrophil production and release from the bone marrow and is already li...

  2. Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon, 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma.

    PubMed

    Liljefors, Maria; Ragnhammar, Peter; Nilsson, Bo; Ullenhag, Gustav; Mellstedt, Håkan; Frödin, Jan-Erik

    2004-09-01

    Monoclonal antibodies (MAbs) have different modes of action and toxicity profile compared to chemotherapeutics, which makes it interesting to combine these drugs. Addition of cytokines to MAb therapy may also augment immune effector functions utilized by MAb. In an effort to improve the therapeutic effect of a MAb-based regimen in colorectal carcinoma (CRC) patients, the effects of a combination of alpha-interferon (alpha-IFN), 5-fluorouracil (5-FU), granulocyte-macrophage colony-stimulating factor (GM-CSF) and mouse MAb17-1A was evaluated in 27 patients with metastatic disease. alpha-IFN was given s.c. once daily for 5 consecutive days and at days 4 and 5, 5-FU was administered as a daily i.v. bolus injection. After 2 days rest, GM-CSF was given s.c. once daily, days 8-14 and on day 10, MAb17-1A was given i.v. The treatment cycle was repeated every 4th week. One patient achieved a partial remission and 13 patients showed a minor response or stable disease >3 months, inducing an overall response rate of 54%. Responding patients survived significantly longer than non-responding patients (p=0.021). Median overall survival time for all patients was 75 weeks and progression-free survival time 15 weeks. Adverse events related to alpha-IFN, GM-CSF and 5-FU were as expected. The frequency of patients with an immediate-type allergic reaction (ITAR) against MAb17-1A at the 1st, 2nd, 3rd and 4th treatment cycles was 11%, 52%, 62% and 64% respectively. The planned MAb17-1A dose had to be reduced by repeated infusions. No patient received full dose of MAb17-1A from the 3rd cycle and onward. Compared to historical control patients treated with MAb17-1A alone, the present combination regimen seemed to improve the response rate (54% vs 15%) as well as progression-free survival (15 vs 7 weeks; p<0.05).

  3. An improved ELISA with linear sweep voltammetry detection.

    PubMed

    Tie, F; Pan, A; Ru, B; Wang, W; Hu, Y

    1992-04-27

    An improved ELISA combined with linear sweep voltammetry detection of p-nitrophenol generated by an enzyme has been investigated in this study. p-nitrophenol, produced from alkaline phosphatase catalysing p-nitrophenyl phosphate, yielded an oxidative peak at 1.06 V (vs. Ag/AgCl) with a wax-impregnated tubular graphite anode. Without separation, the small three-electrode system was directly inserted in the well of an ELISA plate for detection. The detection limit for p-nitrophenol was 1 x 10(-6) M, lower than that obtained by measuring the absorbance of p-nitrophenol. The feasibility of utilizing linear sweep voltammetry as a detection scheme was demonstrated by determining metallothionein, granulocyte-colony stimulating factor and Xenopus laevis keratin using the above new system. The method was simple, reproducible and much more sensitive than traditional spectrophotometry.

  4. Vagus Nerve Stimulation

    MedlinePlus

    Vagus nerve stimulation Overview By Mayo Clinic Staff Vagus nerve stimulation is a procedure that involves implantation of a device that stimulates the vagus nerve with electrical impulses. There's one vagus nerve on ...

  5. Murine Anti-GD2 Monoclonal Antibody 3F8 Combined With Granulocyte-Macrophage Colony-Stimulating Factor and 13-Cis-Retinoic Acid in High-Risk Patients With Stage 4 Neuroblastoma in First Remission

    PubMed Central

    Cheung, Nai-Kong V.; Cheung, Irene Y.; Kushner, Brian H.; Ostrovnaya, Irina; Chamberlain, Elizabeth; Kramer, Kim; Modak, Shakeel

    2012-01-01

    Purpose Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. Patients and Methods One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. Results At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post–cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). Conclusion Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only

  6. Effects of acute feed restriction combined with targeted use of increasing luteinizing hormone content of follicle-stimulating hormone preparations on ovarian superstimulation, fertilization, and embryo quality in lactating dairy cows.

    PubMed

    Bender, R W; Hackbart, K S; Dresch, A R; Carvalho, P D; Vieira, L M; Crump, P M; Guenther, J N; Fricke, P M; Shaver, R D; Combs, D K; Wiltbank, M C

    2014-02-01

    Multiple metabolic and hormonal factors can affect the success of protocols for ovarian superstimulation. In this study, the effect of acute feed restriction and increased LH content in the superstimulatory FSH preparation on numbers of ovulations, fertilization, and embryo quality in lactating dairy cows was evaluated. Two experiments were performed using a Latin square design with treatments arranged as a 2 × 2 factorial: feed restriction (FR; 25% reduction in dry matter intake) compared with ad libitum (AL) feeding, combined with high (H) versus low (L) LH in the last 4 injections of the superstimulatory protocol. As expected, FR decreased circulating insulin concentrations (26.7 vs. 46.0 μU/mL). Two analyses were performed: one that evaluated the complete Latin square in experiment 2 and a second that evaluated only the first periods of experiments 1 and 2. For both analyses, follicle numbers, ovulation rates, and corpora lutea on d 7 were not different. In the first period analysis of experiments 1 and 2, we observed an interaction between feed allowance and amount of LH on fertilization rates, percentage of embryos or oocytes that were quality 1 and 2 embryos, and number of embryos or oocytes that were degenerate. Fertilization rates were greater for the AL-L (89.4%) and FR-H (80.1%) treatments compared with the AL-H (47.9%) and FR-L (59.9%) treatments. Similarly, the proportion of total embryos or oocytes designated as quality 1 and 2 embryos was greater for AL-L (76.7%) and FR-H (73.4%) treatments compared with AL-H (35.6%) and FR-L (47.3%) treatments. In addition, the number of degenerate embryos was decreased for AL-L (1.3) and FR-H (0.4) treatments compared with the AL-H (2.6) and FR-L (2.3) treatments. Thus, cows with either too low (FR-L) or too high (AL-H) insulin and LH stimulation had lesser embryo production after superstimulation because of reduced fertilization rate and increased percentage of degenerate embryos. Therefore, interaction of the

  7. Laser stimulation for pain research

    NASA Astrophysics Data System (ADS)

    Clark, Stuart; Dickinson, Mark R.; King, Terence A.; Jones, Anthony; Chen, Andrew; Derbyshire, Stuart; Townsend, D. W.; Kinahan, Paul E.; Mintun, M. A.; Nichols, T.

    1996-01-01

    Pain is a serious medical problem; it inflicts huge economic loss and personal suffering. Pain signals are conducted via small, non- and partially myelinated A-delta and C nerve fibers and lasers are particularly well suited to stimulating these fibers. Large myelinated fibers convey touch and vibration information and these fibers are also discharged when contact thermodes and other touch pain stimuli are used and this would give a more muddled signal for functional imaging experiments. The advantages of lasers over conventional methods of pain stimulation are good temporal resolution, no variable parameters are involved such as contact area and they give very reproducible results. Accurate inter-stimulus changes can be achieved by computer control of the laser pulse duration, pulse height and repetition rate and this flexibility enables complex stimulation paradigms to be realized. We present a flexible carbon dioxide laser system designed to generate these stimuli for the study of human cerebral pain responses. We discuss the advantages within research of this system over other methods of pain stimulation such as thermal, electrical and magnetic. The stimulator is used in conjunction with functional magnetic resonance imaging, positron emission tomography and electrophysiological methods of imaging the brain's activity. This combination is a powerful tool for the study of pain-induced activity in different areas of the brain. An accurate understanding of the brain's response to pain will help in research into the areas of rheumatoid arthritis and chronic back pain.

  8. EOR by stimulated microflora

    SciTech Connect

    Svarovskaya, L.I.; Altunina, L.K.; Rozhenkova, Z.A.; Bulavin, V.D.

    1995-12-31

    A combined microbiological and physico-chemical method for EOR has been developed for flooded West Siberia oil fields with formation temperature of 45{degrees}-95{degrees}C (318-365K). Formation water includes rich and various biocenoses numbering up to 2 x 10{sup 7} cells per ml. Representatives of genera, i.e, Pseudomonas, Bacillus, Actinomyces, Micrococcus, Mycobacterium, Sarcina, etc. were found to be the most widely distributed microorganisms. The method is based on injection of systems exhibiting high oil displacing capacity and at the same time being an additional nitrous nutrient for endemic populations of microorganisms. Their injection into formation water favors biomass growth by 4-6 orders and promotes syntheses of biosurfactants, biopolymers, acids, etc., and gaseous products. The features of residual oil displacement have been studied on laboratory models using a combined microbiological and physico-chemical method. A curve for the yield of residual oil is presented by two peaks. The first peak is stipulated by the washing action of oil displacement system, and the second one by the effect of metabolites produced at stimulation of biogenic processes. Oil displacement index increases by 15%-30%.

  9. ACTH (cosyntropin) stimulation test

    MedlinePlus

    ... The ACTH stimulation test measures how well the adrenal glands respond to adrenocorticotropic hormone ( ACTH ). ACTH is a ... produced in the pituitary gland that stimulates the adrenal glands to release a hormone called cortisol. How the ...

  10. Optical stimulation of peripheral nerves in vivo

    NASA Astrophysics Data System (ADS)

    Wells, Jonathon D.

    This dissertation documents the emergence and validation of a new clinical tool that bridges the fields of biomedical optics and neuroscience. The research herein describes an innovative method for direct neurostimulation with pulsed infrared laser light. Safety and effectiveness of this technique are first demonstrated through functional stimulation of the rat sciatic nerve in vivo. The Holmium:YAG laser (lambda = 2.12 mum) is shown to operate at an optimal wavelength for peripheral nerve stimulation with advantages over standard electrical neural stimulation; including contact-free stimulation, high spatial selectivity, and lack of a stimulation artifact. The underlying biophysical mechanism responsible for transient optical nerve stimulation appears to be a small, absorption driven thermal gradient sustained at the axonal layer of nerve. Results explicitly prove that low frequency optical stimulation can reliably stimulate without resulting in tissue thermal damage. Based on the positive results from animal studies, these optimal laser parameters were utilized to move this research into the clinic with a combined safety and efficacy study in human subjects undergoing selective dorsal rhizotomy. The clinical Holmium:YAG laser was used to effectively stimulate human dorsal spinal roots and elicit functional muscle responses recorded during surgery without evidence of nerve damage. Overall these results predict that this technology can be a valuable clinical tool in various neurosurgical applications.

  11. Brain Stimulation in Addiction.

    PubMed

    Salling, Michael C; Martinez, Diana

    2016-11-01

    Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction.

  12. Colon emptying induced by sequential electrical stimulation in rats.

    PubMed

    Sevcencu, Cristian; Rijkhoff, Nico J M; Sinkjaer, Thomas

    2005-12-01

    Electrical stimulation could be used to induce colon emptying. The present experiments were performed to establish a stimulation pattern to optimize the stimulation parameters and to test neural involvement in propulsion induced by electrical stimulation. Colon segments were sequentially stimulated using rectangular pulses. The resulting propulsive activity displaced intraluminal content in consecutive propulsion steps. The propulsion steps differed in displacement latency, distance, and velocity along the stimulated colon. Increasing the pulse duration or amplitude resulted in a decrease of the latency. Increasing the stimulation amplitude doubled the displacement distance. The frequencies tested in the present study did not affect propulsion. Inhibition of cholinergic and nitrergic pathways inhibited propulsion. Electrical stimulation can induce colonic propulsion. Motor differences are present along the descending colon. The most suitable combination of pulse parameters regarding colon stimulation is 0.3 ms, 5 mA, 10 Hz. Neural circuits are involved in propulsion when using these values.

  13. The role of LH in ovarian stimulation.

    PubMed

    Munoz, Elkin; Bosch, Ernesto; Fernandez, Iria; Portela, Susana; Ortiz, Ginna; Remohi, Jose; Pellicer, Antonio

    2012-03-01

    LH is a glycoprotein that plays a crucial role in folliculogenesis during the natural ovarian cycles. It has the same activity and shares receptors with hCG. However the use of LH in combination with FSH in controlled ovarian stimulation remains controversial. A practical approach concerning the usefulness of LH according to the endogenous level of LH is described herein. Specific groups of patients can benefit from ovarian stimulation with LH. New applications of LH/hCG activity are also discussed.

  14. Atomic oxygen stimulated outgassing

    NASA Technical Reports Server (NTRS)

    Linton, Roger C.; Reynolds, John M.

    1991-01-01

    The passive Long Duration Exposure Facility (LDEF) Experiment A0034, Atomic Oxygen Simulated Outgassing, consisted of two identical one-sixth tray modules, exposing selected thermal control coatings to atomic oxygen and the combined space environment on the leading edge and, for reference, to the relative wake environment on the trailing edge. Optical mirrors were included adjacent to the thermal coatings for deposition of outgassing products. Ultraviolet grade windows and metal covers were provided for additional assessment of the effects of the various environmental factors. Preliminary results indicate that orbital atomic oxygen is both a degrading and a optically restorative factor in the thermo-optical properties of selected thermal coatings. There is evidence of more severe optical degradation on collector mirrors adjacent to coatings that were exposed to the RAM-impinging atomic oxygen. This evidence of atomic oxygen stimulated outgassing is discussed in relation to alternative factors that could affect degradation. The general effects of the space environment on the experiment hardware as well as the specimens are discussed.

  15. A Systematic Review of Electric-Acoustic Stimulation

    PubMed Central

    Ching, Teresa Y. C.; Cowan, Robert

    2013-01-01

    Cochlear implant systems that combine electric and acoustic stimulation in the same ear are now commercially available and the number of patients using these devices is steadily increasing. In particular, electric-acoustic stimulation is an option for patients with severe, high frequency sensorineural hearing impairment. There have been a range of approaches to combining electric stimulation and acoustic hearing in the same ear. To develop a better understanding of fitting practices for devices that combine electric and acoustic stimulation, we conducted a systematic review addressing three clinical questions: what is the range of acoustic hearing in the implanted ear that can be effectively preserved for an electric-acoustic fitting?; what benefits are provided by combining acoustic stimulation with electric stimulation?; and what clinical fitting practices have been developed for devices that combine electric and acoustic stimulation? A search of the literature was conducted and 27 articles that met the strict evaluation criteria adopted for the review were identified for detailed analysis. The range of auditory thresholds in the implanted ear that can be successfully used for an electric-acoustic application is quite broad. The effectiveness of combined electric and acoustic stimulation as compared with electric stimulation alone was consistently demonstrated, highlighting the potential value of preservation and utilization of low frequency hearing in the implanted ear. However, clinical procedures for best fitting of electric-acoustic devices were varied. This clearly identified a need for further investigation of fitting procedures aimed at maximizing outcomes for recipients of electric-acoustic devices. PMID:23539259

  16. Factors stimulating bone formation.

    PubMed

    Lind, M; Bünger, C

    2001-10-01

    The aim of this review is to describe major approaches for stimulating bone healing and to review other factors affecting bone healing. Spinal bone fusion after surgery is a demanding process requiring optimal conditions for clinical success. Bone formation and healing can be enhanced through various methods. Experimental studies have revealed an array of stimulative measures. These include biochemical stimulation by use of hormones and growth factors, physical stimulation through mechanical and electromagnetic measures, and bone grafting by use of bone tissue or bone substitutes. Newer biological techniques such as stem cell transplantation and gene therapy can also be used to stimulate bone healing. Apart from bone transplantation, clinical experience with the many stimulation modalities is limited. Possible areas for clinical use of these novel methods are discussed.

  17. Multisensory Stimulation in Stroke Rehabilitation

    PubMed Central

    Johansson, Barbro Birgitta

    2012-01-01

    The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, and various kinds of music therapy. Non-invasive brain stimulation has showed promising preliminary results in aphasia and neglect. Patient heterogeneity and the interaction of age, gender, genes, and environment are discussed. Randomized controlled longitudinal trials starting earlier post-stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation. It is proposed that we should pay more attention to age, gender, and laterality in clinical studies. PMID:22509159

  18. Multisensory stimulation in stroke rehabilitation.

    PubMed

    Johansson, Barbro Birgitta

    2012-01-01

    The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, and various kinds of music therapy. Non-invasive brain stimulation has showed promising preliminary results in aphasia and neglect. Patient heterogeneity and the interaction of age, gender, genes, and environment are discussed. Randomized controlled longitudinal trials starting earlier post-stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation. It is proposed that we should pay more attention to age, gender, and laterality in clinical studies.

  19. PIM1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

    DTIC Science & Technology

    2008-10-31

    CA 92S54. USA "Department of Biochemistry and Microbiology. Ijjma Linda University School of Medicine. Ijima Undo. CA 92354. USA ’Department of...372-378, 1987. 13. Devlin J, Devlin P, Myambo K, Lilly M, Rado T, Warren K: Isolation and expression of a cDNA encoding a human granulcyte colony...stimulating factor. J Leukocyte Biol 41:302-306, 1987. 14. Lilly M, Devlin J, Devlin P, Rado T: Production of granulocyte colony-stimulating factor by

  20. Effects of Sensory Modality Stimulation on the Dysarthria of Cerebral Palsy.

    ERIC Educational Resources Information Center

    Love, Russel J.

    To explore the efficacy of improving the dysarthria of cerebral palsy under conditions of aural stimulation, visual stimulation, and combined aural-visual stimulation, 22 subjects (aged 7.6 to 19.0 years) received intensive stimulation for word limitation for 22 consecutive school days. The 87 words of the Irwin Integrated Articulation Test were…

  1. Rhodamine123 reveals heterogeneity within murine Lin-, Sca-1+ hemopoietic stem cells

    PubMed Central

    1992-01-01

    Murine bone marrow Lin-, Ly6A/E+ cells have been fractionated on the basis of rhodamine123 retention into Rh123med/hi and Rh123lo subpopulations. These populations have different responses to hemopoietic growth factors with respect to in vitro colony formation. Cells from either fraction were not stimulated by only granulocyte- colony-stimulating factor (G-CSF), granulocyte/macrophage colony- stimulating factor (GM-CSF), macrophage colony-stimulating factor (M- CSF), interleukins 1 and 6 (IL-1 and -6), or leukemia inhibitory factor (LIF) alone. The Rh123med/hi, but not the Rh123lo fraction, contained cells that could be stimulated by either stem cell factor (SCF) or IL-3 alone. When combinations of growth factors were added, the Rh123med/hi fraction produced more colonies, and responded to a wider range of factor combinations than the Rh123lo population. When tested in vivo, both populations contained no detectable day 8 colony-forming unit- spleen (CFU-S), and similar frequencies of day 13 CFU-S. When transplanted into lethally irradiated recipients (100 cells/recipient), significant numbers of donor cells (67-73%) were found in the peripheral blood of Rh123lo recipients. Both myeloid and lymphoid cells were of donor origin. By comparison, the Rh123med/hi population produced recipients with 1-2% donor cells in peripheral blood, the majority of which were lymphoid. PMID:1375260

  2. Motor cortex inhibition induced by acoustic stimulation.

    PubMed

    Kühn, Andrea A; Sharott, Andrew; Trottenberg, Thomas; Kupsch, Andreas; Brown, Peter

    2004-09-01

    The influence of the brainstem motor system on cerebral motor areas may play an important role in motor control in health and disease. A new approach to investigate this interaction in man is combining acoustic stimulation activating the startle system with transcranial magnetic stimulation (TMS) over the motor cortex. However, it is unclear whether the inhibition of TMS responses following acoustic stimulation occurs at the level of the motor cortex through reticulo-cortical projections or subcortically, perhaps through reticulo-spinal projections. We compared the influence of acoustic stimulation on motor effects elicited by TMS over motor cortical areas to those evoked with subcortical electrical stimulation (SES) through depth electrodes in five patients treated with deep brain stimulation for Parkinson's disease. SES bypasses the motor cortex, demonstrating any interaction with acoustic stimuli at the subcortical level. EMG was recorded from the contralateral biceps brachii muscle. Acoustic stimulation was delivered binaurally through headphones and used as a conditioning stimulus at an interstimulus interval of 50 ms. When TMS was used as the test stimulus, the area and amplitude of the conditioned motor response was significantly inhibited (area: 57.5+/-12.9%, amplitude: 47.9+/-7.4%, as percentage of unconditioned response) whereas facilitation occurred with SES (area: 110.1+/-4.3%, amplitude: 116.9+/-6.9%). We conclude that a startle-evoked activation of reticulo-cortical projections transiently inhibits the motor cortex.

  3. Music acupuncture stimulation method.

    PubMed

    Brătilă, F; Moldovan, C

    2007-01-01

    Harmonic Medicine is the model using the theory that the body rhythms synchronize to an outer rhythm applied for therapeutic purpose, can restores the energy balance in acupuncture channels and organs and the condition of well-being. The purpose of this scientific work was to demonstrate the role played by harmonic sounds in the stimulation of the Lung (LU) Meridian (Shoutaiyin Feijing) and of the Kidney (KI) Meridian (Zushaoyin Shenjing). It was used an original method that included: measurement and electronic sound stimulation of the Meridian Entry Point, measurement of Meridian Exit Point, computer data processing, bio feed-back adjustment of the music stimulation parameters. After data processing, it was found that the sound stimulation of the Lung Meridian Frequency is optimal between 122 Hz and 128 Hz, with an average of 124 Hz (87% of the subjects) and for Kidney Meridian from 118 Hz to 121 Hz, with an average of 120 Hz (67% of the subjects). The acupuncture stimulation was more intense for female subjects (> 7%) than for the male ones. We preliminarily consider that an informational resonance phenomenon can be developed between the acupuncture music stimulation frequency and the cellular dipole frequency, being a really "resonant frequency signature" of an acupoint. The harmonic generation and the electronic excitation or low-excitation status of an acupuncture point may be considered as a resonance mechanism. By this kind of acupunctural stimulation, a symphony may act and play a healer role.

  4. Stimulants for the Control of Hedonic Appetite

    PubMed Central

    Poulton, Alison S.; Hibbert, Emily J.; Champion, Bernard L.; Nanan, Ralph K. H.

    2016-01-01

    The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug. PMID:27199749

  5. Stimulants for the Control of Hedonic Appetite.

    PubMed

    Poulton, Alison S; Hibbert, Emily J; Champion, Bernard L; Nanan, Ralph K H

    2016-01-01

    The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug.

  6. Combined treatment of amyloid-β₁₋₄₂-stimulated bone marrow-derived dendritic cells plus splenocytes from young mice prevents the development of Alzheimer's disease in APPswe/PSENldE9 mice.

    PubMed

    Wang, Fei; Liu, Hanqiu; Shen, Xueyan; Ao, Hong; Moore, Nick; Gao, Lingling; Chen, Long; Hu, Heng; Ma, Huiying; Yang, Zixiao; Zhai, Chunxiao; Qin, Jie; Zhou, Guomin; Peng, Yuwen; Feng, Xiaoyuan; Li, Ruixi; Liang, Chunmin

    2015-01-01

    Anti-amyloid-β (Aβ) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aβ immunotherapy. In this study, a combined treatment of Aβ₁₋₄₂-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aβ antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aβ plaques. In conclusion, the Aβ₁₋₄₂-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.

  7. 5-Androstene-3{beta},17{beta}-diol Promotes Recovery of Immature Hematopoietic Cells Following Myelosuppressive Radiation and Synergizes With Thrombopoietin

    SciTech Connect

    Aerts-Kaya, Fatima S.F.; Visser, Trudi P.; Arshad, Shazia; Frincke, James; Stickney, Dwight R.; Reading, Chris L.; Wagemaker, Gerard

    2012-11-01

    Purpose: 5-Androstene-3{beta},17{beta}-diol (5-AED) stimulates recovery of hematopoiesis after exposure to radiation. To elucidate its cellular targets, the effects of 5-AED alone and in combination with (pegylated) granulocyte colony-stimulating factor and thrombopoietin (TPO) on immature hematopoietic progenitor cells were evaluated following total body irradiation. Methods and Materials: BALB/c mice were exposed to radiation delivered as a single or as a fractionated dose, and recovery of bone marrow progenitors and peripheral blood parameters was assessed. Results: BALB/c mice treated with 5-AED displayed accelerated multilineage blood cell recovery and elevated bone marrow (BM) cellularity and numbers of progenitor cells. The spleen colony-forming unit (CFU-S) assay, representing the life-saving short-term repopulating cells in BM of irradiated donor mice revealed that combined treatment with 5-AED plus TPO resulted in a 20.1-fold increase in CFU-S relative to that of placebo controls, and a 3.7 and 3.1-fold increase in comparison to 5-AED and TPO, whereas no effect was seen of Peg-G-CSF with or without 5-AED. Contrary to TPO, 5-AED also stimulated reconstitution of the more immature marrow repopulating (MRA) cells. Conclusions: 5-AED potently counteracts the hematopoietic effects of radiation-induced myelosuppression and promotes multilineage reconstitution by stimulating immature bone marrow cells in a pattern distinct from, but synergistic with TPO.

  8. Two cases of incidental Podostroma cornu-damae poisoning

    PubMed Central

    Kim, Hee Nyung; Do, Han Ho; Seo, Jun Seok; Kim, Hee Young

    2016-01-01

    Podostroma cornu-damae is a rare, deadly fungus. However, it can be easily mistaken for antler Ganoderma lucidum. In this case report, two patients made tea with the fungus and drank it over a 2-week period. Both patients presented with bicytopenia, and one patient had desquamation of the palms and soles. Both were treated with prophylactic antibiotics and granulocyte colony-stimulating factor. One patient was admitted to the intensive care unit and received a platelet transfusion. Both patients were discharged without complications. Podostroma cornu-damae infections caused by intoxication were successfully treated using our treatment strategy, which consisted of prophylactic antibiotics, platelet transfusion, and granulocyte colony-stimulating factor. We believe this report can guide future treatment. PMID:27752639

  9. RasGRP1 Transgenic Mice Develop Cutaneous Squamous Cell Carcinomas in Response to Skin Wounding

    PubMed Central

    Diez, Federico R.; Garrido, Ann A.; Sharma, Amrish; Luke, Courtney T.; Stone, James C.; Dower, Nancy A.; Cline, J. Mark; Lorenzo, Patricia S.

    2009-01-01

    Models of epidermal carcinogenesis have demonstrated that Ras is a critical molecule involved in tumor initiation and progression. Previously, we have shown that RasGRP1 increases the susceptibility of mice to skin tumorigenesis when overexpressed in the epidermis by a transgenic approach, related to its ability to activate Ras. Moreover, RasGRP1 transgenic mice develop spontaneous papillomas and cutaneous squamous cell carcinomas, some of which appear to originate in sites of injury, suggesting that RasGRP1 may be responding to signals generated during the wound-healing process. In this study, we examined the response of the RasGRP1 transgenic animals to full-thickness incision wounding of the skin, and demonstrated that they respond by developing tumors along the wounded site. The tumors did not present mutations in the H-ras gene, but Rasgrp1 transgene dosage correlated with tumor susceptibility and size. Analysis of serum cytokines showed increased levels of granulocyte colony-stimulating factor in transgenic animals after wounding. Furthermore, in vitro experiments with primary keratinocytes showed that granulocyte colony-stimulating factor stimulated Ras activation, although RasGRP1 was dispensable for this effect. Since granulocyte colony-stimulating factor has been recently associated with proliferation of skin cancer cells, our results may help in the elucidation of pathways that activate Ras in the epidermis during tumorigenesis in the absence of oncogenic ras mutations. PMID:19497993

  10. Vagus Nerve Stimulation.

    PubMed

    Howland, Robert H

    2014-06-01

    The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality.

  11. Vagus Nerve Stimulation

    PubMed Central

    Howland, Robert H.

    2014-01-01

    The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality. PMID:24834378

  12. Gel microdrop technology for rapid isolation of rare and high producer cells.

    PubMed

    Weaver, J C; McGrath, P; Adams, S

    1997-05-01

    Secreted proteins are a therapeutic cornerstone of the biotechnology industry, and numerous recombinant products, including human growth hormone, human erythropoietin and granulocyte-colony stimulating factor, are now widely prescribed. In addition to bioprocessing applications, GMD technology should benefit the emerging fields of cellular and gene therapy. The ability to assess rapidly and precisely the productivity of cells for ex vivo cell screening and expansion is a unique approach with numerous research and therapeutic uses.

  13. Refractory Adult Primary Autoimmune Neutropenia that Responded to Alemtuzumab.

    PubMed

    Neerukonda, Anu R; Lan, Fengshuo; Gabig, Theodore; Saraya, Takeshi

    2016-01-01

    Primary autoimmune neutropenia (P-AIN) is an extremely rare disease. The most effective treatment for primary P-AIN is a granulocyte colony-stimulating factor; however, no curative treatment has been reported. We herein report a case of an adult P-AIN patient with a relatively mild medical history (irrespective of the severe neutropenia) who showed a sustained hematological response over seventeen months after the initiation of treatment with subcutaneous Alemtuzumab.

  14. Muscle Stimulation Technology

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Under a Goddard Space Flight Center contract, Electrologic of America was able to refine the process of densely packing circuitry on personal computer boards, providing significant contributions to the closed-loop systems for the Remote Manipulator System Simulator. The microcircuitry work was then applied to the StimMaster FES Ergometer, an exercise device used to stimulate muscles suffering from paralysis. The electrical stimulation equipment was developed exclusively for V-Care Health Systems, Inc. Product still commercially available as of March 2002.

  15. New York Canyon Stimulation

    SciTech Connect

    Raemy, Bernard

    2012-06-21

    The New York Canyon Stimulation Project was to demonstrate the commercial application of Enhanced Geothermal System techniques in Buena Vista Valley area of Pershing County, Nevada. From October 2009 to early 2012, TGP Development Company aggressively implemented Phase I of Pre-Stimulation and Site/Wellbore readiness. This included: geological studies; water studies and analyses and procurement of initial permits for drilling. Oversubscription of water rights and lack of water needed for implementation of EGS were identified and remained primary obstacles. Despite extended efforts to find alternative solutions, the water supply circumstances could not be overcome and led TGP to determine a "No Go" decision and initiate project termination in April 2012.

  16. Non-invasive neuromuscular electrical stimulation in patients with central nervous system lesions: an educational review.

    PubMed

    Schuhfried, Othmar; Crevenna, Richard; Fialka-Moser, Veronika; Paternostro-Sluga, Tatjana

    2012-02-01

    The aim of this educational review is to provide an overview of the clinical application of transcutaneous electrical stimulation of the extremities in patients with upper motor neurone lesions. In general two methods of electrical stimulation can be distinguished: (i) therapeutic electrical stimulation, and (ii) functional electrical stimulation. Therapeutic electrical stimulation improves neuromuscular functional condition by strengthening muscles, increasing motor control, reducing spasticity, decreasing pain and increasing range of motion. Transcutaneous electrical stimulation may be used for neuromuscular electrical stimulation inducing repetitive muscle contraction, electromyography-triggered neuromuscular electrical stimulation, position-triggered electrical stimulation and subsensory or sensory transcutaneous electric stimulation. Functional electrical stimulation provokes muscle contraction and thereby produces a functionally useful movement during stimulation. In patients with spinal cord injuries or stroke, electrical upper limb neuroprostheses are applied to enhance upper limb and hand function, and electrical lower limb neuroprostheses are applied for restoration of standing and walking. For example, a dropped foot stimulator is used to trigger ankle dorsiflexion to restore gait function. A review of the literature and clinical experience of the use of therapeutic electrical stimulation as well as of functional electrical sti