Recombination suppression at the dominant Rhg1/Rfs2 locus underlying soybean resistance to the cyst nematode.

Science.gov (United States)

Afzal, Ahmed J; Srour, Ali; Saini, Navinder; Hemmati, Naghmeh; El Shemy, Hany A; Lightfoot, David A

2012-04-01

Host resistance to "yellow dwarf" or "moonlight" disease cause by any population (Hg type) of Heterodera glycines I., the soybean cyst nematode (SCN), requires a functional allele at rhg1. The host resistance encoded appears to mimic an apoptotic response in the giant cells formed at the nematode feeding site about 24-48 h after nematode feeding commences. Little is known about how the host response to infection is mediated but a linked set of 3 genes has been identified within the rhg1 locus. This study aimed to identify the role of the genes within the locus that includes a receptor-like kinase (RLK), a laccase and an ion antiporter. Used were near isogeneic lines (NILs) that contrasted at their rhg1 alleles, gene-based markers, and a new Hg type 0 and new recombination events. A syntenic gene cluster on Lg B1 was found. The effectiveness of SNP probes from the RLK for distinguishing homolog sequence variants on LgB1 from alleles at the rhg1 locus on LgG was shown. The resistant allele of the rhg1 locus was shown to be dominant in NILs. None of the recombination events were within the cluster of the three candidate genes. Finally, rhg1 was shown to reduce the plant root development. A model for rhg1 as a dominant multi-gene resistance locus based on the developmental control was inferred.

Effect of filgrastim (recombinant human granulocyte colony stimulating factor) on IgE responses in human asthma: a case study.

Science.gov (United States)

Smith-Norowitz, Tamar A; Joks, Rauno; Norowitz, Kevin B; Chice, Seto; Durkin, Helen G; Bluth, Martin H

2013-10-01

The role of peripheral blood progenitor cell mobilization on Immunoglobulin E (IgE) responses has not been studied. Distributions of blood lymphocytes (CD4+, CD8+, CD8+CD60+, CD19+, CD23+, CD16/56+, CD25, CD45RA+, CD45RO+, CD34+), and levels of serum immunoglobulins (IgM, IgG, IgA, IgE) were studied in an allergic asthmatic serum IgE+ (181IU/mL) adult (m/45 y/o) donor undergoing routine stem cell mobilization protocol (American Society of Hematology) before (day-30), during (day 4), and after (1 wk post last dose) filgrastim (subcutaneous, 480 mcg, 2qd) treatment (flow cytometry, nephelometry, UniCAP Total IgE Fluoro enzyme immunoassay). On day 4 of filgrastim treatment, numbers of CD8+CD60+T cells and CD23+ blood cells dramatically increased (98% and 240% respectively) compared with pre treatment. In contrast on day 4 of treatment, serum IgE levels decreased (>50%) compared with pre treatment. CD8+CD60+T cells and CD23+ blood cells and serum IgE levels approached pre-treatment levels at 1 week post treatment. Filgrastim treatment transiently increases numbers of CD8+CD60+T and CD23+ expressing cells, which are known to regulate human IgE responses, while also transiently suppressing ongoing IgE responses. These results suggest that filgrastim affects IgE related responses, and may be useful in modulating allergic responses. Copyright © 2013 Elsevier Ltd. All rights reserved.

Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia

International Nuclear Information System (INIS)

Kamioner, Didier; Fruehauf, Stefan; Maloisel, Fréderic; Cals, Laurent; Lepretre, Stéphane; Berthou, Christian

2013-01-01

Nivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen ® . Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of Nivestim™ for the prevention and treatment of febrile neutropenia (FN) in patients treated with cytotoxic chemotherapy in general clinical practice. The NEXT (Tolérance de Nivestim chez les patiEnts traités par une chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE (VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der Behandlung malinger Erkrankungen) trials are multicentre, prospective, longitudinal, observational studies evaluating the safety profile of Nivestim™ in 'real-world’ clinical practice. Inclusion criteria include patients undergoing cytotoxic chemotherapy for malignancy and receiving Nivestim as primary or secondary prophylaxis (NEXT and VENICE), or as treatment for ongoing FN (NEXT only). In accordance with European Union pharmacovigilance guidelines, the primary objective is to evaluate the safety of Nivestim™ by gathering data on adverse events in all system organ classes. Secondary objectives include obtaining information on patient characteristics, efficacy of Nivestim™ therapy (including chemotherapy dose intensity), patterns of use of Nivestim™, and physician knowledge regarding filgrastim prescription and the reasons for choosing Nivestim™. Data will be gathered at three visits: 1. At the initial inclusion visit, 2. At a 1-month follow-up visit, and 3. At the end of chemotherapy. Recruitment for VENICE commenced in July 2011 and in November 2011 for NEXT. VENICE completed recruitment in July 2013 with

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

DEFF Research Database (Denmark)

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

2000-01-01

This randomized, placebo-controlled trial examine the long-term effect of granulocyte colony-stimulating factor (G-CSF) on absolute numbers of CD34+ progenitor cells and progenitor cell function in human immunodeficiency virus (HIV)-infected patients. G-CSF (300 microg filgrastim) or placebo was ...

Dgroup: DG01753 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available ocyte colony stimulating factor (G-CSF) ... D03235 ... Filgrastim (USAN/INN); Filgrastim (genetical recombination) (JP17); Filgrastim (gene...tical recombination) [Filgrastim biosimilar 1] (JAN); Filgrastim (genetical recombi...nation) [Filgrastim biosimilar 2] (JAN); Filgrastim (genetical recombination) [Fi...lgrastim biosimilar3] (JAN) ... D03247 ... Lenograstim (USAN/INN); Lenograstim (genetical recombination) (JP17)... ... D06889 ... Pegfilgrastim (INN); Pegfilgrastim (genetical recombination) (JAN) ... D10242 ... Lipegfilgrastim

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

Science.gov (United States)

Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

Science.gov (United States)

Korkmaz, Serdal; Altuntas, Fevzi

2017-12-01

Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity.

Science.gov (United States)

Ifergan, Igal; Davidson, Todd S; Kebir, Hania; Xu, Dan; Palacios-Macapagal, Daphne; Cann, Jennifer; Rodgers, Jane M; Hunter, Zoe N; Pittet, Camille L; Beddow, Sara; Jones, Clare A; Prat, Alexandre; Sleeman, Matthew A; Miller, Stephen D

2017-11-01

In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα + myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Stevenson Matt D

2011-09-01

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

Prevention of chemotherapy-induced neutropenia with pegfilgrastim: pharmacokinetics and patient outcomes.

Science.gov (United States)

Yang, Bing-Bing; Savin, Michael A; Green, Michael

2012-01-01

Patients receiving cytotoxic chemotherapy are at risk for developing chemotherapy-induced neutropenia (CIN). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF) that stimulates the proliferation, differentiation and function of neutrophils, is approved for the prevention of CIN. To eliminate the burden of daily filgrastim injection, pegfilgrastim, a long-acting form of filgrastim, was developed by covalently attaching a 20-kDa polyethylene glycol molecule to filgrastim to increase molecular size and thus reduce renal elimination. Consequently, neutrophil-mediated clearance is the primary mechanism for pegfilgrastim elimination. Therefore, after a single pegfilgrastim injection following chemotherapy treatment, pegfilgrastim concentration is sustained during neutropenia and decreases with neutrophil recovery. Pegfilgrastim has received marketing authorization approval from many regions to reduce the incidence of CIN based on the similar efficacy and safety of a single injection of 6 mg of pegfilgrastim administered once per chemotherapy cycle and 10 to 11 daily injections of filgrastim at 5 µg/kg. The efficient self-regulating clearance of pegfilgrastim allows administration once per chemotherapy cycle, thereby providing a more convenient treatment regimen than filgrastim. Copyright © 2012 S. Karger AG, Basel.

G-CSF in solid tumor chemotherapy: a tailored regimen reduces febrile neutropenia, treatment delays and direct costs.

Science.gov (United States)

Tsavaris, Nicolas; Kosmas, Christos; Gouveris, Panagiotis; Vadiak, Maria; Dimitrakopoulos, Antonis; Karadima, Dimitra; Pagouni, Efterpi; Panagiotakopoulos, George; Tzima, Evanthia; Ispoglou, Sevasti; Sakelariou, Dimitris; Koufos, Christos

2004-02-01

Current guidelines do not recommend G-CSF for patients with risk factors for neutropenia. One-hundred patients undergoing chemotherapy were randomized to treatment with G-CSF at 5 Kg/kg for established febrile neutropenia (ANC <1000/microl) (Group A) or G-CSF at 263 Kg/day if ANC was 1500/microl or less on the day of the expected nadir, with the duration of treatment determined by the severity of neutropenia (Group B). The number of doses of G-CSF was similar in the two groups. There were 34 cases of febrile neutropenia in Group A, but none in Group B (p=0.0001). Hospital admission for febrile neutropenia, antibiotic use and delays in chemotherapy were all significantly more common in Group A. Total direct costs were estimated to be 66, 646 for Group A and 47, 119 for Group B. Tailoring treatment does not increase G-CSF use, but significantly reduces febrile neutropenia and treatment delays and lowers direct costs.

Inductive potential of recombinant human granulocyte colony-stimulating factor to mature neutrophils from X-irradiated human peripheral blood hematopoietic progenitor cells

International Nuclear Information System (INIS)

Katsumori, Takeo; Yoshino, Hironori; Hayashi, Masako; Takahashi, Kenji; Kashiwakura, Ikuo

2009-01-01

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been used for treatment of neutropenia. Filgrastim, Nartograstim, and Lenograstim are clinically available in Japan. However, the differences in potential benefit for radiation-induced disorder between these types of rhG-CSFs remain unknown. Therefore, the effects of three different types of rhG-CSFs on granulocyte progenitor cells and expansion of neutrophils from nonirradiated or 2 Gy X-irradiated human CD34 + hematopoietic progenitor cells were examined. For analysis of granulocyte colony-forming units (CFU-G) and a surviving fraction of CFU-G, nonirradiated or X-irradiated CD34 + cells were cultured in methylcellulose containing rhG-CSF. These cells were cultured in serum-free medium supplemented with rhG-CSF, and the expansion and characteristics of neutrophils were analyzed. All three types of rhG-CSFs increased the number of CFU-G in a dose-dependent manner; however, Lenograstim is superior to others because of CFU-G-derived colony formation at relatively low doses. The surviving fraction of CFU-G was independent of the types of rhG-CSFs. Expansion of neutrophils by rhG-CSF was largely attenuated by X-irradiation, though no significant difference in neutrophil number was observed between the three types of rhG-CSFs under both nonirradiation and X-irradiation conditions. In terms of functional characteristics of neutrophils, Lenograstim-induced neutrophils produced high levels of reactive oxygen species compared to Filgrastim, when rhG-CSF was applied to nonirradiated CD34 + cells. In conclusion, different types of rhG-CSFs lead to different effects when rhG-CSF is applied to nonirradiated CD34 + cells, though Filgrastim, Nartograstim, and Lenograstim show equal effects on X-irradiated CD34 + cells. (author)

Comparison of autologous cell therapy and granulocyte-colony stimulating factor (G-CSF) injection vs. G-CSF injection alone for the treatment of acute radiation syndrome in a non-human primate model

International Nuclear Information System (INIS)

Bertho, Jean-Marc; Frick, Johanna; Prat, Marie; Demarquay, Christelle; Dudoignon, Nicolas; Trompier, Francois; Gorin, Norbert-Claude; Thierry, Dominique; Gourmelon, Patrick

2005-01-01

Purpose: To compare the efficacy of autologous cell therapy after irradiation combined with granulocyte-colony stimulating factor (G-CSF) injections with G-CSF treatment alone in a heterogeneous model of irradiation representative of an accidental situation. Material and Methods: Non-human primates were irradiated at 8.7 Gy whole-body dose with the right arm shielded to receive 4.8 Gy. The first group of animals received G-CSF (lenograstim) injections starting 6 h after irradiation, and a second group received a combination of G-CSF (lenograstim) injections and autologous expanded hematopoietic cells. Animals were followed up for blood cell counts, circulating progenitors, and bone marrow cellularity. Results: No significant differences were seen between the two treatment groups, whatever the parameter observed: time to leukocyte or platelet recovery and duration and severity of aplasia. Conclusion: Our results indicated that identical recovery kinetic was observed when irradiated animals are treated with G-CSF independently of the reinjection of ex vivo expanded autologous hematopoietic cells. Thus G-CSF injections might be chosen as a first-line therapeutic strategy in the treatment of accidental acute radiation victims

Clinical significance of determination of changes of serum GM-CSF, CGRP levels after treatment in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Xu Lihua

2007-01-01

Objective: To explore the changes of serum GM-CSF and CGRP levels both before and after treatment in pediatric patients with bronchial asthma. Methods: Serum GM-CSF and CGRP levels were measured with RIA in 33 pediatric patients with bronchial asthma both before and after treatment as well as in 35 controls. Results: Before treatment, the serum GM-CSF levels was significantly higher in the patients than those in the controls (P 0.05). Conclusion: Abnormal high serum GM -CSF and low CGRP levels played important role in the pathogenesis of bronchial asthma in children. (authors)

Clinical significance of determination of changes of serum NO, NOS and GM-CSF levels after treatment in children with bronchopneumonia

International Nuclear Information System (INIS)

Li Hongmei

2007-01-01

Objective: To investigate the clinical significance of changes of serum NO, NOS and GM-CSF levels after treatment in children with bronchopneumonia. Methods: Serum GM-CSF levels were determined with RIA, and serum NO, NOS levels were determined with biochemical methods both before and after treatment in 48 children with bronehopneumonia as well as in 35 controls. Results: Before treatment the serum concentrations of NO, NOS and GM-CSF in the patients were significantly higher than those in controls (P 0.05). Conclusion: Detection of serum NO, NOS and GM-CSF levels were useful for assessment of therapeutic efficacy. (authors)

Clinical significance of measurement of serum hs-CRP, TNF-α and M-CSF levels after treatment in patients with periodontitis

International Nuclear Information System (INIS)

Zhang Yunming

2007-01-01

Objective: To explore the significance of changes of serum hs-CRP, TNF-α and M-CSF levels after treatment in patients with periodontitis. Methods: Serum TNF-α, M-CSF (with RIA), hs-CRP (with immuneturbitity method) levels were determined in 38 patients with periodontitis both before and after treatment as well as in 35 controls. Results: Before treatment, the serum hs-CRP, TNF-α and M-CSF levels were significantly higher in the patients than those in controls (P 0.05). Conclusion: Detection of serum hs-CRP, TNF-α and M-CSF levels might reflect the progress of disease in patients with periodontitis. (authors)

The receptor like kinase at Rhg1-a/Rfs2 caused pleiotropic resistance to sudden death syndrome and soybean cyst nematode as a transgene by altering signaling responses.

Science.gov (United States)

Srour, Ali; Afzal, Ahmed J; Blahut-Beatty, Laureen; Hemmati, Naghmeh; Simmonds, Daina H; Li, Wenbin; Liu, Miao; Town, Christopher D; Sharma, Hemlata; Arelli, Prakash; Lightfoot, David A

2012-08-02

Soybean (Glycine max (L. Merr.)) resistance to any population of Heterodera glycines (I.), or Fusarium virguliforme (Akoi, O'Donnell, Homma & Lattanzi) required a functional allele at Rhg1/Rfs2. H. glycines, the soybean cyst nematode (SCN) was an ancient, endemic, pest of soybean whereas F. virguliforme causal agent of sudden death syndrome (SDS), was a recent, regional, pest. This study examined the role of a receptor like kinase (RLK) GmRLK18-1 (gene model Glyma_18_02680 at 1,071 kbp on chromosome 18 of the genome sequence) within the Rhg1/Rfs2 locus in causing resistance to SCN and SDS. A BAC (B73p06) encompassing the Rhg1/Rfs2 locus was sequenced from a resistant cultivar and compared to the sequences of two susceptible cultivars from which 800 SNPs were found. Sequence alignments inferred that the resistance allele was an introgressed region of about 59 kbp at the center of which the GmRLK18-1 was the most polymorphic gene and encoded protein. Analyses were made of plants that were either heterozygous at, or transgenic (and so hemizygous at a new location) with, the resistance allele of GmRLK18-1. Those plants infested with either H. glycines or F. virguliforme showed that the allele for resistance was dominant. In the absence of Rhg4 the GmRLK18-1 was sufficient to confer nearly complete resistance to both root and leaf symptoms of SDS caused by F. virguliforme and provided partial resistance to three different populations of nematodes (mature female cysts were reduced by 30-50%). In the presence of Rhg4 the plants with the transgene were nearly classed as fully resistant to SCN (females reduced to 11% of the susceptible control) as well as SDS. A reduction in the rate of early seedling root development was also shown to be caused by the resistance allele of the GmRLK18-1. Field trials of transgenic plants showed an increase in foliar susceptibility to insect herbivory. The inference that soybean has adapted part of an existing pathogen recognition and

The receptor like kinase at Rhg1-a/Rfs2 caused pleiotropic resistance to sudden death syndrome and soybean cyst nematode as a transgene by altering signaling responses

Directory of Open Access Journals (Sweden)

Srour Ali

2012-08-01

Full Text Available Abstract Background Soybean (Glycine max (L. Merr. resistance to any population of Heterodera glycines (I., or Fusarium virguliforme (Akoi, O’Donnell, Homma & Lattanzi required a functional allele at Rhg1/Rfs2. H. glycines, the soybean cyst nematode (SCN was an ancient, endemic, pest of soybean whereas F. virguliforme causal agent of sudden death syndrome (SDS, was a recent, regional, pest. This study examined the role of a receptor like kinase (RLK GmRLK18-1 (gene model Glyma_18_02680 at 1,071 kbp on chromosome 18 of the genome sequence within the Rhg1/Rfs2 locus in causing resistance to SCN and SDS. Results A BAC (B73p06 encompassing the Rhg1/Rfs2 locus was sequenced from a resistant cultivar and compared to the sequences of two susceptible cultivars from which 800 SNPs were found. Sequence alignments inferred that the resistance allele was an introgressed region of about 59 kbp at the center of which the GmRLK18-1 was the most polymorphic gene and encoded protein. Analyses were made of plants that were either heterozygous at, or transgenic (and so hemizygous at a new location with, the resistance allele of GmRLK18-1. Those plants infested with either H. glycines or F. virguliforme showed that the allele for resistance was dominant. In the absence of Rhg4 the GmRLK18-1 was sufficient to confer nearly complete resistance to both root and leaf symptoms of SDS caused by F. virguliforme and provided partial resistance to three different populations of nematodes (mature female cysts were reduced by 30–50%. In the presence of Rhg4 the plants with the transgene were nearly classed as fully resistant to SCN (females reduced to 11% of the susceptible control as well as SDS. A reduction in the rate of early seedling root development was also shown to be caused by the resistance allele of the GmRLK18-1. Field trials of transgenic plants showed an increase in foliar susceptibility to insect herbivory. Conclusions The inference that soybean has

Clinical significance of measurement of changes in serum TNF-α and GM-CSF levels after treatment in children with bronchial asthma

International Nuclear Information System (INIS)

Liu Heng

2006-01-01

Objective: To study the clinical significance of the changes of levels of tumor necrosis factor-α (TNF-α) and granulocyte-macrophage colony stimulating factor (GM-CSF) after treatment in children with bronchial asthma. Methods: Serum TNF-α and GM-CSF levels were measured with RIA in 32 patients with bronchial asthma both before and after treatment as well as in 30 controls. Results: Before treatment the serum TNF-α and GM-CSF levels in patients were significantly higher than those in the controls (P 0.05 ). Conclusion: Changes of serum TNF-α and GM-CSF levels contents after treatment might be of prognostic importance in children with bronchial asthma. (authors)

The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis.

Science.gov (United States)

Li, Jie; Mo, Sien; Chen, Yang

2017-08-01

Evidence for the effect of granulocyte colony stimulating factor (G-CSF) on infertile women undergoing in vitro fertilization (IVF) remains inconsistent. This study aimed to evaluate the effectiveness of G-CSF on infertile women undergoing IVF. PubMed and EMBASE databases were searched before August 2016. Comparing the transvaginal perfusion of G-CSF and placebo or no treatment, the available studies were considered. The pooled risk ratio (RR) with 95% confidence intervals (CIs) was used in the analysis and six studies were included. Transvaginal perfusion of G-CSF was significantly associated with a higher clinical pregnancy rate versus the placebo (RR=1.563, 95%CI: 1.122, 2.176), especially for the Asian population. Among patients with a thin endometrium or repeated IVF failure, the implantation and biochemical pregnancy rates were also significantly increased in patients with the use of G-CSF (implantation rate: RR = 1.887, 95% CI: 1.256, 2.833; biochemical pregnancy rate: RR = 2.385, 95% CI: 1.414, 4.023). However, no statistical significance in increasing endometrial thickness was detected. Transvaginal perfusion of G-CSF for infertile women may play a critical role in assisting human reproduction, especially for patients with a thin endometrium or repeated IVF failure in the Asian population.

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.

Directory of Open Access Journals (Sweden)

Katrin Frauenknecht

Full Text Available 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.

G-CSF therapy with mobilization of bone marrow stem cells for myocardial recovery after acute myocardial infarction - a relevant treatment?

DEFF Research Database (Denmark)

Ripa, R.S.; Kastrup, J.

2008-01-01

-CSF treatment. Current controversies in interpretation of the results include 1) importance of direct cardiac effect of G-CSF vs indirect through bone marrow stem and progenitor cell mobilization, 2) importance of timing of G-CSF therapy, 3) importance of G-CSF dose, and 4) importance of cell types mobilized...... from the bone-marrow. Cell-based therapies to improve cardiac function remain promising and further experimental and clinical studies are warranted to determine the future role of G-CSF Udgivelsesdato: 2008/6......This review of adjunctive therapy with subcutaneous granulocyte-colony stimulating factor (G-CSF) to patients with acute myocardial infarction (AMI) focus on the cardioprotective effects and potential mechanisms of G-CSF and discuss the therapeutic potential of G-CSF. All clinical trials published...

Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

NARCIS (Netherlands)

Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

Clinical significance of determination of changes of serum IGF-II, GM-CSF and TNF-α levels after treatment in children with acute nephritis

International Nuclear Information System (INIS)

Xu Xiaoyan; Zhou Hong; Xu Weiqin; Li Xinghua

2008-01-01

Objective: To explore the clinical significance of determination of changes of serum IGF-II, GM-CSF and TNF- α levels after treatment in children with acute nephritis. Methods: Serum IGF-II, GM-CSF and TNF-α levels (with RIA) were measured in 31 pediatric patients with acute nephritis and 35 controls. Results: Before treatment, the serum IGF-II, GM-CSF and TNF-α levels in the patients were significantly higher than those in controls (P< O.01). After treatment for 3 months, the serum IGF-II, GM-CSF and TNF-α levels, though markedly corrected, remained significantly higher than those in controls (P<0.05). Conclusion: Determination of changes of serum IGF-II, GM-CSF and TNF-α contents after treatment might be of prognostic importance in pediatric patients with acute nephritis. (authors)

SEIFEM 2017: from real life to an agreement on the use of granulocyte transfusions and colony-stimulating factors for prophylaxis and treatment of infectious complications in patients with hematologic malignant disorders.

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Busca, Alessandro; Cesaro, Simone; Teofili, Luciana; Delia, Mario; Cattaneo, Chiara; Criscuolo, Marianna; Marchesi, Francesco; Fracchiolla, Nicola Stefano; Valentini, Caterina Giovanna; Farina, Francesca; Di Blasi, Roberta; Prezioso, Lucia; Spolzino, Angelica; Candoni, Anna; Del Principe, Maria Ilaria; Verga, Luisa; Nosari, Annamaria; Aversa, Franco; Pagano, Livio

2018-02-01

The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 10 8 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

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Holmgaard, Rikke B.; Brachfeld, Alexandra; Gasmi, Billel; Jones, David R.; Mattar, Marissa; Doman, Thompson; Murphy, Mary; Schaer, David; Wolchok, Jedd D.; Merghoub, Taha

2016-01-01

ABSTRACT Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy. Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number

Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF

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Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

2015-01-01

Background: Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3–5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Results: Motoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Conclusions: Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS. PMID:25653590

Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF.

Directory of Open Access Journals (Sweden)

Alexandre eHenriques

2015-01-01

Full Text Available ABSTRACTBackgroundAmyotrophic lateral sclerosis (ALS is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. ResultsMotoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age, when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age. Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12.ConclusionsOur data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

Gene expression changes in spinal motoneurons of the SOD1(G93A) transgenic model for ALS after treatment with G-CSF.

Science.gov (United States)

Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

2014-01-01

Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1(G93A) mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Motoneurons from SOD1(G93A) mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1(G93A) motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1(G93A) motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

Clinical significance of determination of changes of serum GM-CSF and platelet granular membrance protein (PGMP) contents after treatment in patients with cerebral infarction

International Nuclear Information System (INIS)

Zang Zhizhong; Pan Shengying; Tang Yong; Wang Jun

2006-01-01

Objective: To investigate the changes of serum GM-CSF and PGMP levels after treatment in patients with cerebral infarction. Methods: Serum GM-CSF and PGMP contents were measured with RIA in 36 patients with cerebral infarction both before and after treatment as well as in 30 controls. Results: Before treatment, the serum GM-CSF and PGMP levels in the patients were significantly higher than those in the controls (P<0.01). After 6 months' treatment, the levels (though dropped markedly), remained significantly higher (P<0.05). Conclusion: Serum GM-CSF and PGMP levels might be of prognostic value in patients with cerebral infarction. (authors)

Clinical significance of determination of changes of serum GM-CSF, IL-8, IL-6 levels after treatment in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Xue Hongfeng

2006-01-01

Objective: To investigate the changes of serum GM-CSF, IL-8 and IL-6 levels both before and after treatment in pediatric patients with bronchial asthma. Methods: Serum GM-CSF, IL-8 and IL-6 levels were measured with RIA in 32 pediatric patients with bronchial asthma both before and after treatment as well as in 30 controls. Results: Before treatment, the serum GM-CSF, IL-8, IL-6 levels were significantly higher in the patients than those in the controls (P 0.05). Conclusion: Abnormal high serum GM-CSF, IL-8, IL-6 levels played important role in the pathogenesis of bronchial asthma in children. (authors)

CSF LACTATE IN MENINGITIS

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Anjampakuthikal Aboobekar Haris

2017-05-01

Full Text Available BACKGROUND Meningitis is an infection within the subarachnoid space characterised by a CNS inflammatory reaction. It is a serious condition requiring immediate diagnosis and appropriate treatment to be started at the earliest to prevent mortality as well as irreversible neurological deficits. CSF lactate has been found useful in differentiating bacterial meningitis from viral meningitis in many studies in the western population, but studies in Indian population are limited. The aim of the study is to study whether CSF lactate can be used to distinguish bacterial from viral meningitis and to study the levels of CSF lactate in tuberculosis meningitis. MATERIALS AND METHODS This was a descriptive study conducted in a tertiary care hospital. In this study, 78 cases of meningitis were selected. Cases are patients with bacterial, viral or tuberculosis meningitis admitted to the hospital under the Department of Medicine and Neurology. Cases are grouped into bacterial, viral and tuberculosis meningitis based on clinical picture, CSF analysis and imaging characteristics. CSF lactate estimation was done by dry chemistry method. Using appropriate statistical methods and SPSS software, CSF lactate levels were compared among these groups and analysed for any association with the final outcome. RESULTS The levels of CSF lactate in bacterial meningitis were higher than viral meningitis with a statistical significance of p 35 mg/dL for bacterial meningitis in this study was 95% and 100% respectively and the positive predictive value was 100% and the negative predictive value was 96%. The mean CSF lactate values in bacterial, viral and tuberculosis meningitis were 124.40 ± 35.85 mg/dL, 24.34 ± 6.05 mg/dL and 50.13 ± 9.89 mg/dL, respectively. CONCLUSION CSF lactate level was significantly elevated in bacterial meningitis than tuberculosis or viral meningitis and can be used as a marker for differentiating bacterial from viral meningitis.

Treatment of extremely severe acute hemopoietic radiation sickness beagles with RhG-CSF and RhIL-11

International Nuclear Information System (INIS)

Zhao Jianzhi; Zhang Ri; Li Ming; Xing Shuang; Luo Qingliang; Zhang Xueguang; Miao Jingcheng; Zhu Nankang

2010-01-01

Objective: To evaluate the effects of treatment combined recombinant human G-CSF (rhG-CSF) and recombinant human interleukin-11 (rhIL-11) on severe acute hemopoietic radiation sickness (ARS) beagles. Methods: Beagles were irradiated with 4.5 Gy 60 Co γ-ray to establish ARS models, and animals were divided into the irradiated control group and the supportive care and combined cytokines treatment cohort. After irradiation the irradiated control beagles was given no treatment, the supportive care beagles received purely symptomatic treatment including blood transfusion and anti-infection while the combined cytokines treatment beagles received rhG-CSF and rhIL-11 subcutaneously for three weeks besides symptomatic treatment.Results After irradiation, all kinds of cells' population declined sharply, but rebounded to normal basically in the combined cytokines treatment rate in the cohort. The mean blood transfusion volume of cytokines in the cohort and the period of blood transfusion all were less than those in the supportive care cohort (P<0.01). The period of administrated antibiotic of cytokines in the cohort was shorter than that in the supportive care cohort (P<0.05). In the observe period of 45 d, survival rate in the irradiated controls cohort was 0%, in the supportive care cohort was 80%, and in the combined cytokines treatment cohort was 100%(P<0.01). Conclusion: Administration of rhG-CSF and rhIL-11 early after irradiation and continued daily, in combined with supportive care in severe acute hemopoietic radiation sickness beagles can improve hematopoietic function restoration, stimulate blood cells to restore to the normal level quickly, significantly decrease the reguired volume of blood transfusion, shorten the period of anti-infection and increase survival of irradiated canines. (authors)

[Endonasal endoscopic surgery in the treatment of spontaneous or post-traumatic cerebrospinal fluid (csf) leaks].

Science.gov (United States)

Nallet, E; Decq, P; Bezzo, A; Le Lievre, G; Peynegre, R; Coste, A

1998-10-01

The incidence and the risk of meningitidis justify treatment in all cases of cerebrospinal fluid rhinorrhea with spontaneous etiology or after traumatic injury. Endonasal surgery with endoscopic instruments provides many advantages compared with transcranial or transfacial approach used by neurosurgeons. We report our experience and our surgical technique in the treatment of CSF leaks in 5 patients. Intrathecal injection of fluoresceine was very useful in all cases for detecting the CSF leak. Total or selected ethmoidectomy depended on the localization of the leakage. Wide sphenoidotomy enables detection and repair of CSF leaks from the sphenoid cavity. A free graft of inferior turbinal mucosal was used to repair the breache. This rapid low morbidity surgery offered secure closure of rhinorrhea in 4 cases after one procedure and in 1 case after two procedures with an average follow up of 22 months. Cerebrospinal fluid rhinorrhea can be managed in first line therapy with endoscopic intranasal surgical techniques when they are localized in the anterior ethmoid or in the sphenoid cavity.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.

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Aapro, M S; Bohlius, J; Cameron, D A; Dal Lago, Lissandra; Donnelly, J Peter; Kearney, N; Lyman, G H; Pettengell, R; Tjan-Heijnen, V C; Walewski, J; Weber, Damien C; Zielinski, C

2011-01-01

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention

G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells.

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Brunner, Stefan; Huber, Bruno C; Fischer, Rebekka; Groebner, Michael; Hacker, Marcus; David, Robert; Zaruba, Marc-Michael; Vallaster, Marcus; Rischpler, Christoph; Wilke, Andrea; Gerbitz, Armin; Franz, Wolfgang-Michael

2008-06-01

Besides its classical function in the field of autologous and allogenic stem cell transplantation, granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI) by mobilization of bone marrow-derived progenitor cells (BMCs) and in addition by activation of multiple signaling pathways. In the present study, we focused on the impact of G-CSF on migration of BMCs and the impact on resident cardiac cells after MI. Mice (C57BL/6J) were sublethally irradiated, and BM from green fluorescent protein (GFP)-transgenic mice was transplanted. Coronary artery ligation was performed 10 weeks later. G-CSF (100 microg/kg) was daily injected for 6 days. Subpopulations of enhanced GFP(+) cells in peripheral blood, bone marrow, and heart were characterized by flow cytometry. Growth factor expression in the heart was analyzed by quantitative real-time polymerase chain reaction. Perfusion was investigated in vivo by gated single photon emission computed tomography (SPECT). G-CSF-treated animals revealed a reduced migration of c-kit(+) and CXCR-4(+) BMCs associated with decreased expression levels of the corresponding growth factors, namely stem cell factor and stromal-derived factor-1 alpha in ischemic myocardium. In contrast, the number of resident cardiac Sca-1(+) cells was significantly increased. However, SPECT-perfusion showed no differences in infarct size between G-CSF-treated and control animals 6 days after MI. Our study shows that G-CSF treatment after MI reduces migration capacity of BMCs into ischemic tissue, but increases the number of resident cardiac cells. To optimize homing capacity a combination of G-CSF with other agents may optimize cytokine therapy after MI.

Clinical significance of measurement of changes of serum hs-CRP, IL-6, IL-8 M-CSF levels after treatment in patients with endometriosis

International Nuclear Information System (INIS)

Chen Xiaochao; Zhou Dongxia; Zhang Limin; Liu Hongshu

2008-01-01

Objective: To explore the significance of changes of serum hs-CRP, IL-6, IL-8 and M-CSF levels after treatment in patients with endometriosis. Methods: Serum IL-6, IL-8, M -CSF(with RIA), hs-CRP(with immuneturbidity method)levels were determined in 33 patients with endometriosis both before and after treatment as well as in 35 controls. Results: Before treatment, the serum hs-CRP, IL-6, IL-8 and M-CSF levels were significantly higher in the patients than those in controls (P 0.05). Conclusion: Detection of serum hs-CRP, IL-6, IL-8 and M-CSF levels might reflect the progress of diseases in patients with endometriosis. (authors)

Epithelial GM-CSF induction by Candida glabrata.

Science.gov (United States)

Li, L; Dongari-Bagtzoglou, A

2009-08-01

The main cytokine induced by the interaction of oral epithelial cells with C. glabrata is granulocyte monocyte colony-stimulating factor (GM-CSF); however, the mechanisms regulating this response are unknown. Based on previously published information on the interactions of C. albicans with oral epithelial cells, we hypothesized that interaction with viable C. glabrata triggers GM-CSF synthesis via NF-kappaB activation. We found that C. glabrata-induced GM-CSF synthesis was adhesion-dependent, enhanced by endocytosis, and required fungal viability. NF-kappaB activation was noted during interaction of epithelial cells with C. glabrata, and pre-treatment with an NF-kappaB inhibitor partly inhibited GM-CSF synthesis. Blocking TLR4 with anti-TLR4 antibody did not inhibit GM-CSF production. In contrast, an anti-CDw17 antibody triggered significant inhibition of NF-kappaB activation and GM-CSF synthesis. beta-glucans did not stimulate GM-CSF synthesis, suggesting that the CDw17/NF-kappaB/GM-CSF pathway may be beta-glucan-independent. This study provides new insights into the mechanism of GM-CSF induction by C. glabrata.

DHAP plus filgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory lymphoma: A single center experience.

Science.gov (United States)

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Bag, Harika Gozukara; Nizam, Ilknur; Koroglu, Mustafa; Ozgul, Mustafa

2016-02-01

This study aimed to evaluate the efficiency of DHAP regimen plus filgrastim for mobilization of stem cells in patients with recurrent and/or refractory lymphoma. Thirty-four patients who took DHAP as salvage therapy prior to autologous stem cell transplantation were included. After chemotherapies, 2 cycles of DHAP plus filgrastim were administered to the patients. Stem cells from 32 patients (94%) were collected on median 11th day (8-12), and the median collected CD34(+) cell dose was 9.7 × 10(6)/kg (range 3.8-41.6). DHAP plus filgrastim was found to be an effective chemotherapy regimen in mobilizing CD34(+) stem cells into the peripheral. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clinical significance of determination of changes of serum IL-6, IL-10 and GM-CSF levels after treatment in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Qin Wenjing

2008-01-01

Objective: To explore the changes of Serum IL-6, IL-10 and GM-CSF levels after treatment in pediatric patients with bronchial asthma. Methods: Serum IL-6, IL-10 and GM-CSF levels were measured with RIA in 33 pediatric patients with bronchial asthma both before and after treatment as well as in 30 controls. Results: Before treatment, the serum IL-6, IL-10 and GM-CSF levels were significantly higher than those in controls (P 0.05). Conclusion: Detection of serum IL-6, IL-10 and GM-CSF levels were useful for assessment of therapeutic efficacy and were of important clinical values in pediatric patients with bronchial asthma. (authors)

Cost-savings for biosimilars in the United States: a theoretical framework and budget impact case study application using filgrastim.

Science.gov (United States)

Grewal, Simrun; Ramsey, Scott; Balu, Sanjeev; Carlson, Josh J

2018-05-18

Biosimilars can directly reduce the cost of treating patients for whom a reference biologic is indicated by offering a highly similar, lower priced alternative. We examine factors related to biosimilar regulatory approval, uptake, pricing, and financing and the potential impact on drug expenditures in the U.S. We developed a framework to illustrate how key factors including regulatory policies, provider and patient perception, pricing, and payer policies impact biosimilar cost-savings. Further, we developed a budget impact cost model to estimate savings from filgrastim biosimilars under various scenarios. The model uses publicly available data on disease incidence, treatment patterns, market share, and drug prices to estimate the cost-savings over a 5-year time horizon. We estimate five-year cost savings of $256 million, of which 18% ($47 million) are from reduced patient out-of-pocket costs, 34% ($86 million) are savings to commercial payers, and 48% ($123 million) are savings for Medicare. Additional scenarios demonstrate the impact of uncertain factors, including price, uptake, and financing policies. A variety or interrelated factors influence the development, uptake, and cost-savings for Biosimilars use in the U.S. The filgrastim case is a useful example that illustrates these factors and the potential magnitude of costs savings.

Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas.

Science.gov (United States)

Malhotra, Sandeep; Kim, Teresa; Zager, Jonathan; Bennett, Joseph; Ebright, Michael; D'Angelica, Michael; Fong, Yuman

2007-04-01

Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone. Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity. Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes. Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.

Clinical significance of determination of serum IL-2, IL-6 and GM-CSF levels after treatment in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Wang Zhuo; Sun Jin; Yao Li

2009-01-01

Objective: To explore the clinical significance of changes of serum IL-2, IL-6 and GM-CSF levels after treatment in pediatric patients with bronchial asthma. Methods: Serum levels of IL-2, IL-6 and GM-CSF were measured with RIA in 36 pediatric patients with bronchiol asthma and 30 controls. Results: Before treatment, the serum levels of IL-6, GM-CSF were significantly higher in the patients than those in controls (P 0.05), Serum IL-2 levels were negatively correlated with the IL-6 and GM-CSF levels (r=-0.5846, -0.6018, P<0.01). Conclusion: These cytokines participated in the pathogenesis of bronchial asthma in pediatric patients. Mornitoring the changes of their serum levels was helpful for the management of the diseases. (authors)

Molecular CsF 5 and CsF 2 +

KAUST Repository

Rogachev, Andrey Yu.; Miao, Mao-sheng; Merino, Gabriel; Hoffmann, Roald

2015-01-01

D5h star-like CsF5, formally isoelectronic with known XeF5− ion, is computed to be a local minimum on the potential energy surface of CsF5, surrounded by reasonably large activation energies for its exothermic decomposition to CsF+2 F2, or to CsF3 (three isomeric forms)+F2, or for rearrangement to a significantly more stable isomer, a classical Cs+ complex of F5−. Similarly the CsF2+ ion is computed to be metastable in two isomeric forms. In the more symmetrical structures of these molecules there is definite involvement in bonding of the formally core 5p levels of Cs.

Molecular CsF 5 and CsF 2 +

KAUST Repository

Rogachev, Andrey Yu.

2015-06-03

D5h star-like CsF5, formally isoelectronic with known XeF5− ion, is computed to be a local minimum on the potential energy surface of CsF5, surrounded by reasonably large activation energies for its exothermic decomposition to CsF+2 F2, or to CsF3 (three isomeric forms)+F2, or for rearrangement to a significantly more stable isomer, a classical Cs+ complex of F5−. Similarly the CsF2+ ion is computed to be metastable in two isomeric forms. In the more symmetrical structures of these molecules there is definite involvement in bonding of the formally core 5p levels of Cs.

Attenuative effects of G-CSF in radiation induced intestinal injury

International Nuclear Information System (INIS)

Kim, Joong Sun; Gong, Eun Ji; Kim, Sung Dae; Heo, Kyu; Ryoo, Seung Bum; Yang, Kwang Mo

2011-01-01

Granulocyte colony stimulating factor (G-CSF) has been reported to protect from radiationinduced myelosuppression. Growing evidence suggests that G-CSF also has many important non-hematopoietic functions in other tissues, including the intestine (Kim et al., 2010; Kim et al., 2011). However, little is known about the influence of G-CSF on intestinal injury. Examination 12 hours after radiation (5 Gy) revealed that the G-CSF treated mice were significantly protected from apoptosis of jejunal crypt, compared with radiation controls. G-CSF treatment attenuated intestinal morphological changes such as decreased survival crypt, the number of villi, villous shortening, crypt depth and length of basal lamina of 10 enterocytes compared with the radiation control 3.5 days after radiation (10 Gy). G-CSF attenuated the change of peripheral blood from radiation-induced myelosuppression and displayed attenuation of mortality in lethally-irradiated (10 Gy) mice. The present results support the suggestion that G-CSF administrated prior to radiation plays an important role in the survival of irradiated mice, possibly due to the protection of hematopoietic cells and intestinal stem cells against radiation. The results indicate that G-CSF protects from radiation-mediated intestinal damage and from hematopoietic injury. G-CSF treatment may be useful clinically in the prevention of injury following radiation.

A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes.

Science.gov (United States)

Bernell, P; Stenke, L; Wallvik, J; Hippe, E; Hast, R

1996-08-01

In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

A randomized, non-inferiority study comparing efficacy and safety of a single dose of pegfilgrastim versus daily filgrastim in pediatric patients after autologous peripheral blood stem cell transplant.

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Simone Cesaro

Full Text Available PURPOSE: To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT. METHODS: The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes. RESULTS: Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57 and 10.44 days (SD 2.44 in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days, fever of unknown origin (79% vs. 78%, proven infection (34% vs. 28%, mucositis (76% vs. 59%. After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3, 20 deaths were observed due to disease progression. CONCLUSIONS: We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation

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Sarrazin, Sandrine; Redelberger, David

2016-01-01

Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus. M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation. PMID:27811055

Intrasphenoidal encephalocele and spontaneous CSF rhinorrhoea.

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Daniilidis, J; Vlachtsis, K; Ferekidis, E; Dimitriadis, A

1999-12-01

Intrasphenoidal encephalocele is a rare clinical entity. In the international literature only 16 cases have been reported up today, with female predominance. Clinically they manifest at middle and advanced ages (40-67 years), when spontaneous CSF rhinorrhoea or recurrent meningitis occurs. We present our case, a 46 years old female, who had CSF rhinorrhoea from the right vestibule for 10 months. The diagnosis was based on the history and the high-resolution brain and skull base CT-scanning in conjunction with opaque fluid injection in the subarachnoidal space through a lumbar puncture. She was successfully treated with an operation, through an endonasal trans-ethmoid microendoscopic approach, using the Draf and Stammberger technique. We discuss the pathogenesis of the intrasphenoidal encephalocele, the existence of small occult defects in the skull base, which cause, at the middle and advanced ages, CSF fistula with spontaneous CSF rhinorrhoea and/or recurrent meningitis. Finally we emphasize the advantages of the endonasal surgical approach for the treatment of this condition.

Autocrine CSF-1 and CSF-1 Receptor Co-expression Promotes Renal Cell Carcinoma Growth

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Menke, Julia; Kriegsmann, Jörg; Schimanski, Carl Christoph; Schwartz, Melvin M.; Schwarting, Andreas; Kelley, Vicki R.

2011-01-01

Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Co-expression of the monocytic growth factor CSF-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and anti-apoptosis during regeneration of renal tubules. Here we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were co-expressed in RCC and TEC proximally adjacent to RCC. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and EGF signaling in RCC. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R and EGF expression in RCC. Further, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCC. PMID:22052465

Comparison of parathyroid hormone and G-CSF treatment after myocardial infarction on perfusion and stem cell homing.

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Huber, Bruno C; Fischer, Rebekka; Brunner, Stefan; Groebner, Michael; Rischpler, Christoph; Segeth, Alexander; Zaruba, Marc M; Wollenweber, Tim; Hacker, Marcus; Franz, Wolfgang-Michael

2010-05-01

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.

CHEMOTHERAPY-INDUCED NEUTROPENIA IN HIV POSITIVE PATIENTS WITH LYMPHOMA: COMPARISON OF PEGFILGRASTIM WITH DAILY FILGRASTIM ADMINISTRATION.

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Luciana Teofili

2012-01-01

Full Text Available

We retrospectively compared the incidence of neutropenia  in two groups of  HIV patients with lymphoma,  who underwent chemotherapy supported by once-per-cycle administration of pegfilgrastim or by daily subcutaneous injection of filgrastim, respectively. Our findings indicate that pegfilgrastim and filgastrim produce similar results in preventing both neutropenia and febrile neutropenia.

CHEMOTHERAPY-INDUCED NEUTROPENIA IN HIV POSITIVE PATIENTS WITH LYMPHOMA: COMPARISON OF PEGFILGRASTIM WITH DAILY FILGRASTIM ADMINISTRATION.

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Luciana Teofili

2012-10-01

Full Text Available We retrospectively compared the incidence of neutropenia  in two groups of  HIV patients with lymphoma,  who underwent chemotherapy supported by once-per-cycle administration of pegfilgrastim or by daily subcutaneous injection of filgrastim, respectively. Our findings indicate that pegfilgrastim and filgastrim produce similar results in preventing both neutropenia and febrile neutropenia.

Chemical meningitis related to intra-CSF liposomal cytarabine.

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Durand, Bénédicte; Zairi, Fahed; Boulanger, Thomas; Bonneterre, Jacques; Mortier, Laurent; Le Rhun, Emilie

2017-10-01

Therapeutic options of leptomeningeal metastases include intra-cerebrospinal fluid (CSF) chemotherapy. Among intra-CSF agents, liposomal cytarabine has advantages but can induce specific toxicities. A BRAF-V600E-mutated melanoma leptomeningeal metastases patient, treated by dabrafenib and liposomal cytarabine, presented after the first injection of liposomal cytarabine with hyperthermia and headaches. Despite sterile CSF/blood analyses, extended intravenous antibiotics were given and the second injection was delayed. The diagnosis of chemical meningitis was finally made. Dose reduction and appropriate symptomatic treatment permitted the administration of 15 injections of liposomal cytarabine combined with dabrafenib. A confirmation of the diagnosis of chemical meningitis is essential in order (1) not to delay intra-CSF or systemic chemotherapy or (2) to limit the administration of unnecessary but potentially toxic antibiotics.

GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression

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Gutschalk, Claudia M; Yanamandra, Archana K; Linde, Nina; Meides, Alice; Depner, Sofia; Mueller, Margareta M

2013-01-01

Granulocyte–macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion

CSF smear

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... this page: //medlineplus.gov/ency/article/003768.htm CSF smear To use the sharing features on this ... around the spinal cord and brain. Cerebrospinal fluid (CSF) protects the brain and spinal cord from injury. ...

Serum concentrations of GM-CSF and G-CSF correlate with the Th1/Th2 cytokine response in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection

DEFF Research Database (Denmark)

Moser, Claus; Jensen, Peter Østrup; Pressler, Tacjana

2005-01-01

mobilizing monocytes and PMNs from the bone marrow, GM-CSF, G-CSF and IL-3 select subsets of dendritic cells, which subsequently induce distinct Th responses. Therefore, the present study examines the correlation between the mobilizing cytokines in serum and the Th responses. The IFN-gamma and IL-4...... production by peripheral blood mononuclear cells, and the concentrations of GM-CSF and G-CSF in serum as well as lung function, were determined in 37 CF patients with and 6 CF patients without chronic P. aeruginosa lung infection. The GM-CSF/G-CSF ratio correlated both with the IFN-gamma production and good...... lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment....

Treatment of chemotherapy-induced neutropenia in a rat model by using multiple daily doses of oral administration of G-CSF-containing nanoparticles.

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Su, Fang-Yi; Chuang, Er-Yuan; Lin, Po-Yen; Chou, Yi-Chun; Chen, Chiung-Tong; Mi, Fwu-Long; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Lin, Kun-Ju; Sung, Hsing-Wen

2014-04-01

Chemotherapy-induced neutropenia often increases the likelihood of life-threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(γ-glutamic acid) conjugated with diethylene triamine pentaacetic acid (γPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of γPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

CSF analysis

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Cerebrospinal fluid analysis ... Analysis of CSF can help detect certain conditions and diseases. All of the following can be, but ... An abnormal CSF analysis result may be due to many different causes, ... Encephalitis (such as West Nile and Eastern Equine) Hepatic ...

Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.

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Li, Ge; Mayer, Cynthia L; Morelli, Daniel; Millard, Steven P; Raskind, Wendy H; Petrie, Eric C; Cherrier, Monique; Fagan, Anne M; Raskind, Murray A; Peskind, Elaine R

2017-09-19

To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ 42 , total tau, and p-tau 181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ 42 , total tau, and p-tau 181 , respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau 181 ( p = 0.003), where greater decreases from baseline in CSF p-tau 181 concentrations were associated with higher baseline LDL level for the simvastatin group. Simvastatin-related reductions in CSF p-tau 181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia. © 2017 American Academy of Neurology.

ATYPICAL CSF PICTURE IN VIRAL MENINGITIS HSV- TYPE-2

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Vikram

2016-05-01

Full Text Available INTRODUCTION Acute infections of nervous system are among the most important problems in medicine because early recognition, efficient decision making and rapid institution of therapy can be lifesaving. Making a clinical diagnosis of acute meningitis depends on the cornerstone of cerebrospinal fluid (CSF examination. We present a case with the above-mentioned difficulty and the approach involved in establishing the exact diagnosis and institution of appropriate treatment. CONCLUSION About findings in viral meningitis one should be careful while evaluating a CSF report so as to not make a mistaken diagnosis and delay treatment. The most important analysis in patients whose symptoms are consistent with herpes simplex meningitis is the detection of Herpes simplex Virus deoxy-ribo-nucleic acid (HSV-DNA in CSF with Polymerase Chain Reaction (PCR.

A novel combination treatment of armed oncolytic adenovirus expressing IL-12 and GM-CSF with radiotherapy in murine hepatocarcinoma

International Nuclear Information System (INIS)

Kim, Wonwoo; Seong, Jinsil; Oh, Hae-Jin; Koom, Woong-Sub; Choi, Kyung-Joo; Yun, Chae-Ok

2011-01-01

In this study, a novel combination treatment of armed oncolytic adenovirus expressing interleukin 12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiation was investigated for antitumor and antimetastatic effect in a murine hepatic cancer (HCa-I) model. Tumor bearing syngeneic mice were treated with radiation, armed oncolytic virus Ad-ΔE1Bmt7 (dB7) expressing both IL-12 and GM-CSF (armed dB7), or a combination of both. The adenovirus was administered by intratumoral injection 1 x 10 8 plaque forming units (PFU) per tumor in 50 μl of phosphate buffered saline (PBS) four times every other day. Tumor response to treatment was determined by a tumor growth delay assay. Metastatic potential was evaluated by a lung metastasis model. To understand the underlying mechanism, the level of apoptosis was examined as well as the change in microvessel density and expression of immunological markers: CD4+, CD8+ and Cd11c. The combination of armed dB7 and radiation resulted in significant growth delay of murine hepatic cancer, HCa-1, with an enhancement factor of 4.3. The combination treatment also resulted in significant suppression of lung metastasis. Increase of apoptosis level as well as decrease of microvessel density was shown in the combination treatment, suggesting an underlying mechanism for the enhancement of antitumor effect. Expression of immunological markers: CD4+, CD8+ and Cd11c also increased in the combination treatment. This study showed that a novel combination treatment of radiotherapy with armed oncolytic adenovirus expressing IL-12 and GM-CSF was effective in suppressing primary tumor growth. (author)

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part three: individual patient, complication algorithm and quality manage.

NARCIS (Netherlands)

Stinner, B.; Bauhofer, A.; Lorenz, W.; Rothmund, M.; Plaul, U.; Torossian, A.; Celik, I.; Sitter, H.; Koller, M.; Black, A.; Duda, D.; Encke, A.; Greger, B.; Goor, H. van; Hanisch, E.; Hesterberg, R.; Klose, K.J.; Lacaine, F.; Lorijn, R.H.; Margolis, C.; Neugebauer, E.; Nystrom, P.O.; Reemst, P.H.M.; Schein, M.; Solovera, J.

2001-01-01

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased

CSF-ctDNA SMSEQ Analysis to Tailor the Treatment of a Patient with Brain Metastases: A Case Report

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Wen-Tsung  Huang

2018-02-01

Full Text Available Brain metastases are the most common neurological complications of adult cancers, accounting for more than half of brain tumors. The incidence of brain metastases may be increasing due to improved detection of small lesions by advanced imaging technologies. Given the fast evolution of targeted and immunotherapy regimens, it is essential to serially assess brain malignancies during the disease course for disease monitoring and tailoring of the therapeutic management. For such serial and repetitive assessment, cerebrospinal fluid (CSF could be the biological fluid of choice to supplement cytology examination for the presence or absence of CNS malignancy, as well as provide extensive information on tumor mutational profile for personalization of treatment. The case described here emphasizes the importance of CSF-ctDNA analysis with the CellMax SMSEQ technology that led to treatment adjustment resulting in clinical remission of the patient.

G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses

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2013-01-01

Background Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo. Methods We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice. Results We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation. Conclusions Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF. PMID:24279871

Colony-stimulating factor (CSF) radioimmunoassay: detection of a CSF subclass stimulating macrophage production

International Nuclear Information System (INIS)

Stanley, E.R.

1979-01-01

Colony-stimulating factors (CSFs) stimulate the differentiation of immature precursor cells to mature granulocytes and macrophages. Purified 125 I-labeled murine L cell CSF has been used to develop a radioimmunoassay (RIA) that detects a subclass of CSFs that stimulates macrophage production. Murine CSF preparations that contain this subclass of CSF compete for all of the CSF binding sites on anti-L cell CSF antibody. With the exception of mouse serum, which can contain inhibitors of the bioassay, there is complete correspondence between activities determined by RIA and those determined by bioassay. The RIA is slightly more sensitive than the bioassay, detecting approximately 0.3 fmol of purified L cell CSF. It can also detect this subclass of CSF in chickens, rats, and humans. In the mouse, the subclass is distinguished from other CSFs by a murine cell bioassay dose-response curve in which 90% of the response occurs over a 10-fold (rather than a 100-fold) increase in concentration, by stimulating the formations of colonies contaning a high proportion of mononuclear (rather than granulocytic) cells, and by certain physical characteristics

Safety and Efficacy of Pegfilgrastim When Given Less Than 14 Days Before the Next Chemotherapy Cycle: Review of Every 14-Day Chemotherapy Regimen Containing 5-FU Continuous Infusion.

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Donkor, Kofi N; Selim, Julie H; Waworuntu, Ariani; Lewis, Kelsey

2017-10-01

Pegfilgrastim should not be given days from the next chemotherapy because of concerns for cytopenias. Some clinicians are prescribing pegfilgrastim to be given days in patients receiving 5-fluorouracil continuous infusion (5-FUCI) regimens. To determine the effectiveness and safety of pegfilgrastim administered days from the next chemotherapy in patients receiving 5-FUCI administered >46 hours. Single-institution retrospective cohort study of patients who received 5-FUCI administered >46 hours from June 2013 to December 2015. The unit of measurement was chemotherapy cycles. End points included the safety and efficacy of giving pegfilgrastim days from the next chemotherapy (Pegfilgrastim-Less-Than-14-Days-Group) and comparing that to pegfilgrastim given ≥14 days (Pegfilgrastim-More-Than-14-Days-Group), filgrastim only (Filgrastim-Group), and no colony stimulating factors (No-CSF-Group). Generalized estimating equations (GEEs) were used to compare mean absolute neutrophil count (ANC) and white blood cell count (WBC). Poisson regression models with GEE were used to estimate relative risk (RR) for neutropenia. There were no incidences of neutropenia, febrile neutropenia (FN), or hospitalizations for FN with the Pegfilgrastim-Less-Than-14-Days-Group. There was also a high mean ANC of 9.9 (5.7) × 10 9 /L. Mean ANC and WBC were statistically significantly less with the Filgrastim-Group, No-CSF-Group, and Pegfilgrastim-More-Than-14-Days-Group compared with the Pegfilgrastim-Less-Than-14-Days-Group. The Filgrastim-Group and the No-CSF-Group had a 32% (1.10-1.56, P = 0.002) and 8% (1.04-1.12, P Days-Group. The risk of incidence of neutropenia was the same with the Pegfilgrastim-More-Than-14-Days-Group and Pegfilgrastim-Less-Than-14-Days-Group (0.95-1.04, P = 0.821). This study shows a promising possibility that administering pegfilgrastim days from the next chemotherapy cycle could be a safe and effective practice. However, better controlled clinical trials are needed.

T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART

DEFF Research Database (Denmark)

Aladdin, H; Von Essen, M; Schjerling, P

2001-01-01

The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G-CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)-infected individuals...... with a CD4+ T-cell count CSF thrice weekly for 12 weeks (n = 6) or placebo (n = 5). An increase in the mean TRF lengths was observed in PBMC of patients on HAART after 24 weeks of treatment mainly owing to increased mean CD8+ T-cell TRF...... lengths. However, in the group of patients on HAART combined with G-CSF no changes of PBMC mean TRF length was observed during treatment or during 12 weeks of follow-up. The mean CD4+ T-cell TRF length did not change in any of the two groups. These results confirm that HAART induces mainly the lengthening...

Cine-MR imaging aqueductal CSF flow in normal pressure hydrocephalus syndrome before and after CSF shunt

International Nuclear Information System (INIS)

Mascalchi, M.; Arnetoli, G.; Inzitari, D.; Dal Pozzo, G.; Lolli, F.; Caramella, D.; Bartolozzi, C.

1993-01-01

Reproducibility of the aqueductal CSF signal intensity on a gradient echo cine-MR sequence exploiting through plane inflow enhancement was tested in 11 patients with normal or dilated ventricles. Seven patients with normal pressure hydrocephalus (NPH) syndrome were investigated with the sequence before and after CSF shunting. Two patients exhibiting central flow void within a hyperintense aqueductal CSF improved after surgery and the flow void disappeared after shunting. One patient with increased maximum and minimum aqueductal CSF signal as compared to 18 healthy controls also improved and the aqueductal CSF signal was considerably decreased after shunting. Three patients with aqueductal CSF values similar to those in the controls did not improve, notwithstanding their maximum aqueductal CSF signals decreasing slightly after shunting. No appreciable aqueductal CSF flow related enhancement consistent with non-communicating hydrocephalus was found in the last NPH patient who improved after surgery. Cine-MR with inflow technique yields a reproducible evaluation of flow-related aqueductal CSF signal changes which might help in identifying shunt responsive NPH patients. These are likely to be those with hyperdynamic aqueductal CSF or aqueductal obstruction. (orig.)

The influence of protein malnutrition on the production of GM-CSF and M-CSF by macrophages

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Dalila Cunha de Oliveira

Full Text Available ABSTRACT It is well established that protein malnutrition (PM impairs immune defenses and increases susceptibility to infection. Macrophages are cells that play a central role in innate immunity, constituting one of the first barriers against infections. Macrophages produce several soluble factors, including cytokines and growth factors, important to the immune response. Among those growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF and macrophage colony-stimulating factor (M-CSF. GM-CSF and M-CSF are important to monocyte and macrophage development and stimulation of the immune response process. Knowing the importance of GM-CSF and M-CSF, we sought to investigate the influence of PM on macrophage production of these growth factors. Two-month-old male BALB/c mice were subjected to PM with a low-protein diet (2% and compared to a control diet (12% mouse group. Nutritional status, hemogram and the number of peritoneal cells were evaluated. Additionally, peritoneal macrophages were cultured and the production of GM-CSF and M-CSF and mRNA expression were evaluated. To determine if PM altered macrophage production of GM-CSF and M-CSF, they were stimulated with TNF-α. The PM animals had anemia, leukopenia and a reduced number of peritoneal cells. The production of M-CSF was not different between groups; however, cells from PM animals, stimulated with or without TNF-α, presented reduced capability to produce GM-CSF. These data imply that PM interferes with the production of GM-CSF, and consequently would affect the production and maturation of hematopoietic cells and the immune response.

The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics.

Science.gov (United States)

Metzger, Fabian; Mischek, Daniel; Stoffers, Frédéric

2017-01-01

Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in-vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system.

Intracranial CSF flow on cine-MR. 2. Qualitative analysis in CSF dynamics by MR signal ratio of CSF to fat tissue in healthy subjects and patients with aqueduct stenosis

International Nuclear Information System (INIS)

Kadowaki, Chikafusa; Hara, Mitsuhiro; Takeuchi, Kazuo; Saito, Isamu

1994-01-01

Changes in MR signal intensities (SIs) of CSF and relative MR signal ratios (SRs) of intraventricular CSF to fat tissue were evaluated in 5 healthy adults on cine MR images during a cardiac cycle in a study of normal intracranial CSF dynamics. The altered patterns of MR SIs and SRs in 6 patients with aqueduct stenosis were compared with normal CSF flow patterns in a demonstration of CSF dynamics changes. MR SIs of CSF within the ventricles were measured on each cine image obtained by cardiac gated, multiframe, cine MR imaging. Chronological changes in MR SIs and SRs during a cardiac cycle were compared with the actual CSF flow visualized on real cine images. In normal CSF circulation, MR SIs of CSF within the ventricles were reduced quickly following an R-wave on ECG to 15% of the R-R interval, after which SIs fluctuated slightly. These changes in MR SIs of CSF could only be related to the pulsatile CSF flow through the foramen of Monro into the anterior part of the third ventricle during early cardiac systole. MR SRs of CSF to fat tissue fluctuated according to the actual CSF flow within the ventricles during a cardiac cycle. MR SRs in the third ventricle decreased to 20-30% of the R-R interval following the R-wave due to downward CSF flow during early cardiac systole, and decreased again from late cardiac systole to diastole due to caudal CSF flow in the third ventricle. In the fourth ventricle, MR SRs of CSF decreased to 60-80% of the R-R interval because of the CSF flow through the aqueduct during cardiac diastole. In patients with aqueduct stenosis, MR SRs of CSF within the ventricles fluctuated randomly, and the amplitude of MR SRs was also greater than in subjects with a patent aqueduct. These changes were identified as turbulence and stagnation due to obstruction in the CSF pathway. Analysis of chronological changes in MR signal ratios of CSF to fat is useful in demonstrating the pathophysiologic features of intracranial CSF dynamics. (author) 52 refs

EFFECTIVENESS AND SAFETY OF RECOMBINANT HUMAN GRANULOCYTIC COLONY-STIMULATING FACTOR IN TREATMENT OF GRANULOCYTOPENIA DEVELOPED DURING IMMUNOSUPPRESSIVE THERAPY IN PATIENTS WITH JUVENILE RHEUMATOID ARTHRITIS

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E.I. Alexeeva

2010-01-01

Full Text Available Treatment of patients with severe clinical course of juvenile rheumatoid arthritis (JRA is difficult problem. During the last years genetically engineered biological drugs are used equally with traditional immunosuppressive agents in treatment of severe forms of juvenile arthritis. High effectiveness of these drugs can be accompanied with development of unfavorable effects, for example, febrile neutropenia. The article presents results of a study of effectiveness and safety of recombinant human granulocytic colony-stimulating factor — filgrastim (Leucostim — in treatment of granulocytopenia developed during immunosuppressive therapy in 16 patients with JRA. It was shown that administration of filgrastim arrests leucopenia in 100% of patients and granulocytopenia — in 93% of patients in 24 hours after first injection. High effectiveness of drug was combined with good tolerability and safety.Key words: children, treatment, granulocytopenia, filgrastim, juvenile rheumatoid arthritis.(Voprosy sovremennoi pediatrii — Current Pediatrics. – 2010;9(4:94-100

CSF total protein

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CSF total protein is a test to determine the amount of protein in your spinal fluid, also called cerebrospinal fluid (CSF). ... The normal protein range varies from lab to lab, but is typically about 15 to 60 milligrams per deciliter (mg/dL) ...

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System.

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Louis, Cynthia; Cook, Andrew D; Lacey, Derek; Fleetwood, Andrew J; Vlahos, Ross; Anderson, Gary P; Hamilton, John A

2015-07-01

M-CSF (or CSF-1) and GM-CSF can regulate the development and function of the mononuclear phagocyte system (MPS). To address some of the outstanding and sometimes conflicting issues surrounding this biology, we undertook a comparative analysis of the effects of neutralizing mAbs to these CSFs on murine MPS populations in the steady-state and during acute inflammatory reactions. CSF-1 neutralization, but not of GM-CSF, in normal mice rapidly reduced the numbers of more mature Ly6C(-) monocytes in blood and bone marrow, without any effect on proliferating precursors, and also the numbers of the resident peritoneal macrophages, observations consistent with CSF-1 signaling being essential only at a relatively late state in steady-state MPS development; in contrast, GM-CSF neutralization had no effect on the numbers of these particular populations. In Ag-induced peritonitis (AIP), thioglycolate-induced peritonitis, and LPS-induced lung inflammation, CSF-1 neutralization lowered inflammatory macrophage number; in the AIP model, this reduced number was not due to suppressed proliferation. More detailed studies with the convenient AIP model indicated that CSF-1 neutralization led to a relatively uniform reduction in all inflammatory cell populations; GM-CSF neutralization, in contrast, was more selective, resulting in the preferential loss among the MPS populations of a cycling, monocyte-derived inflammatory dendritic cell population. Some mechanistic options for the specific CSF-dependent biologies enumerated are discussed. Copyright © 2015 by The American Association of Immunologists, Inc.

Traumatic orbital CSF leak

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Borumandi, Farzad

2013-01-01

Compared to the cerebrospinalfluid (CSF) leak through the nose and ear, the orbital CSF leak is a rare and underreported condition following head trauma. We present the case of a 49-year-old woman with oedematous eyelid swelling and ecchymosis after a seemingly trivial fall onto the right orbit. Apart from the above, she was clinically unremarkable. The CT scan revealed a minimally displaced fracture of the orbital roof with no emphysema or intracranial bleeding. The fractured orbital roof in combination with the oedematous eyelid swelling raised the suspicion for orbital CSF leak. The MRI of the neurocranium demonstrated a small-sized CSF fistula extending from the anterior cranial fossa to the right orbit. The patient was treated conservatively and the lid swelling resolved completely after 5 days. Although rare, orbital CSF leak needs to be included in the differential diagnosis of periorbital swelling following orbital trauma. PMID:24323381

Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies

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Charlotte E. Teunissen

2011-01-01

Full Text Available There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO, but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.

CSF-VDRL test

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... test - CSF; Neurosyphilis - VDRL Images CSF test for syphilis References Chernecky CC, Berger BJ. Venereal disease research laboratory test (VDRL), test, cerebrospinal fluid – specimen. In: Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures . 6th ed. St Louis, MO: Elsevier Saunders; ...

CSF Venous Fistulas in Spontaneous Intracranial Hypotension: Imaging Characteristics on Dynamic and CT Myelography.

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Kranz, Peter G; Amrhein, Timothy J; Gray, Linda

2017-12-01

The objective of this study is to describe the anatomic and imaging features of CSF venous fistulas, which are a recently reported cause of spontaneous intracranial hypotension (SIH). We retrospectively reviewed the records of patients with SIH caused by CSF venous fistulas who received treatment at our institution. The anatomic details of each fistula were recorded. Attenuation of the veins involved by the fistula was compared with that of adjacent control veins on CT myelography (CTM). Visibility of the CSF venous fistula on CTM and a modified conventional myelography technique we refer to as dynamic myelography was also compared. Twenty-two cases of CSF venous fistula were identified. The fistulas were located between T4 and L1. Ninety percent occurred without a concurrent epidural CSF leak. In most cases (82%), the CSF venous fistula originated from a nerve root sleeve diverticulum. On CTM, the abnormal veins associated with the CSF venous fistula were seen in a paravertebral location in 45% of cases, centrally within the epidural venous plexus in 32%, and lateral to the spine in 23%. Differences in attenuation between the fistula veins and the control veins was highly statistically significant (p CSF venous fistulas are an important cause of SIH that can be detected on both CTM and dynamic myelograph y and may occur without an epidural CSF leak. Familiarity with the imaging characteristics of these lesions is critical to providing appropriate treatment to patients with SIH.

[Treatment of Chemotherapy Related Leukocytopenia by Oral Administration of Multiple Leucogenic Drugs Combined with G-CSF: an Experimental Study].

Science.gov (United States)

Zhang, Xi-ping; Zhang, Xiang; Yang, Hong-jian; Zou, De-hong; He, Xiang-ming; Yu, Xing-fei; Li, Yong-feng

2015-07-01

To evaluate efficacies of three commonly used oral drugs including Berbamine Hydrochloride Tablet (B), Qijiao Shengbai Capsule (Q), and Leucogen Tablet (L) (by single drug, two drugs or three drugs) combined with granulocyte colony-stimulating factor (G-CSF) for treat ment of chemotherapy related leukocytopenia in mice. Totally 156 Kunming male mice were divided into the normal control group (A, n=24), the model group (B, n=24), the G-CSF group (C, n =24), the G-CSF+Q group (D, n=12), G-CSF+ B (E, n=12), the G-CSF+L group (F, n=12), the G-CSF + Q + B group (G, n=12), the G-CSF + Q + L group (H, n=12), the G-CSF + L + B group (I, n=12), and the G-CSF + L + Q + B (J, n=12). Mouse models of chemotherapy related leukocytopenia were established by intraperitoneal injection of cyclophosphamide (CTX). A G-CSF group was set up as a positive control. Mice were treated by a single oral drug, a single oral drug combined with G-CSF, and two or three drugs combined with G-CSF respectively, and the death rate calculated. Hemocytes [such as white blood cells (WBC) and its classification, red blood cells (RBC), platelet (PLT), hemoglobin (Hb)] were calculated by hematology analyzer. Mice were anatomized and important organs weighed. Organ indices were calculated. There was no statistical difference in the mortality rate among all groups (P > 0.05). Compared with Group B, WBC was elevated in all other groups (P drug B and L (P chemotherapy related leukopenia or decreased three blood series was to administrate three commonly oral drugs combined with G-CSF. Authors speculated that G-CSF and Q might have a certain effect on CTX induced immune inhibition.

A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD

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Haldar, Swati; Beveridge, ’Alim J.; Wong, Joseph; Singh, Ajay; Galimberti, Daniela; Borroni, Barbara; Zhu, Xiongwei; Blevins, Janis; Greenlee, Justin; Perry, George; Mukhopadhyay, Chinmay K.; Schmotzer, Christine

2013-01-01

Abstract Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675. PMID:23379482

Use of rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial

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Diana Brasil Pedral-Sampaio

Full Text Available It has been postulated that deficient or incomplete clinical and/or microbiological response to tuberculosis treatment is associated with cell-mediated immunological dysfunction involving monocytes and macrophages. A phase 2 safety trial was conducted by treating patients with either recombinant human granulocyte-macrophage colony-stimulating factor (rhu-GM-CSF or a placebo, both in combination with anti-tuberculosis chemotherapy. Thirty-one patients with documented pulmonary tuberculosis were treated with rifampin/isoniazid for six months, plus pyrazinamide for the first two months. At the beginning of treatment, rhu-GM-CSF (125µg/M² was randomly assigned to 16 patients and injected subcutaneously twice weekly for four weeks; the other 15 patients received a placebo. The patients were accompanied in the hospital for two weeks, then monthly on an out patient basis, for 12 months. Clinical outcomes were similar in both groups, with no difference in acid-fast bacilli (AFB clearance in sputum at the end of the fourth week of treatment. Nevertheless, a trend to faster conversion to negative was observed in the rhu-GM-CSF group until the eighth week of treatment (p=0.07, after which all patients converted to AFB negative. Adverse events in the rhu-GM-CSF group were local skin inflammation and an increase in the leukocyte count after each injection, returning to normal 72 hours after rhu-GM-CSF injection. Three patients developed SGOP and SGPT > 2.5 times the normal values. All patients included in the GM-CSF group were culture negative at six months, except one who had primary TB resistance. None of the patients had to discontinue the treatment in either group. We conclude that rhu-GM-CSF adjuvant immunotherapy could be safely explored in a phase 3 trial with patients who have active tuberculosis.

Use of rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial

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Pedral-Sampaio Diana Brasil

2003-01-01

Full Text Available It has been postulated that deficient or incomplete clinical and/or microbiological response to tuberculosis treatment is associated with cell-mediated immunological dysfunction involving monocytes and macrophages. A phase 2 safety trial was conducted by treating patients with either recombinant human granulocyte-macrophage colony-stimulating factor (rhu-GM-CSF or a placebo, both in combination with anti-tuberculosis chemotherapy. Thirty-one patients with documented pulmonary tuberculosis were treated with rifampin/isoniazid for six months, plus pyrazinamide for the first two months. At the beginning of treatment, rhu-GM-CSF (125µg/M² was randomly assigned to 16 patients and injected subcutaneously twice weekly for four weeks; the other 15 patients received a placebo. The patients were accompanied in the hospital for two weeks, then monthly on an out patient basis, for 12 months. Clinical outcomes were similar in both groups, with no difference in acid-fast bacilli (AFB clearance in sputum at the end of the fourth week of treatment. Nevertheless, a trend to faster conversion to negative was observed in the rhu-GM-CSF group until the eighth week of treatment (p=0.07, after which all patients converted to AFB negative. Adverse events in the rhu-GM-CSF group were local skin inflammation and an increase in the leukocyte count after each injection, returning to normal 72 hours after rhu-GM-CSF injection. Three patients developed SGOP and SGPT > 2.5 times the normal values. All patients included in the GM-CSF group were culture negative at six months, except one who had primary TB resistance. None of the patients had to discontinue the treatment in either group. We conclude that rhu-GM-CSF adjuvant immunotherapy could be safely explored in a phase 3 trial with patients who have active tuberculosis.

Epidural blood patch for refractory low CSF pressure headache

DEFF Research Database (Denmark)

Madsen, Søren Aalbæk; Fomsgaard, Jonna Storm; Jensen, Rigmor

2011-01-01

primary effect parameter was total headache burden defined as area under the curve (AUC: intensity × duration) and as secondary effect parameters we identified: intensity (VAS 0-10), frequency (days per month), duration in hours (total hours/month) and also medication days (days on medication...... of non-invasive/conservative measures and invasive measures with epidural blood patch providing the cornerstone of the invasive measures. In the present pilot study we therefore aimed to evaluate the treatment efficacy of epidural blood patch (EBP) in treatment-refractory low-pressure headache. Our......Once believed an exceedingly rare disorder, recent evidence suggests that low cerebrospinal fluid (CSF) pressure headache has to be considered an important cause of new daily persistent headaches, particularly among young and middle-aged individuals. Treatment of low CSF pressure headache consists...

Epidural blood patch for refractory low CSF pressure headache

DEFF Research Database (Denmark)

Madsen, Søren Aalbæk; Fomsgaard, Jonna Storm; Jensen, Rigmor

2011-01-01

of non-invasive/conservative measures and invasive measures with epidural blood patch providing the cornerstone of the invasive measures. In the present pilot study we therefore aimed to evaluate the treatment efficacy of epidural blood patch (EBP) in treatment-refractory low-pressure headache. Our......Once believed an exceedingly rare disorder, recent evidence suggests that low cerebrospinal fluid (CSF) pressure headache has to be considered an important cause of new daily persistent headaches, particularly among young and middle-aged individuals. Treatment of low CSF pressure headache consists...... primary effect parameter was total headache burden defined as area under the curve (AUC: intensity × duration) and as secondary effect parameters we identified: intensity (VAS 0-10), frequency (days per month), duration in hours (total hours/month) and also medication days (days on medication...

Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke.

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Peña, Ike dela; Borlongan, Cesar V

2015-12-01

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis,and produce behavioral and functional improvement through their "bystander effects." Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates,which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of cotreatment with granulocyte-colony stimulating factor (GCSF)and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here,we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of GCSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells(EPCs), as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further

Changes of CSF-protein pattern in children with acute lymphoblastic leukemia during prophylactic CNS therapy (Berlin protocol)

International Nuclear Information System (INIS)

Siemes, H.; Rating, D.; Siegert, M.; Hanefeld, F.; Mueller, S.; Gadner, H.; Riehm, H.

1980-01-01

The cerebral spinal fluid (CSF)-protein profiles of ten children with previously untreated acute lymphoblastic leukemia (ALL) were investigated by agarose gel electrophoresis. The profiles were determined at diagnosis and during the fifth to eighth week of treatment when preventive therapy for central nervous system (CNS) leukemia (skull irradiation, intrathecal methotrexate (ithMTX) was administered. The profiles were compared with those obtained from a control group of 67 children and those from 42 patients with acute aseptic meningitis. The data from the latter group demonstrated the CSF-protein pattern of partial blood-CSF barrier (B-CSF-B) breakdown. The children with ALL showed no or only minor signs of a B-CSF-B impairment at diagnosis and after four weeks of systemic treatment. However, CSF changes indicative of a lesion of the B-CSF-B increased in all children continuously during CNS prophylaxis. The protein profile at the end of combined chemotherapy and radiotherapy was very similar to that in patients with acute aseptic meningitis. These observations point to neurotoxic side effects on the CNS barrier system with the combination of cranial radiation and ithMTX. A striking finding was restricted heterogeneity of gamma-globulin, observed in the CSF of nine out of the ten children with ALL before or during treatment. The significance of this abnormality is unknown

Fibronectin changes in eosinophilic meningitis with blood-CSF barrier disruption.

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Shyu, Ling-Yuh; Hu, Ming-E; Chou, Chun-Hui; Chen, Ke-Min; Chiu, Ping-Sung; Lai, Shih-Chan

2015-01-01

Fibronectin, which is present at relatively low levels in healthy central nervous systems (CNS), shows increased levels in meningitis. In this study, fibronectin processing was correlated with the increased permeability of the blood-cerebrospinal fluid (CSF) barrier as well as with the formation of eosinophil infiltrates in angiostrongyliasis meningitis. The immunohistochemistry results show matrix metalloproteinase-9 (MMP-9) is localized in the choroid plexus epithelium. Coimmunoprecipitation demonstrated fibronectin strongly binds MMP-9. Furthermore, treatment with the MMP-9 inhibitor GM6001 significantly inhibited fibronectin processing, reduced the blood-CSF barrier permeability, and decreased the eosinophil counts. The decreased fibronectin processing in CSF implies decreased cellular invasion of the subarachnoid space across the blood-CSF barrier. Therefore, increased fibronectin processing may be associated with barrier disruption and participate in the extravasation and migration of eosinophils into the CNS during experimental parasitic infection. Copyright © 2015 Elsevier Inc. All rights reserved.

MR imaging of pulsatile CSF movement in hydrocephalus communicans before and after CSF shunt implantation

International Nuclear Information System (INIS)

Goldmann, A.; Kunz, U.; Rotermund, F.; Friedrich, J.M.; Schnarkowski, P.

1992-01-01

16 patients with hydrocephalus communicans and 5 healthy volunteers were examined to demonstrate the pattern of the pulsatile CSF flow. After implantation of a CSF shunt system the same patients were examined again to show the influence of the shunt on the CSF pulsations. We used a flow-sensitised, cardiac-gated 2D FLASH sequence and analysed the phase and magnitude images. It could be shown that most patients (n=12) had a hyerdynamic pulsatile flow preoperatively. After shunt implantation the pulsatile CSF motion and the clinical symptoms were improved in 8 of these patients. MRI of pulsatile CSF flow movement seems to be a helpful noninvasive tool to estimate the prognosis of a shunt implantation in patients with hydrocephalus communicans. (orig.) [de

CSF oligoclonal banding - slideshow

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... this page: //medlineplus.gov/ency/presentations/100145.htm CSF oligoclonal banding - series—Normal anatomy To use the ... 5 out of 5 Overview The cerebrospinal fluid (CSF) serves to supply nutrients to the central nervous ...

CSF coccidioides complement fixation

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... this page: //medlineplus.gov/ency/article/003526.htm CSF coccidioides complement fixation test To use the sharing features on this page, please enable JavaScript. CSF coccidioides complement fixation is a test that checks ...

Epidural blood patch for refractory low CSF pressure headache: a pilot study.

Science.gov (United States)

Madsen, Søren Aalbæk; Fomsgaard, Jonna Storm; Jensen, Rigmor

2011-08-01

Once believed an exceedingly rare disorder, recent evidence suggests that low cerebrospinal fluid (CSF) pressure headache has to be considered an important cause of new daily persistent headaches, particularly among young and middle-aged individuals. Treatment of low CSF pressure headache consists of non-invasive/conservative measures and invasive measures with epidural blood patch providing the cornerstone of the invasive measures. In the present pilot study we therefore aimed to evaluate the treatment efficacy of epidural blood patch (EBP) in treatment-refractory low-pressure headache. Our primary effect parameter was total headache burden defined as area under the curve (AUC: intensity × duration) and as secondary effect parameters we identified: intensity (VAS 0-10), frequency (days per month), duration in hours (total hours/month) and also medication days (days on medication/month). In our primary effect parameter we found a significant reduction in AUC with more than 25% and this is considered to be clinically relevant. We found also a significant and relevant reduction at -22% in intensity. A trend towards reduction in duration was seen. We found no statistically significant reduction in frequency. An increase in days with use of medication was found. Increased awareness of low CSF pressure headache is emphasized and a controlled larger randomized study is needed to confirm the results. However the present results, allows us to conclude that EBP in treatment-refractory low CSF pressure headache can be considered as a treatment option.

MR evaluation of CSF fistulae

International Nuclear Information System (INIS)

Gupta, V.; Goyal, M.; Mishra, N.; Gaikwad, S.; Sharma, A.

1997-01-01

Purpose: To evaluate the role of MR imaging in the localisation of cerebrospinal fluid (CSF) fistulae. Material and Methods: A total of 36 consecutive unselected patients with either clincally proven CSF leakage (n=26) or suspected CSF fistula (n=10) were prospectively evaluated by MR. All MR examinations included fast spin-echo T2-weighted images in the 3 orthogonal planes. Thin-section CT was performed following equivocal or negative MR examination. MR and CT findings were correlated with surgical results in 33 patients. Results: CSF fistula was visualised as a dural-bone defect with hyperintense fluid signal continuous with that in the basal cisterns on T2-weighted images. MR was positive in 26 cases, in 24 of which the fistula was confirmed surgically. In 2 patients the CSF leakage was directly demonstrated on MR. MR sensitivity of 80% compared favourably with the reported 46-81% of CT cisternography (CTC). No significant difference in MR sensitivity in detecting CSF fistula was found between active and inactive leaks. (orig.)

False localizing sign of cervico-thoracic CSF leak in spontaneous intracranial hypotension.

Science.gov (United States)

Schievink, Wouter I; Maya, M Marcel; Chu, Ray M; Moser, Franklin G

2015-06-16

Spontaneous spinal CSF leaks are an important cause of new-onset headaches. Such leaks are reported to be particularly common at the cervico-thoracic junction. The authors undertook a study to determine the significance of these cervico-thoracic CSF leaks. The patient population consisted of a consecutive group of 13 patients who underwent surgery for CSF leak repair based on CT myelography showing CSF extravasation at the cervico-thoracic junction but without any evidence of an underlying structural lesion. The mean age of the 9 women and 4 men was 41.2 years. Extensive extrathecal longitudinal CSF collections were demonstrated in 11 patients. At surgery, small leaking arachnoid cysts were found in 2 patients. In the remaining 11 patients, no clear source of CSF leakage could be identified at surgery. Resolution of symptoms was achieved in both patients with leaking arachnoid cysts, but in only 3 of the 11 patients with negative intraoperative findings. Postoperative spinal imaging was performed in 9 of the 11 patients with negative intraoperative findings and showed persistence of the longitudinal intraspinal extradural CSF. Further imaging revealed the site of the CSF leak to be ventral to the thoracic spinal cord. Five of these patients underwent microsurgical repair of the ventral CSF leak with resolution of symptoms in all 5 patients. Cervico-thoracic extravasation of dye on myelography does not necessarily indicate the site of the CSF leak. Treatment directed at this site should not be expected to have a high probability of sustained improvement of symptoms. © 2015 American Academy of Neurology.

Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation

Science.gov (United States)

Cioce, M; Canino, C; Goparaju, C; Yang, H; Carbone, M; Pass, H I

2014-01-01

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1Rpos cells exhibit a complex repertoire of pluripotency, epithelial–mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1Rpos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention. PMID:24722292

CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes.

Science.gov (United States)

Gurtner, Kari M; Shosha, Eslam; Bryant, Sandra C; Andreguetto, Bruna D; Murray, David L; Pittock, Sean J; Willrich, Maria Alice V

2018-02-19

Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs. A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]-[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin]). Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity. cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis.

Local application of GM-CSF for treatment of chemoirradiation-induced mucositis in patients with advanced carcinoma of the head and neck: results of controlled clinical trial

International Nuclear Information System (INIS)

Reichtomann, K.A.

2002-01-01

Purpose: the study was designed to assess prospectively the efficacy of GM-CSF (granulocyte-macrophage colony-stimulating factor) mouthwash solution in the management of chemoirradiation induced oral mucositis for head and neck cancer patients. Methods and materials: thirty-five patients with advanced carcinoma of the head and neck were evaluated for mucositis during the first cycle of chemoirradiation therapy. GM-CSF 400 μg in 250 cc of water for 1 h of mouth washing was prescribed. Active comparator was a conventional mucositis therapy combination. The procedure started once mucositis grade 1 (using the WHO grading) was detected. Patients, examined twice a week, were evaluated for oral mucositis and oral infections. Assessment of subjective pain was provided using a visual analogue scale. Blood tests were taken weekly. Results: the results of statistical evaluation of mucositis using the WHO-grading showed no significant differences between the two treatment groups. Local application of GM-CSF significantly reduced subjective pain during the second week of chemoirradiation therapy. Statistical analysis of the leucocytes-, platelet count, haemoglobin level and development of oral infections revealed no significant differences between the two treatment groups. Conclusion: in combined chemoirradiation therapy schemes the RTOG/EORTC toxicity scale should be used. In selected cases of mucositis attended with severe pain, GM-CSF should be observed within the therapeutic considerations. Controlled clinical trials with larger patient population are required to evaluate the role of GM-CSF in this indication. (author)

G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial.

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Thomas Duning

2011-03-01

Full Text Available The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS. The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS, a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days. The total number of adverse events (AE and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI, brain volumetry, and voxel-based morphometry.Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect

Nucleolin Mediates MicroRNA-directed CSF-1 mRNA Deadenylation but Increases Translation of CSF-1 mRNA*

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Woo, Ho-Hyung; Baker, Terri; Laszlo, Csaba; Chambers, Setsuko K.

2013-01-01

CSF-1 mRNA 3′UTR contains multiple unique motifs, including a common microRNA (miRNA) target in close proximity to a noncanonical G-quadruplex and AU-rich elements (AREs). Using a luciferase reporter system fused to CSF-1 mRNA 3′UTR, disruption of the miRNA target region, G-quadruplex, and AREs together dramatically increased reporter RNA levels, suggesting important roles for these cis-acting regulatory elements in the down-regulation of CSF-1 mRNA. We find that nucleolin, which binds both G-quadruplex and AREs, enhances deadenylation of CSF-1 mRNA, promoting CSF-1 mRNA decay, while having the capacity to increase translation of CSF-1 mRNA. Through interaction with the CSF-1 3′UTR miRNA common target, we find that miR-130a and miR-301a inhibit CSF-1 expression by enhancing mRNA decay. Silencing of nucleolin prevents the miRNA-directed mRNA decay, indicating a requirement for nucleolin in miRNA activity on CSF-1 mRNA. Downstream effects followed by miR-130a and miR-301a inhibition of directed cellular motility of ovarian cancer cells were found to be dependent on nucleolin. The paradoxical effects of nucleolin on miRNA-directed CSF-1 mRNA deadenylation and on translational activation were explored further. The nucleolin protein contains four acidic stretches, four RNA recognition motifs (RRMs), and nine RGG repeats. All three domains in nucleolin regulate CSF-1 mRNA and protein levels. RRMs increase CSF-1 mRNA, whereas the acidic and RGG domains decrease CSF-1 protein levels. This suggests that nucleolin has the capacity to differentially regulate both CSF-1 RNA and protein levels. Our finding that nucleolin interacts with Ago2 indirectly via RNA and with poly(A)-binding protein C (PABPC) directly suggests a nucleolin-Ago2-PABPC complex formation on mRNA. This complex is in keeping with our suggestion that nucleolin may work with PABPC as a double-edged sword on both mRNA deadenylation and translational activation. Our findings underscore the complexity of

Calculation of CSF spaces in CT

Energy Technology Data Exchange (ETDEWEB)

Hacker, H; Artmann, H [Frankfurt Univ. (Germany, F.R.). Abt. fuer Neuroradiologie

1978-01-01

Objective digital determination of CSF spaces is discussed, with ventricular and subarachnoid spaces handled separately. This method avoids the difficulty of visual definition of ventricular borders in planimetric measurements. The principle is to count automatically all pixels corresponding to CSF in a given region with a Hounsfield unit and to multiply this number by the pixel size. This will give the total surface area of CSF spaces in square millimeters. The calculation of pixel values for CSF spaces and brain tissue is experimentally formulated taking the intersection of the Gaussian curves for ventricular content and brain tissue. In practice, the determination of CSF spaces is done by first calculating a histogram of the total brain in a given slice defining all CSF spaces. Next a histogram of a region including ventricles with adjoining tissue is calculated and the ventricular size is calculated. By subtraction of the ventricle value from the total CSF space value, the subarachnoid space size is obtained. The advantages of this mehtod will be discussed.

Comparison of the Cerebrospinal Fluid (CSF) Toluidine Red Unheated Serum Test and the CSF Rapid Plasma Reagin Test with the CSF Venereal Disease Research Laboratory Test for Diagnosis of Neurosyphilis among HIV-Negative Syphilis Patients in China

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Zhu, Lin; Gu, Xin; Peng, Rui-Rui; Wang, Cuini; Gao, Zixiao; Gao, Ying; Shi, Mei; Guan, Zhifang; Seña, Arlene C.

2014-01-01

In this study, we aimed to investigate the performance of nontreponemal antibody tests in cerebrospinal fluid (CSF) specimens from syphilis patients. From September 2009 to September 2012, CSF specimens were collected at the Shanghai Skin Disease Hospital in Shanghai, China, from 1,132 syphilis patients without HIV infection, including 154 with symptomatic and 56 with asymptomatic neurosyphilis. All of the CSF specimens underwent testing with a rapid plasma reagin (RPR) test, an RPR-V (commercial RPR antigen diluted 1:2 in 10% saline) test, the toluidine red unheated serum test (TRUST), and the Venereal Disease Research Laboratory (VDRL) test. Specificities, sensitivities, positive predictive values (PPVs), negative predictive values (NPVs), and kappa values were calculated to determine the performances of the tests. We compared results of the CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST among patients with symptomatic and asymptomatic neurosyphilis who had reactive CSF-Treponema pallidum particle agglutination (TPPA) test results. Overall, the CSF-VDRL test was reactive in 261 patients (23.1%). There were no cases in which the CSF-VDRL was nonreactive and CSF-RPR, CSF-RPR-V, or CSF-TRUST was reactive. Agreement between the results of CSF-TRUST and CSF-RPR was almost perfect (κ = 0.861), with substantial agreement between the results of CSF-RPR and CSF-RPR-V (κ = 0.740). The sensitivities of CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST were 81.4%, 76.2%, 79.5%, and 76.2%, respectively. Compared to CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST had comparable PPVs and NPVs. However, the specificity of CSF-VDRL (90.3%) was significantly lower than those of the other tests (92.7 to 93.4%). Therefore, CSF-RPR, CSF-RPR-V, and CSF-TRUST can be considered alternative tests for neurosyphilis diagnosis in HIV-negative populations, particularly when the CSF-VDRL is not available. PMID:24335955

Cloning and expression of porcine Colony Stimulating Factor-1 (CSF-1) and Colony Stimulating Factor-1 Receptor (CSF-1R) and analysis of the species specificity of stimulation by CSF-1 and Interleukin 34

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Gow, Deborah J.; Garceau, Valerie; Kapetanovic, Ronan; Sester, David P.; Fici, Greg J.; Shelly, John A.; Wilson, Thomas L.; Hume, David A.

2012-01-01

Macrophage Colony Stimulating Factor (CSF-1) controls the survival, differentiation and proliferation of cells of the mononuclear phagocyte system. A second ligand for the CSF-1R, Interleukin 34 (IL-34), has been described, but its physiological role is not yet known. The domestic pig provides an alternative to traditional rodent models for evaluating potential therapeutic applications of CSF-1R agonists and antagonists. To enable such studies, we cloned and expressed active pig CSF-1. To provide a bioassay, pig CSF-1R was expressed in the factor-dependent Ba/F3 cell line. On this transfected cell line, recombinant porcine CSF-1 and human CSF-1 had identical activity. Mouse CSF-1 does not interact with the human CSF-1 receptor but was active on pig. By contrast, porcine CSF-1 was active on mouse, human, cat and dog cells. IL-34 was previously shown to be species-specific, with mouse and human proteins demonstrating limited cross-species activity. The pig CSF-1R was equally responsive to both mouse and human IL-34. Based upon the published crystal structures of CSF-1/CSF-1R and IL34/CSF-1R complexes, we discuss the molecular basis for the species specificity. PMID:22974529

Mobilization of hematopoietic stem cells with highest self-renewal by G-CSF precedes clonogenic cell mobilization peak.

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Winkler, Ingrid G; Wiercinska, Eliza; Barbier, Valerie; Nowlan, Bianca; Bonig, Halvard; Levesque, Jean-Pierre

2016-04-01

Harvest of granulocyte colony-stimulating factor (G-CSF)-mobilized hematopoietic stem cells (HSCs) begins at day 5 of G-CSF administration, when most donors have achieved maximal mobilization. This is based on surrogate markers for HSC mobilization, such as CD34(+) cells and colony-forming activity in blood. However, CD34(+) cells or colony-forming units in culture (CFU-C) are heterogeneous cell populations with hugely divergent long-term repopulation potential on transplantation. HSC behavior is influenced by the vascular bed in the vicinity of which they reside. We hypothesized that G-CSF may mobilize sequentially cells proximal and more distal to bone marrow venous sinuses where HSCs enter the blood. We addressed this question with functional serial transplantation assays using blood and bone marrow after specific time points of G-CSF treatment in mice. We found that in mice, blood collected after only 48 hours of G-CSF administration was as enriched in serially reconstituting HSCs as blood collected at 5 days of G-CSF treatment. Similarly, mobilized Lin(-)CD34(+) cells were relatively enriched in more primitive Lin(-)CD34(+)CD38(-) cells at day 2 of G-CSF treatment compared with later points in half of human donors tested (n = 6). This suggests that in both humans and mice, hematopoietic progenitor and stem cells do not mobilize uniformly according to their maturation stage, with most potent HSCs mobilizing as early as day 2 of G-CSF. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study.

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Afifi, S; Adel, N G; Devlin, S; Duck, E; Vanak, J; Landau, H; Chung, D J; Lendvai, N; Lesokhin, A; Korde, N; Reich, L; Landgren, O; Giralt, S; Hassoun, H

2016-04-01

Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾5 × 10(6) CD34+ cells/kg (94 versus 83%, P=0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P<0.001) as well as using Medicare reimbursement rates (P=0.27). Higher rate of hospitalization, increased need for salvage mobilization, and increased G-CSF use account for these differences.

Granulocyte macrophage colony stimulating factor (GM-CSF biological actions on human dermal fibroblasts

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S Montagnani

2009-12-01

Full Text Available Fibroblasts are involved in all pathologies characterized by increased ExtraCellularMatrix synthesis, from wound healing to fibrosis. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF is a cytokine isolated as an hemopoietic growth factor but recently indicated as a differentiative agent on endothelial cells. In this work we demonstrated the expression of the receptor for GM-CSF (GMCSFR on human normal skin fibroblasts from healthy subjects (NFPC and on a human normal fibroblast cell line (NHDF and we try to investigate the biological effects of this cytokine. Human normal fibroblasts were cultured with different doses of GM-CSF to study the effects of this factor on GMCSFR expression, on cell proliferation and adhesion structures. In addition we studied the production of some Extra-Cellular Matrix (ECM components such as Fibronectin, Tenascin and Collagen I. The growth rate of fibroblasts from healthy donors (NFPC is not augmented by GM-CSF stimulation in spite of increased expression of the GM-CSFR. On the contrary, the proliferation of normal human dermal fibroblasts (NHDF cell line seems more influenced by high concentration of GM-CSF in the culture medium. The adhesion structures and the ECM components appear variously influenced by GM-CSF treatment as compared to fibroblasts cultured in basal condition, but newly only NHDF cells are really induced to increase their synthesis activity. We suggest that the in vitro treatment with GM-CSF can shift human normal fibroblasts towards a more differentiated state, due or accompanied by an increased expression of GM-CSFR and that such “differentiation” is an important event induced by such cytokine.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

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Geijselaers, Stefan L C; Aalten, Pauline; Ramakers, Inez H G B; De Deyn, Peter Paul; Heijboer, Annemieke C; Koek, Huiberdina L; OldeRikkert, Marcel G M; Papma, Janne M; Reesink, Fransje E; Smits, Lieke L; Stehouwer, Coen D A; Teunissen, Charlotte E; Verhey, Frans R J; van der Flier, Wiesje M; Biessels, Geert Jan

2018-01-01

Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype. From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau. CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

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

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Dietz Gunnar PH

2009-05-01

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

Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children

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Meraz, Jos? Eugenio V?zquez; Arellano-Galindo, Jos?; Avalos, Armando Mart?nez; Mendoza-Garc?a, Emma; Jim?nez-Hern?ndez, Elva

2016-01-01

Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4?g/m2 of cyclophosphamide (CFA) and 10??g/kg/day of granulocyte colony stimulating factor (G-CSF), B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 ? 109/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 ? 108 (0.1...

Purity assessment of recombinant human granulocyte colony-stimulating factor in finished drug product by capillary zone electrophoresis.

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Benković, Goran; Skrlin, Ana; Madić, Tomislav; Debeljak, Zeljko; Medić-Šarić, Marica

2014-09-01

Current methods for determination of impurities with different charge-to-volume ratio are limited especially in terms of sensitivity and precision. The main goal of this research was to establish a quantitative method for determination of impurities with charges differing from that of recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim) with superior precision and sensitivity compared to existing methods. A CZE method has been developed, optimized, and validated for a purity assessment of filgrastim in liquid pharmaceutical formulations. Optimal separation of filgrastim from the related impurities with different charges was achieved on a 50 μm id fused-silica capillary of a total length of 80.5 cm. A BGE that contains 100 mM phosphoric acid adjusted to pH 7.0 with triethanolamine was used. The applied voltage was 20 kV while the temperature was maintained at 25°C. UV detection was set to 200 nm. Method was validated in terms of selectivity/specificity, linearity, precision, LOD, LOQ, stability, and robustness. Linearity was observed in the concentration range of 6-600 μg/mL and the LOQ was determined to be 0.3% relative to the concentration of filgrastim of 0.6 mg/mL. Other validation parameters were also found to be acceptable; thus the method was successfully applied for a quantitative purity assessment of filgrastim in a finished drug product. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Qualitative analysis of intracranial CSF flow on cine-MR imaging, with special reference to signal ratio of CSF to fat tissue

International Nuclear Information System (INIS)

Kadowaki, Chikafusa; Hara, Mitsuhiro; Numoto, Mitsuo; Takeuchi, Kazuo; Saito, Isamu

1993-01-01

Cine magnetic resonance images (MR) dramatically demonstrate the pulsatile flow of cerebrospinal fluid (CSF) stimulated by the pulsatile motion of the brain following cardiac pulsation. Reduced signal intensity, frequently observed especially in the aqueduct of Sylvius, the third ventricle and the fourth ventricle, is believed to reflect the pulsatile motion of the CSF. Qualitative analysis of MR signal intensity of CSF on each cine frame is compared with CSF flow within the ventricles on real-time cine MR images. While the chronological changes in signal intensities of CSF within the ventricles show only marginal changes in signal intensity in the third ventricle related to downward flow of CSF passing through the foramen of Monro during the early stage of cardiac systole, these changes are thought to have no significant correlation with the CSF flow in the CSF pathway. The chronological changes in relative signal ratios, SR [signal intensities of CSF/signal intensities of fat] can show CSF flow and turbulence within the ventricles. Under normal conditions, within the third ventricle the SR decreases due to pulsatile CSF flow through the foramen of Monro during the early stage of cardiac systole, and decreases because of the flow of CSF from the anterior to the posterior part of the third ventricle, the downward flow of CSF through the aqueduct leads to a lower SR during cardiac diastole. These changes in the fourth ventricle are stimulated by the changes in SR in the third ventricle. The new method of analyzing chronological changes in the relative MR signal ratio of CSF to fat [SR] has the distinct advantage of providing an accurate evaluation of CSF dynamics, and it provides us with important diagnostic information leading to clarification of the pathophysiology of CSF dynamics. (author)

Cerebrospinal fluid (CSF) transient responses induced by hypercapnia

International Nuclear Information System (INIS)

Fisher, M.J.

1984-01-01

CSF transient responses to CO 2 inhalation were measured before and after facilitated perfusate flow through subarachnoid spaces of anesthetized cats during ventriculocisternal perfusion with artificial CSF containing 14 C-dextran. Convective mixing of perfusate in subarachnoid spaces was augmented while infusion constant, either by impeding cisternal efflux of perfusate by raising the cisternal outflow cannula (high CSF pressure), or by preventing CSF outflow by clamping the cisternal outflow cannula (stopflow; S-F). CSF transients were also measured before and after systemic administration of phenoxybenzamine (PBZ) in order to evaluate the contribution of sympatho-adrenergic activity to craniospinal CSF redistribution and mixing. Results from high CSF pressure and S-F experiments indicate that unequilibrated CSF contributes significantly to the reduced tracer concentration in CSF volume (Vd) since SCF effluent tracer concentration (Cd) was decreased after subarachnoid facilitated flow. Further, results from S-F studies indicate that at least 50% of Cd is due to craniospinal fluid redistribution, a process which, along with CSF outflow transients, was unaffected by PBZ. Conversely, PBZ administration decreased steady state SCF formation and absorption through alpha-mediated cerebrovascular responses and/or through beta-adrenoceptor inhibition of metabolism of CSF secretory epithelium

G-CSF in acute myocardial infarction - experimental and clinical findings.

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Ince, Hüseyin; Petzsch, Michael; Rehders, Tim C; Dunkelmann, Simone; Nienaber, Christoph A

2006-09-01

Early data from clinical studies suggest that intracoronary injection of autologous progenitor cells may beneficially affect postinfarction remodeling and perfusion. Beyond intracoronary infusion of autologous bone marrow mononuclear CD34+ cells (MNCCD34+), mobilization of stem cells by G-CSF has recently attracted attention because of various advantages such as the noninvasive nature of MNCCD34+ mobilization by subcutaneous injections. It is the aim of the present work to give an overview about the current experimental and clinical findings of G-CSF treatment in acute myocardial infarction.

Effects of Granulocyte-Macrophage Colony-Stimulating (GM-CSF Factor on Corneal Epithelial Cells in Corneal Wound Healing Model.

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Chang Rae Rho

Full Text Available Granulocyte-macrophage colony-stimulating factor (GM-CSF is a pleiotropic cytokine that activates granulocyte and macrophage cell lineages. It is also known to have an important function in wound healing. This study investigated the effect of GM-CSF in wound healing of human corneal epithelial cells (HCECs. We used human GM-CSF derived from rice cells (rice cell-derived recombinant human GM-CSF; rhGM-CSF. An in vitro migration assay was performed to investigate the migration rate of HCECs treated with various concentrations of rhGM-CSF (0.1, 1.0, and 10.0 μg/ml. MTT assay and flow cytometric analysis were used to evaluate the proliferative effect of rhGM-CSF. The protein level of p38MAPK was analyzed by western blotting. For in vivo analysis, 100 golden Syrian hamsters were divided into four groups, and their corneas were de-epithelialized with alcohol and a blade. The experimental groups were treated with 10, 20, or 50 μg/ml rhGM-CSF four times daily, and the control group was treated with phosphate-buffered saline. The corneal wound-healing rate was evaluated by fluorescein staining at the initial wounding and 12, 24, 36, and 48 hours after epithelial debridement. rhGM-CSF accelerated corneal epithelial wound healing both in vitro and in vivo. MTT assay and flow cytometric analysis revealed that rhGM-CSF treatment had no effects on HCEC proliferation. Western blot analysis demonstrated that the expression level of phosphorylated p38MAPK increased with rhGM-CSF treatment. These findings indicate that rhGM-CSF enhances corneal wound healing by accelerating cell migration.

CSF-1 Receptor Signaling in Myeloid Cells

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Stanley, E. Richard; Chitu, Violeta

2014-01-01

The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We review, the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R. PMID:24890514

Interpretation and value of MR CSF flow studies for paediatric neurosurgery

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Samukelisiwe Sithembile Mbonane

2013-03-01

Full Text Available Imaging techniques may be underutilised when clinicians are unaware of the technique or do not recognise its potential. Phase-contrast MR imaging (PC-MRI is a rapid, simple and non-invasive technique that is sensitive to CSF flow. It demonstrates a mechanical coupling between cerebral blood and CSF flow throughout the cardiac cycle. Neurosurgeons should be able to request this procedure routinely as part of an MRI request. This paper gives an overview of the indications, technical requirements, technique and interpretation, using image examples. Indications for CSF flow studies include assessment and functionality of shunt treatment in patients with hydrocephalus; hydrocephalus associated with achondroplasia; Chiari I malformation; confirmation of aqueductal stenosis; and determining patency of a third ventriculostomy.

The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration.

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Vilalta, Marta; Brune, Jourdan; Rafat, Marjan; Soto, Luis; Graves, Edward E

2018-03-13

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

Comparing the performance characteristics of CSF-TRUST and CSF-VDRL for syphilis: a cross-sectional study

OpenAIRE

Gu, Weiming; Yang, Yang; Wu, Lei; Yang, Sheng; Ng, Lai-King

2013-01-01

Objective In this study, we aimed to determine the performance characteristics of toluidine red unheated serum test on cerebrospinal fluids (CSF-TRUST) as compared to venereal disease research laboratory test on cerebrospinal fluids (CSF-VDRL) for laboratory the diagnosis of neurosyphilis. Design A cross-sectional study. Setting Sexually transmitted infections (STIs) clinics. Participants and methods CSF and serum samples were collected from 824 individual STD clinic patients who have syphili...

Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

DEFF Research Database (Denmark)

Schultz, K; Nilsson, K; Nielsen, Jørgen Erik

2010-01-01

BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients...... with dementia with Lewy bodies (DLB) with or without medication, as well as to reveal whether CSF TTR correlates with depression in dementia. METHODS: CSF samples from 59 patients with AD, 13 patients with DLB and 13 healthy controls were collected, and biochemical analysis was performed. Subjects were assessed...... for the presence of depression. RESULTS: No significant differences in CSF TTR were found between AD, DLB, and control subjects or between depressed and non-depressed dementia patients. Interestingly, we found a significant reduction in CSF TTR (14%) in AD patients who were medicated with cholinesterase inhibitors...

Human granulocyte colony-stimulating factor (hG-CSF) expression in plastids of Lactuca sativa.

Science.gov (United States)

Sharifi Tabar, Mehdi; Habashi, Ali Akbar; Rajabi Memari, Hamid

2013-01-01

Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA terminator. The recombinant vector was coated on nanogold particles and transformed to lettuce chloroplasts through biolistic method. Callogenesis and regeneration of cotyledonary explants were obtained by Murashige and Skoog media containing 6-benzylaminopurine and 1-naphthaleneacetic acid hormones. The presence of hG-CSF gene in plastome was studied with four specific PCR primers and expression by Western immunoblotting. hG-CSF gene cloning was confirmed by digestion and sequencing. Transplastomic lettuce lines were regenerated and subjected to molecular analysis. The presence of hG-CSF in plastome was confirmed by PCR using specific primers designed from the plastid genome. Western immunoblotting of extracted protein from transplastomic plants showed a 20-kDa band, which verified the expression of recombinant protein in lettuce chloroplasts. This study is the first report that successfully express hG-CSF gene in lettuce chloroplast. The lettuce plastome can provide a cheap and safe expression platform for producing valuable biopharmaceuticals for research and treatment.

Granulocyte-colony-stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis.

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Basso, Lilian; Lapointe, Tamia K; Iftinca, Mircea; Marsters, Candace; Hollenberg, Morley D; Kurrasch, Deborah M; Altier, Christophe

2017-10-17

Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony-stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF-induced visceral pain in vivo. Finally, administration of G-CSF-neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron-microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain.

The calculation of CSF spaces in CT

International Nuclear Information System (INIS)

Hacker, H.; Artmann, H.

1978-01-01

Objective digital determination of CSF spaces is discussed, with ventricular and subarachnoid spaces handled separately. This method avoids the difficulty of visual definition of ventricular borders in planimetric measurements. The principle is to count automatically all pixels corresponding to CSF in a given region with a Hounsfield unit and to multiply this number by the pixel size. This will give the total surface area of CSF spaces in square millimeters. The calculation of pixel values for CSF spaces and brain tissue is experimentally formulated taking the intersection of the Gaussian curves for ventricular content and brain tissue. In practice, the determination of CSF spaces is done by first calculating a histogram of the total brain in a given slice defining all CSF spaces. Next a histogram of a region including ventricles with adjoining tissue is calculated and the ventricular size is calculated. By subtraction of the ventricle value from the total CSF space value, the subarachnoid space size is obtained. The advantages of this mehtod will be discussed. (orig.) [de

The effects of p38 MAPK inhibition combined with G-CSF administration on the hematoimmune system in mice with irradiation injury.

Directory of Open Access Journals (Sweden)

Deguan Li

Full Text Available 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.

CSF-1R Inhibitor Development: Current Clinical Status.

Science.gov (United States)

Peyraud, Florent; Cousin, Sophie; Italiano, Antoine

2017-09-05

Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

Epidural blood patch for refractory low CSF pressure headache: a pilot study

OpenAIRE

Madsen, Søren Aalbæk; Fomsgaard, Jonna Storm; Jensen, Rigmor

2011-01-01

Once believed an exceedingly rare disorder, recent evidence suggests that low cerebrospinal fluid (CSF) pressure headache has to be considered an important cause of new daily persistent headaches, particularly among young and middle-aged individuals. Treatment of low CSF pressure headache consists of non-invasive/conservative measures and invasive measures with epidural blood patch providing the cornerstone of the invasive measures. In the present pilot study we therefore aimed to evaluate th...

Inter-relationship between CSF dynamics and CSF to-and-fro movement in the cervical region as assessed by MR velocity imaging with phase encoding in hydrocephalic and normal patients

International Nuclear Information System (INIS)

Kudo, Sumio; Wachi, Akihiko; Sato, Kiyoshi; Sumie, Hirotoshi.

1992-01-01

The to-and-fro velocity of cerebrospinal fluid (CSF) at C-1 and C-2 spinal-cord levels was measured by means of MR velocity-imaging technique, and the correlation of changes in velocity and various biophysical factors influencing the intracranial pressure environment were analyzed. Eight hydrocephalic patients, male and female, of different ages (both infants and adults), and 11 normal volunteers with a similar age range were investigated. The to-and-fro CSF movement was measured by means of phase-shift techniques with a bipolar gradient pulse. The cerebrospinal opening pressure was also recorded in 6 of the 8 hydrocephalic patients, either through a ventricular catheter reservoir or a spinal catheter inserted in the lumbosacral subarachnoid space; the CSF pulse amplitude, the pressure volume index (PVI), and the CSF outflow resistance (Ro) were also evaluated during the procedure. CSF flowed towards caudally in the early systolic phase of a cardiac stroke, but the flow direction was reversed in the early diastolic phase when the maximum flow rate was reached. Although such a flow pattern was commonly observed in all normal and hydrocephalic subjects, whatever the age, there was a marked difference in flow rate between the infants and the pediatric-adults groups, -i.e., it was 5-10 mm/sec for the former and 10-20 mm/sec for the latter. An abnormally high flow rate (33.0 mm/sec) was observed in the hydrocephalic patients when there was a malfunction of the ventriculoperitoneal shunt. A close correlation was found to exist among the changes in the CSF flow velocity, the CSF pressure amplitude, and the CSF outflow resistance (Ro), but not in the PVI. The measurement of the CSF flow velocity by MR velocity imaging appears to have an important role not only in the investigation of CSF dynamics, but also in the diagnosis and treatment of such pathologies as hydrocephalus and ventriculoperitoneal shunt malfunction. (author)

Elevated body mass index and risk of postoperative CSF leak following transsphenoidal surgery

Science.gov (United States)

Dlouhy, Brian J.; Madhavan, Karthik; Clinger, John D.; Reddy, Ambur; Dawson, Jeffrey D.; O’Brien, Erin K.; Chang, Eugene; Graham, Scott M.; Greenlee, Jeremy D. W.

2012-01-01

Object Postoperative CSF leakage can be a serious complication after a transsphenoidal surgical approach. An elevated body mass index (BMI) is a significant risk factor for spontaneous CSF leaks. However, there is no evidence correlating BMI with postoperative CSF leak after transsphenoidal surgery. The authors hypothesized that patients with elevated BMI would have a higher incidence of CSF leakage complications following transsphenoidal surgery. Methods The authors conducted a retrospective review of 121 patients who, between August 2005 and March 2010, underwent endoscopic endonasal transsphenoidal surgeries for resection of primarily sellar masses. Patients requiring extended transsphenoidal approaches were excluded. A multivariate statistical analysis was performed to investigate the association of BMI and other risk factors with postoperative CSF leakage. Results In 92 patients, 96 endonasal endoscopic transsphenoidal surgeries were performed that met inclusion criteria. Thirteen postoperative leaks occurred and required subsequent treatment, including lumbar drainage and/or reoperation. The average BMI of patients with a postoperative CSF leak was significantly greater than that in patients with no postoperative CSF leak (39.2 vs 32.9 kg/m2, p = 0.006). Multivariate analyses indicate that for every 5-kg/m2 increase in BMI, patients undergoing a transsphenoidal approach for a primarily sellar mass have 1.61 times the odds (95% CI 1.10–2.29, p = 0.016, by multivariate logistic regression) of having a postoperative CSF leak. Conclusions Elevated BMI is an independent predictor of postoperative CSF leak after an endonasal endoscopic transsphenoidal approach. The authors recommend that patients with BMI greater than 30 kg/m2 have meticulous sellar reconstruction at surgery and close monitoring postoperatively. PMID:22443502

Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause

NARCIS (Netherlands)

Hasbun, Rodrigo; Bijlsma, Merijn; Brouwer, Matthijs C.; Khoury, Nabil; Hadi, Christiane M.; van der Ende, Arie; Wootton, Susan H.; Salazar, Lucrecia; Hossain, Md Monir; Beilke, Mark; van de Beek, Diederik

2013-01-01

We aimed to derive and validate a risk score that identifies adults with cerebrospinal fluid (CSF) pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Patients with CSF pleocytosis and a negative CSF Gram stain were stratified into a prospective derivation (n = 193)

Rostrocaudal Dynamics of CSF Biomarkers

NARCIS (Netherlands)

Tarnaris, A.; Toma, A.K.; Chapman, M.D.; Petzold, A.F.S.; Keir, G.; Kitchen, N.D.; Watkins, L.D.

2011-01-01

The rostrocaudal gradient (RCG) of markers present in cerebrospinal fluid (CSF) has not been studied adequately due to lack of appropriate control populations and ethical restrictions. The aim of this study is to understand the rostrocaudal gradient of CSF biomarkers. We contacted a study comparing

Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients.

Science.gov (United States)

Khanna, Swati; Graef, Suzanne; Mussai, Francis; Thomas, Anish; Wali, Neha; Yenidunya, Bahar Guliz; Yuan, Constance M; Morrow, Betsy; Zhang, Jingli; Korangy, Firouzeh; Greten, Tim F; Steinberg, Seth M; Stetler-Stevenson, Maryalice; Middleton, Gary; De Santo, Carmela; Hassan, Raffit

2018-03-30

The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition. Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy. Copyright ©2018, American Association for Cancer Research.

Brain metabolic correlates of CSF Tau protein in a large cohort of Alzheimer's disease patients: A CSF and FDG PET study.

Science.gov (United States)

Chiaravalloti, Agostino; Barbagallo, Gaetano; Ricci, Maria; Martorana, Alessandro; Ursini, Francesco; Sannino, Pasqualina; Karalis, Georgios; Schillaci, Orazio

2018-01-01

Physiopathological mechanisms of Alzheimer's disease (AD) are still matter of debate. Especially the role of amyloid β and tau pathology in the development of the disease are still matter of debate. Changes in tau and amyloid β peptide concentration in cerebrospinal fluid (CSF) and hypometabolic patterns at fluorine-18 fluorodeoxyglucose ( 18 F-FDG) PET scanning are considered as biomarkers of AD. The present study was aimed to evaluate the relationships between the concentrations of CSF total Tau (t-Tau), phosphorilated Tau (p-Tau) and Aβ 1-42 amyloid peptide with 18 F-FDG brain distribution in a group of patients with AD. We examined 131 newly diagnosed AD patients according to the NINCDS-ADRDA criteria and 20 healthy controls. The mean (±SD) age of the patients was 70 (±7) years; 57 were male and 74 were female. All patients and controls underwent a complete clinical investigation, including medical history, neurological examination, mini-mental state examination (MMSE), a complete blood screening (including routine exams, thyroid hormones and a complete neuropsychological evaluation). Structural MRI was performed not earlier than 1 month before the 18 F-FDG PET/CT. The following patients were excluded: those with isolated deficits and/or unmodified MMSE (=25/30) on revisit (period of follow-up: 6, 12 and 18 months); patients who had had a clinically manifest acute stroke in the last 6 months with a Hachinsky score greater than 4; and patients with radiological evidence of subcortical lesions. All AD patients were taken off cholinesterase inhibitor treatment throughout the study. We performed lumbar puncture and CSF sampling for diagnostic purposes 2 weeks (±2 days) before the PET/CT scan. The relationship between brain F-FDG uptake and CSF biomarkers was analysed using statistical parametric mapping (SPM8; Wellcome Department of Cognitive Neurology, London, UK) implemented in Matlab R2012b using the MMSE score, sex and age, and other CSF

[The therapeutic effect of HSV1-hGM-CSF combined with doxorubicin on the mouse breast cancer model].

Science.gov (United States)

Zhuang, X F; Zhang, S R; Liu, B L; Wu, J L; Li, X Q; Gu, H G; Shu, Y

2018-03-23

Objective: To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice. Methods: We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed. Results: Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro . Doxorubicin induced the G(2)/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm(3,) (216.80±57.18)mm(3,) (246.10±21.90)mm(3,) (327.50±44.24)mm(3,) (213.30±32.31)mm(3) and (495.80±75.87)mm(3) in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo ( P CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control ( P CSF is observed in 4T1 mouse breast cancer.

Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System.

Science.gov (United States)

Hawley, Catherine A; Rojo, Rocio; Raper, Anna; Sauter, Kristin A; Lisowski, Zofia M; Grabert, Kathleen; Bain, Calum C; Davis, Gemma M; Louwe, Pieter A; Ostrowski, Michael C; Hume, David A; Pridans, Clare; Jenkins, Stephen J

2018-03-15

CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r -mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified Δ Csf1- enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r- driven reporter lines, Csf1r -mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double Δ Csf1r -ECFP- Csf1r -mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r- mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines. Copyright © 2018 The Authors.

Combining G-CSF with a blockade of adhesion strongly improves the reconstitutive capacity of mobilized hematopoietic progenitor cells.

Science.gov (United States)

Christ, O; Kronenwett, R; Haas, R; Zöller, M

2001-03-01

Mobilization of hematopoietic progenitor cells is achieved mainly by application of growth factors and, more recently, by blockade of adhesion. In this report, we describe the advantages of a combined treatment with granulocyte colony-stimulating factor (G-CSF) and anti-VLA4 (CD49d)/anti-CD44 as compared to treatment with the individual components. Mobilization by intravenous injection of anti-CD44, anti-VLA4, or G-CSF was controlled in spleen and bone marrow with regard to frequencies of multipotential colony-forming unit (C-CFU), marrow repopulating ability, long-term reconstitution, recovery of myelopoiesis, and regain of immunocompetence. Mobilization by anti-CD44 had a strong effect on expansion of early progenitor cells in the bone marrow, while the recovery in the spleen was poor. In anti-CD49d-mobilized noncommitted and committed progenitors, progenitor expansion was less pronounced, but settlement in the spleen was quite efficient. Thus, anti-CD44 and anti-CD49d differently influenced mobilization. Accordingly, mobilization and recovery after transfer were improved by combining anti-CD44 with anti-CD49d treatment. Mobilization by G-CSF was most efficient with respect to recovery of progenitor cells in the spleen. However, when transferring G-CSF-mobilized cells, regain of immunocompetence was strongly delayed. This disadvantage could be overridden when progenitor cells were mobilized via blockade of adhesion and when expansion of these mobilized progenitor cells was supported by low-dose G-CSF only during the last 24 hours before transfer. Mobilization of pluripotent progenitor cells via antibody blockade of CD44 or CD49d or via G-CSF relies on distinct mechanisms. Therefore, the reconstitutive capacity of a transplant can be significantly improved by mobilization regimens combining antibody with low-dose G-CSF treatment.

GM-CSF, IL-3 and G-CSF receptors on acute myeloid leukemia cells : function, regulation of expression, and ligand binding characteristics

NARCIS (Netherlands)

L.M. Budel (Leo)

1993-01-01

textabstractIL-3, GM-CSF and G-CSF stimulate proliferation of human acute myeloid leukemia in vitro, but patterns of response among clinical cases are diverse. As described in Chapters 2 and 3, numbers and affinity of IL-3, GM-CSF and G-CSF receptors on cells of patients with AML were assessed and

Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage

Science.gov (United States)

Ushach, Irina; Zlotnik, Albert

2016-01-01

M-CSF and GM-CSF are 2 important cytokines that regulate macrophage numbers and function. Here, we review their known effects on cells of the macrophage-monocyte lineage. Important clues to their function come from their expression patterns. M-CSF exhibits a mostly homeostatic expression pattern, whereas GM-CSF is a product of cells activated during inflammatory or pathologic conditions. Accordingly, M-CSF regulates the numbers of various tissue macrophage and monocyte populations without altering their "activation" status. Conversely, GM-CSF induces activation of monocytes/macrophages and also mediates differentiation to other states that participate in immune responses [i.e., dendritic cells (DCs)]. Further insights into their function have come from analyses of mice deficient in either cytokine. M-CSF signals through its receptor (CSF-1R). Interestingly, mice deficient in CSF-1R expression exhibit a more significant phenotype than mice deficient in M-CSF. This observation was explained by the discovery of a novel cytokine (IL-34) that represents a second ligand of CSF-1R. Information about the function of these ligands/receptor system is still developing, but its complexity is intriguing and strongly suggests that more interesting biology remains to be elucidated. Based on our current knowledge, several therapeutic molecules targeting either the M-CSF or the GM-CSF pathways have been developed and are currently being tested in clinical trials targeting either autoimmune diseases or cancer. It is intriguing to consider how evolution has directed these pathways to develop; their complexity likely mirrors the multiple functions in which cells of the monocyte/macrophage system are involved. PMID:27354413

Inherited biallelic CSF3R mutations in severe congenital neutropenia.

Science.gov (United States)

Triot, Alexa; Järvinen, Päivi M; Arostegui, Juan I; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E Michael; Schäffer, Alejandro A; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P; Unal, Ekrem; Klein, Christoph

2014-06-12

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. © 2014 by The American Society of Hematology.

T2-weighted vs. intrathecal contrast-enhanced MR cisternography in the evaluation of CSF rhinorrhea

International Nuclear Information System (INIS)

Ecin, Gaye; Oner, A. Yusuf; Tokgoz, Nil; Ucar, Murat; Tali, Turgut; Aykol, Sukru

2013-01-01

Background: Endoscopic surgical approach is being more widely used in the treatment of cerebrospinal fluid (CSF) rhinorrhea. Accurate localization of CSF fistulas prior to surgery is essential in increasing the success of dural repair and in decreasing negative or recurrent explorations. Purpose: To evaluate and compare intrathecal contrast medium-enhanced magnetic resonance cisternography (CEMRC) with T2-weighted MR cisternography (T2MRC) in identifying the presence and site of CSF rhinorrhea. Material and Methods: Sixty patients with suspected CSF rhinorrhea underwent MR cisternography including intrathecally enhanced fat-suppressed T1WI in three orthogonal planes and T2WI in the coronal plane. Both set of images were reviewed by two blinded radiologists for the presence and location of CSF leakage. Imaging data were compared with surgical findings and/or beta-2 transferrin testing. Results: With surgery proven CSF leakage in 20 instances as reference, CEMRC detected 18 (90%), whereas T2MRC reported only 13 (65%) correctly. Overall, sensitivity, specificity, positive predictive value, and negative predictive value in detecting CSF fistulas were 92%, 80%, 76%, and 93% for CEMRC, and 56%, 77%, 64%, and 71% for T2MRC, respectively. Conclusion: The minimally invasive CEMRC is an effective method with higher sensitivity and specificity than T2MRC in the evaluation of CSF fistulas

CSF dynamics in children

International Nuclear Information System (INIS)

Oi, Shizuo; Shose, Yoshiteru; Yamada, Hiroshi; Ijichi, Akihiro; Matsumoto, Satoshi.

1986-01-01

Cerebrospinal fluid (CSF) dynamics in infants and children is still obscure. This paper aims to analyze the characteristics of CSF dynamics in the younger age group and to clarify the changes both in the acute/chronic hydrocephalic status and in the post-shunt condition on the basis of our experience with 118 cases of metrizamide CT cisternography. In order to pursue the CSF passive movements, the exact regional CT numbers were obtained by means of the ROI method in each case at 3, 6, and 24 hours after metrizamide injection. The results revealed that, in the normal CSF dynamics in both the major and minor pathways in children, it took more than 24 hours until the regional metrizamide was completely cleared up. In the acute hydrocephalic state, the ventricular reflux and stasis of the contrast was remarkable, and stagnation in the Sylvian fissure continued more than 24 hours. In the minor pathway, the contrast moved into the brain parenchyma, with there obviously being more in the subependymal layer and the adjacent white matter, and lasted more than 24 hours. On the other hand, these phenomena were very much less prominent in the chronic phase of hydrocephalus. This fact may suggest the hypothesis that a reconstituted active major or minor fluid pathway does not play an important role in the compensation of the acute high-pressure progressive hydrocephalic state. The CSF dynamics in a shunted hydrocephalus are obviously improved when in stasis or when stagnated inside or outside of the ventricular system. The timing of the metrizamide clear-up was within 24 hours after achieving a high accumulation of the contrast in the lateral ventricle where the shunt is placed. The contrast movement in the brain parenchyma as the minor pathway was significantly less in a shunted hydrocephalus, and there was almost none in cases of slit-like ventricles. (author)

Decompressive craniectomy and CSF disorders in children.

Science.gov (United States)

Manfiotto, Marie; Mottolese, Carmine; Szathmari, Alexandru; Beuriat, Pierre-Aurelien; Klein, Olivier; Vinchon, Matthieu; Gimbert, Edouard; Roujeau, Thomas; Scavarda, Didier; Zerah, Michel; Di Rocco, Federico

2017-10-01

Decompressive craniectomy (DC) is a lifesaving procedure but is associated to several post-operative complications, namely cerebrospinal fluid (CSF) dynamics impairment. The aim of this multicentric study was to evaluate the incidence of such CSF alterations after DC and review their impact on the overall outcome. We performed a retrospective multicentric study to analyze the CSF disorders occurring in children aged from 0 to 17 years who had undergone a DC for traumatic brain injury (TBI) in the major Departments of Pediatric Neurosurgery of France between January 2006 and August 2016. Out of 150 children, ranging in age between 7 months and 17 years, mean 10.75 years, who underwent a DC for TBI in 10 French pediatric neurosurgical centers. Sixteen (6 males, 10 females) (10.67%) developed CSF disorders following the surgical procedure and required an extrathecal CSF shunting. External ventricular drainage increased the risk of further complications, especially cranioplasty infection (p = 0.008). CSF disorders affect a minority of children after DC for TBI. They may develop early after the DC but they may develop several months after the cranioplasty (8 months), consequently indicating the necessity of clinical and radiological close follow-up after discharge from the neurosurgical unit. External ventricular drainage and permanent CSF shunt placement increase significantly the risk of cranioplasty infection.

Pleocytosis is not fully responsible for low CSF glucose in meningitis.

Science.gov (United States)

Baud, Maxime O; Vitt, Jeffrey R; Robbins, Nathaniel M; Wabl, Rafael; Wilson, Michael R; Chow, Felicia C; Gelfand, Jeffrey M; Josephson, S Andrew; Miller, Steve

2018-01-01

The mechanism of hypoglycorrhachia-low CSF glucose-in meningitis remains unknown. We sought to evaluate the relative contribution of CSF inflammation vs microorganisms (bacteria and fungi) in lowering CSF glucose levels. We retrospectively categorized CSF profiles into microbial and aseptic meningitis and analyzed CSF leukocyte count, glucose, and protein concentrations. We assessed the relationship between these markers using multivariate and stratified linear regression analysis for initial and repeated CSF sampling. We also calculated the receiver operating characteristics of CSF glucose and CSF-to-serum glucose ratios to presumptively diagnose microbial meningitis. We found that increasing levels of CSF inflammation were associated with decreased CSF glucose levels in the microbial but not aseptic category. Moreover, elevated CSF protein levels correlated more strongly than the leukocyte count with low CSF glucose levels on initial ( R 2 = 36%, p CSF sampling ( R 2 = 46%, p CSF glucose and CSF-to-serum glucose ratios had similar low sensitivity and moderate-to-high specificity in diagnosing microbial meningitis at thresholds commonly used. The main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation and proteins, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis. A major notable exception is neurosarcoidosis. Low CSF glucose and CSF-to-serum glucose ratios are useful markers for the diagnosis of microbial meningitis.

Non Invasive Microwave Sensor for the Detection of Lactic Acid in Cerebrospinal Fluid (CSF)

International Nuclear Information System (INIS)

Goh, J H; Mason, A; Al-Shamma'a, A I; Field, M; Shackcloth, M; Browning, P

2011-01-01

This research involves the use of a low power microwave sensor for analysis of lactic acid in cerebrospinal fluid (CSF), an indicator of neurological impairment during aortic aneurysm surgery which could provide the basis for improved treatment regimes and better quality of care with more efficient use of resources. This paper presents initial work using standard lactate curves in water followed by lactate in s ynthetic CSF . A multi-modal spectral signature has been defined for lactate, forming the basis for subsequent development of microwave sensor platform that is able to detect concentrations of lactic acid in CSF of volumes less than 1ml.

Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.

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Ayton, Scott; Diouf, Ibrahima; Bush, Ashley Ian

2018-05-01

To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau. Mixed-effects models of CSF Aβ 1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ 1-42 for up to 5 years. In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ 1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ 1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. Iron might facilitate Aβ deposition in Alzheimer's and accelerate the disease process. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

CSF flow: Correlation between signal void and CSF velocity measured by gated velocity phase-encoded MR imaging

International Nuclear Information System (INIS)

Mark, A.S.; Feinberg, D.A.

1986-01-01

The direction of the cerebrospinal fluid (CSF) flow in the foramen of Monro (FOM) and aqueduct was determined in 15 normal volunteers (5 of whom had also been studied with gated spin-echo sequences) using a cardiac-gated Fourier transform velocity imaging technique (VMR). The VMR showed that the periodic pattern of flow void seen in the aqueduct and FOM on the gated spin-echo images was due to antegrade CSF flow from the lateral ventricles into the third ventricle and aqueduct during systole and retrograde flow from the aqueduct into the third ventricle and lateral ventricles during late diastole. These findings could not be explained if the CSF pulsations originated in the third ventricle, as had been previously proposed, and suggest the lateral ventricles play an important role in the pulsatile motion of CSF

G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer

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Hollmén, Maija; Karaman, Sinem; Schwager, Simon; Lisibach, Angela; Christiansen, Ailsa J.; Maksimow, Mikael; Varga, Zsuzsanna; Jalkanen, Sirpa; Detmar, Michael

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlo macrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called “gate-keeper” subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression. PMID:27141367

Mathematical Modelling of CSF Pulsatile Flow in Aqueduct Cerebri.

Science.gov (United States)

Czosnyka, Zofia; Kim, Dong-Joo; Balédent, Olivier; Schmidt, Eric A; Smielewski, Peter; Czosnyka, Marek

2018-01-01

The phase-contrast MRI technique permits the non-invasive assessment of CSF movements in cerebrospinal fluid cavities of the central nervous system. Of particular interest is pulsatile cerebrospinal fluid (CSF) flow through the aqueduct cerebri. It is allegedly increased in hydrocephalus, having potential diagnostic value, although not all scientific reports contain unequivocally positive conclusions. For the mathematical simulation of CSF flow, we used a computational model of cerebrospinal blood/fluid circulation designed by a former student as his PhD project. With this model, cerebral blood flow and CSF may be simulated in various vessels using a system of non-linear differential equations as time-varying signals. The amplitude of CSF flow seems to be positively related to the amplitude of pulse waveforms of intracranial pressure (ICP) in situations where mean ICP increases, such as during simulated infusion tests and following step increases of resistance to CSF outflow. An additional positive association between the pulse amplitude of ICP and CSF flow can be seen during simulated increases in the amplitude of arterial pulses (without changes in mean arterial pressure, MAP). The opposite effect can be observed during step increases in the resistance of the aqueduct cerebri and with decreasing elasticity of the system, where the CSF flow amplitude and the ICP pulse amplitude are related inversely. Vasodilatation caused by both gradual decreases in MAP and by increases in PaCO2 provokes an elevation in the observed amplitude of pulsatile CSF flow. Preliminary results indicate that the pulsations of CSF flow may carry information about both CSF-circulatory and cerebral vasogenic components. In most cases, the pulsations of CSF flow are positively related to the pulse amplitudes of both arterial pressure and ICP and to a degree of cerebrovascular dilatation.

Reproducibility of CSF quantitative culture methods for estimating rate of clearance in cryptococcal meningitis.

Science.gov (United States)

Dyal, Jonathan; Akampurira, Andrew; Rhein, Joshua; Morawski, Bozena M; Kiggundu, Reuben; Nabeta, Henry W; Musubire, Abdu K; Bahr, Nathan C; Williams, Darlisha A; Bicanic, Tihana; Larsen, Robert A; Meya, David B; Boulware, David R

2016-05-01

Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (Pmethods was high (r≥0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (∼10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 ± 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Occurrence of occult CSF leaks during standard FESS procedures.

Science.gov (United States)

Bucher, S; Kugler, A; Probst, E; Epprecht, L; Stadler, R S; Holzmann, D; Soyka, M B

2018-03-18

To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. Prospective cohort study. An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.

CSF-1R as an inhibitor of apoptosis and promoter of proliferation, migration and invasion of canine mammary cancer cells

Science.gov (United States)

2013-01-01

Background Tumor-associated macrophages (TAMs) have high impact on the cancer development because they can facilitate matrix invasion, angiogenesis, and tumor cell motility. It gives cancer cells the capacity to invade normal tissues and metastasize. The signaling of colony-stimulating factor-1 receptor (CSF-1R) which is an important regulator of proliferation and differentiation of monocytes and macrophages regulates most of the tissue macrophages. However, CSF-1R is expressed also in breast epithelial tissue during some physiological stages i.g.: pregnancy and lactation. Its expression has been also detected in various cancers. Our previous study has showed the expression of CSF-1R in all examined canine mammary tumors. Moreover, it strongly correlated with grade of malignancy and ability to metastasis. This study was therefore designed to characterize the role of CSF-1R in canine mammary cancer cells proliferation, apoptosis, migration, and invasion. As far as we know, the study presented hereby is a pioneering experiment in this field of veterinary medicine. Results We showed that csf-1r silencing significantly increased apoptosis (Annexin V test), decreased proliferation (measured as Ki67 expression) and decreased migration (“wound healing” assay) of canine mammary cancer cells. Treatment of these cells with CSF-1 caused opposite effect. Moreover, csf-1r knock-down changed growth characteristics of highly invasive cell lines on Matrigel matrix, and significantly decreased the ability of these cells to invade matrix. CSF-1 treatment increased invasion of cancer cells. Conclusion The evidence of the expression and functional role of the CSF-1R in canine mammary cancer cells indicate that CSF-1R targeting may be a good therapeutic approach. PMID:23561040

Utility of CSF biomarkers in psychiatric disorders: a national multicentre prospective study.

Science.gov (United States)

Paquet, Claire; Magnin, Eloi; Wallon, David; Troussière, Anne-Cécile; Dumurgier, Julien; Jager, Alain; Bellivier, Frank; Bouaziz-Amar, Elodie; Blanc, Frédéric; Beaufils, Emilie; Miguet-Alfonsi, Carole; Quillard, Muriel; Schraen, Susanna; Pasquier, Florence; Hannequin, Didier; Robert, Philippe; Hugon, Jacques; Mouton-Liger, François

2016-06-13

Affective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life's ordinary demands and routines. These conditions can be a prodromal event of Alzheimer's disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid β, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis. In a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder. Of 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter. This study revealed that about 20 % of patients with a primary

CSF circulation in subjects with the empty sella syndrome

International Nuclear Information System (INIS)

Brismar, K.; Bergstrand, G.

1981-01-01

In the present study the CSF circulation was analyzed in 48 subjects with ESS with gamma cisternography, pneumoencephalography (PEG) und computed tomography (CT). In 80% of the subjects the CSF circulation was retarded with convexity block which was combined with widened CSF transport pathways and basal cisterns. These findings were correlated with the clinical signs and symptoms. Headache, psychiatric symptoms, visual field defects and obesity, however, were not related to the impaired CSF circulation. It is concluded that impaired CSF dynamics leading to intermittent increase of ICP has a major impact on the development of the ESS and that most of the patients' complaints are related to this disturbance. Thus is is important to obtain information of the CSF dynamics concurrent with the diagnosis of ESS. For this purpose PEG or CT may be used as the first examination. Moreover, the patient should be examined at least every second year for symptoms and signs of progressive impairments of the CSF circulation. (orig./MG)

Electronegative L5-LDL induces the production of G-CSF and GM-CSF in human macrophages through LOX-1 involving NF-κB and ERK2 activation.

Science.gov (United States)

Yang, Tzu-Ching; Chang, Po-Yuan; Kuo, Tzu-Ling; Lu, Shao-Chun

2017-12-01

Circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are associated with the severity of acute myocardial infarction (AMI). However, what causes increases in G-CSF and GM-CSF is unclear. In this study, we investigated whether L5-low-density lipoprotein (LDL), a mildly oxidized LDL from AMI, can induce G-CSF and GM-CSF production in human macrophages. L1-LDL and L5-LDL were isolated through anion-exchange chromatography from AMI plasma. Human macrophages derived from THP-1 and peripheral blood mononuclear cells were treated with L1-LDL, L5-LDL, or copper-oxidized LDL (Cu-oxLDL) and G-CSF and GM-CSF protein levels in the medium were determined. In addition, the effects of L5-LDL on G-CSF and GM-CSF production were tested in lectin-type oxidized LDL receptor-1 (LOX-1), CD36, extracellular signal-regulated kinase (ERK) 1, and ERK2 knockdown THP-1 macrophages. L5-LDL but not L1-LDL or Cu-oxLDL significantly induced production of G-CSF and GM-CSF in macrophages. In vitro oxidation of L1-LDL and L5-LDL altered their ability to induce G-CSF and GM-CSF, suggesting that the degree of oxidation is critical for the effects. Knockdown and antibody neutralization experiments suggested that the effects were caused by LOX-1. In addition, nuclear factor (NF)-κB and ERK1/2 inhibition resulted in marked reductions of L5-LDL-induced G-CSF and GM-CSF production. Moreover, knockdown of ERK2, but not ERK1, hindered L5-LDL-induced G-CSF and GM-CSF production. The results indicate that L5-LDL, a naturally occurring mild oxidized LDL, induced G-CSF and GM-CSF production in human macrophages through LOX-1, ERK2, and NF-κB dependent pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA.

Science.gov (United States)

Joseph, Jeymohan; Cinque, Paola; Colosi, Deborah; Dravid, Ameet; Ene, Luminita; Fox, Howard; Gabuzda, Dana; Gisslen, Magnus; Beth Joseph, Sarah; Letendre, Scott; Mukerji, Shibani S; Nath, Avindra; Perez-Valero, Ignacio; Persaud, Deborah; Price, Richard W; Rao, Vasudev R; Sacktor, Ned; Swanstrom, Ronald; Winston, Alan; Wojna, Valerie; Wright, Edwina; Spudich, Serena

2016-10-05

CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most cases, neurological consequences are not apparent. Attempts at characterising the biological substrates of CSF escape and further investigating the neurological consequences need to be made to better understand the implications of this condition for the HIV cure agenda as well as for clinical outcomes. The Global CSF HIV-1 Escape Consortium meeting, convened by the US National Institute of Mental Health, was a first step to gather investigators from diverse sites to discuss opportunities for future collaborative work on this emerging issue. To better understand CSF HIV escape and allow cross-site data reconciliation, it will be useful to reach a consensus set of definitions of the distinct forms of CSF escape, without which concerted cross-site efforts are difficult.

Clinical significance of determination of some serum cytokines (IL-8, IL-10, IL-18, M-CSF) levels in patients with periodontitis

International Nuclear Information System (INIS)

Wei Dong; Zhang Xiaolei; Yang Chunxiu; Chen Guanghua

2008-01-01

Objective: To explore the significance of changes of serum IL-8, IL-10, IL-18 and M-CSF levels in patients with periodontitis. Methods: Serum levels of IL-8, IL-10, M-CSF (with RIA) and IL-18 (with ELISA) were measured in 55 patients with periodontitis both before and after treatment as well as in 35 controls. Results: Before treatment, serum levels of IL-8, IL-10, IL-18 and M-CSF were significantly higher in the patients than those in the controls (P<0.01). After one month of treatment, the serum IL-8, IL-10, IL-18 and M-CSF levels decreased somewhat, but were still significantly higher than those in controls (P<0.05). Conclusion: There was disturbance of immunomodulation in patients with periodontitis as expressed by the changes of several cytokines levels in the eourse of the diseases. (authors)

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

Energy Technology Data Exchange (ETDEWEB)

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

2001-06-01

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

[Intracranial pressure monitoring and CSF dynamics in patients with neurological disorders: indications and practical considerations].

Science.gov (United States)

Poca, M; Sahuquillo, J

2001-01-01

The study of cerebrospinal fluid (CSF) dynamics is central to the diagnosis of adult chronic hydrocephalus (ACH). At present, many neurology and neurosurgery departments use one or more tests to guide diagnosis of this syndrome and to predict patient response to shunting. In specialised centres, the study of CSF dynamics is combined with continuous intracranial pressure (ICP) monitoring. Determination of several variables of CSF dynamics and definitions of qualitative and quantitative characteristics of ICP can be used to establish whether the hydrocephalus is active, compensated or arrested. CSF dynamics and ICP monitoring can also be used to check the correct functioning of the shunt and can be of use in the clinical management of patients with pseudotumor cerebri. Moreover, ICP monitoring is used to guide the treatment of several acute neurological processes. The aim of this review is to describe the fundamentals of CSF dynamics studies and the bases of continuous ICP monitoring. The advantages and disadvantages of several hydrodynamic tests that can be performed by lumbar puncture, as well as the normal and abnormal characteristics of an ICP recording, are discussed.

G-CSF-primed BM for allogeneic SCT: revisited.

Science.gov (United States)

Pessach, I; Resnick, I; Shimoni, A; Nagler, A

2015-07-01

G-SCF-mobilized PBSC (GPB) grafts have a higher cell dose and somewhat more committed progenitor cells than steady-state BM (SBM), resulting in faster engraftment and faster immunological reconstitution. On the other hand, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) are similar both for PB and for BM. In contrast to SBM, G-CSF-primed BM (GBM) grafts stimulate HSC proliferation, increasing cell dose and thus resulting in faster engraftment because of higher cell dose infused, or because of treatment with G-CSF. Furthermore, GBM may induce tolerance and functional modulations in donor hematopoiesis and immunity, further reducing GVHD incidence, which is already lower with SBM compared with GPB grafts. Overall, a growing body of clinical evidence suggests that GBM transplants may share the advantages of GPB transplantations, without the associated increased risk of GVHD, and might be an attractive graft source for allogeneic SCTs.

The effect of CSF-1 administration on lung maturation in a mouse model of neonatal hyperoxia exposure.

Science.gov (United States)

Jones, Christina V; Alikhan, Maliha A; O'Reilly, Megan; Sozo, Foula; Williams, Timothy M; Harding, Richard; Jenkin, Graham; Ricardo, Sharon D

2014-09-06

Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration. Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 μg/g, daily × 5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry. Seven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp + PBS and Hyp + CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp + PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp + PBS and Hyp + CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an

Effects of G-CSF on telomere lengths in PBMCs from human immunodeficiency virus-infected patients

DEFF Research Database (Denmark)

Aladdin, H; Ullum, H; Schjerling, P

2000-01-01

, and not in CD4+ T cells. In this double-blind placebo-controlled study, we investigated the effect of granulocyte colony stimulating factor (G-CSF) treatment combined with highly active antiretroviral therapy (HAART) on mean telomere length in peripheral blood mononuclear cells (PBMC). The terminal restriction...... fragment (TRF) length showed no changes during G-CSF treatment although the number of lymphocytes increased significantly. The mean TRF length correlated positively (R = 0.552, P = 0.009) and negatively (R = -0.503, P = 0.02) to the proportion of CD4+ memory and naïve cells, respectively. Our data suggest...

Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection.

Science.gov (United States)

Price, Richard W; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena; Smith, Richard D; Jacobs, Jon M; Brown, Joseph N; Gisslen, Magnus

2013-12-01

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

Energy Technology Data Exchange (ETDEWEB)

Price, Richard W.; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E.; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena S.; Smith, Richard D.; Jacobs, Jon M.; Brown, Joseph N.; Gisslen, Magnus

2013-12-13

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previouslydefined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

CSF HYPOCRETIN CONCENTRATION IN VARIOUS NEUROLOGICAL AND SLEEP DISORDERS

OpenAIRE

Tsutsui, Kou; Kanbayashi, Takashi; Sawaishi, Yukio; Tokunaga, Jun; Sato, Masahiro; Shimizu, Tetsuo

2011-01-01

Recent CSF and postmortem brain hypocretin measurements in human narcolepsy suggest that hypocretin deficiency is involved in the pathophysiology of the disease. Thus, it is important to study whether neurological disorders also have abnormal CSF hypocretin levels. We therefore measured hypocretins in the CSF of various neurological disorders and obstructive sleep apnea syndrome (OSAS) to identify altered hypocretin levels. CSF hypocretin levels in patients with OSAS and neurological diseases...

Human Granulocyte Colony-Stimulating Factor (hG-CSF) Expression in Plastids of Lactuca sativa

OpenAIRE

Sharifi Tabar, Mehdi; Habashi, Ali Akbar; Rajabi Memari, Hamid

2013-01-01

Background: Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. Methods: hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA ter...

Respiration and the watershed of spinal CSF flow in humans.

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Dreha-Kulaczewski, Steffi; Konopka, Mareen; Joseph, Arun A; Kollmeier, Jost; Merboldt, Klaus-Dietmar; Ludwig, Hans-Christoph; Gärtner, Jutta; Frahm, Jens

2018-04-04

The dynamics of human CSF in brain and upper spinal canal are regulated by inspiration and connected to the venous system through associated pressure changes. Upward CSF flow into the head during inspiration counterbalances venous flow out of the brain. Here, we investigated CSF motion along the spinal canal by real-time phase-contrast flow MRI at high spatial and temporal resolution. Results reveal a watershed of spinal CSF dynamics which divides flow behavior at about the level of the heart. While forced inspiration prompts upward surge of CSF flow volumes in the entire spinal canal, ensuing expiration leads to pronounced downward CSF flow, but only in the lower canal. The resulting pattern of net flow volumes during forced respiration yields upward CSF motion in the upper and downward flow in the lower spinal canal. These observations most likely reflect closely coupled CSF and venous systems as both large caval veins and their anastomosing vertebral plexus react to respiration-induced pressure changes.

Safety of Pegfilgrastim (Neulasta in Patients with Sickle Cell Trait/Anemia

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Pashtoon Murtaza Kasi

2013-01-01

Full Text Available Pegfilgrastim (Neulasta is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF attached to a polyethylene glycol (PEG molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.

Pivotal Roles of GM-CSF in Autoimmunity and Inflammation

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Shiomi, Aoi; Usui, Takashi

2015-01-01

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4+ T cells. Therefore, the mechanism of GM-CSF-producing CD4+ T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review. PMID:25838639

Chimeric classical swine fever (CSF)-Japanese encephalitis (JE) viral replicon as a non-transmissible vaccine candidate against CSF and JE infections.

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Yang, Zhenhua; Wu, Rui; Li, Robert W; Li, Ling; Xiong, Zhongliang; Zhao, Haizhong; Guo, Deyin; Pan, Zishu

2012-04-01

A trans-complemented chimeric CSF-JE virus replicon was constructed using an infectious cDNA clone of the CSF virus (CSFV) Alfort/187 strain. The CSFV E2 gene was deleted, and a fragment containing the region encoding a truncated envelope protein (tE, amino acid 292-402, domain III) of JE virus (JEV) was inserted into the resultant plasmid, pA187delE2, to generate the recombinant cDNA clone pA187delE2/JEV-tE. Porcine kidney 15 (PK15) cells that constitutively express the CSFV E2p7 proteins were then transfected with in vitro-transcribed RNA from pA187delE2/JEV-tE. As a result, the chimeric CSF-JE virus replicon particle (VRP), rv187delE2/JEV-tE, was rescued. In a mouse model, immunization with the chimeric CSF-JE VRP induced strong production of JEV-specific antibody and conferred protection against a lethal JEV challenge. Pigs immunized with CSF-JE VRP displayed strong anti-CSFV and anti-JEV antibody responses and protection against CSFV and JEV challenge infections. Our evidence suggests that E2-complemented CSF-JE VRP not only has potential as a live-attenuated non-transmissible vaccine candidate against CSF and JE but also serves as a potential DIVA (Differentiating Infected from Vaccinated Animals) vaccine for CSF in pigs. Together, our data suggest that the non-transmissible chimeric VRP expressing foreign antigenic proteins may represent a promising strategy for bivalent DIVA vaccine design. Copyright © 2012 Elsevier B.V. All rights reserved.

Exploring the efficacy of endoscopic ventriculostomy for hydrocephalus treatment via a multicompartmental poroelastic model of CSF transport: a computational perspective.

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John C Vardakis

Full Text Available This study proposes the implementation of a Multiple-Network Poroelastic Theory (MPET model coupled with finite-volume computational fluid dynamics for the purpose of studying, in detail, the effects of obstructing CSF transport within an anatomically accurate cerebral environment. The MPET representation allows the investigation of fluid transport between CSF, brain parenchyma and cerebral blood, in an integral and comprehensive manner. A key novelty in the model is the amalgamation of anatomically accurate choroid plexuses with their feeding arteries and a simple relationship relaxing the constraint of a unique permeability for the CSF compartment. This was done in order to account for the Aquaporin-4-mediated swelling characteristics. The aim of this varying permeability compartment was to bring to light a feedback mechanism that could counteract the effects of ventricular dilation and subsequent elevations of CSF pressure through the efflux of excess CSF into the blood system. This model is used to demonstrate the impact of aqueductal stenosis and fourth ventricle outlet obstruction (FVOO. The implications of treating such a clinical condition with the aid of endoscopic third (ETV and endoscopic fourth (EFV ventriculostomy are considered. We observed peak CSF velocities in the aqueduct of the order of 15.6 cm/s in the healthy case, 45.4 cm/s and 72.8 cm/s for the mild and severe cases respectively. The application of ETV reduced the aqueductal velocity to levels around 16-17 cm/s. Ventricular displacement, CSF pressure, wall shear stress (WSS and pressure difference between lateral and fourth ventricles (ΔP increased with applied stenosis, and subsequently dropped to nominal levels with the application of ETV. The greatest reversal of the effects of atresia come by opting for ETV rather than the more complicated procedure of EFV.

GM-CSF ameliorates microvascular barrier integrity via pericyte-derived Ang-1 in wound healing.

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Yan, Min; Hu, Yange; Yao, Min; Bao, Shisan; Fang, Yong

2017-11-01

Skin wound healing involves complex coordinated interactions of cells, tissues, and mediators. Maintaining microvascular barrier integrity is one of the key events for endothelial homeostasis during wound healing. Vasodilation is observed after vasoconstriction, which causes blood vessels to become porous, facilitates leukocyte infiltration and aids angiogenesis at the wound-area, postinjury. Eventually, vessel integrity has to be reestablished for vascular maturation. Numerous studies have found that granulocyte macrophage colony-stimulating factor (GM-CSF) accelerates wound healing by inducing recruitment of repair cells into the injury area and releases of cytokines. However, whether GM-CSF is involving in the maintaining of microvascular barrier integrity and the underlying mechanism remain still unclear. Aim of this study was to investigate the effects of GM-CSF on modulation of microvascular permeability in wound healing and underlying mechanisms. Wound closure and microvascular leakage was investigated using a full-thickness skin wound mouse model after GM-CSF intervention. The endothelial permeability was measured by Evans blue assay in vivo and in vitro endothelium/pericyte co-culture system using a FITC-Dextran permeability assay. To identify the source of angiopoietin-1 (Ang-1), double staining is used in vivo and ELISA and qPCR are used in vitro. To determine the specific effect of Ang-1 on GM-CSF maintaining microvascular stabilization, Ang-1 siRNA was applied to inhibit Ang-1 production in vivo and in vitro. Wound closure was significantly accelerated and microvascular leakage was ameliorated after GM-CSF treatment in mouse wound sites. GM-CSF decreased endothelial permeability through tightening endothelial junctions and increased Ang-1 protein level that was derived by perictye. Furthermore, applications of siRNAAng-1 inhibited GM-CSF mediated protection of microvascular barrier integrity both in vivo and in vitro. Our data indicate that GM-CSF

CSF and plasma testosterone in attempted suicide.

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Stefansson, Jon; Chatzittofis, Andreas; Nordström, Peter; Arver, Stefan; Åsberg, Marie; Jokinen, Jussi

2016-12-01

Very few studies have assessed testosterone levels in the cerebrospinal fluid in suicide attempters. Aggressiveness and impulsivity are common behavioural traits in suicide attempters. Dual-hormone serotonergic theory on human impulsive aggression implies high testosterone/cortisol ratio acting on the amygdala and low serotonin in the prefrontal cortex. Our aim was to examine the CSF and plasma testosterone levels in suicide attempters and in healthy volunteers. We also assessed the relationship between the testosterone/cortisol ratio, aggressiveness and impulsivity in suicide attempters. 28 medication-free suicide attempters and 19 healthy volunteers participated in the study. CSF and plasma testosterone sulfate and cortisol levels were assessed with specific radio-immunoassays. The Karolinska Scales of Personality was used to assess impulsivity and aggressiveness. All patients were followed up for cause of death. The mean follow-up period was 21 years. Male suicide attempters had higher CSF and plasma testosterone levels than age- matched male healthy volunteers. There were no significant differences in CSF testosterone levels in female suicide attempters and healthy female volunteers. Testosterone levels did not differ significantly in suicide victims compared to survivors. In male suicide attempters, the CSF testosterone/cortisol ratio showed a significant positive correlation with both impulsivity and aggressiveness. Higher CSF testosterone levels may be associated with attempted suicide in young men through association with both aggressiveness and impulsivity, a key endophenotype in young male suicide attempters. Copyright © 2016 Elsevier Ltd. All rights reserved.

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).

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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

A short review on a complication of lumbar spine surgery: CSF leak.

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Menon, Sajesh K; Onyia, Chiazor U

2015-12-01

Cerebrospinal fluid (CSF) leak is a common complication of surgery involving the lumbar spine. Over the past decades, there has been significant advancement in understanding the basis, management and techniques of treatment for post-operative CSF leak following lumbar spine surgery. In this article, we review previous work in the literature on the various factors and technical errors during or after lumbar spine surgery that may lead to this feared complication, the available options of management with focus on the various techniques employed, the outcomes and also to highlight on the current trends. We also discuss the presentation, factors contributing to its development, basic concepts and practical aspects of the management with emphasis on the different techniques of treatment. Different outcomes following various techniques of managing post-operative CSF leak after lumbar spine surgery have been well described in the literature. However, there is currently no most ideal technique among the available options. The choice of which technique to be applied in each case is dependent on each surgeon's cumulative experience as well as a clear understanding of the contributory underlying factors in each patient, the nature and site of the leak, the available facilities and equipment. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of lipoproteins in human and canine cerebrospinal fluid (CSF)

International Nuclear Information System (INIS)

Pitas, R.E.; Weisgraber, K.H.; Boyles, J.K.; Lee, S.; Mahley, R.W.

1986-01-01

Previously the authors demonstrated that rat brain astrocytes in vitro synthesize and secrete apo-E and possess apo-B,E(LDL) receptors. The apo-E secreted by astrocytes and apo-E in rat brain extracts differed from serum apo-E in two respects. Brain apo-E had a higher apparent molecular weight and a higher percentage of more acidic isoforms. To characterize further the apo-E within the central nervous system, apo-E in human and canine CSF was investigated. Compared to plasma apo-E, CSF apo-E had a higher apparent M/sub r/ and a higher percentage of acidic isoforms which were sialylated, as shown by neuraminidase digestion. The apo-E in human CSF was approx.5-10% of the plasma level. In CSF 60-80% of the apo-E was in lipoproteins with d = 1.09-1.15. The remainder of the apo-E was in the d > 1.21 fraction. Human CSF lipoproteins were primarily spherical (110-190 A) while canine CSF lipoproteins were a mixture of discs (205 x 65 A) while canine CSF lipoproteins were a mixture of discs (205 x 65 A) and spheres (100-150 A). The CSF also contained apo-AI in the d = 1.09-1.15 g/ml fraction. Human CSF lipoproteins containing both apo-E and apo-AI were isolated on an anti-apo-E affinity column, suggesting that apo-E and AI occurred in the same particles. The CSF apo-E-containing lipoproteins competed for binding of 125 I-LDL to the apo-B,E(LDL) receptor. There was no detectable apo-B in CSF. These data suggest that CSF lipoproteins might transport lipid and regulate lipid homeostasis within the brain

CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders.

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Pranzatelli, Michael R; Tate, Elizabeth D; McGee, Nathan R; Verhulst, Steven J

2014-01-15

Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus-myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Measurement of CSF volume with 3D-FASE MRI

International Nuclear Information System (INIS)

Kanayama, Shoichi; Calderon, A.; Makita, Jun-ichi; Ohara, Yukou; Tsunoda, Akira; Sato, Kiyoshi.

1997-01-01

A noninvasive and fast cerebrospinal fluid (CSF) volume measurement method has been developed using 3D-FASE MRI and a semi-automatic segmentation process. Images with a high CSF/(gray and white matter) ratio (about 10-20) were obtained with a heavily T 2 weighted 3D-FASE sequence. The CSF region was segmented with a region growing method and the volume was calculated from the number of segmented voxels with a signal intensity weighted summation. Total measurement time was about 30 minutes for each study. The errors of the measured volumes were within 10% for the phantom experiments. Intracranial CSF volumes of normal volunteers ranged between about 100 and 200 cc and the ventricle/intracranial CSF ratio was about 10%. 3D display of the segmented intracranial and ventricle CSF regions was also carried out and proved to be useful to understand the anatomy. Increased intracranial and/or ventricle CSF volumes were obtained for a hydrocephalic patient and one patient with probable cerebral atrophy. The results suggest that the developed method could be used for the diagnosis of patients with neurological diseases. (author)

Mobilizing peripheral blood stem cells with high-dose G-CSF alone is as effective as with Dexa-BEAM plus G-CSF in lymphoma patients.

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Kröger, N; Zeller, W; Fehse, N; Hassan, H T; Krüger, W; Gutensohn, K; Lölliger, C; Zander, A R

1998-09-01

We compared retrospectively the efficacy of granulocyte colony stimulating factor (G-CSF) alone with chemotherapy plus G-CSF in mobilizing CD34-positive cells in patients with malignant lymphoma. 35 patients underwent peripheral blood stem cell (PBSC) collection following mobilization either with 24 microg/kg G-CSF for 4 consecutive days (n = 18) or Dexa-BEAM chemotherapy plus 5 microg/kg G-CSF (n = 17). High-dose G-CSF was well tolerated with only slight bone pain and/or myalgia. The Dexa-BEAM therapy required hospitalization with a median duration of 21 d. The median number of apheresis procedures in both groups was two (range two to four), resulting in a median of 5.3 and 5.1 x 10(6) CD34+ cells/kg. No patients in the G-CSF group, but one in the Dexa-BEAM group, failed to reach the target of collecting >2.0 x 10(6) CD34+ cells/kg. The number of CFU-GM (10.4 v 6.0 x 10(5)/kg) and of BFU-E (10.6 v 4.5 x 10(5)/kg; P = 0.04) was higher in the G-CSF group than in the Dexa-BEAM group. A subset analysis of CD34+ cells was performed in 16 patients showing a higher mean of Thy-1 (CD90w) coexpression in the G-CSF than in the Dexa-BEAM group (4.8 v 1.8%, P = 0.12). Additionally the percentage of CD34+/CD38- cells was higher in the G-CSF group (10.66% v 8.8%). However, these differences were not statistically significant. The median time to leucocyte and platelet engraftment after high-dose chemotherapy was slightly shorter in the G-CSF than in the Dexa-BEAM group (9 v 10 and 12 v 13.5 d, respectively). These results demonstrate that high-dose G-CSF is as effective as Dexa-BEAM plus G-CSF in mobilizing peripheral blood stem cells and produces prompt engraftment. The major advantages of G-CSF mobilization were the safe outpatient self-application and the fixed-day apheresis.

Therapeutic use of recombinant human G-CSF (rhG-CSF) in a canine model of sublethal and lethal whole-body irradiation

International Nuclear Information System (INIS)

MacVittie, T.J.; Monroy, R.L.; Patchen, M.L.; Souza, L.M.

1990-01-01

Recombinant human G-CSF (rhG-CSF) was studied for its ability to modulate haemopoiesis in normal dogs as well as to decrease therapeutically the severity and duration of neutropenia in sublethally and lethally irradiated dogs. Data indicate that in the lethally irradiated dog, effective cytokine therapy with rhG-CSF will increase survival through the induction of earlier recovery of neutrophils and platelets. (author)

Computed tomography in the CSF seeding of brain tumors

International Nuclear Information System (INIS)

Nakagawa, Yoshio; Fujimoto, Masahito; Naruse, Shoji; Ueda, Satoshi; Hirakawa, Kimiyoshi

1981-01-01

In the past three years nine cases of brain tumors with CSF seeding have been revealed by computed tomography (CT). We have been analyzing the CT pattern of CSF seeding, CSF cytology, and spinal metastasis. The brain tumors were classified as follows: five medulloblastomas, two glioblastomas, one germinoma, and one meningeal carcinomatosis. Their CT patterns were divided into three groups: 1) diffuse seeding of the basal cisterns. 2) invasion of the ventricular wall. 3) solitary metastasis in the ventricle. The subarachnoid seeding included four medulloblastomas and one meningeal carcinomatosis. The second type of seeding included two glioblastomas and one germinoma. One medulloblastoma had a single metastasis in the lateral ventricle. In the medulloblastomas, the diffuse seeding of the basal cisterns was more common than the invasion of the ventricular wall or solitary metastasis in the ventricle. Medulloblastomas were also accompanied by spinal metastasis. Because there were many cases of spinal metastasis in the first type of seeding, we concluded that there was a definite correlation between the CSF seeding of the basal cisterns and spinal metastasis. Needless to say, CT was the most important method for the diagnosis of the CSF seeding of brain tumors. However, because there was a case of CSF seeding which had not been demonstrated by CT, we also emphasized the importance of neurological examination and CSF cytology in the diagnosis of the CSF seeding of brain tumors. (author)

Radiologic assessment of spinal CSF leakage in spontaneous intracranial hypotension

International Nuclear Information System (INIS)

Han, Chang Jin; Kim, Ji Hyung; Kim, Jang Sung; Kim, Sun Yong; Suh, Jung Ho

1999-01-01

To assess the usefulness of imaging modalities in the detection of spinal CSF leakage in spontaneous intracranial hypotension. Fifteen patients who complained of postural headache without any preceding cause showed typical brain MR findings of intracranial hypotension, including radiologically confirmed CSF leakage. All fifteen underwent brain MRI and radionuclide cisternography. CT myelography was performed in eight patients and spinal MRI in six. Medical records, imaging findings and the incidence of spinal CSF leakage during each modality were retrospectively reviewed. CSF leakage was most common at the cervicothoracic junction, where in seven of 15 cases it was seen on radionuclide cisternography as increased focal paraspinal activity. Leakage was noted at the mid-tho-racic level in three patients, at the upper thoracic level in two, and at the cervical and lumbar levels in the remaining two. In two patients multiple CSF leaks were noted, and in all, early radioactive accumulation in the bladder was visualized. CT myelography revealed extrathecal and paraspinal contrast leakage in three of eight patients, and among those who underwent spinal MRI, dural enhancement was observed at the site of CSF leakage in all six, abnormal CSF signal in the neural foramen in one, and epidural CSF collection in one. Radionuclide cisternography is a useful method for the detection of CSF leakage in spontaneous intracranial hypotension. CT myelography and spinal MRI help determine the precise location of leakage

Quantitative and clinical evaluation of whole CSF-axis RI image

International Nuclear Information System (INIS)

Tomono, Yuji; Nose, Tadao; Maki, Yutaka

1987-01-01

Whole CSF-axis RI scintigraphy was evaluated in 122 adult patients intending to know not only intracranial CSF flow but also the dynamics of whole CSF axis, particularly of spinal CSF flow. The change of radioactivity in several compartments was studied quantitatively with a dataprocessor on 18 cases with dilated ventricles, and more practically, clinical features and the findings of the films were comparatively studied on all the cases. The results were as follows: (1) Roughly speaking, the findings were classified into two types, i.e. a type with early RI movement to the intracranial CSF space and another with stagnation of radioactivity in spinal space till late stage, even 48 hours after RI injection (spinal stasis). (2) Although majority of the cases with spinal stasis did not show ventricular stasis, a shunt operation was not effective even when ventricular stasis was observed. (3) Spinal stasis tended to increase with aging, and was observed more frequently in cases with possible severe cerebral damage, as severe cerebrovascular disease and severe deterioration of mental activity. (4) The clearance of radioactivity of whole CSF-axis was remarkably delayed. It is considered that the spinal CSF flow is generated by intracranial CSF pulsation and, so, that spinal stasis shows the condition of lowered CSF flow by pulsation due to cerebral parenchymal damages. (author)

The European iNPH Multicentre Study on the predictive values of resistance to CSF outflow and the CSF Tap Test in patients with idiopathic normal pressure hydrocephalus

DEFF Research Database (Denmark)

Wikkelsø, Carsten; Hellström, Per; Klinge, Petra Margarete

2013-01-01

The objective was to determine the sensitivity, specificity, and positive and negative predictive values of the CSF Tap Test (CSF TT) and resistance to CSF outflow (Rout) for the outcome of shunting in a sample of patients with idiopathic normal pressure hydrocephalus (iNPH).......The objective was to determine the sensitivity, specificity, and positive and negative predictive values of the CSF Tap Test (CSF TT) and resistance to CSF outflow (Rout) for the outcome of shunting in a sample of patients with idiopathic normal pressure hydrocephalus (iNPH)....

Post craniotomy extra-ventricular drain (EVD) associated nosocomial meningitis: CSF diagnostic criteria.

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Muñoz-Gómez, Sigridh; Wirkowski, Elizabeth; Cunha, Burke A

2015-01-01

Because external ventricular drains (EVDs) provide access to cerebrospinal fluid (CSF), there is potential for EVD associated acute bacterial meningitis (EVD-AM). Post-craniotomy, in patients with EVDs, one or more CSF abnormalities are commonly present making the diagnosis of EVD-AM problematic. EVD-AM was defined as elevated CSF lactic acid (>6 nmol/L), plus CSF marked pleocytosis (>50 WBCs/mm(3)), plus a positive Gram stain (same morphology as CSF isolate), plus a positive CSF culture of neuropathogen (same morphology as Gram stained organism). We reviewed 22 adults with EVDs to determine if our four CSF parameters combined accurately identified EVD-AM. No single or combination of <4 CSF parameters correctly diagnosed or ruled out EVD-AM. Combined our four CSF parameters clearly differentiated EVD-AM from one case of pseudomeningitis due to E. cloacae. We conclude that our four CSF criteria combined are useful in diagnosing EVD-AM in adults. Copyright © 2015 Elsevier Inc. All rights reserved.

Haematological effects of rhG-CSF on dogs exposed to 6.5 Gy uneven γ-radiation

International Nuclear Information System (INIS)

Luo Qingliang; Xia Zhenbiao; Dong Bo

1996-01-01

The stimulative effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) on hematopoietic regeneration were studied in dogs receiving an uneven γ-irradiation with the pelvis shielded at a dose of 6.5 Gy. In the treated dogs, intravenous administration of rhG-CSF at 5 or 10 μg/kg per day for 16 to 20 days caused significant increases of peripheral blood leucocytes, neutrophils, reticulocytes, and platelets. The nucleated cell and CFU-GM counts of bone marrow also showed an obvious rise, while the hemoglobin level did not significantly change during the course of treatment. In the irradiated dogs treated with rhG-CSF, the severity of neutropenia decreased, and its duration shortened

Normalization of periodontal tissues in osteopetrotic mib mutant rats, treated with CSF-1

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Wojtowicz, A.; Yamauchi, M.; Sotowski, R.; Ostrowski, K.

1998-01-01

The osteopetrotic mib mutation in rats causes defects in the skeletal bone tissue in young animals. These defects, i.e. slow bone remodelling, changes in both crystallinity and mineral content, are transient and undergo normalization, even without any treatment in 6-wk-old animals. Treatment with CSF-1 (colony stimulating factor-1) accelerates the normalization process in skeletal bones. The periodontal tissues around the apices of incisors show abnormalities caused by the slow remodelling process of the mandible bone tissue, the deficiency of osteoclasts and their abnormal morphology, as well as the disorganization of periodontal ligament fibres. In contrast to the skeletal tissues, these abnormalities would not undergo spontaneous normalization. Under treatment with colony stimulating factor 1 (CSF-1), the primitive bone trabeculae of mandible are resorbed and the normalization of the number of osteoclasts and their cytology occurs. The organization of the periodontal ligament fibres is partially restored, resembling the histological structure of the normal one.

Variability of CSF Alzheimer's disease biomarkers: implications for clinical practice.

Directory of Open Access Journals (Sweden)

Stephanie J B Vos

Full Text Available BACKGROUND: Cerebrospinal fluid (CSF biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD. OBJECTIVE: We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. METHODS: We measured CSF amyloid-β (Aβ 1-42, total tau (t-tau, and phosphorylated tau (p-tau by INNOTEST enzyme-linked-immunosorbent assays (ELISA in a memory clinic population (n = 126. Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern. RESULTS: CSF intralaboratory variability was higher for Aβ1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal of 26% of the subjects based on Aβ1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Aβ1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Aβ1-42, 1% based on t-tau, and 22% based on p-tau. CONCLUSIONS: Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Aβ1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.

Tumor-Derived G-CSF Facilitates Neoplastic Growth through a Granulocytic Myeloid-Derived Suppressor Cell-Dependent Mechanism

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Waight, Jeremy D.; Hu, Qiang; Miller, Austin; Liu, Song; Abrams, Scott I.

2011-01-01

Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy. PMID:22110722

Influence of rhTPO/GM-CSF fusion protein on hemopoiesis in mice irradiated with 60Co γ-rays

International Nuclear Information System (INIS)

Cao Hua; Ge Zhongliang; Zhang Qunwei; Liu Xiuzhen

1999-01-01

Objective: To find a new biological therapy for secondary hematopoietic failure including anemia, infection and hemorrhage after administration of chemotherapeutic drugs etc. Methods: hGM-CSF gene was ligated with hTPO gene isolated from human fetal liver mRNA and a new fusion protein rh TPO/GM-CSF obtained. Results: The new fusion protein could promote recovery of peripheral WBC and PLT of 5.0 Gy irradiated mice. BFU-E, CFU-Meg and CFU-GM in bone marrow of mice after irradiation recovered significantly by treatment with rhTPO/GM-CSF fusion protein for 10 days. Conclusion: These results suggest that the new fusion protein has the biological activity of both hTPO and hGM-CSF simultaneously and can stimulate the proliferation of megakaryocytes and granulocyte progenitors

Absence of systemic oxidative stress and increased CSF prostaglandin F2α in progressive MS

DEFF Research Database (Denmark)

Lam, Magda A.; Maghzal, Ghassan J.; Khademi, Mohsen

2016-01-01

Objective: We aimed to investigate the role of oxidative stress in the progression of multiple sclerosis (MS).  Methods: We determined by liquid chromatography-tandem mass spectrometry nonenzymatic (F2-isoprostanes) and enzymatic oxidation products of arachidonic acid (prostaglandin F2α [PGF2α......]) in plasma and CSF of 45 controls (other neurologic disease [OND] with no signs of inflammation) and 62 patients with MS. Oxidation products were correlated with disease severity and validated biomarkers of inflammation (chemokine ligand 13; matrix metalloproteinase-9; osteopontin) and axonal damage...... with natalizumab and methylprednisolone treatment and was unaffected by the use of nonsteroidal anti-inflammatory drug in secondary progressive MS. CSF PGF2α did not associate with validated CSF markers of inflammation and axonal damage that themselves did not associate with the Expanded Disability Status Scale...

Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children

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José Eugenio Vázquez Meraz

2016-01-01

Full Text Available Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m2 of cyclophosphamide (CFA and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF, B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 109/L. The average number of MNC/kg body weight (BW/aphaeresis was 0.4 × 108 (0.1–1.4, 2.25 × 108 (0.56–6.28, and 1.02 × 108 (0.34–2.5 whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 106/kg (0.09–0.34, 1.04 × 106 (0.19–9.3, and 0.59 × 106 (0.17–0.87 and the count of CFU/kg BW/aphaeresis was 1.11 × 105 (0.31–2.12, 1.16 × 105 (0.64–2.97, and 1.12 × 105 (0.3–6.63 in groups A, B, and C, respectively. The collection was better in group B versus group A (p=0.007 and p=0.05, resp. and in group C versus group A (p=0.08 and p=0.05, resp.. The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 103/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy.

Stem Cell Mobilization with G-CSF versus Cyclophosphamide plus G-CSF in Mexican Children.

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Meraz, José Eugenio Vázquez; Arellano-Galindo, José; Avalos, Armando Martínez; Mendoza-García, Emma; Jiménez-Hernández, Elva

2016-01-01

Fifty-six aphaereses were performed in 23 pediatric patients with malignant hematological and solid tumors, following three different protocols for PBPC mobilization and distributed as follows: A: seventeen mobilized with 4 g/m(2) of cyclophosphamide (CFA) and 10 μg/kg/day of granulocyte colony stimulating factor (G-CSF), B: nineteen with CFA + G-CSF, and C: twenty only with G-CSF when the WBC count exceeded 10 × 10(9)/L. The average number of MNC/kg body weight (BW)/aphaeresis was 0.4 × 10(8) (0.1-1.4), 2.25 × 10(8) (0.56-6.28), and 1.02 × 10(8) (0.34-2.5) whereas the average number of CD34+ cells/kg BW/aphaeresis was 0.18 × 10(6)/kg (0.09-0.34), 1.04 × 10(6) (0.19-9.3), and 0.59 × 10(6) (0.17-0.87) and the count of CFU/kg BW/aphaeresis was 1.11 × 10(5) (0.31-2.12), 1.16 × 10(5) (0.64-2.97), and 1.12 × 10(5) (0.3-6.63) in groups A, B, and C, respectively. The collection was better in group B versus group A (p = 0.007 and p = 0.05, resp.) and in group C versus group A (p = 0.08 and p = 0.05, resp.). The collection of PBPCs was more effective in the group mobilized with CFM + G-CSF when the WBC exceeded 10 × 10(3)/μL in terms of MNC and CD34+ cells and there was no toxicity of the chemotherapy.

CSF glial markers correlate with survival in amyotrophic lateral sclerosis.

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Süssmuth, S D; Sperfeld, A D; Hinz, A; Brettschneider, J; Endruhn, S; Ludolph, A C; Tumani, H

2010-03-23

In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.

Delivery of GM-CSF to Protect against Influenza Pneumonia.

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Renuka Subramaniam

Full Text Available Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza.Granulocyte-macrophage colony stimulating factor (GM-CSF contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production.Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM. In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV.We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.

Delivery of GM-CSF to Protect against Influenza Pneumonia

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Subramaniam, Renuka; Hillberry, Zachary; Chen, Han; Feng, Yan; Fletcher, Kalyn; Neuenschwander, Pierre; Shams, Homayoun

2015-01-01

Background Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV) pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza. Methods Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production. Results Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM). In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV. Conclusion We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection. PMID:25923215

The New PTB Caesium Fountain Clock CSF2

National Research Council Canada - National Science Library

Wynands, R; Bauch, A; Griebsch, D; Schroeder, R; Weyers, S

2005-01-01

At PTB a second caesium fountain clock, CSF2, is in the process of being set up. It differs from the first PTB caesium fountain standard CSF1 in a number of details, which are consecutively specified...

Elevated CSF Corticotropin-Releasing Factor Concentrations in Posttraumatic Stress Disorder

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Bremner, J. Douglas; Licinio, Julio; Darnell, Adam; Krystal, John H.; Owens, Michael J.; Southwick, Steven M.; Nemeroff, Charles B.; Charney, Dennis S.

2011-01-01

Objective Corticotropin-releasing factor (CRF) and somatostatin both play important roles in mediating responses to acute and chronic stress. The purpose of this study was to measure CSF concentrations of CRF and somatostatin in patients with chronic combat-related post-traumatic stress disorder (PTSD) and comparison subjects. Method Lumbar punctures for collection of CSF were performed in Vietnam combat veterans with PTSD (N=11) and comparison subjects (N=17). CSF concentrations of CRF and somatostatin were compared between the two groups. Results CSF concentrations of CRF were higher in the PTSD patients than in the comparison subjects (mean=29.0 pg/ml, SD=7.8, versus mean=21.9 pg/ml, SD=6.0). This group difference remained significant after covariance for age. CSF somatostatin concentrations in PTSD patients were higher than those of the comparison subjects (mean=19.9 pg/ml, SD=5.4, versus mean=13.7 pg/ml, SD=8.0). However, covarying for age reduced the level of significance. Conclusions Higher CSF CRF concentrations in patients with PTSD may reflect alterations in stress-related neurotransmitter systems. The higher CSF CRF concentrations may play a role in disturbances of arousal in patients with PTSD. PMID:9137116

Elevation of extracellular adenosine enhances haemopoiesis-stimulating effects of G-CSF in normal and gamma-irradiated mice

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Hofer, M.; Pospisil, M.; Netikiva, J.; Hola, J. [Institute of Biophysics, Academy of Sciences of the Czech Republic (Czech Republic)

1997-03-01

Effects of combined treatment with drugs elevating extracellular adenosine (dipyridamole /DP/, inhibiting the extracellular uptake of adenosine, and adenosine monophosphate /AMP/, an adenosine pro-drug), and G-CSF (granulocyte colony-stimulating factor) on haemopoiesis of normal and gamma-irradiated mice were ascertained. The agents were administered alone or in combination in a 4-day regimen. In normal, unirradiated animals, the haematological endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, i.e., increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC) and morphologically recognizable granulocyte cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of DP plus AMP administrated 30 minutes before G-CSF. Furthermore, it was found that the stimulatory action of DP plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 {mu}g/d). In experiments with irradiated mice, when the 4-day therapeutic regimen was applied on days 3 to 6 following irradiation with the dose of 4 Gy, analogical stimulation of granulopoiesis was observed in the recovery phase on days 14 and 18 after irradiation. As example, see Fig. 1 for counts of granulocyte cells in femoral bone marrow. (authors)

Elevation of extracellular adenosine enhances haemopoiesis-stimulating effects of G-CSF in normal and gamma-irradiated mice

International Nuclear Information System (INIS)

Hofer, M.; Pospisil, M.; Netikiva, J.; Hola, J.

1997-01-01

Effects of combined treatment with drugs elevating extracellular adenosine (dipyridamole /DP/, inhibiting the extracellular uptake of adenosine, and adenosine monophosphate /AMP/, an adenosine pro-drug), and G-CSF (granulocyte colony-stimulating factor) on haemopoiesis of normal and gamma-irradiated mice were ascertained. The agents were administered alone or in combination in a 4-day regimen. In normal, unirradiated animals, the haematological endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, i.e., increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC) and morphologically recognizable granulocyte cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of DP plus AMP administrated 30 minutes before G-CSF. Furthermore, it was found that the stimulatory action of DP plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 μg/d). In experiments with irradiated mice, when the 4-day therapeutic regimen was applied on days 3 to 6 following irradiation with the dose of 4 Gy, analogical stimulation of granulopoiesis was observed in the recovery phase on days 14 and 18 after irradiation. As example, see Fig. 1 for counts of granulocyte cells in femoral bone marrow. (authors)

G-CSF prevents caspase 3 activation in Schwann cells after sciatic nerve transection, but does not improve nerve regeneration.

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Frost, Hanna K; Kodama, Akira; Ekström, Per; Dahlin, Lars B

2016-10-15

Exogenous granulocyte-colony stimulating factor (G-CSF) has emerged as a drug candidate for improving the outcome after peripheral nerve injuries. We raised the question if exogenous G-CSF can improve nerve regeneration following a clinically relevant model - nerve transection and repair - in healthy and diabetic rats. In short-term experiments, distance of axonal regeneration and extent of injury-induced Schwann cell death was quantified by staining for neurofilaments and cleaved caspase 3, respectively, seven days after repair. There was no difference in axonal outgrowth between G-CSF-treated and non-treated rats, regardless if healthy Wistar or diabetic Goto-Kakizaki (GK) rats were examined. However, G-CSF treatment caused a significant 13% decrease of cleaved caspase 3-positive Schwann cells at the lesion site in healthy rats, but only a trend in diabetic rats. In the distal nerve segments of healthy rats a similar trend was observed. In long-term experiments of healthy rats, regeneration outcome was evaluated at 90days after repair by presence of neurofilaments, wet weight of gastrocnemius muscle, and perception of touch (von Frey monofilament testing weekly). The presence of neurofilaments distal to the suture line was similar in G-CSF-treated and non-treated rats. The weight ratio of ipsi-over contralateral gastrocnemius muscles, and perception of touch at any time point, were likewise not affected by G-CSF treatment. In addition, the inflammatory response in short- and long-term experiments was studied by analyzing ED1 stainable macrophages in healthy rats, but in neither case was any attenuation seen at the injury site or distal to it. G-CSF can prevent caspase 3 activation in Schwann cells in the short-term, but does not detectably affect the inflammatory response, nor improve early or late axonal outgrowth or functional recovery. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Significance Of 30 KD Protein As A Diagnostic Marker In CSF Of tuberculour Meningits

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Kashyap R.S

2001-01-01

Full Text Available Tuberculous meningitis (TBM is a sub acute or chronic inflammation of the cerebral meninges caused by tubercule bacilli, the diagnosis for which is still very intricate. To establish a rapid diagnosis, we used Sodium dodecyl suplhate polyacrylamide gel electrophoresis (SDS-PAGE for the detection of marker protein in CSF specific to TBM patients. CSF was collected by standard lumbar puncture technique. Polyclonal antibody was raised against sonicated M.tuberculosis of H37RV in rabbit. 145 CSF samples were collected for this study over a period of two and half years which included 44 suspected and one proven case of TBM. In this communication we have investigated for a possible presence of a marker protein(s in cerebrospinal fluid (CSF of TBM patients. Two bands, a 30kd and a 14kd were detected. The 30kd band was observed in 92% cases of TBM patients. The 14kd band was not much of diagnostic importance since it was found in only about 45%. None of the control group patients had these protein bands. The 30 kd protein band either disappeared or became faint on anti-TB medication. To evaluate whether the eluted 30 kd protein was a mycobacterium tuberculosis product, gel retardation assay was also performed. The 30kd protein did not react with the polyclonal antisera. The CSF biochemical picture correlated well with the presence of this protein band. This study suggests that 30kd protein band observed in CSF is not a Mycobacterium product and is not only an important diagnostic marker for early diagnosis of TBM but may also be useful for monitoring the post treatment phase.

Application of RI-counting method for posttraumatic CSF rhinorrhea

International Nuclear Information System (INIS)

Itoh, Takahiko; Terai, Yoshinori; Fujimoto, Shunichiro; Kawauchi, Masamitsu.

1987-01-01

Numerous techniques and procedures have been reported for the evaluation of CSF fistulas. Especially metrizamide CT cisternography and radioisotope (RI) cisternography have been reported to be reliable for localizing the site of CSF leakage, however, it has been difficult to diagnose the existence and the site of CSF leakages in some cases. RI-counting method, measuring RI-count of intranasal cotton pledgets after the intrathecal injection of RI ( 111 In-DTPA) is thought to be the most reliable method for detecting the presence of CSF leakage in these cases. We used six cotton pledgets which were inserted into upper, middle, and lower meatuses on both side. Because the site of pledgets with ghest RI-count has anatomical relationship to the opening of the paranasal sinus, we can surmise the leakage of dural defect and CSF leakage. RI counting method was applied to two patients in whom it was difficult to diagnose the presence of CSF leakage with other procedures. The patients were free in position for four hours after the intrathecal injection of RI, and in the prone position for 30 minutes before RI-counting of intranasal cotton pledgets. After measuring the RI-counts of six pledgets, the counts were compared with each other. The cotton pledget inserted into left middle meatus showed the highest count in both cases. From this result and finding of conventional skull tomography we speculated the site of CSF leakage to be frontal sinus or ethmoid sinus. Operation demonstrated the opening of dura into the frontal sinus in one case, and ethmoid sinus in another case. As mentioned above, RI-counting method has the advantages of detecting the existence and the site of CSF leakage. (author)

Beneficial effect of bilingualism on Alzheimer's disease CSF biomarkers and cognition.

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Estanga, Ainara; Ecay-Torres, Mirian; Ibañez, Almudena; Izagirre, Andrea; Villanua, Jorge; Garcia-Sebastian, Maite; Iglesias Gaspar, M Teresa; Otaegui-Arrazola, Ane; Iriondo, Ane; Clerigue, Monserrat; Martinez-Lage, Pablo

2017-02-01

Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, n CSF  = 59), early (n = 81, n CSF  = 55) and late bilinguals (n = 97, n CSF  = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau (p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile. Copyright © 2016 Elsevier Inc. All rights reserved.

CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.

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Wang, Rui; Guan, Hong-Zhi; Ren, Hai-Tao; Wang, Wei; Hong, Zhen; Zhou, Dong

2015-07-01

Anti-NMDAR-encephalitis is a recently described form of autoimmune encephalitis. Here, we characterize CSF changes in Chinese patients with anti-NMDAR encephalitis, and explore the relationship between CSF findings and disease outcome. The presence of NMDAR antibodies in serum or CSF samples was evaluated in patients diagnosed with encephalitis between October 1, 2010 and August 1, 2014 at the West China Hospital. All patients fulfilling our diagnostic criteria were included and CSF findings were analyzed. Patient outcome was assessed after 4, 8, 12, 16, 20, and 24 months using the modified Rankin scale (mRS). Out of 3000 people with encephalitis screened, 43 patients were anti-NMDAR antibody positive in CSF or serum and included in this study. 62.8% of the patients identified with positive CSFs had positive serum anti-NMDAR samples, while 100% patients with positive serum had positive CSF samples. In the CSF white cell counts were elevated in 58.1% of cases; protein was increased in 18.6%; QAlb>Qlim(Alb) of the blood-CSF barrier was found in 29.3%; intrathecal immunoglobulin synthesis was detected in 17.1%, and 39.5% patients exhibited increased CSF pressures. A longer follow-up period was associated with better outcomes. There was no relationship between changes in CSF findings and outcome. The sensitivity of NMDA receptor antibody testing is higher in CSF compared to serum. Other CSF abnormalities are present in some patients with Anti-NMDAR-encephalitis, however these changes do not appear to affect prognosis. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

MafB antagonizes phenotypic alteration induced by GM-CSF in microglia

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Koshida, Ryusuke, E-mail: rkoshida-myz@umin.ac.jp; Oishi, Hisashi, E-mail: hoishi@md.tsukuba.ac.jp; Hamada, Michito; Takahashi, Satoru

2015-07-17

Microglia are tissue-resident macrophages which are distributed throughout the central nervous system (CNS). Recent studies suggest that microglia are a unique myeloid population distinct from peripheral macrophages in terms of origin and gene expression signature. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine regulating myeloid development, has been shown to stimulate proliferation and alter phenotype of microglia in vitro. However, how its signaling is modulated in microglia is poorly characterized. MafB, a bZip transcriptional factor, is highly expressed in monocyte-macrophage lineage cells including microglia, although its role in microglia is largely unknown. We investigated the crosstalk between GM-CSF signaling and MafB by analyzing primary microglia. We found that Mafb-deficient microglia grew more rapidly than wild-type microglia in response to GM-CSF. Moreover, the expression of genes associated with microglial differentiation was more downregulated in Mafb-deficient microglia cultured with GM-CSF. Notably, such differences between the genotypes were not observed in the presence of M-CSF. In addition, we found that Mafb-deficient microglia cultured with GM-CSF barely extended their membrane protrusions, probably due to abnormal activation of RhoA, a key regulator of cytoskeletal remodeling. Altogether, our study reveals that MafB is a negative regulator of GM-CSF signaling in microglia. These findings could provide new insight into the modulation of cytokine signaling by transcription factors in microglia. - Highlights: • GM-CSF alters the phenotype of microglia in vitro more potently than M-CSF. • Transcription factor MafB antagonizes the effect of GM-CSF on microglia in vitro. • MafB deficiency leads to RhoA activation in microglia in response to GM-CSF. • We show for the first time the function of MafB in microglia.

Cloning and Genomic Organization of a Rhamnogalacturonase Gene from Locally Isolated Strain of Aspergillus niger.

Science.gov (United States)

Damak, Naourez; Abdeljalil, Salma; Taeib, Noomen Hadj; Gargouri, Ali

2015-08-01

The rhg gene encoding a rhamnogalacturonase was isolated from the novel strain A1 of Aspergillus niger. It consists of an ORF of 1.505 kb encoding a putative protein of 446 amino acids with a predicted molecular mass of 47 kDa, belonging to the family 28 of glycosyl hydrolases. The nature and position of amino acids comprising the active site as well as the three-dimensional structure were well conserved between the A. niger CTM10548 and fungal rhamnogalacturonases. The coding region of the rhg gene is interrupted by three short introns of 56 (introns 1 and 3) and 52 (intron 2) bp in length. The comparison of the peptide sequence with A. niger rhg sequences revealed that the A1 rhg should be an endo-rhamnogalacturonases, more homologous to rhg A than rhg B A. niger known enzymes. The comparison of rhg nucleotide sequence from A. niger A1 with rhg A from A. niger shows several base changes. Most of these changes (59 %) are located at the third base of codons suggesting maintaining the same enzyme function. We used the rhamnogalacturonase A from Aspergillus aculeatus as a template to build a structural model of rhg A1 that adopted a right-handed parallel β-helix.

Lipegfilgrastim in the management of chemotherapy-induced neutropenia of cancer patients

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Guariglia R

2016-01-01

Full Text Available Roberto Guariglia,1 Maria Carmen Martorelli,1 Rosa Lerose,2 Donatella Telesca,2 Maria Rita Milella,2 Pellegrino Musto3 1Unit of Hematology and Stem Cell Transplantation, 2Pharmacy Service, 3Scientific Direction, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy Abstract: Neutropenia and febrile neutropenia (FN are frequent and potentially fatal toxicities of myelosuppressive anticancer treatments. The introduction of granulocyte colony-stimulating factors (G-CSFs in clinical practice has remarkably reduced the duration and severity of neutropenia, as well as the incidence of FN, thus allowing the administration of chemotherapeutic agents at the optimal dose and time with lower risk. The current scenario of G-CSFs in Europe includes filgrastim, lenograstim, some G-CSF biosimilars, and pegfilgrastim. Recently, a novel long-acting G-CSF, lipegfilgrastim, became available. Lipegfilgrastim is a glycopegylated G-CSF, alternative to pegfilgrastim, and has shown in randomized trials, to be equivalent to pegfilgrastim in reducing the incidence of severe neutropenia and FN in patients with breast cancer receiving chemotherapy, with a similar safety profile. Furthermore, lipegfilgrastim was more effective than the placebo in reducing the incidence of severe neutropenia, its duration, and time to absolute neutrophil count recovery, in patients with non-small cell lung cancer receiving myelosuppressive therapy. Although the number of studies currently published is still limited, lipegfilgrastim seems to be a promising drug in the management of chemotherapy-induced neutropenia. Keywords: neutropenia, febrile neutropenia, granulocyte colony-stimulating factors, G-CSF, pegfilgrastim, lipegfilgrastim

Intra-articular administration of an antibody against CSF-1 receptor reduces pain-related behaviors and inflammation in CFA-induced knee arthritis.

Science.gov (United States)

Alvarado-Vazquez, P A; Morado-Urbina, C E; Castañeda-Corral, G; Acosta-Gonzalez, R I; Kitaura, H; Kimura, K; Takano-Yamamoto, T; Jiménez-Andrade, J M

2015-01-01

Several studies have shown that blockade of colony stimulating factor-1 (CSF-1) or its receptor (CSF-1R) inhibits disease progression in rodent models of rheumatoid arthritis (RA); however, the role of the CSF-1/CSF-1R pathway in RA-induced pain and functional deficits has not been studied. Thus, we examined the effect of chronic intra-articular administration of a monoclonal anti-CSF-1R antibody (AFS98) on spontaneous pain, knee edema and functional disabilities in mice with arthritis. Unilateral arthritis was produced by multiple injections of complete Freund's adjuvant (CFA) into the right knee joint of adult male ICR mice. CFA-injected mice were then treated twice weekly from day 10 until day 25 with anti-CSF-1R antibody (3 and 10 μg/5 μL per joint), isotype control (rat IgG 10 μg/5 μL per joint) or PBS (5 μl/joint). Knee edema, spontaneous flinching, vertical rearing and horizontal exploratory activity were assessed at different days. Additionally, counts of peripheral leukocytes and body weight were measured to evaluate general health status. Intra-articular treatment with anti-CSF-1R antibody significantly increased horizontal exploratory activity and vertical rearing as well as reduced spontaneous flinching behavior and knee edema as compared to CFA-induced arthritis mice treated with PBS. Treatment with this antibody neither significantly affect mouse body weight nor the number of peripheral leukocytes. These results suggest that blockade of CSF-1R at the initial injury site (joint) could represent a therapeutic alternative for improving the functional disabilities and attenuating pain and inflammation in patients with RA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Immunological and virological changes in antiretroviral naïve human immunodeficiency virus infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART

DEFF Research Database (Denmark)

Aladdin, H; Ullum, H; Katzenstein, T

2000-01-01

To determine the efficacy of combined G-CSF and highly active antiretroviral treatment (HAART), a randomized, double blind, placebo controlled study was conducted. Treatment naive human immunodeficiency virus (HIV) infected patients were randomized to receive either placebo or G-CSF (0.3 mg/ml, 3...... = 6) or placebo group (n = 5). In both groups plasma HIV RNA decreased significantly in response to HAART. However, plasma HIV RNA changed significantly different between the two groups with the decrease being less pronounced in the G-CSF group (P = 0.02). The concentrations of CD4+ memory T cells...... and CD8+ naive and memory T cells increased in response to HAART, and there was a trend towards more pronounced increases in several T-cell subpopulations in the G-CSF group. The CD56+ NK cells increased significantly more in the G-CSF group compared with placebo (P = 0. 000). All patients in the G...

Filgrastim as a Rescue Therapy for Persistent Neutropenia in a Case of Dengue Hemorrhagic Fever with Acute Respiratory Distress Syndrome and Myocarditis

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Desh Deepak

2011-01-01

Full Text Available Pathogenesis of dengue involves suppression of immune system leading to development of characteristic presentation of haematological picture of thrombocytopenia and leucopenia. Sometimes, this suppression in immune response is responsible for deterioration in clinical status of the patient in spite of all specific and supportive therapy. Certain drugs like steroids are used for rescue therapy in conditions like sepsis. We present a novel use of filgrastim as a rescue therapy in a patient with dengue hemorrhagic fever (DHF with acute respiratory distress syndrome (ARDS, myocarditis, and febrile neutropenia and not responding to standard management.

Molecular cloning of a second subunit of the receptor for human granulocyte - macrophage colony-stimulating factor (GM-CSF): Reconstitution of a high-affinity GM-CSF receptor

International Nuclear Information System (INIS)

Hayashida, Kazuhiro; Kitamura, Toshio; Gorman, D.M.; Miyajima, Atsushi; Arai, Kenichi; Yokota, Takashi

1990-01-01

Using the mouse interleukin 3 (IL-3) receptor cDNA as a probe, the authors obtained a monologous cDNA (KH97) from a cDNA library of a human hemopoietic cell line, TF-1. The protein encoded by the KH97 cDNA has 56% amino acid sequence identity with the mouse IL-3 receptor and retains features common to the family of cytokine receptors. Fibroblasts transfected with the KH97 cDNA expressed a protein of 120 kDa but did not bind any human cytokines, including IL-3 and granulocyte - macrophage colony-stimulating factor (GM-CSF). Interestingly, cotransfection of cDNAs for KH97 and the low-affinity human GM-CSF receptor in fibroblasts resulted in formation of a high-affinity receptor for GM-CSF. The dissociation rate of GM-CSF from the reconstituted high-affinity receptor was slower than that from the low-affinity site, whereas the association rate was unchanged. Cross-linking of 125 I-labeled GM-CSF to fibroblasts cotransfected with both cDNAs revealed the same cross-linking patterns as in TF-1 cells - i.e., two major proteins of 80 and 120 kDa which correspond to the low-affinity GM-CSF receptor and the KH97 protein, respectively. These results indicate that the high-affinity GM-CSF receptor is composed of at least two components in a manner analogous to the IL-2 receptor. They therefore propose to designate the low-affinity GM-CSF receptor and the KH97 protein as the α and β subunits of the GM-CSF receptor, respectively

Developmental and functional significance of the CSF-1 proteoglycan chondroitin sulfate chain

OpenAIRE

Nandi, Sayan; Akhter, Mohammed P.; Seifert, Mark F.; Dai, Xu-Ming; Stanley, E. Richard

2006-01-01

The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of s...

Heterogeneous effects of M-CSF isoforms on the progression of MLL-AF9 leukemia.

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Wang, Rong; Feng, Wenli; Yang, Feifei; Yang, Xiao; Wang, Lina; Chen, Chong; Hu, Yuting; Ren, Qian; Zheng, Guoguang

2018-02-01

Macrophage colony-stimulating factor (M-CSF) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M-CSF in patients with hematopoietic malignancies was analyzed. The roles of M-CSF isoforms on the progression of acute myeloid leukemia (AML) were studied by establishing MLL-AF9-induced mouse AML models with high level membrane-bound M-CSF (mM-CSF) or soluble M-CSF (sM-CSF). Total M-CSF was highly expressed in myeloid leukemia patients. Furthermore, mM-CSF but not sM-CSF prolonged the survival of leukemia mice. While sM-CSF was more potent to promote proliferation and self-renew, mM-CSF was more potent to promote differentiation. Moreover, isoforms had different effects on leukemia-associated macrophages (LAMs) though they both increase monocytes/macrophages by growth-promoting and recruitment effects. In addition, mM-CSF promoted specific phagocytosis of leukemia cells by LAMs. RNA-seq analysis revealed that mM-CSF enhanced phagocytosis-associated genes and activated oxidative phosphorylation and metabolism pathway. These results highlight heterogeneous effects of M-CSF isoforms on AML progression and the mechanisms of mM-CSF, that is, intrinsically promoting AML cell differentiation and extrinsically enhancing infiltration of macrophages and phagocytosis by macrophages, which may provide potential clues for clinical diagnosis and therapy. © 2017 Australasian Society for Immunology Inc.

Comparison of the Cerebrospinal Fluid (CSF) Toluidine Red Unheated Serum Test and the CSF Rapid Plasma Reagin Test with the CSF Venereal Disease Research Laboratory Test for Diagnosis of Neurosyphilis among HIV-Negative Syphilis Patients in China

OpenAIRE

Zhu, Lin; Gu, Xin; Peng, Rui-Rui; Wang, Cuini; Gao, Zixiao; Zhou, Pingyu; Gao, Ying; Shi, Mei; Guan, Zhifang; Seña, Arlene C.

2014-01-01

In this study, we aimed to investigate the performance of nontreponemal antibody tests in cerebrospinal fluid (CSF) specimens from syphilis patients. From September 2009 to September 2012, CSF specimens were collected at the Shanghai Skin Disease Hospital in Shanghai, China, from 1,132 syphilis patients without HIV infection, including 154 with symptomatic and 56 with asymptomatic neurosyphilis. All of the CSF specimens underwent testing with a rapid plasma reagin (RPR) test, an RPR-V (commer...

[Therapeutic use of hematopoietic growth factors. II. GM-CSF and G-CSF].

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Royer, B; Arock, M

1998-01-01

The second part of this review on haematopoietic growth factors is focused on the therapeutic use of GM-CSF and G-CSF. Such therapeutic applications have raised very great hopes for clinical haematology. However, it should not be forgotten that these haematopoietic growth factors, which are very costly, are powerful two-edged weapons capable of triggering a cascade of reactions, and have a field of activity that often goes beyond the single highly specific property which it is hoped they possess. The risks and costs of their use are currently being evaluated. Waited developments concerning these molecules focus on three axes: a best use of factors already commercialized, especially concerning adaptation of posologies and new indications, the development of hybrid molecules from already known haematopoietic growth factors, possessing the advantages of respective factors, but not their disadvantages, the discovery of new haematopoietic growth factors with potential therapeutic application.

Macrophage colony stimulating factor (M-CSF) induces Fc receptor expression on macrophages

International Nuclear Information System (INIS)

Magee, D.M.; Wing, E.J.; Waheed, A.; Shadduck, R.K.

1986-01-01

M-CSF is a glycoprotein that stimulates bone marrow progenitor cells to proliferate and differentiate into macrophages (M theta). In addition, M-CSF can modulate the function of mature M theta. In this study, the authors determined the effect of M-CSF on expression of receptors for IgG (Fc receptors). Murine resident peritoneal M theta monolayers were incubated with either M-CSF, recombinant gamma interferon (IFN), or left untreated for 48 hrs. Expression of Fc receptors was assessed by microscopy using an antibody coated sheet erythrocytes (EA) rosette assay. The results indicated that M-CSF treated M theta had significantly higher numbers of bound EA (7.1 erythrocytes/M theta), than IFN M theta (4.4), or untreated M theta (2.5) (p 51 Cr labelled EA assay, CSF M theta (16,411 cpm), IFN M theta (10,887), untreated M theta (6897) (p < 0.001). Additionally, the maximal response was noted between 10 and 500 units M-CSF. Purified anti-M-CSF IgG, when included in the cultures, ablated the enhancement of EA binding, whereas normal rabbit IgG did not. These findings indicate that M-CSF is a potent inducer of Fc receptor expression on M theta and supports other data concerning the role of M-CSF as a biological response modifier

[Hematopoietic cells raising with plerixafor in non-Hodgkin lymphoma].

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Pérez-Lozano, Uendy; Tripp-Villanueva, Francisco; Ramírez-Alvarado, Aline; Vela-Ojeda, Jorge; Limón-Flores, Alejandro; Kramis-Cerezo, José Luis

2012-01-01

bone marrow autologous transplantation (BMAT) has proven benefits in patients treated for non-Hodgkin's lymphoma (NHL). Plerixafor is an inhibitor of CXCR4 receptor. The aim was to report the raise of hematopoietic cells with plerixafor in patients with NHL. patient 1 with follicular NHL, GI, intermediate FLIPI, CD20+, CD45+, BCL-2+, who reached complete response after three chemotherapy regimes. Mobilization failed after use of filgrastim (G-CSF) alone and G-CSF + cyclophosphamide. A new attempt was made with G-CSF + plerixafor (G-CSF, 10 μg/kg for 7 days + plerixafor, 240 μg/kg in days 4 to 7). Patient 2 with follicular NHL and CD20+ reached complete remission with MINE after therapeutic failure with other regimes, but develops severe marrow toxicity. Mobilization was supported with G-CSF 10 μg/kg/d + plerixafor in days 4 and 5. In case one, proper cell counts where obtained after three aphaeresis. In the second case, two harvests add of 2.7 × 106/kg were obtained. plerixafor raised the hematopoietic stem cells in peripheral blood and improves mobilization of proper cell population.

Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs. G-CSF.

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Weisdorf, D; Miller, J; Verfaillie, C; Burns, L; Wagner, J; Blazar, B; Davies, S; Miller, W; Hannan, P; Steinbuch, M; Ramsay, N; McGlave, P

1997-10-01

Autologous transplantation for non-Hodgkins lymphoma and Hodgkin's disease is widely used as standard therapy for those with high-risk or relapsed tumor. Peripheral blood stem cell (PBSC) collections have nearly completely replaced bone marrow stem cell (BMSC) harvests because of the perceived advantages of more rapid engraftment, less tumor contamination in the inoculum, and better survival after therapy. The advantage of PBSC, however, may derive from the hematopoietic stimulating cytokines used for PBSC mobilization. Therefore, we tested a randomized comparison of GM-CSF vs. G-CSF used to prime either BMSC or PBSC before collection for use in autologous transplantation. Sixty-two patients receiving transplants (31 PBSC; 31 BMSC) for non-Hodgkin's lymphoma (n = 51) or Hodgkin's disease (n = 11) were treated. All patients received 6 days of randomly assigned cytokine. Those with cellular marrow in morphologic remission underwent BMSC harvest, while those with hypocellular marrow or microscopic marrow tumor involvement had PBSC collected. Neutrophil recovery was similarly rapid in all groups (median 14 days; range 10-23 days), though two patients had delayed neutrophil recovery using GM-CSF primed PBSC (p = 0.01). Red cell and platelet recovery were significantly quicker after BMSC mobilized with GM-CSF or PBSC mobilized with G-CSF. This speedier hematologic recovery resulted in earlier hospital discharge as well. However, in multivariate analysis, neither the stem cell source nor randomly assigned G-CSF vs. GM-CSF was independently associated with earlier multilineage hematologic recovery or shorter hospital stay. Relapse-free survival was not independently affected by either the assigned stem cell source or the randomly assigned priming cytokine, though malignant relapse was more frequent in those assigned to PBSC (RR of relapse 3.15, p = 0.03). These data document that BMSC, when collected following cytokine priming, can yield a similarly rapid hematologic

Medical visits for chemotherapy and chemotherapy-induced neutropenia: a survey of the impact on patient time and activities

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Moore Kelley

2004-05-01

Full Text Available Abstract Background Patients with cancer must make frequent visits to the clinic not only for chemotherapy but also for the management of treatment-related adverse effects. Neutropenia, the most common dose-limiting toxicity of myelosuppressive chemotherapy, has substantial clinical and economic consequences. Colony-stimulating factors such as filgrastim and pegfilgrastim can reduce the incidence of neutropenia, but the clinic visits for these treatments can disrupt patients' routines and activities. Methods We surveyed patients to assess how clinic visits for treatment with chemotherapy and the management of neutropenia affect their time and activities. Results The mean amounts of time affected by these visits ranged from approximately 109 hours (hospitalization for neutropenia and 8 hours (physician and chemotherapy to less than 3 hours (laboratory and treatment with filgrastim or pegfilgrastim. The visits for filgrastim or pegfilgrastim were comparable in length, but treatment with filgrastim requires several visits per chemotherapy cycle and treatment with pegfilgrastim requires only 1 visit. Conclusions This study provides useful information for future modelling of additional factors such as disease status and chemotherapy schedule and provides information that should be considered in managing chemotherapy-induced neutropenia.

Infections in the differential diagnosis of Bell's palsy: a plea for performing CSF analysis.

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Henkel, Katrin; Lange, Peter; Eiffert, Helmut; Nau, Roland; Spreer, Annette

2017-04-01

Peripheral facial nerve palsy (FP) is the most common single nerve affection. Most cases are idiopathic, but a relevant fraction is caused by potentially treatable aetiologies including infections. Not all current diagnosis and treatment guidelines recommend routine cerebrospinal fluid (CSF) analysis in the diagnostic workup of this symptom. In this study, we evaluated frequency of aetiologies and relevance of CSF analysis in an interdisciplinary cohort. We retrospectively analysed all cases of newly diagnosed FP treated at a German university medical centre in a 3-year period. Diagnostic certainty was classified for infectious aetiologies according to clinical and CSF parameters. 380 patients with FP were identified, 63 children and 317 adults. Idiopathic Bell´s palsy was predominant in 61 %. 25 % of FP was attributed to infections, and other causes were identified in 14 %. Clinical presentation alone was not conclusive for infectious aetiology, in almost half of patients with infection-attributed FP the reported symptoms or clinical signs did not differ from common symptoms of idiopathic Bell`s palsy. Determination of C-reactive protein or white blood cell count was not helpful in the identification of infectious causes, and radiological imaging was performed in a high proportion of adult patients without conclusive results. Nuchal rigidity was found only in 7 % of patients with CSF pleocytosis. The predominant infectious agents were Borrelia burgdorferi, VZV and HSV, and in most of these cases diagnosis relied on the findings of CSF analysis. This study outlines the importance of careful differential diagnosis to identify infectious causes of facial nerve palsy. The high incidence and frequent unspecific clinical presentation of infectious FP underlines the importance of including CSF analysis in the diagnostic routine workup of FP.

Predictors for successful PBSC collection on the fourth day of G-CSF-induced mobilization in allogeneic stem cell donors.

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van Oostrum, Anja; Zwaginga, Jaap Jan; Croockewit, Sandra; Overdevest, Jacqueline; Fechter, Mirjam; Ruiterkamp, Bart; Brand, Anneke; Netelenbos, Tanja

2017-12-01

Peripheral blood stem cells (PBSCs) used for allogeneic transplantation are collected by apheresis after pre-treatment of donors with G-CSF. Using modern apheresis devices stem cells can be collected more efficiently. It was studied whether collection on the 4th instead of the 5th day after initiation of G-CSF treatment might be feasible. Stem cell yields that could have been collected on day 4 were calculated in two cohorts treated with 10 µg/kg G-CSF once daily (n = 106, cohort I) or 5 µg/kg twice daily schedule (n = 85, cohort II). Harvests were predicted using the median collection efficiency (CE) of the apheresis machine and regarded successful when > 5.0 x10 6 CD34 +/ kg recipient body weight. Successful harvests at day 4 could have been obtained in only 22.6% and 41.2% of donors in cohort I and II respectively, while the expected successful collections on day 5 were 55.7% and 76.5%. Individual donor factors that correlated with a successful harvest on day 4 were weight, BMI, age, ratio donor/recipient weight and total G-CSF dose in cohort I, whereas ratio donor/recipient weight was the only significant predictor in cohort II. Donor weight, BMI and total G-CSF dose correlated positively with CD34 + values in the blood on day 4 in all donors. However, donor characteristics were not able to be used as strong predictors in daily practice. In conclusion, PBSC collection on day 4 will not result in a successful harvest in most stem cell donors, however using a twice daily G-CSF scheme increases the yield. © 2017 Wiley Periodicals, Inc.

Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

Science.gov (United States)

Chitu, Violeta; Gokhan, Solen; Nandi, Sayan; Mehler, Mark F.; Stanley, E. Richard

2016-01-01

The colony stimulating factor-1 receptor (CSF-1R) kinase regulates tissue macrophage homeostasis, osteoclastogenesis, and Paneth cell development. However, recent studies in mice have revealed that CSF-1R signaling directly controls the development and maintenance of microglia, and cell autonomously regulates neuronal differentiation and survival. While the CSF-1R-cognate ligands, CSF-1 and interleukin-34 (IL-34), compete for binding to the CSF-1R, they are expressed in a largely non-overlapping manner by mature neurons. The recent identification of a dominantly inherited, adult-onset, progressive dementia associated with inactivating mutations in the CSF-1R highlights the importance of CSF-1R signaling in the brain. We review the roles of the CSF-1R and its ligands in microglial and neural development and function, and their relevance to our understanding of neurodegenerative disease. PMID:27083478

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

Science.gov (United States)

Xie, Jie; Cao, Jun; Wang, Jing-Fen; Zhang, Bai-Hong; Zeng, Xiao-Hua; Zheng, Hong; Zhang, Yang; Cai, Li; Wu, Yu-Dong; Yao, Qiang; Zhao, Xiao-Chun; Mao, Wei-Dong; Jiang, Ai-Mei; Chen, Shao-Shui; Yang, Shun-E; Wang, Shu-Sen; Wang, Jian-Hong; Pan, Yue-Yin; Ren, Bi-Yong; Chen, Yan-Ju; Ouyang, Li-Zhi; Lei, Kai-Jian; Gao, Jing-Hua; Huang, Wen-He; Huang, Zhan; Shou, Tao; He, Yan-Ling; Cheng, Jing; Sun, Yang; Li, Wei-Ming; Cui, Shu-de; Wang, Xin; Rao, Zhi-Guo; Ma, Hu; Liu, Wei; Wu, Xue-Yong; Shen, Wei-Xi; Cao, Fei-Lin; Xiao, Ze-Min; Wu, Biao; Tian, Shu-Yan; Meng, Dong; Shen, Peng; Wang, Bi-Yun; Wang, Zhonghua; Zhang, Jian; Wang, Leiping; Hu, Xi-Chun

2018-04-01

PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

CSF 5-HIAA and DST non-suppression--orthogonal biologic risk factors for suicide in male mood disorder inpatients.

Science.gov (United States)

Jokinen, Jussi; Nordström, Anna-Lena; Nordström, Peter

2009-01-30

Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims (n=6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims (n=5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.

Study of cysticercosis in the fourth ventricle by CSF cinema MRI

International Nuclear Information System (INIS)

Wang Lianqing; Liu Lianxiang; Wu Jie; Wu Jing; Zhang Renshu; Wu Yujin

1997-01-01

Purpose: To evaluate the diagnostic value of cysticercosis in the fourth ventricle by CSF cinema MRI. Materials and methods: Nine patients with intraventricular cysticercosis in the fourth ventricle were studied. The diagnosis was confirmed by surgery in all cases. All of these patients were examined systematically before the operation and studied with CSF cinema MRI in mid sagittal section and finger-gated scan technique. Results: (1) The path of CSF flow was directly displayed. All cysticercosis presented as a filling defect, and a cyst with a smooth wall. (2) The ventricular compliance was normal in cysticercosis. (3) The cysticercosis in active stage was free in the fourth ventricle and could be rolled over, its shape might change slightly within a cardiac cycle. In the degenerative stage, its wall could adhere to the ependyma and obstruct the CSF flow. Conclusion: CSF cinema MRI can demonstrate the degree of obstruction and pattern of CSF flow in cysticercosis of the fourth ventricle, thereby providing useful information for proper management

Inhibition of CSF-1R supports T-cell mediated melanoma therapy.

Directory of Open Access Journals (Sweden)

Marjolein Sluijter

Full Text Available Tumor associated macrophages (TAM can promote angiogenesis, invasiveness and immunosuppression. The cytokine CSF-1 (or M-CSF is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R have been developed to regulate TAM in solid cancers. We show that the kinase inhibitor PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1(+ myeloid derived suppressor cells. Removal of intratumoral macrophages was remarkably efficient and a modest, but statistically significant, delay in melanoma outgrowth was observed. Importantly, CSF-1R inhibition strongly enhanced tumor control by immunotherapy using tumor-specific CD8 T cells. Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy. These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

Continuous monitoring of intracranial pressure after endoscopic third ventriculostomy in the management of CSF shunt failure.

Science.gov (United States)

Elgamal, E A

2010-04-01

The effectiveness of continuous intracranial pressure (ICP) monitoring in the adaptation period, after endoscopic third ventriculostomy (ETV), and removal of the failed shunt in the management of CSF shunt failure is assessed. Nine patients with active hydrocephalus presenting with CSF shunt obstruction or infection were managed by ETV, removal of the shunt and insertion of an external ventricular drain (EVD) containing an ICP sensor for the purpose of postoperative monitoring of the ICP, and intermittent drainage of CSF. Patient ages ranged from 8 months to 24 years, and six of them were females. Hydrocephalus was obstructive in seven patients, and multiloculated in two. Six patients had an ventriculoperitoneal shunt (VPS), one with a bilateral VPS, one patient had a ventriculoatrial shunt, and one had a VPS and cystoperitoneal shunt (CPS). Shunt failure was caused by obstruction in six patients and infection in three. The post-operative ICP monitoring period ranged from 1-7 days. Intracranial hypertension was persistent in the first day after ETV in 3 patients, and up to 110 mL of CSF were drained to improve its symptoms. ETV was successful in six patients and 3 had permanent VPS. Post-operative continuous ICP monitoring and EVD insertion were very useful in the treatment of CSF shunt failure with ETV. This procedure allowed intermittent CSF drainage, relieving symptoms of elevated ICP, and provided accurate assessment of the success of the ETV and patency of the stoma in the early postoperative days by CT ventriculography and can also be used to install antibiotics in cases of infection.

Observation of the CSF pulsatile flow on MRI, (2)

International Nuclear Information System (INIS)

Ohara, Shigeki; Nagai, Hajime; Suzuka, Tomonao; Matsumoto, Takashi; Banno, Tatsuo

1988-01-01

In a retrospective study of the MR images of 289 neurosurgical patients, a loss of the signal intensity (the signal-void phenomenon =SVP) of the cerebrospinal fluid in the mesencephalic aqueduct was observed in 77 patients. The CSF in the cranial cavity flows toward the spinal sac in a to-and-fro manner in response to the pulsations of the brain. Because the intracranial compliance is lower than the intraspinal compliance, the systolic expansions and diastolic reductions in the brain volume are buffered by the spinal cavity via this to-and-fro flow of CSF. The SVP reflects the CSF pulsatile flow forced out of the intracranial space into the intraspinal space by the brain's pulsations. Intracranial abnormalities can be divided into two categories according to the craniospinal compliance (CC): normal CC (communicating hydrocephalus) and decreased CC (supratentorial tumor). We may expect those conditions which increase compliance to increase the CSF flow and yield a more prominent SVP. Conversely, conditions which decrease compliance may be expected to decrease the flow and extinguish the SVP. Both the brain's pulsations and the compliance of the craniospinal cavity are closely related to the presence of the SVP in CSF, as revealed by MRI. The SVP in CSF may reflect the pressure-buffering capacity of the cranio-spinal cavity. If further investigation supports our hypothesis, it may be possible to estimate the intracranial pressure noninvasively. (author)

3D steady-state MR cisternography in CSF rhinorrhoea

International Nuclear Information System (INIS)

Jayakumar, P.N.; Kovoor, J.M.E.; Srikanth, S.G.; Praharaj, S.S.

2001-01-01

Purpose: To determine the utility of 3D steady-state MR cisternography in the demonstration and localisation of cerebrospinal fluid (CSF) leak in patients with clinically suspected CSF rhinorrhoea. Material and Methods: Six consecutive patients with clinically suspected CSF rhinorrhoea were examined with routine MR evaluation and MR cisternography (MRC). All MR examinations included fast spin-echo (SE) T1WI in axial and sagittal planes, fast SE T2WI in axial and coronal planes and fluid attenuated inversion recovery (FLAIR) images in the axial plane. 3D evaluation was done using the CISS technique with 0.7-mm thickness in the sagittal and coronal planes. The site and extent of the defect, and any brain herniation detected on MRC were correlated with surgical findings. Results: In the 6 patients who underwent surgical exploration and repair, intraoperative findings correlated with the defect revealed by MRC in all cases. Conclusion: In clinically suspected CSF rhinorrhoea, MRC is highly accurate in localising the site and extent of CSF fistula and may be used as the first investigation due to its efficacy and non-invasive nature

Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages

Science.gov (United States)

Lou, Jieqiong; Low-Nam, Shalini T.; Kerkvliet, Jason G.; Hoppe, Adam D.

2014-01-01

ABSTRACT Activation of the macrophage colony stimulating factor-1 receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. Although the role of macropinocytosis in CSF-1R signaling remains unknown, we show here that, despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1–CSF-1R complex. Rather, internalization of the CSF-1R in small endocytic vesicles that are sensitive to clathrin disruption, outcompetes macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into their lumen and degraded. Inhibition of macropinocytosis delayed receptor degradation despite no disruption to CSF-1R endocytosis. These data indicate that CSF-1-stimulated macropinosomes are sites of multivesicular body formation and accelerate CSF-1R degradation. Furthermore, we demonstrate that macropinocytosis and cell growth have a matching dose dependence on CSF-1, suggesting that macropinosomes might be a central mechanism coupling CSF-1R signaling and macrophage growth. PMID:25335894

M-CSF deficiency leads to reduced metallothioneins I and II expression and increased tissue damage in the brain stem after 6-aminonicotinamide treatment

DEFF Research Database (Denmark)

Penkowa, Milena; Poulsen, Christian; Carrasco, Javier

2002-01-01

6-Aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray-matter astrocytes followed by a vigorous inflammatory response. Macrophage colony stimulating factor (M-CSF) is important during inflammation, and in order to further clarify the roles for M-CSF...... in neurodegeneration and brain cell death, we have examined the effect of 6-AN on osteopetrotic mice with genetic M-CSF deficiency (op/op mice). The 6-AN-induced degeneration of gray-matter areas was comparable in control and op/op mice, but the numbers of reactive astrocytes, macrophages, and lymphocytes...... for caspases and cytochrome c) were significantly increased in 6-AN-injected op/op mice relative to controls. From a number of antioxidant factors assayed, only metallothioneins I and II (MT-I+II) were decreased in op/op mice in comparison to controls. Thus, the present results indicate that M-CSF...

GM-CSF: An Immune Modulatory Cytokine that can Suppress Autoimmunity

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Bhattacharya, Palash; Thiruppathi, Muthusamy; Elshabrawy, Hatem A.; Alharshawi, Khaled; Kumar, Prabhakaran; Prabhakar, Bellur S.

2015-01-01

GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune-modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases like Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune-modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance. PMID:26113402

Drug: D03235 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D03235 Drug Filgrastim (USAN/INN); Filgrastim (genetical recombination) (JP17); Filgrastim (genetica...l recombination) [Filgrastim biosimilar 1] (JAN); Tbo-filgrastim; Filgrastim (genetical re...combination) [Filgrastim biosimilar 2] (JAN); Filgrastim (genetical recombination) [Filgrastim biosimilar3

Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis.

Science.gov (United States)

Al-Mossawi, M H; Chen, L; Fang, H; Ridley, A; de Wit, J; Yager, N; Hammitzsch, A; Pulyakhina, I; Fairfax, B P; Simone, D; Yi, Yao; Bandyopadhyay, S; Doig, K; Gundle, R; Kendrick, B; Powrie, F; Knight, J C; Bowness, P

2017-11-15

Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A + GM-CSF + double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF + CD4 + cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF + and IL-17A + GM-CSF + double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.

Clinical significance of determination of serum TNF, IL-8 and GM-CSF levels in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Xu Donglin

2005-01-01

Objective: To investigate the clinical significance of changes of serum TNF, IL-8 and GM-CSF in pediatric patients with bronchial asthma. Methods: Serum TNF, IL-8 and GM-CSF levels were measured with RIA in 32 pediatric patients with bronchial asthma and 30 controls. Results: Serum levels of TNF, IL-8 and GM-CSF were very significantly higher in pediatric patients with bronchial asthma than those in controls (P<0.01). After one week treatment, the levels dropped considerably but still remained significantly higher than those in controls (P<0.05). Conclusion: These cytokines participated in the pathogenesis of bronchial asthma. Monitoring the changes of their serum levels was helpful for the management of the diseases. (authors)

GM-CSF augments the immunosuppressive capacity of neonatal spleen cells in vitro

International Nuclear Information System (INIS)

Morrissey, P.J.; Ireland, R.

1991-01-01

Addition of exogenous granulocyte-macrophage colony stimulating factor (GM-CSF) to cultures of adult murine spleen cells with sheep red blood cells (SRBC) results in an augmented plaque forming cell (PFC) response. The influence of GM-CSF on the ability of neonatal spleen cells to suppress the anti-SRBC plaque forming response of adult spleen cells was tested by adding GM-CSF to cultures of neonatal and adult spleen cells. The suppressive capacity of the neonatal spleen cells was augmented by exogenous GM-CSF. The augmented suppression of the neonatal spleen cells was dependent on a G-10 adherent population since the addition of GM-CSF to cultures containing G-10 passed neonatal spleen cells resulted in an augmented PFC response and not suppression. Neonatal splenic glass adherent cells were also capable of suppressing the response. Neonatal spleen cells or purified neonatal glass adherent spleen cells cultured in the presence of GM-CSF had markedly increased levels of PGE2 in the culture supernatant. Neonatal spleen cells cultured with GM-CSF had increased numbers of morphologically identifiable macrophages after 48 hr of culture. Both irradiation and G-10 passage of the neonatal spleen diminished the numbers of macrophages formed in response to GM-CSF, and both of these manipulations resulted in reversal of suppression in response to GM-CSF. Thus, the augmented suppressive capacity of neonatal spleen cells in response to GM-CSF is probably mediated by its ability to drive monocyte to macrophage differentiation as well as increase the suppressive capacity of the existing neonatal splenic macrophages by increasing their production of PGE2

MRT measurements of the CSF spaces in HIV associated cerebral atrophy

International Nuclear Information System (INIS)

Handwerker, M.; Krahe, T.; Klinker, H.; Schindler, R.

1992-01-01

The CSF volume of 45 patients with HIV infection was measured at various clinical stages and the results compared with 24 normals. 60% of all patients showed increased CSF spaces as an indication of cerebral atrophy. Serial measurements were particularly valuable during the early stages of atrophy since there is marked variation in the normal CSF volume. Conventional measurements, with the exception of the width of the third ventricle, were much less sensitive than these quantitative measurements. Classification of HIF infection according to the clinical stage was useful since CSF volume and volume increase correlated with the stage of HIV infection. (orig.) [de

Diagnostic problems of MRI in studying the effect of G-CSF therapy in bone marrow of patients with malignoma

International Nuclear Information System (INIS)

Layer, G.; Sander, W.; Traeber, F.; Block, W.; Koenig, R.; Vahlensieck, M.; Schild, H.H.; Ko, Y.; Ziske, C.G.

2000-01-01

Aim. To study the effect of G-CSF therapy directly by MRI and 1 H MRS in the lumbar and femoral bone marrow and differentiate between malignant bone marrow infiltration (MBMI) and reconversion of red marrow. Methods. Thirteen patients could be examined twice, before and during G-CSF medication and another six only during treatment. T1 weighted spin-echo and opposed-phase gradient-echo images as well as the spectroscopic data (T2 values, water content) were analysed. Results. After G-CSF a pathologic bone marrow signal intensity was seen in 8/13 (lumbar) and 11/13 (femoral) patients respectively. The majority of the signal alterations were diffuse (6 and 8), the minority focal (2 and 3). If a patient was successfully stimulated, a significant increase in water content occurred (21% lumbar, 34% femoral). T2 values did not change significantly, nor did they correlate with the stimulation success. Conclusions. MR tomography and -spectroscopy are suitable to detect lumbar and femoral bone marrow stimulation by G-CSF quantitatively and qualitatively. The changes may simulate MBMI. The adequate judgement of G-CSF treated bone marrow without pretherapeutic images is not possible. (orig.) [de

Effect of Bacterial Endotoxins on Superovulated Mouse Embryos In Vivo: Is CSF-1 Involved in Endotoxin-Induced Pregnancy Loss?

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Yogesh Kumar Jaiswal

2006-01-01

Full Text Available Mammalian embryonic development is regulated by several cytokines and growth factors from embryonic or maternal origins. Since CSF-1 plays important role in embryonic development and implantation, we investigated its role in gram-negative bacterial LPS-induced implantation failure. The effect of LPS on normal (nonsuperovulated and superovulated in vivo-produced embryos was assessed by signs of morphological degeneration. A significantly similar number of morphologically degenerated embryos recovered from both nonsuperovulated and superovulated LPS treated animals on day 2.5 of pregnancy onwards were morphologically and developmentally abnormal as compared to their respective controls (P < .001. Normal CSF-1 expression level and pattern were also altered through the preimplantation period in the mouse embryos and uterine horns after LPS treatment. This deviation from the normal pattern and level of CSF-1 expression in the preimplantation embryos and uterine tissues suggest a role for CSF-1 in LPS-induced implantation failure.

MR cisternography: a new method for the diagnosis of CSF fistulae

International Nuclear Information System (INIS)

Eberhardt, K.E.W.; Tomandl, B.F.; Huk, W.J.; Hollenbach, H.P.; Deimling, M.

1997-01-01

The aim of this study was to compare a new MRI method for detecting the existence of cerebrospinal fluid (CSF) fistulae, i. e. MR cisternography, with CT cisternography. In a prospective study, 30 patients with post-traumatic CSF fistulae were examined. The MR examinations were performed with a 1.0-T whole-body MR system, using two T2 * -weighted sequences, a 3D PSIF (time-inversed fast imaging with steady-state precession, FISP) and a 3D constructive interference steady-state (CISS) sequence. The results of MRI and CT cisternography were compared with the surgical findings. The sensitivity in detecting CSF fistulae with MR cisternography (PSIF: 89.9 %; CISS: 93.6 %) was higher than with CT cisternography (72.3 %). The sensitivity of CT cisternography at detecting CSF fistulae in patients with a size of dural lesion less than 2 mm or in patients with multiple dural lesions is significantly lower compared with the MR method. Although the localization of CSF fistulae always proved possible with MR cisternography, this could only be accomplished wih CT in 70 % of cases. The MR cisternography technique is a new examination method with a higher sensitivity for the detection of CSF fistulae than CT cisternography. The CISS technique is superior compared with PSIF and should be used in patients with high-flow CSF fistulas. (orig.)

Inhibiting the Ca2+ Influx Induced by Human CSF

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Anna Drews

2017-12-01

Full Text Available One potential therapeutic strategy for Alzheimer’s disease (AD is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca2+ influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ; and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca2+ influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials.

CSF Flow in the Brain in the Context of Normal Pressure Hydrocephalus.

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Bradley, W G

2015-05-01

CSF normally flows back and forth through the aqueduct during the cardiac cycle. During systole, the brain and intracranial vasculature expand and compress the lateral and third ventricles, forcing CSF craniocaudad. During diastole, they contract and flow through the aqueduct reverses. Hyperdynamic CSF flow through the aqueduct is seen when there is ventricular enlargement without cerebral atrophy. Therefore, patients presenting with clinical normal pressure hydrocephalus who have hyperdynamic CSF flow have been found to respond better to ventriculoperitoneal shunting than those with normal or decreased CSF flow. Patients with normal pressure hydrocephalus have also been found to have larger intracranial volumes than sex-matched controls, suggesting that they may have had benign external hydrocephalus as infants. While their arachnoidal granulations clearly have decreased CSF resorptive capacity, it now appears that this is fixed and that the arachnoidal granulations are not merely immature. Such patients appear to develop a parallel pathway for CSF to exit the ventricles through the extracellular space of the brain and the venous side of the glymphatic system. This pathway remains functional until late adulthood when the patient develops deep white matter ischemia, which is characterized histologically by myelin pallor (ie, loss of lipid). The attraction between the bare myelin protein and the CSF increases resistance to the extracellular outflow of CSF, causing it to back up, resulting in hydrocephalus. Thus idiopathic normal pressure hydrocephalus appears to be a "2 hit" disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood. © 2015 by American Journal of Neuroradiology.

Parathyroid hormone related protein concentration in human serum and CSF correlates with age.

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Kushnir, Mark M; Peterson, Lisa K; Strathmann, Frederick G

2018-02-01

Parathyroid Hormone-Related Protein (PTHrP) is involved in intracellular calcium (Ca) regulation, and has been demonstrated to participate in regulation of Ca in brain cells, activation of neurons, and modulation of pain. However, there are conflicting reports regarding the presence of PTHrP in CSF. PTHrP and Ca were quantified in paired CSF and serum samples using mass spectrometry-based methods. Associations between PTHrP and Ca concentrations with age, sex and concentrations of nine CSF diagnostic markers in a set of 140 paired serum and CSF patient samples were evaluated. The observed median PTHrP concentration in CSF was 51 times higher than in serum; the median concentration of Ca in CSF was 1.8 times lower than in serum. We observed positive correlation between concentrations of PTHrP in CSF and serum (p=0.013). Distribution of PTHrP concentrations in serum was associated with age (p=0.0068) and the concentrations were higher in women. In samples with serum calcium concentrations within the reference intervals (n=118), central 95% distribution of concentrations for Ca-CSF, PTHrP-serum and PTHrP-CSF were 5.4 (4.5-6.1) mg/dL, 1.2 (0.5-2.5) pmol/L, 62 (22-125) pmol/L, respectively. Our data demonstrate that PTHrP is a normal constituent of human CSF with median concentrations 51 fold higher than in serum. Elevated serum PTHrP concentrations were positively correlated with age and significantly higher in women. Our data suggest that CSF could be a significant source of circulating PTHrP. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Chloride flux from blood to CSF: inhibition by furosemide and bumetanide

International Nuclear Information System (INIS)

Johnson, D.C.; Singer, S.; Hoop, B.; Kazemi, H.

1987-01-01

Movement of chloride from blood to cerebrospinal fluid (CSF) is one of the factors that may be involved in regulation of CSF [Cl-], which is important to CSF acid-base balance. We made quantitative measurements of the unidirectional flux of radiolabeled chloride between blood and CSF in anesthetized dogs, using 38 Cl, a short-lived isotope (half-life 37.3 min). This allowed multiple studies to be performed in a given animal. A three-compartment model for the blood, CSF, brain extracellular fluid, and ventriculocisternal perfusion system was used to determine the flux rate. With normocapnia, the flux was 0.01.1 min-1. The influx could be reproducibly measured for three separate determinations in the same animal over a period of 6 h, being 98 +/- 6% of the control first run on the second run and 113 +/- 6% on the third. Furosemide and bumetanide, inhibitors of sodium-coupled chloride movement, lowered the flux to 43 +/- 3% and 55 +/- 6% of control, respectively. The combination of hypercapnia and furosemide lowered the influx to 63 +/- 9% of control. These results indicate that a major mechanism of chloride entry into CSF is sodium-coupled chloride transport

Autophagy is required for stem cell mobilization by G-CSF

DEFF Research Database (Denmark)

Leveque-El Mouttie, Lucie; Vu, Therese; Lineburg, Katie E.

2015-01-01

Granulocyte colony-stimulating factor (G-CSF) is widely used clinically to prevent neutropenia after cytotoxic chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Autophagy, a process of cytoplasmic component recycling, maintains cellular homeostasis and protects...... the cell during periods of metabolic stress or nutrient deprivation. We have observed that G-CSF activates autophagy in neutrophils and HSCs from both mouse and human donors. Furthermore, G-CSF-induced neutrophil and HSC mobilization is impaired in the absence of autophagy. In contrast, autophagy...... is dispensable for direct HSC mobilization in response to the CXCR4 antagonist AMD3100. Altogether, these data demonstrate an important role for G-CSF in invoking autophagy within hematopoietic and myeloid cells and suggest that this pathway is critical for ensuring cell survival in response to clinically...

CD14-dependent monocyte isolation enhances phagocytosis of listeria monocytogenes by proinflammatory, GM-CSF-derived macrophages.

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Caroline Neu

Full Text Available Macrophages are an important line of defence against invading pathogens. Human macrophages derived by different methods were tested for their suitability as models to investigate Listeria monocytogenes (Lm infection and compared to macrophage-like THP-1 cells. Human primary monocytes were isolated by either positive or negative immunomagnetic selection and differentiated in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF or macrophage colony-stimulating factor (M-CSF into pro- or anti-inflammatory macrophages, respectively. Regardless of the isolation method, GM-CSF-derived macrophages (GM-Mφ stained positive for CD206 and M-CSF-derived macrophages (M-Mφ for CD163. THP-1 cells did not express CD206 or CD163 following incubation with PMA, M- or GM-CSF alone or in combination. Upon infection with Lm, all primary macrophages showed good survival at high multiplicities of infection whereas viability of THP-1 was severely reduced even at lower bacterial numbers. M-Mφ generally showed high phagocytosis of Lm. Strikingly, phagocytosis of Lm by GM-Mφ was markedly influenced by the method used for isolation of monocytes. GM-Mφ derived from negatively isolated monocytes showed low phagocytosis of Lm whereas GM-Mφ generated from positively selected monocytes displayed high phagocytosis of Lm. Moreover, incubation with CD14 antibody was sufficient to enhance phagocytosis of Lm by GM-Mφ generated from negatively isolated monocytes. By contrast, non-specific phagocytosis of latex beads by GM-Mφ was not influenced by treatment with CD14 antibody. Furthermore, phagocytosis of Lactococcus lactis, Escherichia coli, human cytomegalovirus and the protozoan parasite Leishmania major by GM-Mφ was not enhanced upon treatment with CD14 antibody indicating that this effect is specific for Lm. Based on these observations, we propose macrophages derived by ex vivo differentiation of negatively selected human primary monocytes as the most

CSF N-glycoproteomics for early diagnosis in Alzheimer's disease.

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Palmigiano, Angelo; Barone, Rita; Sturiale, Luisa; Sanfilippo, Cristina; Bua, Rosaria Ornella; Romeo, Donata Agata; Messina, Angela; Capuana, Maria Luisa; Maci, Tiziana; Le Pira, Francesco; Zappia, Mario; Garozzo, Domenico

2016-01-10

This work aims at exploring the human CSF (Cerebrospinal fluid) N-glycome by MALDI MS techniques, in order to assess specific glycosylation pattern(s) in patients with Alzheimer's disease (n:24) and in subjects with mild cognitive impairment (MCI) (n:11), these last as potential AD patients at a pre-dementia stage. For comparison, 21 healthy controls were studied. We identified a group of AD and MCI subjects (about 40-50% of the studied sample) showing significant alteration of CSF N-glycome profiling, consisting of a decrease in the overall sialylation degree and an increase in species bearing bisecting GlcNAc. Noteworthy, all the MCI patients that converted to AD within the clinical follow-up, had an abnormal CSF glycosylation profile. Based on the studied cohort, CSF glycosylation changes may occur before an AD clinical onset. Previous studies specifically focused on the key role of glycosyltransferase GnT-III on AD-pathogenesis, addressing the patho-mechanism to specific sugar modification of BACE-1 glycoprotein with bisecting GlcNAc. Our patients addressed protein N-glycosylation changes at an early phase of the whole biomolecular misregulation on AD, pointing to CSF N-glycome analyses as promising tool to enhance early detection of AD and also suggesting alternative therapeutics target molecules, such as specific glyco-enzymes. Copyright © 2015 Elsevier B.V. All rights reserved.

Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach

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Thelin, Eric P.; Nelson, David W.; Ghatan, Per Hamid; Bellander, Bo-Michael

2014-01-01

Background: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. Materials and Methods: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6–8) and unfavorable (GOSe 1–5) outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusion: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the

Microdialysis monitoring of CSF parameters in severe traumatic brain injury patients: A novel approach

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Eric Peter Thelin

2014-09-01

Full Text Available Background: Neuro-intensive care following traumatic brain injury is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebral spinal fluid (CSF monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome.Materials and method: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using 1. A MD catheter (CMA64-iView, n=7448 MD samples located in a CSF-pump connected to the ventricular drain and 2. An intraparenchymal MD catheter (CMA70, n=8358 MD samples. CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6-8 and unfavorable (GOSe 1-5 outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median extraction ratio using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64 lactate- (p=0.0057 and pyruvate (p=0.0011 levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR, or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusions: This new technique of global MD-CSF monitoring correlates with conventional CSF-levels of glucose and lactate and the extraction ratio for the MD catheter is higher than previously described. Increase in lactate and pyruvate in CSF, without any effect on the LPR, correlates to unfavorable outcome.

Meta-Review of CSF core biomarkers in Alzheimer’s disease: the state-of-the-art after the new revised diagnostic criteria

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Daniel eFerreira

2014-03-01

Full Text Available Background: Current research criteria for Alzheimer’s disease (AD include Cerebrospinal Fluid (CSF biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable. Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD. Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD.Eligibility criteria: 1a Systematic reviews with meta-analysis; 1b Primary studies published after the new revised diagnostic criteria; 2 Evaluation of the diagnostic performance of at least one CSF core biomarker.Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for Mild Cognitive Impairment (MCI prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia. Limitations: 1 use of clinical diagnosis as standard instead of pathological postmortem confirmation; 2 variability of methodological aspects; 3 insufficiently long follow-up periods in MCI studies; and 4 lower diagnostic accuracy in primary care compared with memory clinics. Conclusions: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development.

Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

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Ferreira, Daniel; Perestelo-Pérez, Lilisbeth; Westman, Eric; Wahlund, Lars-Olof; Sarría, Antonio; Serrano-Aguilar, Pedro

2014-01-01

Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable. Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD. Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker. Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia. Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics. Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development. PMID:24715863

Proteomic investigations of the ventriculo-lumbar gradient in human CSF

DEFF Research Database (Denmark)

Simonsen, Anja Hviid; Bech, Sara Brynhild Winther; Laursen, Inga

2010-01-01

Cerebrospinal fluid (CSF) is an ideal biological material in which to search for new biomarkers for improved diagnosis of neurological diseases. During a lumbar puncture between 5 and 15 mL of CSF are obtained. Previous studies have assessed the ventriculo-lumbar concentration gradient of a number...... of specific proteins. In the present study we took a proteomics approach to investigate the possible concentration gradient of a panel of proteins and peptides in the CSF of 16 patients with neurodegenerative diseases. Using two different mass spectrometry techniques, matrix assisted laser desorption...... ionization time of flight (MALDI-TOF) and surface enhanced laser desorption ionization time of flight (SELDI-TOF), we found that only one of the investigated proteins, apolipoprotein CI, was significantly decreased between the 1st and the 10th mL of CSF. Furthermore, we confirmed previous results showing...

Recent Advances of Colony-Stimulating Factor-1 Receptor (CSF-1R) Kinase and Its Inhibitors.

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El-Gamal, Mohammed I; Al-Ameen, Shahad K; Al-Koumi, Dania M; Hamad, Mawadda G; Jalal, Nouran A; Oh, Chang-Hyun

2018-01-17

Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is overstimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the CSF-1R. Another ligand, interlukin-34 (IL-34), was recently reported to activate the CSF-1R receptor in a different manner. The relationship between CSF-1R and microglia has been reviewed. Both CSF-1 antibodies and small molecule CSF-1R kinase inhibitors have now been tested in animal models and in humans. In this Perspective, we discuss the role of CSF-1 and IL-34 in producing cancer, bone disorders, and inflammation. We also review the newly discovered and improved small molecule kinase inhibitors and monoclonal antibodies that have shown potent activity toward CSF-1R, reported from 2012 until 2017.

Herpes Simplex Encephalitis Presenting with Normal CSF Analysis

International Nuclear Information System (INIS)

Ahmed, R.; Kiani, I. G.; Shah, F.; Rehman, R. N.; Haq, M. E.

2013-01-01

A 28 years old female presented with headache, fever, altered sensorium and right side weakness for one week. She was febrile and drowsy with right sided hemiplegia and papilledema. Tuberculous or bacterial meningitis, tuberculoma and abscess were at the top of the diagnosis list followed by Herpes simplex meningo-encephalitis (HSE). MRI showed abnormal signal intensity of left temporal lobe without significant post-contrast enhancement and midline shift. CSF examination was normal, gram stain and Ziehl-Neelsen stain showed no micro-organism, or acid fast bacilli. CSF for MTB PCR was negative. PCR DNA for Herpes simplex 1 on CSF was detected. Acyclovir was started and the patient was discharged after full recovery. A high index of suspicion is required for HSE diagnosis in Pakistan where other infections predominantly affect the brain and HSE may be overlooked as a potential diagnosis. (author)

Correlation of MRI and CSF cytology in the diagnosis of medulloblastoma spinal metastases

International Nuclear Information System (INIS)

Harrison, S.K.; Ditchfield, M.R.; Waters, K.

1998-01-01

Background. Medulloblastoma frequently spreads to involve the spinal cord, which significantly reduces patient survival and determines whether chemotherapy is utilised and the dose of irradiation to the neuraxis. Staging is usually achieved by MRI of the spine and/or cytology of CSF, both methods having their limitations. Objective. To determine whether there is a correlation between CSF cytology and the demonstration of spinal metastases by MRI and whether CSF cytology is useful when spinal MRI is equivocal. Materials and methods. All cases of medulloblastoma diagnosed at our hospital between 1992 and 1997 were identified. Of 26 cases, 11 presentations (age range 4 months to 12 years) had both CSF cytology (either from the cisterna magna or lumbar puncture) and spinal MRI. The MR studies were reviewed for the presence of metastases and the CSF cytology for the presence of tumour cells. Results. We found 100 % correlation between MRI and CSF cytology for samples taken by lumbar puncture (four negative and three positive on both investigations). No correlation was demonstrated when CSF samples were taken from the cisterna magna. Conclusions. Our data suggest that lumbar CSF cytology may be useful when the MRI is equivocal for the presence of metastatic involvement of the spine by medulloblastoma. (orig.)

Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls.

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Mollenhauer, Brit; Caspell-Garcia, Chelsea J; Coffey, Christopher S; Taylor, Peggy; Shaw, Leslie M; Trojanowski, John Q; Singleton, Andy; Frasier, Mark; Marek, Kenneth; Galasko, Douglas

2017-11-07

To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical measures of PD, and identify what may influence them. CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1-42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson's Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes. CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists. These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Highly Expressed Granulocyte Colony-Stimulating Factor (G-CSF) and Granulocyte Colony-Stimulating Factor Receptor (G-CSFR) in Human Gastric Cancer Leads to Poor Survival.

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Fan, Zhisong; Li, Yong; Zhao, Qun; Fan, Liqiao; Tan, Bibo; Zuo, Jing; Hua, Kelei; Ji, Qiang

2018-03-23

BACKGROUND Chemotherapy for advanced gastric cancer (GC) patients has been the mainstay of therapy for many years. Although adding anti-angiogenic drugs to chemotherapy improves patient survival slightly, identifying anti-angiogenic therapy-sensitive patients remains challenging for oncologists. Granulocyte colony-stimulating factor (G-CSF) promotes tumor growth and angiogenesis, which can be minimized with the anti-G-CSF antibody. Thus, G-CSF might be a potential tumor marker. However, the effects of G-CSF and G-CSFR expression on GC patient survival remain unclear. MATERIAL AND METHODS Seventy GC tissue samples were collected for G-CSF and G-CSFR detection by immunohistochemistry. A total of 40 paired GC tissues and matched adjacent mucosa were used to measure the G-CSF and G-CSFR levels by ELISA. Correlations between G-CSF/G-CSFR and clinical characteristics, VEGF-A levels and overall survival were analyzed. Biological function and underlying mechanistic investigations were carried out using SGC7901 cell lines, and the effects of G-CSF on tumor proliferation, migration, and tube formation were examined. RESULTS The levels of G-CSFR were upregulated in GC tissues compared to normal mucosa tissues. Higher G-CSF expression was associated with later tumor stages and higher tumor VEGF-A and serum CA724 levels, whereas higher G-CSFR expression was associated with lymph node metastasis. Patients with higher G-CSF expression had shorter overall survival times. In vitro, G-CSF stimulated SGC7901 proliferation and migration through the JAK2/STAT3 pathway and accelerated HUVEC tube formation. CONCLUSIONS These data suggest that increased G-CSF and G-CSFR in tumors leads to unfavorable outcomes for GC patients by stimulating tumor proliferation, migration, and angiogenesis, indicating that these factors are potential tumor targets for cancer treatment.

G-CSF Analogue Treatment Increases Peripheral Neutrophil Numbers in Pigs - a Potential Alternative for In-Feed Antibiotics

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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...

Time trends in utilization of G-CSF prophylaxis and risk of febrile neutropenia in a Medicare population receiving adjuvant chemotherapy for early-stage breast cancer.

Science.gov (United States)

Goyal, Ravi K; Tzivelekis, Spiros; Rothman, Kenneth J; Candrilli, Sean D; Kaye, James A

2018-02-01

The purpose of this study is to assess temporal trends in the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis and risk of febrile neutropenia (FN) among older women receiving adjuvant chemotherapy for early-stage breast cancer. Women aged ≥ 66 years with diagnosis of early-stage breast cancer who initiated selected adjuvant chemotherapy regimens were identified using the SEER-Medicare data from 2002 to 2012. Adjusted, calendar-year-specific proportions were estimated for use of G-CSF primary prophylaxis (PP) and secondary prophylaxis and FN risk in the first and the second/subsequent cycles during the first course of chemotherapy, using logistic regression models. calendar-year-specific mean probabilities were estimated with covariates set to modal values. Among 11,107 eligible patients (mean age 71.7 years), 74% received G-CSF in the first course of chemotherapy. Of all patients, 5819 (52%) received G-CSF PP, and among those not receiving G-CSF PP, only 5% received G-CSF secondary prophylaxis. The adjusted proportion using G-CSF PP increased from 6% in 2002 to 71% in 2012. During the same period, the adjusted risk of FN in the first cycle increased from 2% to 3%; the adjusted risk increased from 1.5% to 2.9% among those receiving G-CSF PP and from 2.3% to 3.5% among those not receiving G-CSF PP. The use of G-CSF PP increased substantially during the study period. Although channeling of higher-risk patients to treatment with G-CSF PP is expected, the adjusted risk of FN among patients treated with G-CSF PP tended to be lower than among those not receiving G-CSF PP.

Functional changes in CSF volume estimated using measurement of water T2 relaxation

NARCIS (Netherlands)

Piechnik, S.K.; Evans, J.; Bary, L.H.; Wise, R.G.; Jezzard, P.

2009-01-01

Cerebrospinal fluid (CSF) provides hydraulic suspension for the brain. The general concept of bulk CSF production, circulation, and reabsorption is well established, but the mechanisms of momentary CSF volume variation corresponding to vasoreactive changes are far less understood. Nine individuals

GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization.

Science.gov (United States)

Halstead, E Scott; Umstead, Todd M; Davies, Michael L; Kawasawa, Yuka Imamura; Silveyra, Patricia; Howyrlak, Judie; Yang, Linlin; Guo, Weichao; Hu, Sanmei; Hewage, Eranda Kurundu; Chroneos, Zissis C

2018-01-05

Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established. Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi. Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an "M1-like" to a more "M2-like" activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ). Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic "M1-like" macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury.

Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia.

Directory of Open Access Journals (Sweden)

Elaine Holmes

2006-08-01

Full Text Available The identification of schizophrenia biomarkers is a crucial step towards improving current diagnosis, developing new presymptomatic treatments, identifying high-risk individuals and disease subgroups, and assessing the efficacy of preventative interventions at a rate that is not currently possible.(1H nuclear magnetic resonance spectroscopy in conjunction with computerized pattern recognition analysis were employed to investigate metabolic profiles of a total of 152 cerebrospinal fluid (CSF samples from drug-naïve or minimally treated patients with first-onset paranoid schizophrenia (referred to as "schizophrenia" in the following text and healthy controls. Partial least square discriminant analysis showed a highly significant separation of patients with first-onset schizophrenia away from healthy controls. Short-term treatment with antipsychotic medication resulted in a normalization of the disease signature in over half the patients, well before overt clinical improvement. No normalization was observed in patients in which treatment had not been initiated at first presentation, providing the first molecular evidence for the importance of early intervention for psychotic disorders. Furthermore, the alterations identified in drug-naïve patients could be validated in a test sample set achieving a sensitivity and specificity of 82% and 85%, respectively.Our findings suggest brain-specific alterations in glucoregulatory processes in the CSF of drug-naïve patients with first-onset schizophrenia, implying that these abnormalities are intrinsic to the disease, rather than a side effect of antipsychotic medication. Short-term treatment with atypical antipsychotic medication resulted in a normalization of the CSF disease signature in half the patients well before a clinical improvement would be expected. Furthermore, our results suggest that the initiation of antipsychotic treatment during a first psychotic episode may influence treatment response

Chimeric classical swine fever (CSF)-Japanese encephalitis (JE) viral particles as a non-transmissible bivalent marker vaccine candidate against CSF and JE infections

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A trans-complemented CSF- JE chimeric viral replicon was constructed using an infectious cDNA clone of the CSF virus (CSFV) Alfort/187 strain. The E2 gene of CSFV Alfort/187 strain was deleted and the resultant plasmid pA187delE2 was inserted by a fragment containing the region coding for a truncate...

Inhibition of the CSF-1 receptor sensitizes ovarian cancer cells to cisplatin.

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Yu, Rong; Jin, Hao; Jin, Congcong; Huang, Xuefeng; Lin, Jinju; Teng, Yili

2018-03-01

Ovarian cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely used in locally advanced ovarian cancer patients. Acquired or de novo cisplatin resistance remains the barrier to patient survival, and the mechanisms of cisplatin resistance are still not well understood. In the current study, we found that colony-stimulating-factor-1 receptor (CSF-1R) was upregulated in cisplatin-resistant SK-OV-3 and CaoV-3 cells. Colony-stimulating-factor-1 receptor knockdown suppressed proliferation and enhanced apoptosis in cisplatin-resistant SK-OV-3 and CaoV-3 cells. However, CSF-1R overexpression had inverse effects. While parental SK-OV-3 and CaoV-3 cells were more resistant to cisplatin after CSF-1R overexpression, CSF-1R knockdown in SK-OV-3 and CaoV-3 cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that CSF-1R significantly promoted active AKT and ERK1/2 signalling pathways in cisplatin-resistant cells. Furthermore, a combination of cisplatin and CSF-1R inhibitor effectively inhibited tumour growth in xenografts. Taken together, our results provide the first evidence that CSF-1R inhibition can sensitize cisplatin-refractory ovarian cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumours. Copyright © 2018 John Wiley & Sons, Ltd.

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

International Nuclear Information System (INIS)

Malur, Anagha; Huizar, Isham; Wells, Greg; Barna, Barbara P.; Malur, Achut G.; Thomassen, Mary Jane

2011-01-01

but improved significantly after lenti-ABCG1 treatment. Data demonstrate that in vivo instillation of lenti-ABCG1 in GM-CSF KO mice is sufficient to restore pulmonary homeostasis by: (1) upregulating ABCG1; (2) reducing intra and extracellular lipids; and (3) improving lung function. Results suggest that the ABCG1 lipid transporter is the key downstream target of GM-CSF-induced PPARγ necessary for surfactant catabolism.

Systemic granulocyte colony-stimulating factor (G-CSF) enhances wound healing in dystrophic epidermolysis bullosa (DEB): Results of a pilot trial.

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Fine, Jo-David; Manes, Becky; Frangoul, Haydar

2015-07-01

Chronic nonhealing wounds are the norm in patients with inherited epidermolysis bullosa (EB), especially those with dystrophic EB (DEB). A possible benefit in wound healing after subcutaneous treatment with granulocyte colony-stimulating factor (G-CSF) was suggested from an anecdotal report of a patient given this during stem cell mobilization before bone-marrow transplantation. We sought to determine whether benefit in wound healing in DEB skin might result after 6 daily doses of G-CSF and to confirm its safety. Patients were assessed for changes in total body blister and erosion counts, surface areas of selected wounds, and specific symptomatology after treatment. Seven patients with DEB (recessive, 6; dominant, 1) were treated daily with subcutaneous G-CSF (10 μg/kg/dose) and reevaluated on day 7. For all patients combined, median reductions of 75.5% in lesional size and 36.6% in blister/erosion counts were observed. When only the 6 responders were considered, there were median reductions of 77.4% and 38.8% of each of these measured parameters, respectively. No adverse side effects were noted. Limitations include small patient number, more than 1 DEB subtype included, and lack of untreated age-matched control subjects. Subcutaneous G-CSF may be beneficial in promoting wound healing in some patients with DEB when conventional therapies fail. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

CSF lactate alone is not a reliable indicator of bacterial ventriculitis in patients with ventriculostomies.

Science.gov (United States)

Hill, Emily; Bleck, Thomas P; Singh, Kamaljit; Ouyang, Bichun; Busl, Katharina M

2017-06-01

In a febrile patient with a ventriculostomy, diagnosing or excluding bacterial or microbial ventriculitis is difficult, as conventional markers in analysis of cerebrospinal fluid (CSF) are not applicable due to presence of blood and inflammation. CSF lactate has been shown to be a useful indicator of bacterial meningitis in CSF obtained via lumbar puncture, but little and heterogenous data exist on patients with ventriculostomies. We reviewed all CSF analyses obtained via ventriculostomy in patients admitted to our tertiary medical center between 2008 and 2013, and constructed receiver operating characteristic (ROC) curves to evaluate the accuracy of CSF lactate concentration in discriminating a positive CSF culture from a negative one in setting of ventriculostomy and prophylactic antibiosis. Among 467 CSF lactate values, there were 22 corresponding CSF cultures with bacterial growth. Sensitivities and specificities for CSF lactate at threshold values 3, 4, 5 and 6mmol/L showed sensitivity and specificity greater than 70% for CSF lactate threshold 4mmol/L. The lowest threshold value of 3mmol/L resulted in higher sensitivity of 81.8%, and the highest chosen threshold value resulted in high specificity of 94.2%, but these values had poor corresponding specificity and sensitivity, respectively. The area under the curve was 0.82 (95% CI 0.72, 0.91). Our data from a large sample of CSF studies in patients with ventriculostomy indicate that no single value of CSF lactate provided both sensitivity and specificity high enough to be regarded as reliable test. Copyright © 2017 Elsevier B.V. All rights reserved.

Increased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer's disease.

LENUS (Irish Health Repository)

Ewers, Michael

2012-02-01

The enzyme beta-secretase (BACE1) is essentially involved in the production of cerebral amyloidogenic pathology in Alzheimer\\'s disease (AD). The measurement of BACE1 activity in cerebrospinal fluid (CSF) has been reported, which may render CSF measurement of BACE1 a potential biomarker candidate of AD. In order to investigate whether BACE1 protein activity is correlated with regional brain atrophy in AD, we investigated the association between CSF levels of BACE1 and MRI-assessed hippocampus volume in patients with AD (n = 30). An increase in CSF-BACE1 activity was associated with decreased left and right hippocampus volume corrected for global head volume in the AD patients. Boot-strapped regression analysis showed that increased CSF levels of BACE1 activity were associated with increased CSF concentration of total tau but not amyloid-beta1-42 in AD. White matter hyperintensities did not influence the results. BACE1 activity and protein levels were significantly increased in AD compared to 19 elderly healthy controls. Thus, the CSF biomarker candidate of BACE1 activity was associated with hippocampus atrophy in AD in a robust manner and may reflect neurotoxic amyloid-beta-related processes.

CSF and blood oxytocin concentration changes following intranasal delivery in macaque.

Directory of Open Access Journals (Sweden)

Olga Dal Monte

Full Text Available Oxytocin (OT in the central nervous system (CNS influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline to 15 primates (Macaca mulatta, using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.

Chimeric HIV-1 envelope glycoproteins with potent intrinsic granulocyte-macrophage colony-stimulating factor (GM-CSF activity.

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Gözde Isik

Full Text Available HIV-1 acquisition can be prevented by broadly neutralizing antibodies (BrNAbs that target the envelope glycoprotein complex (Env. An ideal vaccine should therefore be able to induce BrNAbs that can provide immunity over a prolonged period of time, but the low intrinsic immunogenicity of HIV-1 Env makes the elicitation of such BrNAbs challenging. Co-stimulatory molecules can increase the immunogenicity of Env and we have engineered a soluble chimeric Env trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF domain. This chimeric molecule induced enhanced B and helper T cell responses in mice compared to Env without GM-CSF. We studied whether we could optimize the activity of the embedded GM-CSF as well as the antigenic structure of the Env component of the chimeric molecule. We assessed the effect of truncating GM-CSF, removing glycosylation-sites in GM-CSF, and adjusting the linker length between GM-CSF and Env. One of our designed Env(GM-CSF chimeras improved GM-CSF-dependent cell proliferation by 6-fold, reaching the same activity as soluble recombinant GM-CSF. In addition, we incorporated GM-CSF into a cleavable Env trimer and found that insertion of GM-CSF did not compromise Env cleavage, while Env cleavage did not compromise GM-CSF activity. Importantly, these optimized Env(GM-CSF proteins were able to differentiate human monocytes into cells with a macrophage-like phenotype. Chimeric Env(GM-CSF should be useful for improving humoral immunity against HIV-1 and these studies should inform the design of other chimeric proteins.

Chimeric HIV-1 Envelope Glycoproteins with Potent Intrinsic Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Activity*

Science.gov (United States)

Boot, Maikel; Cobos Jiménez, Viviana; Kootstra, Neeltje A.; Sanders, Rogier W.

2013-01-01

HIV-1 acquisition can be prevented by broadly neutralizing antibodies (BrNAbs) that target the envelope glycoprotein complex (Env). An ideal vaccine should therefore be able to induce BrNAbs that can provide immunity over a prolonged period of time, but the low intrinsic immunogenicity of HIV-1 Env makes the elicitation of such BrNAbs challenging. Co-stimulatory molecules can increase the immunogenicity of Env and we have engineered a soluble chimeric Env trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain. This chimeric molecule induced enhanced B and helper T cell responses in mice compared to Env without GM-CSF. We studied whether we could optimize the activity of the embedded GM-CSF as well as the antigenic structure of the Env component of the chimeric molecule. We assessed the effect of truncating GM-CSF, removing glycosylation-sites in GM-CSF, and adjusting the linker length between GM-CSF and Env. One of our designed EnvGM-CSF chimeras improved GM-CSF-dependent cell proliferation by 6-fold, reaching the same activity as soluble recombinant GM-CSF. In addition, we incorporated GM-CSF into a cleavable Env trimer and found that insertion of GM-CSF did not compromise Env cleavage, while Env cleavage did not compromise GM-CSF activity. Importantly, these optimized EnvGM-CSF proteins were able to differentiate human monocytes into cells with a macrophage-like phenotype. Chimeric EnvGM-CSF should be useful for improving humoral immunity against HIV-1 and these studies should inform the design of other chimeric proteins. PMID:23565193

Research Upregulation of CD23 (FcεRII Expression in Human Airway Smooth Muscle Cells (huASMC in Response to IL-4, GM-CSF, and IL-4/GM-CSF

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Lew D Betty

2005-05-01

Full Text Available Abstract Background Airway smooth muscle cells play a key role in remodeling that contributes to airway hyperreactivity. Airway smooth muscle remodeling includes hypertrophy and hyperplasia. It has been previously shown that the expression of CD23 on ASMC in rabbits can be induced by the IgE component of the atopic serum. We examined if other components of atopic serum are capable of inducing CD23 expression independent of IgE. Methods Serum starved huASMC were stimulated with either IL-4, GM-CSF, IL-13, IL-5, PGD2, LTD4, tryptase or a combination of IL-4, IL-5, IL-13 each with GM-CSF for a period of 24 h. CD23 expression was analyzed by flow cytometry, western blot, and indirect immunofluorescence. Results The CD23 protein expression was upregulated in huASMC in response to IL-4, GM-CSF, and IL-4/GM-CSF. The percentage of cells with increased fluorescence intensity above the control was 25.1 ± 4.2% (IL-4, 15.6 ± 2.7% (GM-CSF and 32.9 ± 13.9% (IL-4/GMCSF combination(n = 3. The protein content of IL-4/GMCSF stimulated cells was significantly elevated. Expression of CD23 in response to IL-4, GM-CSF, IL-4/GM-CSF was accompanied by changes in cell morphology including depolymerization of isoactin fibers, cell spreading, and membrane ruffling. Western blot revealed abundant expression of the IL-4Rα and a low level expression of IL-2Rγc in huASMC. Stimulation with IL-4 resulted in the phosphorylation of STAT-6 and an increase in the expression of the IL-2Rγc. Conclusion CD23 on huASMC is upregulated by IL-4, GM-CSF, and IL-4/GM-CSF. The expression of CD23 is accompanied by an increase in cell volume and an increase in protein content per cell, suggesting hypertrophy. Upregulation of CD23 by IL-4/GM-CSF results in phenotypic changes in huASMC that could play a role in cell migration or a change in the synthetic function of the cells. Upregulation of CD23 in huASMC by IL-4 and GM-CSF can contribute to changes in huASMC and may provide an avenue

Use of amyloid-PET to determine cutpoints for CSF markers

DEFF Research Database (Denmark)

Zwan, Marissa D; Rinne, Juha O; Hasselbalch, Steen G

2016-01-01

OBJECTIVES: To define CSF β-amyloid 1-42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice. METHODS: We included 433 participants (57 controls......, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C......]PiB-PET images. RESULTS: Amyloid-PET-based calculated CSF Aβ42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ42 and amyloid-PET was 84%. Similar...

CSF flow image using phase-contrast cine MR technique : preliminary clinical application

International Nuclear Information System (INIS)

Kim, Hyae Young; Choi, Hye Young; Baek, Seung Yeon; Lee, Sun Wha; Ko, Eun Joo; Lee, Myung Sook

1997-01-01

To evaluate the clinical usefulness of 2-D Cine PC (phase contrast) technique in visualizing the pattern and the site of abnormal CSF flow and to assess the effect of a third ventriculostomy in patients with hydrocephalus. The study group consisted of three normal controls and 13 patients with hydrocephalus, as shown on CT or MRI, and two patients who had undergone their third ventriculostomy. The technique was EKG-gated 2-D Cine PC MRI with velocity encoding 5cm/sec, TR 80msec, TE 12.3-15msec, and flip angle 15-60 degrees. Image quality was analyzed for variable sequences, and CSF flow was observed along the CSF flow pathway. We analyzed continuity and intensity of the CSF flow signal, and obstruction site and flow velocity degree were then defined. Systolic high and diastolic low signal intensity along the CSF flow-pathway, with normal asynchronicity and continuation, were clearly seen in normal controls. In three patients, there was obstruction at the ventricular level while others were either normal or showed a normal pattern with a weak signal. 'Normal' was defined as noncommunicating hydrocephalus and the latter as communicating hydrocephalus. In the two patients who had undergone ventriculostomy, a signal was in one case detected at the site of the third operation. A 2-D Cine PC CSF flow study enables us to see CSF flow signals noninvasively and to detect the site of obstruction of a CSF flow-pathway. It can therefore it can be useful for determining the application of a ventriculoperitoneal shunt and assessing the effect of a third ventriculostomy

MDSCs are involved in the protumorigenic potentials of GM-CSF in colitis-associated cancer.

Science.gov (United States)

Ma, Ning; Liu, Qilin; Hou, Lin; Wang, Yalin; Liu, Ziling

2017-06-01

Chronic inflammation is thought to be a major driving force for the development of colitis-associated colorectal cancer (CAC). As one member of proinflammatory cytokine family, granulocyte macrophage colony-stimulating factor (GM-CSF) has been identified to play a key role in CAC pathogenesis recently. The underlying mechanisms, however, remain largely unknown. In this study, we found that myeloid-derived suppressor cells (MDSCs) accumulated increasingly in the lesions during the progression from colitis to cancer, which was critical for CAC formation. Importantly, this MDSC accumulation was controlled by GM-CSF. MDSC number decreased significantly in GM-CSF-deficient mice suffering from CAC induction, and transfusion of MDSCs from wild-type CAC-bearing mice into GM-CSF-deficient counterparts led to recurrence of CAC. Furthermore, the supernatants of CAC lesions or GM-CSF alone was sufficient to differentiate hematopoietic precursors into MDSCs. Addition of neutralizing anti-GM-CSF antibody impaired the MDSC-differentiating effects of the supernatants of CAC lesions. Overall, these findings shed new insights into the mechanisms of GM-CSF underlying CAC development, by inducing/recruiting CAC-promoting MDSCs. Blocking GM-CSF activity or MDSC function may represent new therapeutic strategies for CAC in clinic.

Gait in normal pressure hydrocephalus: characteristics and effects of the CSF tap test

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Ricardo Krause Martinez de Souza

Full Text Available ABSTRACT Normal pressure hydrocephalus (NPH, described by Hakim and Adams in 1965, is characterized by gait apraxia, urinary incontinence, and dementia. It is associated with normal cerebrospinal fluid (CSF pressure and ventricular dilation that cannot be attributed to cerebral atrophy. Objectives: To evaluate gait characteristics in patients with idiopathic NPH and investigate the effect of the CSF tap test (CSF-TT on gait. Methods: Twenty-five patients diagnosed with probable idiopathic NPH were submitted to the CSF-TT. The procedure aimed to achieve changes in gait parameters. Results: Fifteen gait parameters were assessed before and after the CSF-TT. Five showed a statistically significant improvement (p < 0.05: walking speed (p < 0.001, cadence (p < 0.001, step length (p < 0.001, en bloc turning (p = 0.001, and step height (p = 0.004. Conclusion: This study demonstrated that gait speed was the most responsive parameter to the CSF-TT, followed by cadence, step length, en bloc turning, and step height.

Clinical implications of medulloblastoma subgroups: incidence of CSF diversion surgery.

Science.gov (United States)

Schneider, Christian; Ramaswamy, Vijay; Kulkarni, Abhaya V; Rutka, James T; Remke, Marc; Tabori, Uri; Hawkins, Cynthia; Bouffet, Eric; Taylor, Michael D

2015-03-01

While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality

Prognosis of cerebral ischemia, significance of CSF-lactate-level and computerized tomography

International Nuclear Information System (INIS)

Busse, O.

1982-01-01

In patients (n = 120) with supratentorial ischemic cerebral infarction CSF lactate was determined and a CT was carried out on the 1st, 3rd and 7th day after the stroke. On the 3rd and 7th day the comparative investigation revealed a close correlation between the measure of the ischemic edema and the level of CSF-lactate. Thus the lactate-concentration can be regarded as a measure for the spread of the edema after cerebral infarction. Already on the 3rd day CT- and CSF-lactate results allow a relatively reliable prediction for the course of the stroke. An edema grade III in CT and a CSF-lactate concentration more than 4 mmol/l were prognostically critical. On the other hand good chances of survival were indicated by a CSF lactate level under 2.5 mmol/l and an edema grade I. (orig.) [de

High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis.

Science.gov (United States)

Calcagno, Andrea; Cusato, Jessica; Simiele, Marco; Motta, Ilaria; Audagnotto, Sabrina; Bracchi, Margherita; D'Avolio, Antonio; Di Perri, Giovanni; Bonora, Stefano

2014-01-01

To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier. Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 α (HNF4α) were determined by real-time PCR. In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF. Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood-brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.

Distinct Properties of Human M-CSF and GM-CSF Monocyte-Derived Macrophages to Simulate Pathological Lung Conditions In Vitro: Application to Systemic and Inflammatory Disorders with Pulmonary Involvement.

Science.gov (United States)

Lescoat, Alain; Ballerie, Alice; Augagneur, Yu; Morzadec, Claudie; Vernhet, Laurent; Fardel, Olivier; Jégo, Patrick; Jouneau, Stéphane; Lecureur, Valérie

2018-03-17

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.

Beta-trace protein in ascites and pleural effusions: limits of CSF leakage detection.

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Dietzel, Joanna; Krebs, Alexander; Böttcher, Dominique; Sieb, Manuela; Glocker, Michael O; Lüdemann, Jan; Roser, Markus; Dressel, Alexander

2012-06-10

Rhino- and/or otoliquorrhea can be diagnosed by detecting beta-trace protein (β-TP) in nasal or ear secretions, as β-TP is found in high concentrations in cerebrospinal fluid (CSF) but not in serum. CSF fistulae following trauma or surgery can also occur at other anatomical sites, resulting in CSF leakage into the thoracic and abdominal cavities. By analogy, determination of ß-TP has also been used to diagnose CSF admixture in pleural effusions and ascites. However, no systematic study has yet evaluated the concentrations of β-TP in such fluids in the absence of CSF. To determine the validity of β-TP determination as a marker for the presence of CSF, we investigated β-TP concentrations in pleural effusions and ascites without CSF admixture. Patients from whom samples of ascites or pleural effusion and a paired plasma sample were available were investigated. One hundred sixty-four patients were prospectively recruited. ß-TP concentrations were determined by nephelometry. Mass spectrometric proteome analysis confirmed the presence of ß-TP in the samples. Median β-TP concentrations detected in ascites and pleural effusions (range, 0.014-26.5 mg/L, median 2.29 mg/L) exceeded the corresponding plasma concentrations 2.6-fold. According to cutoffs published to diagnose rhino- and otoliquorrhea, between 6.1% and 95.7% of the specimens would have been erroneously rated CSF-positive. Protein analysis confirmed the presence of β-TP in pleural effusion and ascites. Ascites and pleural effusion contain high concentrations of β-TP that exceed the levels in corresponding plasma. Therefore, β-TP is not a specific marker for the presence of CSF in these fluids.

Comparison of two regimens of RhG-CSF in neutropenic neonatal septicemia: a randomized clinical trial.

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Nayeri, Fatemeh; Soheili, Habib; Kaveh, Mahbod; Oloomi Yazdi, Zohre; Shariat, Mamak; Dalili, Hosein

2011-01-01

Considering the 50% mortality rate of neonatal septicemia associated with neutropenia and increasing resistance to antibiotics, simultaneous antibiotic therapy strategies are becoming more important. However, few studies have been performed to evaluate effectiveness of RhG-CSF in the treatment of neutropenia in neonates. This randomized clinical trial was performed on 40 neutropenic neonates with septicemia who were hospitalized in Vali-e-Asr and Mirza Koochak Khan Hospitals (Tehran, Iran). The neonates were randomly divided into two equal groups RhG-CSF was administered as a subcutaneous single dose of 10 μg/kg/s.c. to neonates in group A and as 10 μg/kg/s.c./day once daily for 3 days to neonates in group B. CBC and differential count was checked 6, 24 and 48 hours after the last dose. There was no significant difference in mean birth weight, gender, age, and risk factors between two groups. Neutropenia was improved 48 hours after the last dose, whilst there was no significant statistical difference between two groups (P>0.05). The final outcome including death, duration of hospitalization and duration of antibiotics therapy after RhG-CSF administration did not differ between two groups (P>0.05). The results of this study showed that administration of a single dose of RhG-CSF (10 μg/kg) was effective in treating neonatal septicemic neutropenia.

Interpretation and value of MR CSF flow studies for paediatric ...

African Journals Online (AJOL)

Imaging techniques may be underutilised when clinicians are unaware of the technique or do not recognise its potential. Phase-contrast MR imaging (PC-MRI) is a rapid, simple and non-invasive technique that is sensitive to CSF flow. It demonstrates a mechanical coupling between cerebral blood and CSF flow throughout ...

IIH with normal CSF pressures?

Directory of Open Access Journals (Sweden)

Soh Youn Suh

2013-01-01

Full Text Available Idiopathic intracranial hypertension (IIH is a condition of raised intracranial pressure (ICP in the absence of space occupying lesions. ICP is usually measured by lumbar puncture and a cerebrospinal fluid (CSF pressure above 250 mm H 2 O is one of the diagnostic criteria of IIH. Recently, we have encountered two patients who complained of headaches and exhibited disc swelling without an increased ICP. We prescribed acetazolamide and followed both patients frequently; because of the definite disc swelling with IIH related symptoms. Symptoms and signs resolved in both patients after they started taking acetazolamide. It is generally known that an elevated ICP, as measured by lumbar puncture, is the most important diagnostic sign of IIH. However, these cases caution even when CSF pressure is within the normal range, that suspicion should be raised when a patient has papilledema with related symptoms, since untreated papilledema may cause progressive and irreversible visual loss.

Persistent CSF Rhinorrhoea, Pneumocephalus, and Recurrent Meningitis Following Misdiagnosis of Olfactory Neuroblastoma

Directory of Open Access Journals (Sweden)

Neil Barua

2010-01-01

Full Text Available A 41-year-old female patient was admitted with streptococcal meningitis on a background of 5-month history of CSF rhinorrhoea. Imaging revealed an extensive skull base lesion involving the sphenoid and ethmoid sinuses, the pituitary fossa with suprasellar extension and bony destruction. Histological examination of an endonasal transethmoidal biopsy suggested a diagnosis of olfactory neuroblastoma. A profuse CSF leak occurred and the patient developed coliform meningitis. A second endonasal endoscopic biopsy was undertaken which demonstrated the tumour to be a prolactinoma. Following endonasal repair of the CSF leak and lumbar drainage, she developed profound pneumocephalus. The patient underwent three further unsuccessful CSF leak repairs. Definitive control of the CSF leak was finally achieved through a transcranial approach with prolonged lumbar drainage. This case illustrates some of the potentially devastating complications which can occur as a consequence of complex skull base lesions. A multidisciplinary approach may be required to successfully manage such cases.

Crystals seen on CSF microscopy in a case of suspected subarachnoid haemorrhage

Science.gov (United States)

Weiand, Daniel; Hanning, Ian; Mouhamadou, Moussa; Wearmouth, Debbie

2015-01-01

Although crystals are rarely identified on cerebrospinal fluid (CSF) microscopy, their presence can be of significant diagnostic value. We report a case of oxalate crystals seen on CSF microscopy of a 43-year-old woman. The patient presented with headaches, nausea and vomiting. CT of the head showed a small focus of hyper-density, suspicious of haemorrhage, in the right side of the pontine cistern. CSF cell count was within the normal range. Although no organisms were seen on microscopy, copious oxalate crystals were seen. The same crystals were seen on microscopy of CSF collected in a fluoride oxalate container used for glucose analysis. A follow-up contrast-enhanced CT angiogram did not demonstrate any abnormalities. It transpired that excess CSF had been collected into a fluoride oxalate container. This had subsequently been decanted into a plain container for microbiological analysis. Correct specimen collection should be emphasised when teaching lumbar puncture technique. PMID:26139652

CSF and Serum Biomarkers Focusing on Cerebral Vasospasm and Ischemia after Subarachnoid Hemorrhage

Directory of Open Access Journals (Sweden)

Carla S. Jung

2013-01-01

Full Text Available Delayed cerebral vasospasm (CVS and delayed cerebral ischemia (DCI remain severe complications after subarachnoid hemorrhage (SAH. Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF of patients after SAH. CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC. In serum, neuron-specific enolase (NSE and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT scans. All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts.

G-CSF loaded nanofiber/nanoparticle composite coated with collagen promotes wound healing in vivo.

Science.gov (United States)

Tanha, Shima; Rafiee-Tehrani, Morteza; Abdollahi, Mohamad; Vakilian, Saeid; Esmaili, Zahra; Naraghi, Zahra Safaei; Seyedjafari, Ehsan; Javar, Hamid Akbari

2017-10-01

Sustained release of functional growth factors can be considered as a beneficial methodology for wound healing. In this study, recombinant human granulocyte colony-stimulating factor (G-CSF)-loaded chitosan nanoparticles were incorporated in Poly(ε-caprolactone) (PCL) nanofibers, followed by surface coating with collagen type I. Physical and mechanical properties of the PCL nanofibers containing G-CSF loaded chitosan nanoparticles PCL/NP(G-CSF) and in vivo performance for wound healing were investigated. G-CSF structural stability was evaluated through SDS_PAGE, reversed phase (RP) HPLC and size-exclusion chromatography, as well as circular dichroism. Nanofiber/nanoparticle composite scaffold was demonstrated to have appropriate mechanical properties as a wound dresser and a sustained release of functional G-CSF. The PCL/NP(G-CSF) scaffold showed a suitable proliferation and well-adherent morphology of stem cells. In vivo study and histopathological evaluation outcome revealed that skin regeneration was dramatically accelerated under PCL/NP(G-CSF) as compared with control groups. Superior fibroblast maturation, enhanced collagen deposition and minimum inflammatory cells were also the beneficial properties of PCL/NP(G-CSF) over the commercial dressing. The synergistic effect of extracellular matrix-mimicking nanofibrous membrane and G-CSF could develop a suitable supportive substrate in order to extensive utilization for the healing of skin wounds. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2830-2842, 2017. © 2017 Wiley Periodicals, Inc.

CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders.

Science.gov (United States)

Irwin, David J; Xie, Sharon X; Coughlin, David; Nevler, Naomi; Akhtar, Rizwan S; McMillan, Corey T; Lee, Edward B; Wolk, David A; Weintraub, Daniel; Chen-Plotkin, Alice; Duda, John E; Spindler, Meredith; Siderowf, Andrew; Hurtig, Howard I; Shaw, Leslie M; Grossman, Murray; Trojanowski, John Q

2018-03-20

To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine 181 , and Aβ 1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ 1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD ( p CSF t-tau ( R 2 = 0.15-0.16, p CSF Aβ 1-42 ( R 2 = 0.31, p CSF t-tau/Aβ 1-42 ratio ( R 2 = 0.27, p = 0.01). CSF t-tau/Aβ 1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ 1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. Higher antemortem CSF t-tau/Aβ 1-42 and lower Aβ 1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies. © 2018 American Academy of Neurology.

Cataplexy with Normal Sleep Studies and Normal CSF Hypocretin: An Explanation?

Science.gov (United States)

Drakatos, Panagis; Leschziner, Guy

2016-03-01

Patients with narcolepsy usually develop excessive daytime sleepiness (EDS) before or coincide with the occurrence of cataplexy, with the latter most commonly associated with low cerebrospinal fluid (CSF) hypocretin-1 levels. Cataplexy preceding the development of other features of narcolepsy is a rare phenomenon. We describe a case of isolated cataplexy in the context of two non-diagnostic multiple sleep latency tests and normal CSF-hypocretin-1 levels (217 pg/mL) who gradually developed EDS and low CSF-hypocretin-1 (< 110 pg/mL). © 2016 American Academy of Sleep Medicine.

Diagnosis of central nervous system relapse of pediatric acute lymphoblastic leukemia: Impact of routine cytological CSF analysis at the time of intrathecal chemotherapy.

Science.gov (United States)

Gassas, Adam; Krueger, Joerg; Alvi, Saima; Sung, Lillian; Hitzler, Johanne; Lieberman, Lani

2014-12-01

Despite the success of central nervous system (CNS) directed therapy in pediatric acute lymphoblastic leukemia (ALL), relapse involving the CNS continues to be observed in 5-10% of children when utilizing standard intrathecal prophylactic chemotherapy. While most pediatric ALL treatment protocols mandate regular lumbar punctures (LP) for the intrathecal injection of chemotherapy, the value of routine cytological analysis of cerebrospinal fluid (CSF) during therapy is unknown. Our objective was to assess the diagnostic value of routine CSF analysis during ALL therapy. To allow for at least 10 years of follow up from ALL diagnosis, children (0-18 years) with ALL diagnosed and treated at SickKids, Toronto, Canada between 1994-2004 were studied. Medical records of patients with CNS relapse were examined to determine whether CNS relapse was diagnosed based on cytology of a routinely obtained CSF sample, a CSF sample obtained because of signs and symptoms or a CSF sample obtained after the diagnosis of a bone marrow relapse. Of 494 children treated for ALL, 31 (6.6%) developed a relapse of ALL involving the CNS. Twenty-two had an isolated CNS relapse and nine had a combined bone marrow and CNS relapse. Among patients with isolated CNS relapse, 73% (16/22) were diagnosed based on routine CSF samples obtained from asymptomatic children. Conversely, 89% (8/9) of children with combined bone marrow and CNS relapse presented with symptoms and signs that prompted CSF examination. Routine CSF examination at the time of LP for intrathecal chemotherapy is useful in detecting CNS relapse. © 2014 Wiley Periodicals, Inc.

Targeting Beta-Amyloid at the CSF: A New Therapeutic Strategy in Alzheimer's Disease.

Science.gov (United States)

Menendez-Gonzalez, Manuel; Padilla-Zambrano, Huber S; Alvarez, Gabriel; Capetillo-Zarate, Estibaliz; Tomas-Zapico, Cristina; Costa, Agustin

2018-01-01

Although immunotherapies against the amyloid-β (Aβ) peptide tried so date failed to prove sufficient clinical benefit, Aβ still remains the main target in Alzheimer's disease (AD). This article aims to show the rationale of a new therapeutic strategy: clearing Aβ from the CSF continuously (the "CSF-sink" therapeutic strategy). First, we describe the physiologic mechanisms of Aβ clearance and the resulting AD pathology when these mechanisms are altered. Then, we review the experiences with peripheral Aβ-immunotherapy and discuss the related hypothesis of the mechanism of action of "peripheral sink." We also present Aβ-immunotherapies acting on the CNS directly. Finally, we introduce alternative methods of removing Aβ including the "CSF-sink" therapeutic strategy. As soluble peptides are in constant equilibrium between the ISF and the CSF, altering the levels of Aβ oligomers in the CSF would also alter the levels of such proteins in the brain parenchyma. We conclude that interventions based in a "CSF-sink" of Aβ will probably produce a steady clearance of Aβ in the ISF and therefore it may represent a new therapeutic strategy in AD.

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice.

Science.gov (United States)

Wang, Xianzheng; Dong, Aihua; Xiao, Jingjing; Zhou, Xingjun; Mi, Haili; Xu, Hanqian; Zhang, Jiming; Wang, Bin

2016-11-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic (HBsAg-Tg) animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-γ production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8 + T cells from immunized animals, antigen-specific CD8 + T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients.

Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF) : A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression.

Science.gov (United States)

Grant, Susan M; Heel, Rennie C

1992-04-01

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a polypeptide hormone produced through recombinant DNA technologies in glycosylated (yeast or mammalian expression systems) or nonglycosylated (Escherichia coli expression system) form. It is a multilineage haematopoietin which stimulates proliferation and differentiation of bone marrow myeloid progenitors and increases peripheral white blood cell counts when administered systemically. Treatment is generally well tolerated, although mild to moderate flu-like symptoms are common and rGM-CSF-induced fever and fluid retention may be problematic in occasional patients. rGM-CSF accelerates recovery of peripheral neutrophil counts after bone marrow transplantation, and results of a placebo-controlled randomised trial correlate this with reduced infectious episodes and shortened length of hospitalisation in patients with lymphoid malignancies. A substantial number of patients with graft failure after bone marrow transplantation also respond to rGM-CSF. The duration of myelosuppression secondary to cancer chemotherapy can be significantly reduced by rGM-CSF which has permitted investigation of antineoplastic dose-intensity escalation. In some haematopoietic disorders (e.g. aplastic anaemia, myelodysplasia and neutropenia secondary to HIV infection and antiviral therapy), rGM-CSF produces clinically useful increases in peripheral blood granulocyte counts, although the effect is generally not sustained after drug withdrawal. The potential for rGM-CSF to stimulate proliferation of the abnormal clone in myelodysplasia and in acute myelogenous leukaemia following induction therapy is of concern. Available data suggest, however, that with appropriate monitoring and exclusion of high-risk patients this serious potential risk can be avoided, and that myelopoiesis is enhanced in such patients by rGM-CSF treatment. Recombinant colony-stimulating factors are a new therapeutic modality; hence many aspects of

Macrophage colony-stimulating factor, CSF-1, and its proto-oncogene-encoded receptor

International Nuclear Information System (INIS)

Sherr, C.J.; Rettenmier, C.W.; Roussel, M.F.

1988-01-01

The macrophage colony-stimulating factor, CSF-1, or M-CSF, is one of a family of hematopoietic growth factors that stimulates the proliferation of monocytes, macrophages, and their committed bone marrow progenitors. Unlike pluripotent hemopoietins such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3 or multi-CSF), which affect the growth of myeloid cells of several different hematopoietic lineages, CSF-1 acts only on cells of the mononuclear phagocyte series to stimulate their growth and enhance their survival. Retroviral transduction of the feline c-fms gene in the Susan McDonough and Hardy Zuckerman-5 (HZ-5) strains of feline sarcoma virus (FeSV) led to genetic alterations that endowed the recombined viral oncogene (v-fms) with the ability to transform cells in culture morphologically and to induce firbrosarcomas and hematopoietic neoplasms in susceptible animals. The v-fms oncogene product differs from the normal CSF-1 receptor in certain of its cardinal biochemical properties, most notably in exhibiting constitutively high basal levels of tyrosine kinase activity in the absence of its ligand. Comparative studies of the c-fms and v-fms genes coupled with analyses of engineered mutants and receptor chimeras have begun to pinpoint pertinent genetic alterations in the normal receptor gene that unmask its latent oncogenic potential. In addition, the availability of biologically active c-fms, v-fms, and CSF-1 cDNAs has allowed these genes to be mobilized and expressed in naive cells, thereby facilitating assays for receptor coupling with downstream components of the mitogenic pathway in diverse cell types

Dgroup: DG01781 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available grastim (USAN/INN); Filgrastim (genetical recombination) (JP17); Filgrastim (genetical recombination) [Filgr...astim biosimilar 1] (JAN); Filgrastim (genetical recombination) [Filgrastim biosimilar 2] (JAN); Filgrastim (genetica...USAN/INN); Lenograstim (genetical recombination) (JP17) ... D06889 ... Pegfilgrastim (INN); Pegfilgrastim (genetica...l recombination) (JAN) ... D10242 ... Lipegfilgrastim (USAN) D03245 ... Nartograstim (genetical recombination) (...l recombination) [Filgrastim biosimilar3] (JAN) ... D03247 ... Lenograstim (

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis

DEFF Research Database (Denmark)

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars

2016-01-01

BACKGROUND: There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. OBJECTIVE: To evaluate the effect of monthly oral...... methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. METHODS: In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin...... no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. CONCLUSION: Monthly methylprednisolone pulse treatment was safe, but had...

CSF lactate level: a useful diagnostic tool to differentiate acute bacterial and viral meningitis.

Science.gov (United States)

Abro, Ali Hassan; Abdou, Ahmed Saheh; Ustadi, Abdulla M; Saleh, Ahmed Alhaj; Younis, Nadeem Javeed; Doleh, Wafa F

2009-08-01

To evaluate the potential role of CSF lactate level in the diagnosis of acute bacterial meningitis and in the differentiation between viral and bacterial meningitis. This was a hospital based observational study, conducted at Infectious Diseases Unit, Rashid Hospital Dubai, United Arab Emirates, from July 2004 to June 2007. The patients with clinical diagnosis of acute bacterial meningitis and who had CSF Gram stain/culture positive, CSF analysis suggestive of bacterial meningitis with negative Gram stain and culture but blood culture positive for bacteria and patients with clinical diagnosis suggestive of viral meningitis supported by CSF chemical analysis with negative Gram stain and culture as well as negative blood culture for bacteria were included in the study. CT scan brain was done for all patients before lumber puncture and CSF and blood samples were collected immediately after admission. CSF chemical analysis including lactate level was done on first spinal tap. The CSF lactate level was tested by Enzymatic Colorimetric method. A total 95 adult patients of acute meningitis (53 bacterial and 42 viral) fulfilled the inclusion criteria. Among 53 bacterial meningitis patients, Neisseria meningitides were isolated in 29 (54.7%), Strept. Pneumoniae in 18 (33.96%), Staph. Aureus in 2 (3.77%), Klebsiell Pneumoniae in 2 (3.77%), Strept. Agalactiae in 1 (1.8%) and E. Coli in 1 (1.8%). All the patients with bacterial meningitis had CSF lactate > 3.8 mmol/l except one, whereas none of the patients with viral meningitis had lactate level > 3.8 mmol/l. The mean CSF lactate level in bacterial meningitis cases amounted to 16.51 +/- 6.14 mmol/l, whereas it was significantly lower in viral group 2.36 +/- 0.6 mmol/l, p < .0001. CSF lactate level was significantly high in bacterial than viral meningitis and it can provide pertinent, rapid and reliable diagnostic information. Furthermore, CSF lactate level can also differentiate bacterial meningitis from viral one in a quick

Visualization and quantitative analysis of the CSF pulsatile flow with cine MR phase imaging

International Nuclear Information System (INIS)

Katayama, Shinji; Itoh, Takahiko; Kinugasa, Kazushi; Asari, Shoji; Nishimoto, Akira; Tsuchida, Shohei; Ono, Atsushi; Ikezaki, Yoshikazu; Yoshitome, Eiji.

1991-01-01

The visualization and the quantitative analysis of the CSF pulsatile flow were performed on ten healthy volunteers with cine MR phase imaging, a combination of the phase-contrast technique and the cardiac-gating technique. The velocities appropriate for the visualization and the quantitative analysis of the CSF pulsatile flow were from 6.0 cm/sec to 15.0 cm/sec. The applicability of this method for the quantitative analysis was proven with a steady-flow phantom. Phase images clearly demonstrated a to-and-fro motion of the CSF flow in the anterior subarachnoid space and in the posterior subarachnoid space. The flow pattern of CSF on healthy volunteers depends on the cardiac cycle. In the anterior subarachnoid space, the cephalic CSF flow continued until a 70-msec delay after the R-wave of the ECG and then reversed to caudal. At 130-190 msec, the caudal CSF flow reached its maximum velocity; thereafter it reversed again to cephalic. The same turn appeared following the phase, but then the amplitude decreased. The cephalic peaked at 370-430 msec, while the caudal peaked at 490-550 msec. The flow pattern of the CSF flow in the posterior subarachnoid space was almost identical to that in the anterior subarachnoid space. Cine MR phase imaging is thus useful for the visualization and the quantitative analysis of the CSF pulsative flow. (author)

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

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Malur, Anagha; Huizar, Isham [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Wells, Greg [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Barna, Barbara P. [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States)

2011-11-18

analysis of bronchoalveolar lavage fluid. Lung compliance was diminished in untreated GMCSF KO mice but improved significantly after lenti-ABCG1 treatment. Data demonstrate that in vivo instillation of lenti-ABCG1 in GM-CSF KO mice is sufficient to restore pulmonary homeostasis by: (1) upregulating ABCG1; (2) reducing intra and extracellular lipids; and (3) improving lung function. Results suggest that the ABCG1 lipid transporter is the key downstream target of GM-CSF-induced PPAR{gamma} necessary for surfactant catabolism.

Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice.

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Menke, Julia; Hsu, Mei-Yu; Byrne, Katelyn T; Lucas, Julie A; Rabacal, Whitney A; Croker, Byron P; Zong, Xiao-Hua; Stanley, E Richard; Kelley, Vicki R

2008-11-15

Sunlight (UVB) triggers cutaneous lupus erythematosus (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø)-mediated mechanism in MRL-Fas(lpr) mice. By constructing mutant MRL-Fas(lpr) strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex vivo gene transfer to deliver CSF-1 intradermally, we determined that CSF-1 induces CLE in lupus-susceptible MRL-Fas(lpr) mice, but not in lupus-resistant BALB/c mice. UVB incites an increase in Møs, apoptosis in the skin, and CLE in MRL-Fas(lpr), but not in CSF-1-deficient MRL-Fas(lpr) mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Møs that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Fas(lpr) but not lupus-resistant BALB/c mice. Taken together, CSF-1 is envisioned as the match and lupus susceptibility as the tinder leading to CLE.

The inner CSF-brain barrier

DEFF Research Database (Denmark)

Whish, Sophie; Dziegielewska, Katarzyna M; Møllgård, Kjeld

2015-01-01

outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11...

The use of granulocyte colony stimulating factor (G-CSF) and management of chemotherapy delivery during adjuvant treatment for early-stage breast cancer--further observations from the IMPACT solid study.

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Mäenpää, Johanna; Varthalitis, Ioannis; Erdkamp, Frans; Trojan, Andreas; Krzemieniecki, Krzysztof; Lindman, Henrik; Bendall, Kate; Vogl, Florian D; Verma, Shailendra

2016-02-01

To investigate the use and impact of granulocyte colony-stimulating factors (G-CSF) on chemotherapy delivery and neutropenia management in breast cancer in a clinical practice setting. IMPACT Solid was an international, prospective observational study in patients with a physician-assessed febrile neutropenia (FN) risk of ≥20%. This analysis focused on stages I-III breast cancer patients who received a standard chemotherapy regimen for which the FN risk was published. Chemotherapy delivery and neutropenia-related outcomes were reported according to the FN risk of the regimen and intent of G-CSF use. 690 patients received a standard chemotherapy regimen; 483 received the textbook dose/schedule with a majority of these regimens (84%) having a FN risk ≥10%. Patients receiving a regimen with a FN risk ≥10% were younger with better performance status than those receiving a regimen with a FN risk <10%. Patients who received higher-risk regimens were more likely to receive G-CSF primary prophylaxis (48% vs 22%), complete their planned chemotherapy (97% vs 88%) and achieve relative dose intensity ≥85% (93% vs 86%) than those receiving lower-risk regimens. Most first FN events (56%) occurred in cycles not supported with G-CSF primary prophylaxis. Physicians generally recommend standard adjuvant chemotherapy regimens and were more likely to follow G-CSF guidelines for younger, good performance status patients in the curative setting, and often modify standard regimens in more compromised patients. However, G-CSF support is not optimal, indicated by G-CSF primary prophylaxis use in <50% of high-risk patients and observation of FN without G-CSF support. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of prostaglandin D2 as a CSF leak marker: implications in safe epidural anesthesia

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Kondabolu S

2011-07-01

Full Text Available Sirish Kondabolu, Rishimani Adsumelli, Joy Schabel, Peter Glass, Srinivas PentyalaDepartment of Anesthesiology, School of Medicine, Stony Brook Medical Center, Stony Brook, New York, USABackground: It is accepted that there is a severe risk of dural puncture in epidural anesthesia. Of major concern to anesthesiologists is unintentional spinal block. Reliable identification of cerebrospinal fluid (CSF from the aspirate is crucial for safe epidural anesthesia. The aim of this study was to determine whether prostaglandin D2 could be clinically used as a marker for the detection of CSF traces.Methods: After obtaining Institutional Review Board approval and patient consent, CSF was obtained from patients undergoing spinal anesthesia, and blood, urine, and saliva were obtained from normal subjects and analyzed for prostaglandin D2 (PGD. CSF (n=5 samples were diluted with local anesthetic (bupivacaine, normal saline and blood in the ratios of 1:5 and 1:10. PGD levels in the CSF samples were analyzed with a PGD-Methoxime (MOX EIA Kit (Cayman Chemicals, MI. This assay is based on the conversion of PGD to a stable derivative, which is analyzed with antiserum specific for PGD-MOX. Results: Different concentrations of pure PGD-MOX conjugate were analyzed by EIA and a standard curve was derived. PGD levels in CSF and CSF with diluents were determined and the values were extrapolated onto the standard curve. Our results show a well-defined correlation for the presence of PGD both in straight CSF samples and in diluted CSF (dilution factor of 1:5 and 1:10. Conclusion: Prostaglandin D2 was reliably identified in CSF by enzyme-linked immunosorbent assay when diluted with local anesthetic, saline, and serum, and can be used as a marker to identify the presence of CSF in epidural aspirates.Keywords: epidural, cerebrospinal fluid, leak, marker, prostaglandin D2

Frequency analyses of CSF flow on cine MRI in normal pressure hydrocephalus

Energy Technology Data Exchange (ETDEWEB)

Miyati, Tosiaki; Kasuga, Toshio; Koshida, Kichiro; Sanada, Shigeru; Onoguchi, Masahisa [Department of Radiological Technology, School of Health Sciences, Faculty of Medicine, Kanazawa University, 5-11-80, Kodatsuno, Kanazawa, Ishikawa 920-0942 (Japan); Mase, Mitsuhito; Yamada, Kazuo [Department of Neurosurgery, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8602 (Japan); Banno, Tatsuo [Department of Central Radiology, Nagoya City University Hospital, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8602 (Japan); Fujita, Hiroshi [Department of Information Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193 (Japan)

2003-05-01

Our objective was to clarify intracranial cerebrospinal fluid (CSF) flow dynamics in normal-pressure hydrocephalus (NPH). Frequency analyses of CSF flow measured with phase-contrast cine MRI were performed. The CSF flow spectra in the aqueduct were determined in patients (n=51) with NPH, brain atrophy or asymptomatic ventricular dilation (VD), and in healthy volunteers (control group; n=25). The changes in CSF flow spectra were also analyzed after intravenous injection of acetazolamide. Moreover, a phase transfer function (PTF) calculated from the spectra of the driving vascular pulsation and CSF flow in the aqueduct were assessed. These values were compared with the pressure volume response (PVR). The amplitude in the NPH group was significantly larger than that in the VD or control group because of a decrease in compliance. The phase in the NPH group was significantly different from that in either the VD or the control group, but no difference was found between the VD and control groups. The amplitude increased in all groups after acetazolamide injection. The PTF in the NPH group was significantly larger than in the control group, and a positive correlation was noted between PTF and PVR. Frequency analyses of CSF flow measured by cine MRI make it possible to noninvasively obtain a more detailed picture of the pathophysiology of NPH. (orig.)

CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.

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Rojas, Julio C; Bang, Jee; Lobach, Iryna V; Tsai, Richard M; Rabinovici, Gil D; Miller, Bruce L; Boxer, Adam L

2018-01-23

To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). We compared the ability of baseline CSF β-amyloid 1-42 , tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS ( p = 0.004, false discovery rate-corrected) and SEADL ( p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS ( p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL ( p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau ( p = 0.003) or NfL ( p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease. Copyright © 2017 American Academy of Neurology.

CSF Markers in Guillain-Barre Syndrome

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J Gordon Millichap

2007-01-01

Full Text Available A positive 14-3-3 protein assay of CSF was observed in 29 of 38 patients with GBS and in 4 with motor neuron disease and other neuropathies studied at Universities of Milan and Verona, Italy.

Comparison of Two Regimens of RhG-CSF in Neutropenic Neonatal Septicemia: A Randomized Clinical Trial

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Fatemeh Nayeri

2011-09-01

Full Text Available "nConsidering the 50% mortality rate of neonatal septicemia associated with neutropenia and increasing resistance to antibiotics, simultaneous antibiotic therapy strategies are becoming more important. However, few studies have been performed to evaluate effectiveness of RhG-CSF in the treatment of neutropenia in neonates. This randomized clinical trial was performed on 40 neutropenic neonates with septicemia who were hospitalized in Vali-e-Asr and Mirza Koochak Khan Hospitals (Tehran, Iran. The neonates were randomly divided into two equal groups RhG-CSF was administered as a subcutaneous single dose of 10μg/kg/s.c. to neonates in group A and as 10μg/kg/s.c./day once daily for 3 days to neonates in group B. CBC and differential count was checked 6, 24 and 48 hours after the last dose. There was no significant difference in mean birth weight, gender, age, and risk factors between two groups. Neutropenia was improved 48 hours after the last dose, whilst there was no significant statistical difference between two groups (P>0.05. The final outcome including death, duration of hospitalization and duration of antibiotics therapy after RhG-CSF administration did not differ between two groups (P>0.05. The results of this study showed that administration of a single dose of RhG-CSF (10μg/kg was effective in treating neonatal septicemic neutropenia.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

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Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Toward improving mucosal barrier defenses: rhG-CSF plus IgG antibody.

Science.gov (United States)

Simmonds, Aryeh; LaGamma, Edmund F

2006-11-01

have identified a clear clinical benefit of rhG-CSF therapy. This manuscript will review the literature and evidence available for identifying the ideal subject for cytokine treatment using NEC as the model disease target.

Identification of Ambiguous Activities in Radionuclide Cisternography Using SPECT/CT: Aspirated and Ingested CSF Rhinorrhea

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Lee, Dong Yun; Kim, Jae Seung [Univ. of Ulsan College of Medicine, Ulsan (Korea, Republic of)

2014-03-15

A 2 year-old little girl underwent Tc-99m diethylenthriamine pentaacetic acid (DTPA) radionuclide cisternography to evaluate CSF rhinorrhea (Fig. 1). Cisternography clearly showed consecutive tracer activity in the nasal cavity and nasal tip, reflecting cerebrospinal fluid (CSF) leakage. However, several unexpected activities appeared on the bilateral mid- and unilateral lower thorax on delayed images, respectively. We performed additional SPECT/CT to delineate the CSF leakage tract and identify the unexpected activities. Through SPECT/CT, we could confirm that the mid-thoracic activity was in the lung parenchyma, while the lower thoracic activity was in the stomach. Thus, we speculated that these unexpected activities were the result of aspirated and ingested CSF rhinorrhea. CSF rhinorrhea occurs when there is a fistula between the dura mater and the skull base and discharge of CSF from the nose. A spinal fluid leak from the intracranial space to the nasal respiratory tract is potentially very serious because of the risk of an ascending infection that could produce fulminant meningitis. Therefore, identification of the fistulous tract is helpful for patient management. Radionuclide cisternography is an important imaging modality to detect the site of leakage in patients with CSF rhinorrhea. The combination of radionuclide cistenography and SPECT/CT has led to a major improvement in the diagnostic accuracy for localization of CSF leakage. This case also shows an important role for SPECT/CT fusion imaging in radionuclide cisternography not only for localizing the primary CSF fistula tract, but also for evaluating ambiguous radiotracer activities in planar imaging; these ultimately turned out to be aspirated and ingested CSF rhinorrhea.

Identification of Ambiguous Activities in Radionuclide Cisternography Using SPECT/CT: Aspirated and Ingested CSF Rhinorrhea

International Nuclear Information System (INIS)

Lee, Dong Yun; Kim, Jae Seung

2014-01-01

A 2 year-old little girl underwent Tc-99m diethylenthriamine pentaacetic acid (DTPA) radionuclide cisternography to evaluate CSF rhinorrhea (Fig. 1). Cisternography clearly showed consecutive tracer activity in the nasal cavity and nasal tip, reflecting cerebrospinal fluid (CSF) leakage. However, several unexpected activities appeared on the bilateral mid- and unilateral lower thorax on delayed images, respectively. We performed additional SPECT/CT to delineate the CSF leakage tract and identify the unexpected activities. Through SPECT/CT, we could confirm that the mid-thoracic activity was in the lung parenchyma, while the lower thoracic activity was in the stomach. Thus, we speculated that these unexpected activities were the result of aspirated and ingested CSF rhinorrhea. CSF rhinorrhea occurs when there is a fistula between the dura mater and the skull base and discharge of CSF from the nose. A spinal fluid leak from the intracranial space to the nasal respiratory tract is potentially very serious because of the risk of an ascending infection that could produce fulminant meningitis. Therefore, identification of the fistulous tract is helpful for patient management. Radionuclide cisternography is an important imaging modality to detect the site of leakage in patients with CSF rhinorrhea. The combination of radionuclide cistenography and SPECT/CT has led to a major improvement in the diagnostic accuracy for localization of CSF leakage. This case also shows an important role for SPECT/CT fusion imaging in radionuclide cisternography not only for localizing the primary CSF fistula tract, but also for evaluating ambiguous radiotracer activities in planar imaging; these ultimately turned out to be aspirated and ingested CSF rhinorrhea

G-CSF Intrauterine for Thin Endometrium, and Pregnancy Outcome

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Ensieh Tehraninejad

2015-10-01

Full Text Available Objective:To evaluate effects ofG-CSF on a cancelled ART cycle due to thin endometrium.Materials and methods:In a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient.Results:The G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from3.593±0.251 mm to 7.120±0.84 mm. The mean age, gravidity, parity, and FSH were 35.13± 9.531 years,3, 1 and32.78± 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM.Conclusion:G-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy.

Improved survival and marrow engraftment of mice transplanted with bone marrov of GM-CSF-treated donors

International Nuclear Information System (INIS)

Ballin, A.; Sagi, O.; Schiby, G.; Meytes, D.

1993-01-01

Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administered to bone marrow (BM) transplant recipients is associated with earlier recovery. We have investigated the possibility of stimulating normal donor mice in vivo with GM-CSF. Donor balb/c mice were injected i.p. with GM-CSF (5000 u) or saline. Seventy-two hours later 5 x 105 BM cells from either GM-CSF-treated or control donors were infused into lethally irradiated (850 R) recipients. In the recipients of BM from GM-CSF-treated donors, significantly higher CFU-S and significantly higher survival rate (57% [n = 65]; vs. 30% [n = 63]; p < 0.05) were noted. Donor mice of the GM-CSF group did not differ in bone-marrow cellularity and composition from their controls. However, recipients of BM from GM-CSF-treated mice had higher blood counts of haemoglobin, Leukocytes and platelets compared to controls. These data demonstrate that pretreatment of BM donors with GM-CSF may be of benefit in improving survival and marrow engraftment in mice. (au) (13 refs.)

Healthy human CSF promotes glial differentiation of hESC-derived neural cells while retaining spontaneous activity in existing neuronal networks

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Heikki Kiiski

2013-05-01

The possibilities of human pluripotent stem cell-derived neural cells from the basic research tool to a treatment option in regenerative medicine have been well recognized. These cells also offer an interesting tool for in vitro models of neuronal networks to be used for drug screening and neurotoxicological studies and for patient/disease specific in vitro models. Here, as aiming to develop a reductionistic in vitro human neuronal network model, we tested whether human embryonic stem cell (hESC-derived neural cells could be cultured in human cerebrospinal fluid (CSF in order to better mimic the in vivo conditions. Our results showed that CSF altered the differentiation of hESC-derived neural cells towards glial cells at the expense of neuronal differentiation. The proliferation rate was reduced in CSF cultures. However, even though the use of CSF as the culture medium altered the glial vs. neuronal differentiation rate, the pre-existing spontaneous activity of the neuronal networks persisted throughout the study. These results suggest that it is possible to develop fully human cell and culture-based environments that can further be modified for various in vitro modeling purposes.

Ubiquitin fusion expression and tissue-dependent targeting of hG-CSF in transgenic tobacco

Science.gov (United States)

2011-01-01

Background Human granulocyte colony-stimulating factor (hG-CSF) is an important human cytokine which has been widely used in oncology and infection protection. To satisfy clinical needs, expression of recombinant hG-CSF has been studied in several organisms, including rice cell suspension culture and transient expression in tobacco leaves, but there was no published report on its expression in stably transformed plants which can serve as a more economical expression platform with potential industrial application. Results In this study, hG-CSF expression was investigated in transgenic tobacco leaves and seeds in which the accumulation of hG-CSF could be enhanced through fusion with ubiquitin by up to 7 fold in leaves and 2 fold in seeds, leading to an accumulation level of 2.5 mg/g total soluble protein (TSP) in leaves and 1.3 mg/g TSP in seeds, relative to hG-CSF expressed without a fusion partner. Immunoblot analysis showed that ubiquitin was processed from the final protein product, and ubiquitination was up-regulated in all transgenic plants analyzed. Driven by CaMV 35S promoter and phaseolin signal peptide, hG-CSF was observed to be secreted into apoplast in leaves but deposited in protein storage vacuole (PSV) in seeds, indicating that targeting of the hG-CSF was tissue-dependent in transgenic tobacco. Bioactivity assay showed that hG-CSF expressed in both seeds and leaves was bioactive to support the proliferation of NFS-60 cells. Conclusions In this study, the expression of bioactive hG-CSF in transgenic plants was improved through ubiquitin fusion strategy, demonstrating that protein expression can be enhanced in both plant leaves and seeds through fusion with ubiquitin and providing a typical case of tissue-dependent expression of recombinant protein in transgenic plants. PMID:21985646

Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway.

Science.gov (United States)

Digiacomo, Graziana; Tusa, Ignazia; Bacci, Marina; Cipolleschi, Maria Grazia; Dello Sbarba, Persio; Rovida, Elisabetta

2017-07-04

Integrins, following binding to proteins of the extracellular matrix (ECM) including collagen, laminin and fibronectin (FN), are able to transduce molecular signals inside the cells and to regulate several biological functions such as migration, proliferation and differentiation. Besides activation of adaptor molecules and kinases, integrins transactivate Receptor Tyrosine Kinases (RTK). In particular, adhesion to the ECM may promote RTK activation in the absence of growth factors. The Colony-Stimulating Factor-1 Receptor (CSF-1R) is a RTK that supports the survival, proliferation, and motility of monocytes/macrophages, which are essential components of innate immunity and cancer development. Macrophage interaction with FN is recognized as an important aspect of host defense and wound repair. The aim of the present study was to investigate on a possible cross-talk between FN-elicited signals and CSF-1R in macrophages. FN induced migration in BAC1.2F5 and J774 murine macrophage cell lines and in human primary macrophages. Adhesion to FN determined phosphorylation of the Focal Adhesion Kinase (FAK) and Src Family Kinases (SFK) and activation of the SFK/FAK complex, as witnessed by paxillin phosphorylation. SFK activity was necessary for FAK activation and macrophage migration. Moreover, FN-induced migration was dependent on FAK in either murine macrophage cell lines or human primary macrophages. FN also induced FAK-dependent/ligand-independent CSF-1R phosphorylation, as well as the interaction between CSF-1R and β1. CSF-1R activity was necessary for FN-induced macrophage migration. Indeed, genetic or pharmacological inhibition of CSF-1R prevented FN-induced macrophage migration. Our results identified a new SFK-FAK/CSF-1R signaling pathway that mediates FN-induced migration of macrophages.

Long-active granulocyte colony-stimulating factor for peripheral blood hematopoietic progenitor cell mobilization.

Science.gov (United States)

Martino, Massimo; Laszlo, Daniele; Lanza, Francesco

2014-06-01

Peg-filgrastim (PEG-FIL), a polyethylene glycol-conjugated form of granulocyte colony-stimulating factor (G-CSF), has been introduced in clinical practice and is effective in shortening the time of neutropenia after cytotoxic chemotherapy. G-CSF has emerged as the preferred cytokine for hematopoietic progenitor cells' (HPC) mobilization. Nevertheless, data on the ability of PEG-FIL in this field have been published. We review publications in the field with the goal of providing an overview of this approach. PEG-FIL may be able to mobilize CD34(+) cells in a more timely fashion than G-CSF, with the advantages of only a single-dose administration, an earlier start and a reduction in the number of apheresis procedures. The main controversies concern the dosage of the drug and the optimal dose. In the context of chemo-mobilization, a single dose of 6 mg PEG-FIL seems effective in terms of HPC's mobilization and there is no increase in this effect if the dose is doubled to 12 mg. Steady-state mobilization requires higher doses of PEG-FIL and this approach is not cost-effective when compared with G-CSF. The experiences with PEG-FIL in the healthy donor setting are very limited.

Heat shock protein 27-derived atheroprotection involves reverse cholesterol transport that is dependent on GM-CSF to maintain ABCA1 and ABCG1 expression in ApoE-/- mice.

Science.gov (United States)

Pulakazhi Venu, Vivek Krishna; Adijiang, Ayinuer; Seibert, Tara; Chen, Yong-Xiang; Shi, Chunhua; Batulan, Zarah; O'Brien, Edward R

2017-06-01

Recently, we demonstrated that heat shock protein (HSP)-27 is protective against the development of experimental atherosclerosis, reducing plaque cholesterol content by more than 30%. Moreover, elevated HSP-27 levels are predictive of relative freedom from clinical cardiovascular events. HSP-27 signaling occurs via the activation of NF-κB, which induces a marked up-regulation in expression of granulocyte-monocyte colony-stimulating factor (GM-CSF), a cytokine that is known to alter ABC transporters involved in reverse cholesterol transport (RCT). Therefore, we hypothesized that HSP-27-derived GM-CSF has a potent role in impeding plaque formation by promoting macrophage RCT and sought to better characterize this pathway. Treatment of THP-1 cells, RAW-Blue cells, and primary macrophages with recombinant HSP-27 resulted in NF-κB activation via TLR-4 and was inhibited by various pharmacologic blockers of this pathway. Moreover, HSP-27-induced upregulation of GM-CSF expression was dependent on TLR-4 signaling. Recombinant (r)HSP-27 treatment of ApoE -/- female (but not male) mice for 4 wk yielded reductions in plaque area and cholesterol clefts of 33 and 47%, respectively, with no effect on GM-CSF -/- ApoE -/- mice. With 12 wk of rHSP-27 treatment, both female and male mice showed reductions in plaque burden (55 and 42%, respectively) and a 60% reduction in necrotic core area but no treatment effect in GM-CSF -/- ApoE -/- mice. In vitro functional studies revealed that HSP-27 enhanced the expression of ABCA1 and ABCG1, as well as facilitated cholesterol efflux in vitro by ∼10%. These novel findings establish a paradigm for HSP-27-mediated RCT and set the stage for the development of HSP-27 atheroprotective therapeutics.-Pulakazhi Venu, V. K., Adijiang, A., Seibert, T., Chen, Y.-X., Shi, C., Batulan, Z., O'Brien, E. R. Heat shock protein 27-derived atheroprotection involves reverse cholesterol transport that is dependent on GM-CSF to maintain ABCA1 and ABCG1

Changes in Gene Expression during G-CSF-Induced Emergency Granulopoiesis in Humans

DEFF Research Database (Denmark)

Pedersen, Corinna C.; Borup, Rehannah; Fischer-Nielsen, Anne

2016-01-01

Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for G-CSF as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF...... stimulation on the transcriptome of neutrophils and their precursors have not yet been investigated in humans. In this work, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy...... individuals after 5 d of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNA was subjected to microarray analysis. mRNA levels were compared with previously published expression levels in corresponding populations of neutrophil precursors...

Efficient CsF interlayer for high and low bandgap polymer solar cell

Science.gov (United States)

Mitul, Abu Farzan; Sarker, Jith; Adhikari, Nirmal; Mohammad, Lal; Wang, Qi; Khatiwada, Devendra; Qiao, Qiquan

2018-02-01

Low bandgap polymer solar cells have a great deal of importance in flexible photovoltaic market to absorb sun light more efficiently. Efficient wide bandgap solar cells are always available in nature to absorb visible photons. The development and incorporation of infrared photovoltaics (IR PV) with wide bandgap solar cells can improve overall solar device performance. Here, we have developed an efficient low bandgap polymer solar cell with CsF as interfacial layer in regular structure. Polymer solar cell devices with CsF shows enhanced performance than Ca as interfacial layer. The power conversion efficiency of 4.5% has been obtained for PDPP3T based polymer solar cell with CsF as interlayer. Finally, an optimal thickness with CsF as interfacial layer has been found to improve the efficiency in low bandgap polymer solar cells.

CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients.

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Skillbäck, Tobias; Delsing, Louise; Synnergren, Jane; Mattsson, Niklas; Janelidze, Shorena; Nägga, Katarina; Kilander, Lena; Hicks, Ryan; Wimo, Anders; Winblad, Bengt; Hansson, Oskar; Blennow, Kaj; Eriksdotter, Maria; Zetterberg, Henrik

2017-11-01

A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology. Copyright © 2017 Elsevier Inc. All rights reserved.

Observation of the CSF pulsatile flow in the aqueduct using cine MRI with presaturation bolus tracking, 3

International Nuclear Information System (INIS)

Nakajima, Satoshi

1992-01-01

The to-and-fro motion patterns of the CSF flow in the aqueduct in ten normal adults, ten patients with secondary normal-pressure hydrocephalus (NPH), and fourteen patients with idiopathic ventriculomegaly were analyzed using cine MRI with presaturation bolus tracking. The to-and-fro motion patterns of the CSF flow in the aqueduct were thus classified into four types according to their maximum velocity and the relative time duration of their flow in the rostral and caudal directions. The correlation between the clinical symptoms, the CT findings, the RI-cisternography findings, the results of the ICP monitorings, and the CSF pulsatile-flow patterns were then analyzed. In secondary NPH disclosing frequent B waves on ICP monitoring, the maximum velocity of the CSF flow in the aqueduct was over 15 mm/sec, and the duration of the CSF flow was longer in the caudal direction than in the rostral direction. Furthermore, the faster the maximum velocity of the CSF flow, the larger the ventricular size on CT and the more severe the CSF malabsorption on cisternography. In idiopathic ventriculomegaly, only two cases demonstrated the same CSF flow pattern as was shown in secondary NPH; the other cases demonstrated other CSF flow patterns, which were considered to indicate hydrocephalus ex vacuo or arrested hydrocephalus. The CSF pulsatile-flow pattern was assumed to change according to the degree of the CSF circulatory disorder, its compensatory process, and the plasticity of the brain. The investigation of the CSF pulsatile flow gives important information for the evaluation of various hydrocephalic conditions. (author)

CSF tapping also improves mental imagery of gait in normal pressure hydrocephalus.

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Marques, Bruno; Laidet, Magali; Armand, Stéphane; Assal, Frédéric; Allali, Gilles

2017-11-01

This study aims to compare the changes of Timed Up and Go (TUG) and its imagined version (iTUG) after CSF tapping between patients with idiopathic normal pressure hydrocephalus (iNPH) and its mimics. TUG and iTUG were performed before and 24 h after CSF tapping in 117 patients (75.8 ± 6.9 years; 35% female) with suspicion of iNPH (68 iNPH and 49 mimics). Mental imagery of locomotion was modified after CSF tapping in iNPH patients, but not in the mimics.

DMPD: CSF-1 and cell cycle control in macrophages. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 8981359 CSF-1 and cell cycle control in macrophages. Hamilton JA. Mol Reprod Dev. 1...997 Jan;46(1):19-23. (.png) (.svg) (.html) (.csml) Show CSF-1 and cell cycle control in macrophages. PubmedI...D 8981359 Title CSF-1 and cell cycle control in macrophages. Authors Hamilton JA. Publication Mol Reprod Dev

Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease

DEFF Research Database (Denmark)

Vinther-Jensen, Tua; Börnsen, Lars Svend; Budtz-Jorgensen, Esben

2016-01-01

Objective: To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score. Methods: We collected CSF from 32...

Identification of a gene involved in the regulation of hyphal growth of Epichloë festucae during symbiosis.

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Bassett, Shalome A; Johnson, Richard D; Simpson, Wayne R; Laugraud, Aurelie; Jordan, T William; Bryan, Gregory T

2016-10-01

Secreted proteins, those involved in cell wall biogenesis, are likely to play a role in communication in the symbiotic interaction between the fungal endophyte Epichloë festucae with perennial ryegrass (Lolium perenne), particularly given the close association between fungal hyphae and the plant cell wall. Our hypothesis was that secreted proteins are likely to be responsible for establishing and maintaining a normal symbiotic relationship. We analyzed an endophyte EST database for genes with predicted signal peptide sequences. Here, we report the identification and characterization of rhgA; a gene involved in the regulation of hyphal growth in planta In planta analysis of ΔrhgA mutants showed that disruption of rhgA resulted in extensive unregulated hyphal growth. This phenotype was fully complemented by insertion of the rhgA gene and suggests that rhgA is important for maintaining normal hyphal growth during symbiosis. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Choroid Plexus of the Lateral Ventricle As the Origin of CSF Pulsation Is Questionable.

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Takizawa, Ken; Matsumae, Mitsunori; Hayashi, Naokazu; Hirayama, Akihiro; Sano, Fumiya; Yatsushiro, Satoshi; Kuroda, Kagayaki

2018-01-15

The advent of magnetic resonance imaging (MRI) enables noninvasive measurement of cerebrospinal fluid (CSF) motion, and new information about CSF motion has now been acquired. The driving force of the CSF has long been thought to be choroid plexus (CP) pulsation, but to investigate whether this phenomenon actually occurs, CSF motion was observed in the ventricular system and subarachnoid space using MRI. Eleven healthy volunteers, ranging in age from 23 to 58 years, participated in this study. The MRI sequences used were four-dimensional phase-contrast (4D-PC) and time-spatial labeling inversion pulse (t-SLIP). The 4D-PC images included sagittal images in the cranial midline, coronal images focusing on the foramen of Monro (FOM), and oblique coronal images of the trigone to quantify CSF velocity and acceleration. These values were compared and analyzed as non-parametric data using the Kolmogorov-Smirnov test and the Mann-Whitney U test. 4D-PC showed that the median CSF velocity was significantly lower in the posterior part of the lateral ventricle than in other regions. The quantitative analysis of velocity and acceleration showed that they were decreased around the CP in the trigone. Image analysis of both velocity mapping and t-SLIP showed suppressed CSF motion around the CP in the trigone. These findings cast doubt on CP pulsation being the driving force for CSF motion.

Direct anti-inflammatory effects of granulocyte colony-stimulating factor (G-CSF) on activation and functional properties of human T cell subpopulations in vitro.

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Malashchenko, Vladimir Vladimirovich; Meniailo, Maxsim Evgenievich; Shmarov, Viacheslav Anatolievich; Gazatova, Natalia Dinislamovna; Melashchenko, Olga Borisovna; Goncharov, Andrei Gennadievich; Seledtsova, Galina Victorovna; Seledtsov, Victor Ivanovich

2018-03-01

We investigated the direct effects of human granulocyte colony-stimulating factor (G-CSF) on functionality of human T-cell subsets. CD3 + T-lymphocytes were isolated from blood of healthy donors by positive magnetic separation. T cell activation with particles conjugated with antibodies (Abs) to human CD3, CD28 and CD2 molecules increased the proportion of cells expressing G-CSF receptor (G-CSFR, CD114) in all T cell subpopulations studied (CD45RA + /CD197 + naive T cells, CD45RA - /CD197 + central memory T cells, CD45RA - /CD197 - effector memory T cells and CD45RA + /CD197 - terminally differentiated effector T cells). Upon T-cell activation in vitro, G-CSF (10.0 ng/ml) significantly and specifically enhanced the proportion of CD114 + T cells in central memory CD4 + T cell compartment. A dilution series of G-CSF (range, 0.1-10.0 ng/ml) was tested, with no effect on the expression of CD25 (interleukin-2 receptor α-chain) on activated T cells. Meanwhile, G-CSF treatment enhanced the proportion of CD38 + T cells in CD4 + naïve T cell, effector memory T cell and terminally differentiated effector T cell subsets, as well as in CD4 - central memory T cells and terminally differentiated effector T cells. G-CSF did not affect IL-2 production by T cells; relatively low concentrations of G-CSF down-regulated INF-γ production, while high concentrations of this cytokine up-regulated IL-4 production in activated T cells. The data obtained suggests that G-CSF could play a significant role both in preventing the development of excessive and potentially damaging inflammatory reactivity, and in constraining the expansion of potentially cytodestructive T cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Long-term effects of enriched environment following neonatal hypoxia-ischemia on behavior, BDNF and synaptophysin levels in rat hippocampus: Effect of combined treatment with G-CSF.

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Griva, Myrsini; Lagoudaki, Rosa; Touloumi, Olga; Nousiopoulou, Evangelia; Karalis, Filippos; Georgiou, Thomas; Kokaraki, Georgia; Simeonidou, Constantina; Tata, Despina A; Spandou, Evangelia

2017-07-15

Increasing evidence shows that exposure to an enriched environment (EE) is neuroprotective in adult and neonatal animal models of brain ischemia. However, the mechanisms underlying this effect remain unclear. The aim of the current study was to investigate whether post-weaning EE would be effective in preventing functional deficits and brain damage by affecting markers of synaptic plasticity in a neonatal rat model of hypoxia-ischemia (HI). We also examined the possibility that granulocyte-colony stimulating factor (G-CSF), a growth factor with known neuroprotective effects in a variety of experimental brain injury models, combined with EE stimulation could enhance the potential beneficial effect of EE. Seven-day-old Wistar rats of either sex were subjected to permanent ligation of the left common carotid artery followed by 60min of hypoxia (8% O 2 ) and immediately after weaning (postnatal day 21) were housed in enriched conditions for 4weeks. A group of enriched-housed rats had been treated with G-CSF immediately after HI for 5 consecutive days (50μg/kg/day). Behavioral examination took place approximately at three months of age and included assessments of learning and memory (Morris water maze) as well as motor coordination (Rota-Rod). Infarct size and hippocampal area were estimated following behavioral assessment. Synaptic plasticity was evaluated based on BDNF and synaptophysin expression in the dorsal hippocampus. EE resulted in recovery of post-HI motor deficits and partial improvement of memory impairments which was not accompanied by reduced brain damage. Increased synaptophysin expression was observed in the contralateral to carotid ligation hemisphere. Hypoxia-ischemia alone or followed by enriched conditions did not affect BDNF expression which was increased only in enriched-housed normal rats. The combined therapy of G-CSF and EE further enhanced cognitive function compared to EE provided as monotherapy and prevented HI-induced brain damage by

IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential.

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Boulakirba, Sonia; Pfeifer, Anja; Mhaidly, Rana; Obba, Sandrine; Goulard, Michael; Schmitt, Thomas; Chaintreuil, Paul; Calleja, Anne; Furstoss, Nathan; Orange, François; Lacas-Gervais, Sandra; Boyer, Laurent; Marchetti, Sandrine; Verhoeyen, Els; Luciano, Frederic; Robert, Guillaume; Auberger, Patrick; Jacquel, Arnaud

2018-01-10

CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-34. CSF-1R engagement by one or the other ligands leads to AKT and caspase activation and autophagy induction through expression and activation of AMPK and ULK1. As no differences were detected on monocyte differentiation, we investigated the effect of CSF-1 and IL-34 on macrophage polarization into the M1 or M2 phenotype. We highlighted a striking increase in IL-10 and CCL17 secretion in M1 and M2 macrophages derived from IL-34 stimulated monocytes, respectively, compared to CSF-1 stimulated monocytes. Variations in the secretome induced by CSF-1 or IL-34 may account for their different ability to polarize naïve T cells into Th1 cells. In conclusion, our findings indicate that CSF-1 and IL-34 exhibit the same ability to induce human monocyte differentiation but may have a different ability to polarize macrophages.

Brillouin spectroscopy as a new method of screening for increased CSF total protein during bacterial meningitis.

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Steelman, Zachary; Meng, Zhaokai; Traverso, Andrew J; Yakovlev, Vladislav V

2015-05-01

Bacterial meningitis is a disease of pronounced clinical significance, especially in the developing world. Immediate treatment with antibiotics is essential, and no single test can provide a conclusive diagnosis. It is well established that elevated total protein in cerebrospinal fluid (CSF) is associated with bacterial meningitis. Brillouin spectroscopy is a widely used optical technique for noninvasive determination of the elastic moduli of materials. We found that elevated protein levels in CSF alter the fluid elasticity sufficiently to be measurable by Brillouin spectroscopy, with model healthy and diseased fluids distinguishable to marked significance (P = 0.014), which increases with sample concentration by dialysis. Typical raw output of a 2-stage VIPA Brillouin spectrometer: inelastically scattered Brillouin peaks (arrows) and elastically scattered incident radiation (center cross). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis.

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Stojić-Vukanić, Zorica; Pilipović, Ivan; Vujnović, Ivana; Nacka-Aleksić, Mirjana; Petrović, Raisa; Arsenović-Ranin, Nevena; Dimitrijević, Mirjana; Leposavić, Gordana

2016-01-01

Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms

One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond.

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Dayon, Loïc; Guiraud, Seu Ping; Corthésy, John; Da Silva, Laeticia; Migliavacca, Eugenia; Tautvydaitė, Domilė; Oikonomidi, Aikaterini; Moullet, Barbara; Henry, Hugues; Métairon, Sylviane; Marquis, Julien; Descombes, Patrick; Collino, Sebastiano; Martin, François-Pierre J; Montoliu, Ivan; Kussmann, Martin; Wojcik, Jérôme; Bowman, Gene L; Popp, Julius

2017-06-17

Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/β-Amyloid 1-42 peptide chain [Aβ 1-42 ] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ε4 carrier status. The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aβ 1-42 , tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis.

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Ramakrishna, Chandran; Cantin, Edouard M

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection.

Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.

Science.gov (United States)

Dravid, Ameet N; Natrajan, Kartik; Kulkarni, Milind M; Saraf, Chinmay K; Mahajan, Uma S; Kore, Sachin D; Rathod, Niranjan M; Mahajan, Umakant S; Wadia, Rustom S

2018-02-01

Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.

Staphylococcus warneri ventriculoperitoneal shunt infection: failure of diagnosis by ventricular CSF sampling.

Science.gov (United States)

Martínez-Lage, Juan F; Martínez-Lage Azorín, Laura; Almagro, María-José

2010-12-01

The definite diagnosis of hydrocephalus valve infection is generally made by cerebrospinal fluid (CSF) sampling via the valve reservoir, which is considered to be more dependable than that of the CSF obtained by lumbar puncture. We treated a 17-year-old boy with an intra-abdominal pseudocyst due to ventriculoperitoneal shunt infection caused by Staphylococcus warneri whose ventricular CSF, obtained via the valve reservoir, was repeatedly sterile thus causing a considerable delay in the management of the complication. S. warneri constitutes an emergent contaminant of catheters and prostheses. We found only a detailed report of S. warneri infection of a ventriculoatrial shunt. If manifestations of peritoneal involvement in shunted patients would occur, the attention should be shifted to the distal component of the shunt hardware, even in the presence of a normal ventricular CSF as happened in our case to avoid unnecessary delay in diagnosis and management.

Circulation of progenitor cells after intensive chemotherapy followed by combination G-CSF and EPO in breast carcinoma

International Nuclear Information System (INIS)

Filip, S.; Vanasek, J.; Blaha, M.; Vavrova, J.

1997-01-01

Hematologic effects of granulocyte colony-stimulating factor (G-CSF) and erythropoietic (EPO) combination after priming intensive chemotherapy in the treatment of female breast carcinoma are presented. In a previous group treated with G-CSF alone, 36% of patients became anemic and to be transfused for correction of their anemia. To the present study consecutive patients with different stages of breast carcinoma were admitted. All were given priming intensive chemotherapy (epirubicin 150 m/m 2 and cyclophosphamide 1300 mg/m 2 ) followed by subcutaneous application of G-CSF at a dose of 5 μg/kg/day and EPO 250 IU/kg/day. In cases where leucocyte counts dropped below 1 x 10 9 /dm 3 and hemoglobin level fell to 85 g/dm 3 administration of growth factors was started. The therapy was stopped when normal leukocyte count reached 4 x 10 9 /dm 3 for G-CSF and hemoglobin level rose to 115 g/dm 3 for EPO. Our results show significant difference between MNC/Tl (min.), CD34 + cells/μl (min.), CFU-GM/ml (min.), BFU-E/ml (min) and MNC/μl (max.), CD34 + cells/μl (max.), CFU-GM/ml (max.), BFU-E/ml (ml) p + cells/μl, 23.4-fold for CFU-GM/ml and 28.7-fold increase for BFU-E/ml. Side effects were minimal, no infectious complications occurred, body temperature did not rise over 3 grad C and no corrections of anemia were needed. It is concluded that the administration of G-CSF plus EPO combination following intensive chemotherapy reduces hematologic toxicity and induces large amount of hemopoietic progenitors suitable for autologous transplantation in women with breast carcinoma. (author)

Dedifferentiated chondrosarcoma with leukocytosis and elevation of serum G-CSF. A case report

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Oda Yoshinao

2006-07-01

Full Text Available Abstract Background G-CSF is known to function as a hematopoietic growth factor and it is known to be responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies. Case presentation We report the case of a 72-year-old man with dedifferentiated chondrosarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma- or osteosarcoma-like features in addition to conventional chondrosarcoma, arising from his pelvic bone. After hemipelvectomy, when local recurrence and metastasis were identified, leukocytosis appeared and an elevated level of serum granulocyte-colony-stimulating factor (G-CSF was also recognized. The patient died of multiple organ failure 2 months after surgery. Autopsy specimens showed that the histological specimens of the recurrence and metastasis were dedifferentiated components, without any conventional chondrosarcoma components. G-CSF was expressed only in the dedifferentiated components, not in the chondrosarcoma components, immunohistochemically. Conclusion This is the first report of chondrosarcoma, or any other primary bone tumor, with leukocytosis, probably stimulated by tumor-produced G-CSF from the dedifferentiated components.

CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis.

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Rossi, Daniela; Volanti, Paolo; Brambilla, Liliana; Colletti, Tiziana; Spataro, Rossella; La Bella, Vincenzo

2018-03-01

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and ΔFS was used to rate the disease progression. Controls were divided into two cohorts: (1) patients with non-inflammatory neurological diseases (CTL-1); (2) patients with acute/subacute inflammatory diseases and tumors, expected to lead to significant axonal and tissue damage (CTL-2). For each patient and control, CSF was taken at the time of the diagnostic work-up and stored following the published guidelines. CSF NF-L and pNF-H were assayed with commercially available ELISA-based methods. Standard curves (from independent ELISA kits) were highly reproducible for both NFs, with a coefficient of variation CSF NF-L and pNF-H levels in ALS were significantly increased when compared to CTL-1 (NF-L: ALS, 4.7 ng/ml vs CTL-1, 0.61 ng/ml, p CSF NF-L and pNF-H represent valuable diagnostic and prognostic biomarkers in ALS.

On the pulsatile nature of intracranial and spinal CSF-circulation demonstrated by MR imaging

International Nuclear Information System (INIS)

Greitz, D.; Franck, A.; Nordell, B.

1993-01-01

Cerebrospinal fluid (CSF) flow was studied in 24 healthy volunteers using gated MR phase imaging. The subarachnoid space (SAS) was divided into 5 compartments depending on the magnitude of the pulsatile CSF flows: a high velocity compartment in the area of the brain stem and spinal cord, 2 slow ones at the upper and lower extremes of the SAS, and finally 2 intermediate velocity compartments in between. The main pulsatile spinal flow channel had a meandering pattern. The extraventricular CSF-circulation can be explained by pulsatile CSF flow without the necessity of assuming existence of a net flow. A successive time offset during the cardiac cycle has been found in the fronto-occipital direction of the interplay between the arterial expansion, brain expansion, volume changes of the CSF spaces and of the veins. It is proposed to name this time offset the intracranial ''volume wave'' (VoW). (orig.)

Contribution of isotopic data in cerebrospinal fluid (CSF) studies

International Nuclear Information System (INIS)

Askienazy, S.; Ducassou, D.

The growing interest in isotopic CSF studies is explained by the fact that the mechanism and classification of hydrocephalus cases are based not only on anatomoclinical data but also on physiological information inaccessible by static image methods. This article shows the full importance of dynamic CSF research (ideal tracer: 111 In-DTPA); the possibilities of myeloscintigraphy to study the permeability of the medullary sub-arachnoid spaces (tracers used: sup(99m)Tc-DTPA in the liquid phase or xenon bubble technique in the gas phase); ventricular morphology; existence of meningeal gaps [fr

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

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Simon, Matthew J; Iliff, Jeffrey J

2016-03-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Copyright © 2015 Elsevier B.V. All rights reserved.

Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease.

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Schirinzi, Tommaso; Di Lazzaro, Giulia; Sancesario, Giulia Maria; Colona, Vito Luigi; Scaricamazza, Eugenia; Mercuri, Nicola Biagio; Martorana, Alessandro; Sancesario, Giuseppe

2017-12-01

Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer's disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Aβ42), total-tau (t-tau), phosphorylated-tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman's test in each group. The groups significantly differed in biomarkers' concentration with lower Aβ42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0 ± 2.8 vs. 13.3 ± 3.0 mmHg, p < 0.05) and directly correlated with Aβ42 levels (R = 0.512; p < 0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Aβ42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD.

CSF 5-HIAA and exposure to and expression of interpersonal violence in suicide attempters.

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Moberg, T; Nordström, P; Forslund, K; Kristiansson, M; Asberg, M; Jokinen, J

2011-07-01

Serotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult. The aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS). 42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour. In women, but not in men, CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood. Although central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate impaired aggression control in traumatized suicide attempters. Copyright © 2011 Elsevier B.V. All rights reserved.

Hematopoietic properties of granulocyte colony-stimulating factor/immunoglobulin (G-CSF/IgG-Fc fusion proteins in normal and neutropenic rodents.

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George N Cox

Full Text Available Previously we showed that granulocyte colony-stimulating factor (G-CSF in vitro bioactivity is preserved when the protein is joined via a flexible 7 amino acid linker to an immunoglobulin-1 (IgG1-Fc domain and that the G-CSF/IgG1-Fc fusion protein possessed a longer circulating half-life and improved hematopoietic properties compared to G-CSF in normal rats. We have extended this analysis by comparing the relative hematopoietic potencies of G-CSF/IgG1-Fc to G-CSF in normal mice and to G-CSF and polyethylene glycol (PEG -modified G-CSF in neutropenic rats. Mice were treated for 5 days using different doses and dosing regimens of G-CSF/IgG1-Fc or G-CSF and circulating neutrophil levels in the animals measured on Day 6. G-CSF/IgG1-Fc stimulated greater increases in blood neutrophils than comparable doses of G-CSF when administered using daily, every other day or every third day dosing regimens. In rats made neutropenic with cyclophosphamide, G-CSF/IgG1-Fc accelerated recovery of blood neutrophils to normal levels (from Day 9 to Day 5 when administered as 5 daily injections or as a single injection on Day 1. By contrast, G-CSF accelerated neutrophil recovery when administered as 5 daily injections, but not when administered as a single injection. G-CSF/IgG1-Fc was as effective as PEG-G-CSF at accelerating neutrophil recovery following a single injection in neutropenic rats. G-CSF/IgG1-Fc and G-CSF/IgG4-Fc fusion proteins in which the 7 amino acid linker was deleted also were effective at accelerating neutrophil recovery following a single injection in neutropenic rats. These studies confirm the enhanced in vivo hematopoietic properties of G-CSF/IgG-Fc fusion proteins.

Frequency analysis of CSF flow on cine-MRI in normal pressure hydrocephalus

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Miyati, Tosiaki; Kasuga, Toshio; Imai, Hiroshi; Fujita, Hiroshi; Mase, Mitsuhito; Itikawa, Katuhiro

2001-01-01

To clarify the flow dynamics of intracranial cerebrospinal fluid (CSF) in normal pressure hydrocephalus (NPH), frequency analyses of CSF flow measured with an ECG-gated phase contrast cine magnetic resonance imaging (MRI) were performed. The amplitude and phase in the CSF flow spectra in the aqueduct were determined in patients with NPH after a subarachnoid hemorrhage (SAH-NPH group, n=26), an idiopathic NPH (I-NPH group, n=4), an asymptomatic ventricular dilation or a brain atrophy (VD group, n=21), and in healthy volunteers (control group, n=25). The changes of CSF flow spectra were also analyzed 5 and 15 minutes after an intravenous injection of acetazolamide. Moreover, a phase transfer function (PTF) calculated from the spectra of the driving vascular pulsation and CSF flow in the aqueduct were assessed in patients with SAH-NPH and control groups before and after acetazolamide injection. There values were compared with the pressure volume response (PVR). The amplitude of the 1st-3rd harmonics in the SAH-NPH or I-NPH group was significantly larger than in the control or VD group because of a decrease in compliance (increase in PVR). The phase of the 1st harmonic in the SAH-NPH group was significantly different from that in the control or VD group, but no difference was found between the control and VD groups. The amplitude of the 0-3rd harmonics increased, and the phase of the 1st harmonic changed in all groups after an acetazolamide injection. An evaluation of the time course of the direct current of CSF flow provided further information about the compensatory faculty of the cerebrospinal cavity. A PTF of the 1st harmonic in the SAH-NPH group was significantly larger than in the control group, and a positive correlation was noted between PTF of the 1st harmonic and PVR. In conclusion, frequency analyses of CSF flow measured by cine-MRI make it possible to obtain noninvasively a more detailed picture of the pathophysiology of NPH and of changes in intracranial

Frequency analysis of CSF flow on cine-MRI in normal pressure hydrocephalus

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Miyati, Tosiaki; Kasuga, Toshio; Imai, Hiroshi [Kanazawa Univ. (Japan). School of Medicine; Fujita, Hiroshi; Mase, Mitsuhito; Itikawa, Katuhiro

2001-09-01

To clarify the flow dynamics of intracranial cerebrospinal fluid (CSF) in normal pressure hydrocephalus (NPH), frequency analyses of CSF flow measured with an ECG-gated phase contrast cine magnetic resonance imaging (MRI) were performed. The amplitude and phase in the CSF flow spectra in the aqueduct were determined in patients with NPH after a subarachnoid hemorrhage (SAH-NPH group, n=26), an idiopathic NPH (I-NPH group, n=4), an asymptomatic ventricular dilation or a brain atrophy (VD group, n=21), and in healthy volunteers (control group, n=25). The changes of CSF flow spectra were also analyzed 5 and 15 minutes after an intravenous injection of acetazolamide. Moreover, a phase transfer function (PTF) calculated from the spectra of the driving vascular pulsation and CSF flow in the aqueduct were assessed in patients with SAH-NPH and control groups before and after acetazolamide injection. There values were compared with the pressure volume response (PVR). The amplitude of the 1st-3rd harmonics in the SAH-NPH or I-NPH group was significantly larger than in the control or VD group because of a decrease in compliance (increase in PVR). The phase of the 1st harmonic in the SAH-NPH group was significantly different from that in the control or VD group, but no difference was found between the control and VD groups. The amplitude of the 0-3rd harmonics increased, and the phase of the 1st harmonic changed in all groups after an acetazolamide injection. An evaluation of the time course of the direct current of CSF flow provided further information about the compensatory faculty of the cerebrospinal cavity. A PTF of the 1st harmonic in the SAH-NPH group was significantly larger than in the control group, and a positive correlation was noted between PTF of the 1st harmonic and PVR. In conclusion, frequency analyses of CSF flow measured by cine-MRI make it possible to obtain noninvasively a more detailed picture of the pathophysiology of NPH and of changes in intracranial

Stimulating effect of low dose radiation expression of G-CSF receptors in bone marrow cells in mice

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Zhang Honglai; Liu Shuzheng; Zhang Ming

1993-01-01

The expression of G-CSF receptors in bone marrow cells (BMC) was studied by using 125 I labelled G-CSF ( 1 '2 5 I-G-CSF). The results showed that the reaction equilibrium of 125 I-G-CSF bound to BMC at 37 degree C was reached in 60 minutes, the maximum binding (Bmax) to 3 x 10 6 BMC being 15.1 pmol, the dissociation constant (Kd) being 78.6 pmol, and the estimated number of G-CSF receptors per cell being about 3100. The number of G-CSF receptors in BMC in mice 48 hours after whole body exposure to doses of 50, 75 and 100 mGy X-rays increased significantly to 161%, 169% and 342% of controls, respectively. The results suggested that the expression of G-CSF receptors in BMC was enhanced markedly following low dose radiation, which would lead to stimulation of BMC proliferation

A novel method to calculate the extent and amount of drug transported into CSF after intranasal administration.

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Shi, Zhenqi; Zhang, Qizhi; Jiang, Xinguo

2005-01-31

The aim of this paper is to establish a novel method to calculate the extent and amount of drug transported to brain after administration. The cerebrospinal fluid (CSF) was chosen as the target region. The intranasal administration of meptazinol hydrochloride (MEP) was chosen as the model administration and intravenous administration was selected as reference. According to formula transform, the extent was measured by the equation of X(A)CSF, infinity/X0 = Cl(CSF) AUC(0-->infinity)CSF/X0 and the drug amount was calculated by multiplying the dose with the extent. The drug clearance in CSF (Cl(CSF)) was calculated by a method, in which a certain volume of MEP solution was injected directly into rat cistern magna and then clearance was assessed as the reciprocal of the zeroth moment of a CSF level-time curve normalized for dose. In order to testify the accurateness of the method, 14C-sucrose was chosen as reference because of its impermeable characteristic across blood-brain barrier (BBB). It was found out that the MEP concentrations in plasma and CSF after intranasal administration did not show significant difference with those after intravenous administration. However, the extent and amount of MEP transported to CSF was significantly lower compared with those to plasma after these two administrations. In conclusion, the method can be applied to measure the extent and amount of drug transported to CSF, which would be useful to evaluate brain-targeting drug delivery.

Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: obstacles and perspectives in translating a novel marker panel to the clinic.

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Nils von Neuhoff

Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. METHODS AND FINDINGS: CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. CONCLUSIONS: ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be

A Hospital Based Study on Estimation of Adenosine Deaminase Activity (ADA) in Cerebrospinal Fluid (CSF) in Various Types of Meningitis.

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Agarwal, Ashok Kumar; Bansal, Sonia; Nand, Vidya

2014-02-01

Tuberculosis kills 3.70 lakh patients in India every year,out of which 7-12 % are meningeal involvement. Delay in its diagnosis and initiation of treatment results in poor prognosis and squeal in up to 25% of cases. The aim of the present study is to look for a simple, rapid, cost effective, and fairly specific test in differentiating tubercular aetiology from other causes of meningitis. In the present study we measured the adenosine deaminase activity (ADA) in Cerebrospinal Fluid (CSF) of Tubercular Meningitis (TBM) and non-TBM patients. Fifty six patients attending hospital with symptoms and signs of meningitis were selected and divided into three groups: tubercular, pyogenic, and aseptic meningitis, depending upon the accepted criteria. CSF was drawn and ADA estimated. Out of 32 tubercular patients, 28 had CSF-ADA at or above the cut-off value while four had below. Out of 24 non-tuberculous patients (pyogenic and aseptic meningitis), two aseptic meningitis (AM) patient had ADA levels at or above the cut-off value while 22 had below this value. RESULTS of our study indicate that ADA level estimation in CSF is not only of considerable value in the diagnosis of TBM, CSF, and ADA level 10 U/L as a cut-off value with sensitivity 87.5% and specificity 83.33% and positive predictive value of the test was 87.5%.and 83.3% negative predictive value. It can be concluded that ADA estimation in CSF is not only simple, inexpensive and rapid but also fairly specific method for making a diagnosis of tuberculous aetiology in TBM, especially when there is a dilemma of differentiating the tuberculous aetiology from non-tuberculous ones. For this reason ADA estimation in TBM may find a place as a routine investigation.

Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly.

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Chhatwal, Jasmeer P; Schultz, Aaron P; Marshall, Gad A; Boot, Brendon; Gomez-Isla, Teresa; Dumurgier, Julien; LaPoint, Molly; Scherzer, Clemens; Roe, Allyson D; Hyman, Bradley T; Sperling, Reisa A; Johnson, Keith A

2016-08-30

To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of (18)F-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p-tau), and β-amyloid 1-42 (Aβ42). T-tau, p-tau, and Aβ42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of (18)F-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. After controlling for sex and age, total cortical (18)F-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional (18)F-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with (18)F-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. These data support the link between (18)F-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with (18)F-T807 binding largely restricted to the temporal lobe, (18)F-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure. © 2016 American Academy of Neurology.

Clinico-pathological studies of CSF dissemination of glioblastoma and medulloblastoma

International Nuclear Information System (INIS)

Kato, Kyozo; Yoshida, Jun; Kageyama, Naoki

1986-01-01

Clinico-pathological findings of CSF dissemination which was diagnosed on CT scan, were studied on 13 cases of glioblastoma and 9 cases of medulloblastoma. The type of CSF dissemination and the prognosis of patients were both different between glioblastoma and medulloblastoma. In the former, the dissemination was predominantly in ventricular walls and in the latter, in basal cisterns. The mean survival time after the diagnosis of dissemination is 6 months of glioblastoma as compared with 13 months of medulloblastoma. The Pathological studies show that subependymal and/or subpial infiltration of tumor cells, and thickness of arachnoid membrane by marked mesodermal reaction were demonstrated in cases of glioblastoma. On the contrary, tumor cells of medulloblastoma grow markedly in the subarachnoid space and/or on the ependymal layers. From these pathological findings of CSF dissemination, it will be resulted that the prognosis of glioblastoma is much more poor that of medulloblastoma. (author)

Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.

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Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Shacklett, Barbara L; Hagberg, Lars; Yiannoutsos, Constantin T; Spudich, Serena S; Price, Richard W

2014-01-01

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis

Cerebrospinal fluid (CSF neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.

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Julia Peterson

Full Text Available The character of central nervous system (CNS HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL, total and phosphorylated tau (t-tau, p-tau, soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ and amyloid beta (Aβ fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic

Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease.

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Llorens, Franc; Kruse, Niels; Karch, André; Schmitz, Matthias; Zafar, Saima; Gotzmann, Nadine; Sun, Ting; Köchy, Silja; Knipper, Tobias; Cramm, Maria; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel P; Sánchez-Valle, Raquel; Fischer, Andre; Mollenhauer, Brit; Zerr, Inga

2018-03-01

The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression.

Are Patients with Spontaneous CSF Otorrhea and Superior Canal Dehiscence Congenitally Predisposed to Their Disorders?

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Stevens, Shawn M; Hock, Kiefer; Samy, Ravi N; Pensak, Myles L

2018-04-01

Objectives (1) Compare lateral skull base (LSB) height/thickness in patients with spontaneous cerebrospinal fluid otorrhea (CSF), superior canal dehiscence (SCD), acoustic neuromas (AN), and otosclerosis (OTO). (2) Perform correlations between age, body mass index (BMI), sex, and LSB height/thickness. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods Patients with CSF, SCD, AN, and OTO diagnosed from 2006 to 2016 were included if they had high-definition temporal bone computed tomography (CT) and absence of trauma, radiation, chronic ear disease, and/or congenital anomaly. CT-based measurements included LSB height/thickness and pneumatization rates overlaying the external auditory canal (EAC), tegmen tympani (TgT), perigeniculate region (PG), and internal auditory canal (IAC). LSB height/thickness, age, sex, and BMI were statistically correlated. In total, 256 patients and 493 ears (109 CSF, 115 SCD, 269 AN/OTO) were measured. Results Patients with CSF had significantly higher BMIs than the other groups ( P CSF and SCD had similar radiographic LSB phenotypes at most measured locations. Both groups exhibited a significantly lower LSB height compared to the AN and OTO groups (mean, 3.9-4.2 mm vs 4.9-5.6 mm; P CSF and SCD also demonstrated significantly lower pneumatization rates, as low as 17% to 23% overlaying the PG and IAC ( P CSF and SCD exhibit similar radiographic LSB phenotypes. Age, sex, and BMI do not significantly correlate with LSB height/thickness. These data support the theory that CSF and SCD arise via similar congenital pathoetiologic mechanisms.

Cerebral blood flow, glucose use, and CSF ionic regulation in potassium-depleted rats

International Nuclear Information System (INIS)

Schroek, H.; Kuschinsky, W.

1988-01-01

Rats were kept on a low-K + diet for 25 or 70 days. Local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were measured in 31 different structures of the brain by means of the [ 14 C]iodoantipyrine and [ 14 C]2-deoxy-D-glucose method. After 25 and 70 days of K + depletion LCBF was decreased significantly in 27 and 30 structures, respectively, the average decrease being 19 and 25%. In contrast, average LCGU was not changed. Cisternal cerebrospinal fluid (CSF) K + concentration decreased significantly from 2.65 ± 0.02 mM in controls to 2.55 ± 0.02 mM and 2.47 ± 0.02 mM in the two treated groups. CSF [HCO 3 - ], pH, and Pco 2 were increased in K + -depleted animals. These data show that K + depletion induces an increase in CSF pH and a decrease in CSF K + concentration, both of which cause a reduction in cerebral blood flow. The increased CSF Pco 2 is secondary to the reduction of blood flow, since brain metabolism and arterial Pco 2 remained constant

The Results of the Surgical Treatment of Spontaneous Rhinorrhea via Craniotomy and the Contribution of CT Cisternography to the Detection of Exact Leakage Side of CSF.

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Tumturk, Abdulfettah; Ulutabanca, Halil; Gokoglu, Abdulkerim; Oral, Sukru; Menku, Ahmet; Kurtsoy, Ali

2016-01-01

To share the results of conventional surgery in rhinorrhea and the contribution of computerized tomography (CT) cisternography to determination of the site of cerebrospinal fluid (CSF) leak. Twelve cases treated for spontaneous rhinorrhea were included in this study. All the cases underwent cranial CT and magnetic resonance imaging (MRI). CT cisternography was performed in four patients whose bone defect or leakage site could not be detected by CT and MRI. In order to repair the defect, either the galea or galea together with collagen matrix was used and the procedure was supported with fibrin glue. In the cases, postoperative rhinorrhea was seen in neither the early nor the late follow up period. We observed no complications related to CT cisternography or craniotomy. The leakage area was successfully detected with CT cisternography when the other methods failed. Bone defect can usually be shown by means of CT. However, when bone-defect cannot be shown or the dura in the defective area is intact, CT cisternography is useful to show the CSF leak. Conventional surgery was very succesful in the treatment of spontaneous rhinorrhea but it was cosmetically problematic. In the patients both treated with galea and galea together with collagen matrix, the repair of the defect was successful.

Quantitative analysis of the aqueductal CSF flow dynamics with FLASH sequence

International Nuclear Information System (INIS)

Seki, Kouji; Tsuji, Shoji; Yuasa, Tatsuhiko; Miyatake, Tadashi.

1993-01-01

Aqueductal cerebrospinal fluid (CSF) flow image and its dynamics were analyzed with 1.5 T MR system using ECG-gated Fast Low Flip Angle Shot (FLASH). High flip angle (90 degree) and short echo time (10 ms) were applicated. Seventeen ECG gated nine images were obtained in one cardiac cycle from the inferior midbrain. Axial imaging plane (across at 60 degree to the aqueduct) and 6 mm of slice thickness is available. The CSF flow velocity was estimated by a standard curve of signal intensity ratio, obtained by the running water in model tubes. Examinations of five normal subjects (male/female=2/3, 48.4±15 years old) were performed. The aqueductal flow signal had two peaks in one cardiac cycle. The latter oval signals within the diastolic phase represent the caudal (downward) CSF flow, and the former wedge shaped signals represent the cephalad (reverse) flow. The peak velocity of the caudal CSF flow is about 6.5 mm/s, the cephalad flow is about 4.5 mm/s. We defined two zero points of the to-and-fro curve as turning points, the first (caudal to cephalad) zero point as the 'first turning point', the second (cephalad to caudal) zero point as the 'second turning point'. In normal subjects, the first turning points are at 236±28 ms (±SD), the second turning points are at 723±67 ms (±SD) after ECG R wave. This new method is highly useful for the analyzing disorders with CSF flow abnormalities. (author)

Positron emission tomography with 68Ga-EDTA in the diagnosis and localization of CSF fistulas

International Nuclear Information System (INIS)

Bergstrand, G.; Bergstroem, M.; Eriksson, L.; Edner, G.; Widen, L.

1982-01-01

Five patients with cerebrospinal fluid (CSF) rhinorrhea were investigated with computed tomography (CT) and positron emission tomography (PET) to localize the site of a CSF fistula. After intrathecal injection of 10 MBq of 68 Ga-EDTA, radioactivity was demonstrated in the basal cisterns. In three cases, the site of the fistula was visualized with PET. It is not always possible to demonstrate a CSF leakage with CT cisternography (CTC) using metrizamide, particularly in cases with minute fistulas or intermittent CSF rhinorrhea. With further experience and improved PET techniques, it may be possible to detect even very small fistulas

High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions.

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Franceschini, Alessia; Baiardi, Simone; Hughson, Andrew G; McKenzie, Neil; Moda, Fabio; Rossi, Marcello; Capellari, Sabina; Green, Alison; Giaccone, Giorgio; Caughey, Byron; Parchi, Piero

2017-09-06

An early and accurate in vivo diagnosis of rapidly progressive dementia remains challenging, despite its critical importance for the outcome of treatable forms, and the formulation of prognosis. Real-Time Quaking-Induced Conversion (RT-QuIC) is an in vitro assay that, for the first time, specifically discriminates patients with prion disease. Here, using cerebrospinal fluid (CSF) samples from 239 patients with definite or probable prion disease and 100 patients with a definite alternative diagnosis, we compared the performance of the first (PQ-CSF) and second generation (IQ-CSF) RT-QuIC assays, and investigated the diagnostic value of IQ-CSF across the broad spectrum of human prions. Our results confirm the high sensitivity of IQ-CSF for detecting human prions with a sub-optimal sensitivity for the sporadic CJD subtypes MM2C and MM2T, and a low sensitivity limited to variant CJD, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. While we found no difference in specificity between PQ-CSF and IQ-CSF, the latter showed a significant improvement in sensitivity, allowing prion detection in about 80% of PQ-CSF negative CJD samples. Our results strongly support the implementation of IQ-CSF in clinical practice. By rapidly confirming or excluding CJD with high accuracy the assay is expected to improve the outcome for patients and their enrollment in therapeutic trials.

Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation.

Science.gov (United States)

Schmitt, Michael; Publicover, Amy; Orchard, Kim H; Görlach, Matthias; Wang, Lei; Schmitt, Anita; Mani, Jiju; Tsirigotis, Panagiotis; Kuriakose, Reeba; Nagler, Arnon

2014-01-01

The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen (®) ) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.

Neurological assessment and its relationship to CSF biomarkers in amateur boxers.

Directory of Open Access Journals (Sweden)

Sanna Neselius

Full Text Available BACKGROUND: Mild traumatic brain injury (TBI or concussion is common in many sports. Today, neuropsychological evaluation is recommended in the monitoring of a concussion and in return-to-play considerations. To investigate the sensitivity of neuropsychological assessment, we tested amateur boxers post bout and compared with controls. Further the relationship between neuropsychological test results and brain injury biomarkers in the cerebrospinal fluid (CSF were investigated. METHOD: Thirty amateur boxers on high elite level with a minimum of 45 bouts and 25 non-boxing matched controls were included. Memory tests (Rey Osterrieth Complex Figure, Listening Span, Digit Span, Controlled Word Association Test, and computerized testing of episodic memory, tests of processing speed and executive functions (Trail Making, Reaction Time, and Finger Tapping were performed and related to previously published CSF biomarker results for the axonal injury marker neurofilament light (NFL. RESULTS: The neurological assessment showed no significant differences between boxers and controls, although elevated CSF NFL, as a sign of axonal injury, was detected in about 80% of the boxers 1-6 days post bout. The investigation of the relationship between neuropsychological evaluation and CSF NFL concentrations revealed that boxers with persisting NFL concentration elevation after at least 14 days resting time post bout, had a significantly poorer performance on Trail Making A (p = 0.041 and Simple Reaction Time (p = 0.042 compared to other boxers. CONCLUSION: This is the first study showing traumatic axonal brain injury can be present without measureable cognitive impairment. The repetitive, subconcussive head trauma in amateur boxing causes axonal injury that can be detected with analysis of CSF NFL, but is not sufficient to produce impairment in memory tests, tests of processing speed, or executive functions. The association of prolonged CSF NFL increase in

IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential

OpenAIRE

Boulakirba, Sonia; Pfeifer, Anja; Mhaidly, Rana; Obba, Sandrine; Goulard, Michael; Schmitt, Thomas; Chaintreuil, Paul; Calleja, Anne; Furstoss, Nathan; Orange, François; Lacas-Gervais, Sandra; Boyer, Laurent; Marchetti, Sandrine; Verhoeyen, Els; Luciano, Frederic

2018-01-01

CSF-1 and IL-34 share the CSF-1 receptor and no differences have been reported in the signaling pathways triggered by both ligands in human monocytes. IL-34 promotes the differentiation and survival of monocytes, macrophages and osteoclasts, as CSF-1 does. However, IL-34 binds other receptors, suggesting that differences exist in the effect of both cytokines. In the present study, we compared the differentiation and polarization abilities of human primary monocytes in response to CSF-1 or IL-...

Distribution of HIV RNA in CSF and Blood is linked to CD4/CD8 Ratio During Acute HIV.

Science.gov (United States)

Chan, Phillip; Patel, Payal; Hellmuth, Joanna; Colby, Donn J; Kroon, Eugène; Sacdalan, Carlo; Pinyakorn, Suteeraporn; Jagodzinski, Linda; Krebs, Shelly; Ananworanich, Jintanat; Valcour, Victor; Spudich, Serena

2018-05-07

HIV RNA levels in the plasma and cerebrospinal fluid (CSF) are correlated in chronic HIV infection but their dynamics have not been characterized during acute infection. This study analyzed predictors of CSF HIV RNA and relative degree of CNS viral transmigration expressed as plasma minus CSF HIV log10 RNA (PCratio) during untreated acute HIV infection. CSF immune markers were compared between groups with different PCratio. 117 mostly male (97%) participants in the RV254 cohort in Bangkok, Thailand, had median age 28 years and an estimated median 18 days duration of infection; forty-three (37%) were Fiebig stages I/II. Twenty-seven (23%) had CSF HIV RNA CSF HIV RNA and PCratio of 3.76 and 2.36 Log10 copies/mL, respectively. HIV RNA peaked at Fiebig III in plasma and Fiebig IV in CSF. In multivariable analyses, plasma HIV RNA and CD4/CD8 ratio independently correlated with CSF HIV RNA (pCSF neopterin, sCD163, IL-6 and sCD14 levels (all pCSF HIV RNA and PCratio, suggesting that immune responses modulate CNS viral entry at early infection.

Relationship between intracranial pressure and antifungal agents levels in the CSF of patients with cryptococcal meningitis.

Science.gov (United States)

Wirth, Fernanda; de Azevedo, Maria Isabel; Pilla, Carmen; Aquino, Valério Rodrigues; Neto, Gustavo Wissmann; Goldani, Luciano Zubaran

2018-04-01

The purpose of this study was to evaluate the influence of intracranial hypertension in the cerebrospinal fluid (CSF) levels of amphotericin B and fluconazole levels of patients with cryptococcal meningitis. CSF samples and intracranial pressure were obtained by means of routine punctures performed at days 1, 7, and 14 of therapy, respectively. Amphotericin B and fluconazole CSF levels were measured by HPLC method as previously described. The minimum inhibitory concentration for amphotericin B, fluconazole, 5΄flucytosine, and voriconazole of each Cryptococcus isolate was performed according to CLSI. The predominant Cryptococcus species found was C. neoformans, and the major underlying condition was AIDS. Only one CSF sample had a detectable level for amphotericin B during the 14 days of therapy. Fluconazole CSF levels progressively increased from day 1 to day 14 of therapy for most cases. Fluconazole levels in the CSF were above the minimum inhibitory concentrations (MICs) for Cryptococcus during the initial 14 days of antifungal therapy. Variations of intracranial pressure did not affect amphotericin B and fluconazole levels in the CSF. The generalized estimating correlation (GEE) and Spearman correlation test (SCT) showed no significant correlation between the amphotericin B or fluconazole concentrations in the CSF and intracranial pressure (P = .953 and P = .093, respectively for GEE test and P = .477 and P = .847, respectively, for SCT). Combination therapy of amphotericin B with fluconazole was effective in 60% of the patients considering CSF cultures were negative in 9 of 15 patients after 14 days of therapy. Further studies are necessary to evaluate the role of intracranial hypertension on the therapeutic efficacy of different antifungal agents in patients with cryptococcal meningitis.

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation

Directory of Open Access Journals (Sweden)

Kowarik Markus C

2012-05-01

Full Text Available Abstract Background The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF, we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels. Methods Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20, clinically isolated syndrome (CIS, n = 30, multiple sclerosis (MS, n = 20, Lyme neuroborreliosis (LNB, n = 8 and patients with other inflammatory neurological diseases (OIND, n = 30. Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry. Results CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis. Conclusions CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.

Different Cholinesterase Inhibitor Effects on CSF Cholinesterases in Alzheimer Patients

Science.gov (United States)

Nordberg, Agneta; Darreh-Shori, Taher; Peskind, Elaine; Soininen, Hilkka; Mousavi, Malahat; Eagle, Gina; Lane, Roger

2014-01-01

Background The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. Methods and Findings AD patients aged 50–85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman’s colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2%increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. Conclusion The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation. PMID:19199870

Variation in reproductive outcomes for captive male rhesus macaques (macaca mulatta) differing in CSF 5-hydroxyindoleacetic acid concentrations.

Science.gov (United States)

Gerald, Melissa S; Higley, Sue; Lussier, I sabelle D; Westergaard, Greg C; Suomi, Stephen J; Higley, J Dee

2002-01-01

In rhesus macaque males, lower than average cerebrospinal fluid (CSF) concentrations of the principle metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), have been linked to impulsivity, involvement in escalated aggression, failure to elicit consort relationships, production of fewer sperm plugs, and a relatively early age of mortality. Given these potential fitness costs, we performed two studies aimed at elucidating the effects of CSF 5-HIAA on reproduction. Study 1 retrospectively evaluated over a four-year period, the relative reproductive outcome for pairs of adult male rhesus macaques (n = 15) who lived in social groups and who differed in concentrations of CSF 5-HIAA. Study 2 examined the relationship between CSF 5-HIAA and sperm motility and density (n = 12), as a potential mechanism for maintaining variability in CSF 5-HIAA. For Study 1, an average measure from two CSF 5-HIAA samples was calculated for the two males who were present during the time when conception most likely took place (offspring birth date -165 +/- 14 days). Within-pair comparisons of CSF 5-HIAA concentrations between the sire and the non-successful male were drawn for each of the 72 offspring in the study. We found that while sires were typically the male with relatively higher CSF 5-HIAA within the pair, there were no absolute differences in CSF 5-HIAA between males who sired at least one offspring (sires) and those who failed to reproduce (non-sires). Furthermore, while absolute age was not predictive of reproductive outcome, sires with relatively high CSF 5-HIAA also tended to be also relatively older than their competitors. By contrast, for the males with relatively low CSF 5-HIAA who reproduced, sires were relatively younger than the non-sires. These differences in reproductive outcome for males differing in CSF 5-HIAA could not be explained by variability in sperm quantity or quality as we did not find evidence of a relationship between CSF 5-HIAA and either sperm

The Combined Impact of Surgery and Immunomodulation With Low Dose Cytoxan and GM-CSF in the Early Treatment of Breast Cancer

National Research Council Canada - National Science Library

Kendra, Kari L

2004-01-01

The purpose of this study was to evaluate the combined impact of surgery and immunomodulation with low dose cytoxan and GM-CSF on the development of dendritic cells and the activation of T cells in vivo...

Chasing the effects of Pre-analytical Confounders - a Multicentre Study on CSF-AD biomarkers

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Maria Joao Leitao

2015-07-01

Full Text Available Core cerebrospinal fluid (CSF biomarkers-Aβ42, Tau and pTau–have been recently incorporated in the revised criteria for Alzheimer’s disease (AD. However, their widespread clinical application lacks standardization. Pre-analytical sample handling and storage play an important role in the reliable measurement of these biomarkers across laboratories. In this study, we aim to surpass the efforts from previous studies, by employing a multicentre approach to assess the impact of less studied CSF pre-analytical confounders in AD-biomarkers quantification. Four different centres participated in this study and followed the same established protocol. CSF samples were analysed for three biomarkers (Aβ42, Tau and pTau and tested for different spinning conditions (temperature: Room temperature (RT vs. 4oC; speed: 500g vs. 2000g vs. 3000g, storage volume variations (25%, 50% and 75% of tube total volume as well as freezing-thaw cycles (up to 5 cyles. The influence of sample routine parameters, inter-centre variability and relative value of each biomarker (reported as normal/abnormal, was analysed. Centrifugation conditions did not influence biomarkers levels, except for samples with a high CSF total protein content, where either non centrifugation or centrifugation at RT, compared to 4ºC, led to higher Aβ42 levels. Reducing CSF storage volume from 75% to 50% of total tube capacity, decreased Aβ42 concentration (within analytical CV of the assay, whereas no change in Tau or pTau was observed. Moreover, the concentration of Tau and pTau appears to be stable up to 5 freeze-thaw cycles, whereas Aβ42 levels decrease if CSF is freeze-thawed more than 3 times. This systematic study reinforces the need for CSF centrifugation at 4ºC prior to storage and highlights the influence of storage conditions in Aβ42 levels. This study contributes to the establishment of harmonized standard operating procedures that will help reducing inter-lab variability of CSF

Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection

Directory of Open Access Journals (Sweden)

Hopkins Stephen J

2012-11-01

Full Text Available Abstract Background Cytokines and cytokine receptor concentrations increase in plasma and cerebrospinal fluid (CSF of patients following subarachnoid haemorrhage (SAH. The relationship between plasma and CSF cytokines, and factors affecting this, are not clear. Methods To help define the relationship, paired plasma and cerebrospinal fluid (CSF samples were collected from patients subject to ventriculostomy. Concentrations of key inflammatory cytokines, interleukin (IL-1ß, IL-1 receptor antagonist (IL-1Ra, IL-1 receptor 2, IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α, and TNF receptors (TNF-R 1 and 2 were determined by immunoassay of CSF and plasma from 21 patients, where samples were available at three or more time points. Results Plasma concentrations of IL-1ß, IL-1Ra, IL-10, TNF-α and TNF-R1 were similar to those in CSF. Plasma TNF-R2 and IL-1R2 concentrations were higher than in CSF. Concentrations of IL-8 and IL-6 in CSF were approximately10 to 1,000-fold higher than in plasma. There was a weak correlation between CSF and plasma IL-8 concentrations (r = 0.26, but no correlation for IL-6. Differences between the central and peripheral pattern of IL-6 were associated with episodes of ventriculostomy-related infection (VRI. A VRI was associated with CSF IL-6 >10,000 pg/mL (P = 0.0002, although peripheral infection was not significantly associated with plasma IL-6. Conclusions These data suggest that plasma cytokine concentrations cannot be used to identify relative changes in the CSF, but that measurement of CSF IL-6 could provide a useful marker of VRI.

Promotive effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on recovery from neutropenia induced by fractionated irradiation in mice

Energy Technology Data Exchange (ETDEWEB)

Kabaya, Koji; Watanabe, Masahiko; Kusaka, Masaru; Seki, Masatoshi (Kirin Brewery Co., Ltd., Gunma (Japan). Pharmaceutical Research Laboratory); Fushiki, Masato

1994-08-01

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the recovery from neutropenia induced by fractionated whole-body irradiation was investigated in mice. Male 7-week old C3H/HeN mice received a total of ten exposures of 0.25 Gy/day from day 1 to 5 and from day 8 to 12. Peripheral neutropenia with a nadir on day 17 was caused by the fractionated irradiation. Daily subcutaneous injections of rhG-CSF at 0.25 and 2.5 [mu]g/body/day from day from day 1 to 21 promoted the recovery of neutrophils in a dose-dependent manner. The kinetics of morphologically identifiable bone marrow cells were studied to clarify the mechanism behind the promotive effect of this factor. A slight decrease in mitotic immature granulocytes, such as myeloblasts, promyelocytes and myelocytes on day 5, and a drastic decrease in metamyelocytes and marrow neutrophils on days 5, 9, and 17 were seen in the femur of irradiated mice. Treatment using rhG-CSF caused an increase in immature granulocytes of all differential stages in the femur. Microscopic findings of the femurs and spleens also reveals an increase in immature granulocytes in these organs in mice injected with rhG-CSF. These results indicate that rhG-CSF accelerates granulopoiesis in the femur and spleen, thereby promoting recovery from neutropenia induced by fractionated irradiation. (author).

Promotive effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on recovery from neutropenia induced by fractionated irradiation in mice

International Nuclear Information System (INIS)

Kabaya, Koji; Watanabe, Masahiko; Kusaka, Masaru; Seki, Masatoshi; Fushiki, Masato.

1994-01-01

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the recovery from neutropenia induced by fractionated whole-body irradiation was investigated in mice. Male 7-week old C3H/HeN mice received a total of ten exposures of 0.25 Gy/day from day 1 to 5 and from day 8 to 12. Peripheral neutropenia with a nadir on day 17 was caused by the fractionated irradiation. Daily subcutaneous injections of rhG-CSF at 0.25 and 2.5 μg/body/day from day from day 1 to 21 promoted the recovery of neutrophils in a dose-dependent manner. The kinetics of morphologically identifiable bone marrow cells were studied to clarify the mechanism behind the promotive effect of this factor. A slight decrease in mitotic immature granulocytes, such as myeloblasts, promyelocytes and myelocytes on day 5, and a drastic decrease in metamyelocytes and marrow neutrophils on days 5, 9, and 17 were seen in the femur of irradiated mice. Treatment using rhG-CSF caused an increase in immature granulocytes of all differential stages in the femur. Microscopic findings of the femurs and spleens also reveals an increase in immature granulocytes in these organs in mice injected with rhG-CSF. These results indicate that rhG-CSF accelerates granulopoiesis in the femur and spleen, thereby promoting recovery from neutropenia induced by fractionated irradiation. (author)

Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59.

Science.gov (United States)

Zelek, Wioleta M; Watkins, Lewis M; Howell, Owain W; Evans, Rhian; Loveless, Sam; Robertson, Neil P; Beenes, Marijke; Willems, Loek; Brandwijk, Ricardo; Morgan, B Paul

2018-02-01

CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source.

CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers

DEFF Research Database (Denmark)

Rostgaard, Nina; Roos, Peter; Portelius, Erik

2018-01-01

OBJECTIVE: A rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease. METHODS: In this cross-sectional explorative study, we...... analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ38, Aβ......40, and Aβ42) to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs. RESULTS: CSF NfL concentration was significantly increased...

Computer tomography of the brain and spectrophotometry of the CSF in cerebral concussion and contusion

International Nuclear Information System (INIS)

Bergvall, U.; Kjellin, K.G.; Levander, B.; Svendsen, P.; Soederstroem, C.E.

1978-01-01

Computer tomography (CT) and spectrophotometry of CSF were performed in 30 patients with the clinical diagnosis of cerebral concussion or contusion. The patients with concussion all had normal CT-findings. Spectrophotometry of CSF was sometimes positive for cerebral contusion with normal CT-findings, but the two methods were complementary so that the extent of the lesion was determined by CT and spectrophotometry of CSF indicated the cause. (Auth.)

Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements.

Science.gov (United States)

Cogswell, Petrice M; Siero, Jeroen C W; Lants, Sarah K; Waddle, Spencer; Davis, L Taylor; Gilbert, Guillaume; Hendrikse, Jeroen; Donahue, Manus J

2018-03-31

Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo. To evaluate experimentally how IC vessel wall and lumen measurements change in identical subjects when evaluated using the most commonly available blood and cerebrospinal fluid (CSF) flow suppression modules and VWI sequences. Prospective. Healthy adults (n = 13; age = 37 ± 15 years) were enrolled. A 3.0T 3D T 1 /proton density (PD)-weighted turbo-spin-echo (TSE) acquisition with post-readout anti-driven equilibrium module, with and without Delay-Alternating-with-Nutation-for-Tailored-Excitation (DANTE) was applied. DANTE flip angle (8-12°) and TSE refocusing angle (sweep = 40-120° or 50-120°) were varied. Basilar artery and internal carotid artery (ICA) wall thicknesses, CSF signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal ratio (SR) were assessed. Measurements were made by two readers (radiology resident and board-certified neuroradiologist). A Wilcoxon signed-rank test was applied with corrected two-sided P CSF suppression. Addition of the DANTE preparation reduced CSF SNR from 17.4 to 6.7, thereby providing significant (P CSF suppression. The DANTE preparation also resulted in a significant (P CSF CNR improvement (P = 0.87). There was a trend for a difference in blood SNR with vs. without DANTE (P = 0.05). The outer vessel wall diameter and wall thickness values were lower (P CSF suppression and CNR of the approaches evaluated. However, improvements are heterogeneous, likely owing to intersubject vessel pulsatility and CSF flow variations, which can lead to variable flow suppression efficacy in these velocity-dependent modules. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells

Science.gov (United States)

Greter, Melanie; Helft, Julie; Chow, Andrew; Hashimoto, Daigo; Mortha, Arthur; Agudo-Cantero, Judith; Bogunovic, Milena; Gautier, Emmanuel L.; Miller, Jennifer; Leboeuf, Marylene; Lu, Geming; Aloman, Costica; Brown, Brian D.; Pollard, Jeffrey W.; Xiong, Huabao; Randolph, Gwendalyn J.; Chipuk, Jerry E.; Frenette, Paul S.; Merad, Miriam

2012-01-01

SUMMARY GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103+ DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103+ and CD11b+ DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8+ T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8+ T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo. PMID:22749353

Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies.

Science.gov (United States)

Germovsek, Eva; Lutsar, Irja; Kipper, Karin; Karlsson, Mats O; Planche, Tim; Chazallon, Corine; Meyer, Laurence; Trafojer, Ursula M T; Metsvaht, Tuuli; Fournier, Isabelle; Sharland, Mike; Heath, Paul; Standing, Joseph F

2018-04-19

Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking. To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS). Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed. A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome. Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.